Oncology,Oecology,Radiology,Pediatric Drugs,Pediatric Surgery,Patients

Clinical Oncology RFA experiences, indications and clinical outcomes Abstract Backgound Early-stage breast cancer is increasingly detected by screening mammography, and we aim to establish radiofrequency ablation therapy (RFA) as a minimally invasive, cost-efficient, and cosmetically acceptable local treatment. Although there were many studies on resection after RFA, none of them provided sufficient evidence to support RFA as a standard therapy for breast cancer. Results In our Phase I study, localized tumors with a maximum diameter of 2 cm, preoperatively diagnosed by imaging and histopathology, were treated with RFA. A 90% complete ablation rate was confirmed histopathologically. Our phase II multicenter study of RFA without resection for early breast cancer will evaluate the long-term safety and efficacy of RFA as well as its cosmetic results, which are a perceived advantage of this technique. We started a phase III multicenter study to demonstrate the non-inferiority of RFA compared with standard treatment (breast-conserving surgery) in terms of ipsilateral breast tumor recurrence (IBTR) rate, which is the best index of local control. Conclucion To standardize RFA for breast cancer, the results of our multicenter study, Radiofrequency Ablation Therapy for Early Breast Cancer as Local Therapy (the RAFAELO study) that began in 2013, are eagerly awaited. Control of intracranial disease is associated with improved survival in patients with brain metastasis from hepatocellular carcinoma Abstract Background Brain metastasis is a rare event in patients with hepatocellular carcinoma (HCC). This retrospective study aimed to identify the prognostic factors and determine the outcomes of patients with brain metastases from HCC. Methods About 86 patients with brain metastases (0.6%) from HCC were identified from two institutions; of them, 32 underwent tumor-removing surgery or stereotactic radiosurgery (SRS) with or without adjuvant whole brain radiotherapy (WBRT) (group 1), 30 had WBRT alone (group 2), and 24 received conservative treatment (group 3). Estimates for overall survival (OS) after brain metastases were determined, and clinical prognostic factors were identified. Results The median OS after development of brain metastases was 50 days. About 75 (87.2%) patients had lung metastases at the time of brain metastasis diagnosis. Group 1 showed better OS, followed by group 2 and group 3, sequentially (p < 0.001). Univariate analyses showed that treatment with curative intent (surgery or SRS), Child–Pugh class A, alpha-fetoprotein level < 400 ng/ml, and recursive partitioning analysis classification I or II were associated with improved survival (p < 0.001, 0.002, 0.029, and 0.012, respectively). Multivariate analysis showed that treatment with curative intent and Child–Pugh class A was associated with improved OS (p < 0.001 and 0.009, respectively). Conclusion Although the overall prognosis of patients with brain metastases from HCC is extremely poor, patients actively treated with surgery or radiosurgery have prolonged survival, suggesting that interventions to control intracranial disease are important in these patients. Adjuvant therapy in renal cell carcinoma: the perspective of urologists Abstract Background Until recently, there was no approved adjuvant therapy (AT) for renal cell carcinoma (RCC) unless sunitinib was approved in the US. We evaluated clinical opinion and estimated use regarding different treatment options and patient selection of AT in RCC patients based on current scientific data and individual experience in Germany. Methods We conducted an anonymous survey during a national urology conference in 01/2017. Answers of 157 urologists treating RCC patients could be included. Questions were related to practice setting, treatment of RCC, follow-up strategy, physicians' personal opinion and individually different important parameters regarding S-TRAC and ASSURE-trial. Results 82% were office based. 67% were located in larger cities. 83% reported that nephron-sparing surgery (NSS) was performed in tumors with diameter < 4 cm. Follow-up was done mainly in concordance with guideline recommendations. 68% treated an average of 2.9 patients/year with systemic therapy. Therapy was predominantly advocated using sunitinib (94%). Urologists were informed about S-TRAC and ASSURE-trial. For 47%, reported hazard ratio is the most important parameter to understand trial results followed by overall survival (OS) in 46%, disease-free survival in 38%, and results of other trials in 34%. The most convincing parameter to decide on AT is OS (69%). 62% placed their confidence in ASSURE over STRAC-trial. 44% would use AT for 12 months. Nodal involvement was the most common denominator for use of AT. 82% favor sunitinib as AT. Conclusions A minority of urologists would use AT and are more confident in ASSURE-trial. Reluctance of prescribing AT mainly is based on lack of OS data and conflicting trial results. Optimal treatment strategy for rectal cancer based on the risk factors for recurrence patterns Abstract Background For rectal cancer, multimodality therapeutic approach is necessary to prevent local recurrence and distant metastasis. However, the efficacy of additional treatments, such as neoadjuvant chemoradiotherapy (nCRT), neoadjuvant chemotherapy (NAC), and lateral pelvic lymph node dissection (LPLND), has not been scrutinized. Methods Recurrence patterns were categorized into local recurrence and distant metastasis. Local recurrence was classified into two types: (1) pelvic cavity recurrence and (2) LPLN recurrence. First, we analyzed the risk factors for each recurrence pattern. Second, based on the status of clinically suspected involvement of circumferential resection margin (cCRM), the efficacy of additional treatments was investigated. Results A total of 240 patients was enrolled. nCRT was performed for 25 (10%), NAC was for 46 (19%), and LPLND was for 35 patients (15%). As the recurrence patterns, pelvic cavity recurrence occurred in 15 (6%), LPLN recurrence in 8 (3%), and distant metastasis in 42 patients (18%). Five-year overall survival and relapse-free survival were 87% and 70%, respectively. Multivariate analysis indicated that pelvic cavity recurrence was associated with cCRM status and tumor histology, that LPLN recurrence was with serum carcinoembryonic antigen level and LPLN swelling, and that distant metastasis was with clinical N category. In the cCRM-positive subgroup (n = 66), cumulative rate of pelvic cavity recurrence was lower in the nCRT group than in the NAC or non-NAC/nCRT group (P = 0.02 and 0.09, respectively). Conclusion cCRM status was associated with pelvic cavity recurrence, and LPLN swelling was with LPLN recurrence. nCRT could reduce pelvic cavity recurrence in cCRM-positive subgroup. Cryosurgery for primary breast cancers, its biological impact, and clinical outcomes Abstract Recently, a number of new minimally invasive image-guided percutaneous ablation treatments, including cryoablation, radiofrequency ablation, microwave ablation, high-intensity focused ultrasound, laser ablation, and irreversible electroporation have been developed. Several studies have shown the feasibility and safety of these cryoablation therapies for the treatment of benign breast tumors and small invasive breast cancer. Although the complete response rate of cryoablation for breast cancer is reported to be relatively good, most studies enrolled a small number of patients, and so reliable conclusions could not be drawn. In this review, we introduce the mechanisms of action of cryoablation, and summarize the current literature on the efficacy and safety of cryoablation for breast cancer. Cryoablation also induces an immunomodulatory effect, which is an interesting topic of research in the era of immune checkpoint inhibitors. Cryoablation for primary tumor may enhance the treatment effect of immune checkpoint inhibitors in patients with breast cancer. Further investigations of this new therapeutic strategy are needed. CT and clinical characteristics that predict risk of EGFR mutation in non-small cell lung cancer: a systematic review and meta-analysis Abstract Introduction To systematically analyze CT and clinical characteristics to find out the risk factors of epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer (NSCLC). Then the significant characteristics were used to set up a mathematic model to predict EGFR mutation in NSCLC. Materials and methods PubMed, Web of Knowledge and EMBASE up to August 17, 2018 were systematically searched for relevant studies that investigated the evidence of association between CT and clinical characteristics and EGFR mutation in NSCLC. After study selection, data extraction, and quality assessment, the pooled odds ratios (ORs) were calculated. Then from May 2017 to August 2018, all NSCLC received EGFR mutation examination and CT examination in our hospital were chosen to test the prediction model by receiver operating characteristic (ROC) curves. Results Seventeen original studies met the inclusion criteria. The results showed that the ORs of ground-glass opacity (GGO), air bronchogram, pleural retraction, vascular convergence, smoking history, female gender were, respectively, 1.93 (P = 0.003), 2.09 (P = 0.03), 1.59 (P < 0.01), 1.61 (P = 0.001), 0.28 (P < 0.01), 0.35 (P < 0.01). The result of speculation, cavitation/bubble-like lucency, lesion shape, margin, pathological stage were, respectively, 1.19 (P = 0.32), 0.99 (P = 0.97), 0.82 (P = 0.42), 1.02 (P = 0.90), 0.77 (P = 0.30). 121 NSCLC received EGFR mutation test were included to test the prediction model. The mathematical model based on the results of meta-analysis was: 0.74 × air bronchogram + 0.46 × pleural retraction + 0.48 × vascular convergence − 1.27 × non-smoking history − 1.05 × female. The area under the ROC curve was 0.68. Conclusion Based on the current evidence, GGO presence, air bronchogram, pleural retraction, vascular convergence were significant risk factors of EGFR mutation in NSCLC. And the prediction model can help to predict EGFR mutation status. Lymph node ratio has impact on relapse and outcome in patients with stage III melanoma Abstract Background Even though both the involvement of regional lymph nodes and the number of metastatic lymph nodes are regarded as major determinants of survival in cutaneous melanoma, the extent of node dissection has been analyzed as an independent prognostic indicator in only a few studies. This study aims to determine how the lymph node ratio (NR) (ratio of positive nodes to total nodes removed) might predict the disease relapse and survival in node-positive melanoma. Materials and methods A total of 317 patients with stage III primary melanoma were included in the study and reviewed retrospectively. All patients had nodal staging (N) by radical lymph node dissection. Patients were divided into three groups based on NR1 ≤ 10%, NR2 10–25%, and NR3 > 25%. Results The median age was 50 years (range 16–86) and men were predominant (59.3%). The majority of the patients had thicker Breslow depth (> 2 mm) (83.3%), higher mitotic rate (> 2/mm2) (64.1%) and ulcerated lesions (69.4%). The median number of positive nodes was 1 (range 1–32). The largest group was N1 (52.4%), which was followed by N2 (29.6%) and N3 (18%). The ratios of patients were 37.5%, 35.3%, and 27.1% in NR1, NR2, and NR3, respectively. The median number of excised lymph nodes was 13 (range 1–73). For all patients the estimated 5-and 10-year relapse-free survival (RFS) rates were 41% and 39%, respectively; and the estimated 5-and 10-year overall survival (OS) rates were 51% and 42%, respectively. Nodular histopathology, ulcerated lesions, higher mitotic rates, and higher node substages were the independent variables that were inversely correlated with survival for all patients; and NR was one of the significant prognostic factors and strongest predictors of relapse and survival (p = 0.03 and p = 0.01, respectively). Conclusion Our results suggest that, apart from the conventional nodal status, NR is an independent prognostic factor-regarding both RFS and OS in stage III cutaneous melanoma. Radiotherapy alone as a possible de-intensified treatment for human papillomavirus-related locally advanced oropharyngeal squamous cell carcinoma Abstract Background Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) is defined by p16 positivity and/or HPV DNA positivity. Because survival of patients with HPV-related OPSCC after chemoradiotherapy is favorable, a de-intensified treatment is expected to lead to less morbidity while maintaining low mortality. The association of tumor p16 and HPV DNA status with survival after radiotherapy alone remains unknown. Methods We retrospectively examined survival of 107 patients with locally advanced OPSCC after radiotherapy alone (n = 43) or chemoradiotherapy (n = 64) with respect to tumor p16 and HPV DNA status, using Cox's proportional hazard model. Results Survival after radiotherapy alone was significantly worse in p16-positive/HPV DNA-negative locally advanced OPSCC than in p16-positive/HPV DNA-positive locally advanced OPSCC. In bivariable analyses that included T category, N category, TNM stage, and smoking history, the survival disadvantage of p16-positive/HPV DNA-negative locally advanced OPSCC remained significant. There was no significant difference in survival after chemoradiotherapy between p16-positive/HPV DNA-positive locally advanced OPSCC and p16-positive/HPV DNA-negative locally advanced OPSCC. Survival in p16-positive/HPV DNA-positive locally advanced OPSCC after radiotherapy alone was similar to that after chemoradiotherapy, which stayed unchanged in bivariable analyses after adjustment of every other covariable. Survival of p16-negative/HPV DNA-negative locally advanced OPSCC was poor irrespective of treatment modality. Conclusions Survival in p16-positive locally advanced OPSCC differs depending on HPV DNA status. Radiotherapy alone can serve as a de-intensified treatment for p16-positive/HPV DNA-positive locally advanced OPSCC, but not for p16-positive/HPV DNA-negative locally advanced OPSCC. Resection of pancreatic metastatic renal cell carcinoma: experience and long-term survival outcome from a large center in China Abstract Purpose This study aimed to determine the outcome of pancreatic metastatic renal cell carcinoma (PmRCC) after treatment and share the relevent results. Methods In total, 13 patients with PmRCC were diagnosed and treated in our institution from December 2013 to October 2017. We retrospectively reviewed the records and analyzed the patient demographics, perioperative outcomes, and overall survival. Simultaneously, our experience including treatment and misdiagnosis was shared. Results The median time between nephrectomy and reoperation for pancreatic recurrence was 11 years (range 1–20 years). Four patients had multiple tumors and nine patients had solitary tumor. Five patients accepted distal pancreatectomy, and five patients underwent pancreaticoduodenectomy. One patient underwent total pancreatectomy, one patient underwent duodenum-preserving pancreatic head resection plus distal pancreatectomy, and one patient underwent exploratory laparotomy and gastrointestinal bypass due to widespread metastasis with clear obstructive symptoms. The misdiagnosis rate of preoperative diagnosis at our center was 69.2% (9/13). The median follow-up duration was 26 months (range 7–53 months, until June 2018). By the end of follow-up, 12 patients were alive and one patient died of gastrointestinal bleeding within 1 month after surgery. Conclusions PmRCCs are uncommon, but pancreatic metastasectomy has a relatively good prognosis and may, therefore, be a good therapeutic choice for patients with PmRCCs. Because PmRCC occurs long after the primary tumor resection, long-term follow-up is necessary. Besides, detailed medical history and specific manifestation in imaging features could contribute to avoiding misdiagnosis. Saddle pulmonary embolism and in-hospital mortality in patients with cancer Abstract Purpose Saddle pulmonary embolism (PE) has been associated with an increased risk of 1 year mortality when compared to non-saddle PE among patients with cancer. We sought to evaluate the association between saddle PE and in-hospital outcomes among patients with comorbid cancer. Methods The 2013 and 2014 United States National Inpatient Sample was used to identify adult patients hospitalized for acute PE. Only patients with an International Classification Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code indicating comorbid cancer were included. Identified admissions were stratified into the following 2 cohorts: saddle (defined as ICD-9-CM code = 415.13) and non-saddle PE. Multivariable logistic regression was performed to determine the association between saddle PE and the odds of in-hospital mortality after adjustment for age ≥ 80 years and sex. Results A total of 10,660 admissions for acute PE in patients with comorbid cancer were identified. Of which, 4.5% (n = 475) had a saddle PE. Median age was 67 years (interquartile range = 58–76) and 48.9% were male. In-hospital mortality occurred in 6.1% of patients. Upon multivariable adjustment, the odds of in-hospital mortality were higher in saddle versus non-saddle PE (odds ratio = 1.51; 95% confidence interval 1.08–2.10). Conclusion In this retrospective study of admissions for acute PE in patients with comorbid cancer, saddle PE was associated with a higher odds of in-hospital mortality.

Acta Oecologica Earthworms contribute to ecosystem process in no-till systems with high crop rotation intensity in Argentina Publication date: July 2019 Source: Acta Oecologica, Volume 98 Author(s): J.C. Bedano, F. Vaquero, A. Domínguez, M.P. Rodríguez, L. Wall, P. Lavelle Abstract In the Pampas region of Argentina agriculture is dominated by intensive no-till (NT) soybean cropping which produce negative consequences on soil quality. A group of farmers started to use the Good Agricultural Practices (GAP) which include a higher crop rotation, use of winter cover crops and nutrient restoration. In this NT system earthworms have a significant role in soil functioning, particularly in organic matter cycling and soil structure formation. The aim of this paper was to examine the contribution of earthworm activity to the process of C incorporation and soil structure maintenance in soils with different NT variants of: NT with GAP for 30 years (NT + r30); NT with some of the GAP for 12 years (NT-r12) and NT with soybean monoculture (NTm). Also a natural grassland (NA) was sampled as a reference. Earthworm aggregates were obtained by gently separating them from surrounding soil. Fine (HOC) and coarse (POC) organic matter fractions, water-stable aggregates (WSA) and mean weight diameter (MWD) were calculated for earthworm aggregates and bulk soil. In all sites only one species (Aporrectodea caliginosa) was found, with higher density in the NA, followed by NT + r30, that had about 9 times more earthworms than NTm. The number of earthworm aggregates was higher in the NT + r30 followed by the NA, both showing differences with the other NT systems. The earthworm aggregates in NA and NT + r30 had significantly more POC than the surrounding soil (230% increase in NA and 100% NT + r30). Earthworm casts had higher values of MWD and WSA than physical soil aggregates in both NA and NT + r30 management treatments. Our results show the existence of a positive feedback loop we called earthworm-driven virtuous cycle. The increase in earthworm abundance promotes higher production of earthworm aggregates which are richer in organic matter and more water stable than the surrounding soil. This has favourable results in terms of soil quality but also increase crop yields (57% in maize and 18% in soybean), by means of biologically mediated soil processes, which is a highly desirable way to sustainability of agricultural production. Farmers, politicians and the whole society should pay more attention to soil as a key component supporting agricultural production by means of internal biological soil functioning. Heterogeneity in millipede communities (Diplopoda) within a forest–forest edge–meadow habitat complex Publication date: July 2019 Source: Acta Oecologica, Volume 98 Author(s): Slavomír Stašiov, Vladimír Kubovčík, Marek Čiliak, Andrea Diviaková, Ivan Lukáčik, Vladimír Pätoprstý, Martin Dovciak Abstract The positive influence of heterogeneity in vegetation and land-use on animal diversity is generally well established, but it has not been conclusively confirmed yet in millipede communities inhabiting karst canyons where biodiversity is to large extent determined by variation in topography (e.g., elevation). We studied how millipede assemblages (Diplopoda) vary between forest, forest edge, and meadow habitats in this specific karst environment. We sampled millipedes by pitfall trapping during two vegetation seasons (from March to October in 2001 and 2002) in approximately monthly intervals across nine sites in Central Slovakia (Veľká Fatra Mts). In total, 951 individuals belonging to 12 species from 6 families and 10 orders were collected. The dominant species was Unciger foetidus, which was also one of the two most frequent species along with Polydesmus complanatus. Although the total number of captured millipedes was greatest on forest edges (395 individuals), intermediate in meadows, and lowest in forests (214 individuals), millipede abundance and species composition varied considerably within each habitat type among the sites. Total millipede species richness in meadow and forest edge habitats was the same (11 species) and it was lower in forest habitats (7 species), while species diversity (Shannon's H′) and equitability (E) were greatest in meadows. Millipede diversity measures (species richness or equitability) were correlated positively with species richness of herb layer and negatively with shrub layer equitability, soil conductivity, and soil phosphorus. Thus, we found complex patterns of heterogeneity in millipede community composition and richness across studied habitats and elevations that were driven by habitat type and plant community and soil characteristics. While millipede abundance patterns varied, open habitats supported most species-rich millipede communities at lower elevations, while forest edges were most species-rich at the high elevation. Fear alone reduces energy processing by resident 'keystone' prey threatened by an invader; a non-consumptive effect of 'killer shrimp' invasion of freshwater ecosystems is revealed Publication date: July 2019 Source: Acta Oecologica, Volume 98 Author(s): Calum MacNeil, Mark Briffa Abstract Non-consumptive effects (NCEs) of predators – so called 'fear' responses – encompass costly antipredator behaviours, such as reduced feeding efficiency. NCEs can influence prey population dynamics and community structure, if prey are 'keystone' species such as Gammarus spp. amphipod 'shrimps'. These freshwater macroinvertebrates have the ecosystem functional role of shredding fallen leaf litter, making it accessible to other taxa. Across Europe, the invasive predatory 'killer shrimp' Dikerogammarus villosus is replacing resident Gammarus spp., potentially threatening this vital ecosystem function. While predation (consumptive effects (CEs)) of this invader has been well studied, for the first time we test whether NCEs can be evident in prey only exposed to D. villosus presence and whether this could potentially impact on the prey's functional role. In mesocosms, exposure to constrained D. villosus did not result in mortalities of any of three Gammarus prey species but the leaf shredding efficiencies of all prey were significantly reduced compared to a control treatment. This clear NCE has the potential to propagate through the ecological community via decreased energy processing. This study demonstrates the potential for fear of invasive predator presence alone to impact on ecosystem function. Determinants of spatial patterns of plant diversity depend on the biogeographical affinities of the taxa − a case study in Northwest Yunnan, Southwest China Publication date: May 2019 Source: Acta Oecologica, Volume 97 Author(s): Jianmeng Feng Abstract The influence of the biogeographical affinities of taxa on the spatial determinants of plant diversity remains largely unknown. I explored the spatial patterns of tropical and temperate plant diversity in Northwest Yunnan and their primary determinants. Generalized linear models (GLMs) and variance partitioning were used to investigate the influences of predictors. Temperate genus diversity significantly increased with latitude, whereas tropical genus diversity did not show any obvious latitudinal trends. Proportions of tropical genera decreased with latitude, whereas those of temperate genera were on the contrary. Environment heterogeneity explained higher percentage of the spatial variation of temperate genus diversity than for that of tropical genus diversity. It may imply that the influence of environment heterogeneity on plant diversity may depend on the taxa's biogeographic affinities, which might modify the exploitation of environment heterogeneity, though the flora diversification induced by the uplifting of the Tibet Plateau may also play important roles. Climate predictors explained higher percentages of variation in the proportions of tropical genera than for the variations in tropical genus diversity. It may suggest that compared with the associations between genus diversity with tropical affinities and climatic conditions, the associations between the proportions of tropical plants and climatic conditions might more accurately reflect niche conservatism of tropical plants in the study area. Microclimatic effects on the incubation success, hatchling morphology and locomotor performance of marine turtles Publication date: May 2019 Source: Acta Oecologica, Volume 97 Author(s): Melissa N. Staines, David T. Booth, Colin J. Limpus Abstract Global atmospheric temperatures are predicted to rapidly increase within the next hundred years, consequently altering the microclimates of the sand dune environment where marine turtles lay their eggs. High nest temperatures can increase embryonic mortality, decrease hatchling vigour and size (i.e. quality), and also feminises the sex-ratio of clutches. Sand composition, vegetation cover, rainfall and sun exposure affect the temperature of sand surrounding a nest, however the effect of this variability in the beach environment on the incubation success of a sea turtle clutch is still relatively unknown. We conducted a manipulative study on loggerhead turtle nests at Mon Repos, Queensland, Australia, to investigate the effect of ground-cover vegetation vs bare sand and tree-shade vs no shade on incubation success, hatchling morphology and hatchling locomotor performance. Twenty-four nests were used in a two-factor experimental design, with tree-shade/sun and, ground-cover vegetated/cleared as fixed factors. Sun-exposed nests experienced higher nest temperatures (∼2 °C warmer), shorter incubation periods and poorer incubation success than those in tree-shade. Ground-cover-vegetated nests in tree-shade had lower hatching and emergence success (73%, 66% respectively) than sun-exposed nests placed in sites cleared of ground-cover vegetation (79%, 83% respectively). Hatchlings that emerged from cooler, tree-shaded nests were also larger and crawled faster than hatchlings from sun-exposed nests. We suggest for conservation projects on naturally 'hot' beaches, active management strategies such as selective groundcover vegetation removal and increased shading could be implemented to increase high quality hatchling production. Graphical abstract Linking local people's perception of wildlife and conservation to livelihood and poaching alleviation: A case study of the Dja biosphere reserve, Cameroon Publication date: May 2019 Source: Acta Oecologica, Volume 97 Author(s): Manfred Aimé Epanda, André Junior Mukam Fotsing, Thomas Bacha, Daniel Frynta, Luc Lens, Isaac Roger Tchouamo, Dupain Jef Abstract This Paper examines how people's livelihoods and perceptions of wildlife are related to self-reported poaching (here defined as commercial bushmeat hunting) in 25 villages at the northern buffer zone of the Dja Biosphere Reserve, East Cameroon. Using a six-point Likert scale questionnaire among 263 households interviewed form March to June 2017, the following hypothesis were tested: (1) Households with positive perceptions of wildlife are less involved in poaching; (2) Positive perceptions of wildlife are linked to sustainable livelihood improvement of households; and (3) Sustainable livelihood improvement of households leads to poaching alleviation. The study area has been the site since 2010 for a community-centered conservation Program that aims to improve local people's livelihoods (through the creation of income sources based on cocoa-based agroforestry and Non Timber Forest Products (NTFPs) Valorization) and their perceptions of wildlife (mainly through awareness raising and wildlife education) and therefore divert them from poaching. The main findings of the study indicates that positive perceptions of wildlife are linked to lower levels of poaching. Similarly, positive perception of wildlife was positively related to Livelihood improvement of the respondents. However, livelihood improvement alone did not predict poaching alleviation though we reported a significant difference in poaching frequencies of cocoa and non-cocoa producers with the firsts less involved in poaching. The findings of this study recommend more holistic approaches of biodiversity conservation that integrate simultaneously perception and livelihood improvement. Snake diversity in floodplains of central South America: Is flood pulse the principal driver? Publication date: May 2019 Source: Acta Oecologica, Volume 97 Author(s): Liliana Piatti, Dan F. Rosauer, Cristiano de C. Nogueira, Christine Strussmann, Vanda Lúcia Ferreira, Marcio Martins Abstract Seasonal flood pulses drive important seasonal ecosystem changes, trigger ecological processes that control spatial and temporal distribution of organisms and their life-history strategies, and are considered a key ecological process shaping diversity in floodplains. We used generalized dissimilarity modelling (GDM) to analyse the relative importance of flooding as a driver of snake community composition in the Paraguay River Basin (PRB), which encompasses discontinuous seasonal flooded areas, including the Pantanal floodplain, one of the largest Neotropical wetland systems. We modelled the beta diversity of pairs of PRB snake communities (based on species occurrence and phylogenetic relationships) as a function of biogeographical and environmental dissimilarities between areas, considering predictors that represent distinct limitations of species' ability to use an area. Annual flooding directly drives snake diversity, mainly when ancient evolutionary relationships between species were considered to calculate the phylogenetic diversity of the communities. Floods recurrently produce major changes in the environment and probably limit the persistency of species extremely specialized in habitat use. Despite the confirmation of the effect of flooding, the most important predictor of beta diversity between snake communities in the PRB was forest cover where communities were placed. Forest cover seems to constrain the occurrence of some species in both gradient extremities through the absence of suitable conditions for either specialized habitat use or thermoregulatory behaviours. Geographical distance was also an important predictor of beta diversity, highlighting the importance of neutral process in the assembly of local communities in systems such as seasonally flooded areas, where annual disturbances of varying intensities continually disassemble and reassemble biological communities. For the first time, we quantified the relative importance of flooding affecting patterns of biological communities in the Pantanal floodplain, compared to multiple factors also acting on species turnover in the area. Prey abundance drives habitat occupancy by jaguars in Amazonian floodplain river islands Publication date: May 2019 Source: Acta Oecologica, Volume 97 Author(s): Rafael M. Rabelo, Susan Aragón, Júlio César Bicca-Marques Abstract The jaguar (Panthera onca) is widely distributed across a broad range of habitat types, where its feeding habits and habitat use patterns vary significantly. The jaguar and its main arboreal prey – the brown-throated sloth (Bradypus variegatus) and the red howler monkey (Alouatta juara) – are widespread in the Amazonian floodplain forests of the Mamirauá Reserve. These forest-dwelling species are the most common mammal species both in the continuous forest and the forest patches surrounded by a river matrix – the fluvial islands – of the Solimões and Japurá rivers. We used sign surveys along line-transects to assess the pattern of habitat occupancy by jaguars in Amazonian floodplain forests. Specifically, we (i) tested whether habitat occupancy by jaguars differs between river islands and continuous forest; and (ii) evaluated whether and how the local abundance of sloths and howler monkeys influence the probability of site occupancy by jaguars. We built an occupancy model and used Bayesian inference to reach these goals. The proportion of sites estimated to be used by jaguars was ψ = 0.75 (HPD95: 0.36–1.00), and it did not differ between islands and continuous forest. The abundance of both prey species had a direct influence on jaguar's habitat use, whereas the aquatic matrix seems to have a negligible effect on the use of islands by jaguars. We conclude that the isolation of the river islands within the aquatic matrix does not hamper jaguars to use them. We also conclude that prey search modulates jaguars' habitat occupancy patterns with both prey species having a similar effect. This finding is compatible with the previously reported importance of sloths to the diet of jaguars in the study region despite its lower abundance than howlers. Finally, we suggest that sign surveys are an alternative method to assess the pattern of jaguar habitat occupancy in floodplain forests. Environmental adaptation and ecological distribution of streamside annual plants in northern Japan Publication date: May 2019 Source: Acta Oecologica, Volume 97 Author(s): Mayuko Suzuki, Takashi Nakamura, Takeshi Shindo, Masahito T. Kimura Abstract Environmental adaptation and distribution of three annual plants, Impatiens noli-tangere, I. textori and Persicaria thunbergii, occurring in streamside environments were studied in Sapporo, northern Japan. Impatiens noli-tangere was found along steep streams as well as gentle streams, whereas I. textori and P. thunbergii were less frequent along steep streams than along gentle streams. Impatiens noli-tangere was the least tolerant or resistant to environmental disturbances such as submergence, rapid water current, herbivory and possibly shading. P. thunbergii was the most tolerant or resistant, and I. textori showed an intermediate response. On the other hand, I. noli-tangere started reproduction earliest, followed by I. textori and P. thunbergii. Earlier start of reproduction of I. noli-tangere is assumed to serve as a means to reduce risks to encounter catastrophic events before reproduction. In addition, I. noli-tangere was the tallest per stem dry-weight unit. Growing taller would be an adaptation to reduce risk of shading. It is assumed that earlier reproduction enables I. noli-tangere to leave offspring along steep streams where water current after heavy rain is more rapid and catastrophic. Quad bike impacts on vegetation and soil physicochemical properties in an arid ecosystem Publication date: May 2019 Source: Acta Oecologica, Volume 97 Author(s): Ana L. Navas Romero, Mario A. Herrera Moratta, Antonio D. Dalmasso, Agustina Barros Abstract The increase use of Off-Road Vehicles (ORVs) coupled with the absence of control strategies have led to extensive use of natural areas for the creation of recreational trails. We assessed the effects of quad bikes on vegetation and soils in an arid ecosystem subjected to intensive quad bike use. We selected randomly eight traffic sites (disturbed sites) and eight adjacent control sites (undisturbed sites). Plant cover and composition were assessed with the point-intercept method and phytosociological census. In each site, we collected soil samples to assess soil physicochemical properties, including apparent specific weight (ASG), actual specific weight (RSG), porosity, texture, electric conductivity (EC) and pH. Soil compaction was measured at 30 spaces points per site. Plant cover and richness was significant lower in disturbed sites, with only four species present in areas subjected to disturbance. There were also changes in species dominance, with native perennial shrubs and grasses characterizing the undisturbed sites while the disturbed sites were mainly dominated by the invasive exotic herb Salsola kali. ORVs traffic also affected soil physicochemical properties including soil compaction, ASG, EC and soil pH. Soil compaction was more than double in disturbed sites and ASG tended to be higher under this condition. The EC was significantly higher and soil pH was significantly lower in the disturbed sites. Reduced vegetation cover and changes to soils physicochemical properties on quadbike trails highlights the impacts of ORVs in the landscape and the need to develop management strategies to minimize disturbance from ORVs on vegetation and soils.

Radiology Global Outreach for U.S. Radiology Training Programs Abstract Purpose of Review Utilization of medical imaging is increasing in the developing world, creating new opportunities for U.S. radiology training programs to establish international electives for interested faculty and residents. Though the nature of each initiative will vary, the process of creating a global outreach elective involves core elements. Recent Findings Development of a sustainable and impactful global elective requires forethought and planning, including abiding by regulations from governing bodies and preparation for practicing in a culturally different and often resource-limited environment. Summary This article will provide a summary of requirements for creating and sustaining a global outreach elective and provide ideas and resources for overcoming common roadblocks. Imaging in Lung Cancer Abstract Purpose of Review To describe the current role of imaging in the detection, staging, therapy planning and response assessment in lung cancer. Recent Findings Lung cancer screening using low-dose CT has been shown to reduce mortality in risk groups of active or former smokers and has, thus, been recommended by several societies and organisations worldwide. There remain, however, questions regarding optimum definition of risk factors and screening intervals. Staging criteria for lung cancer have been updated in the 8th edition of the TNM staging to better reflect prognosis. Preliminary research in radiomics in lung cancer has provided data that may add to identification of early lung cancer, prediction of prognosis and therapy response. Targeted systemic therapy has recently had a significant impact in advanced lung cancer both in terms of efficacy and toxicity, but radiologists need to be aware that response assessment criteria differ from those used for classic chemotherapy, and new side effects that may occur. Summary Modern imaging, particulary exploiting radiomics will improve early detection, classification, staging, therapy planning and ultimately, hopefully, prognosis in lung cancer. PET Imaging of Hepatocellular Carcinoma Abstract Purpose of Review Positron emission tomography has not traditionally played a major role in the evaluation of hepatocellular carcinoma (HCC). Owing to high background liver uptake and molecular mechanisms within HCC lesions, uptake of 18F-fluorodeoxyglucose (FDG) is variable and prior studies have shown only modest overall detection of intrahepatic disease. Recent Findings Tracers such as 18F- and 11C-choline as well as 11C-acetate have been explored either in isolation or together with 18F-FDG have shown greater promise in detection of intrahepatic lesions, but yet are not in widespread clinical use. 68 Ga-Prostate specific membrane antigen is a tracer developed for use in prostate cancer but a pilot study and several case reports have indicated that there may be the potential for use in the evaluation of HCC. Summary Increased rates of lesion detection using 18F-FDG may be seen in poorly differentiated tumors and in the setting of metastatic disease or within recurrent tumor following loco-regional therapies and FDG uptake may indicate a greater risk of recurrence following transplantation. Further work will be required to elucidate the precise role of other non FDG tracers in the evaluation of patients at risk for or with HCC. Humanitarian Teleradiology Abstract Purpose of Review To outline the current state of humanitarian teleradiology: scope of projects, technical and organization challenges, and to outline how recent technological developments will change the face of humanitarian teleradiology and global health. Recent Findings Technical and information technology improvements in recent years have enabled small- and large-scale teleradiology projects in many regions, some quite remote, of low- and middle-income countries (LMICs). These are aimed at alleviating the severe shortage of radiologists in LMICs. Teleradiology offers an opportunity for radiologists in high-income countries (HICs) to volunteer and contribute on an ongoing basis without the commitment of time and effort required by volunteers in other forms of global health. Recent and anticipated improvements in internet availability, as well as the emergence of artificial intelligence (AI), will continue to change the face of teleradiology and radiology in LMICs. Summary Humanitarian teleradiology provides valuable benefits to patient care in LMICs, and the combination of AI and widespread access to high-speed internet will revolutionize the field within the next decade. Emerging Role of Fluciclovine and Other Next Generation PET Imaging Agents in Prostate Cancer Management Abstract Purpose of Review Prostate cancer recurrence after definitive therapy is not uncommon. Recurrent disease is first detected by the elevation of prostate specific antigen (PSA) and may often be radiographically occult. The use of molecular imaging for the localization and staging of recurrent prostate cancer is promising. 18F-Fluciclovine is a synthetic amino acid analog positron emission tomography (PET) tracer which has demonstrated great utility in the evaluation of patients with suspected recurrence disease. Other newer PET tracers such 68Ga/18F-PSMA-ligands are being investigated for prostate imaging with promising results. The purpose of this article is to review the emerging role of fluciclovine in clinical practice for patients with prostate cancer. Recent Findings Since the approval of fluciclovine by the Food and Drug Administration, the modality is widely used in the USA for patients with suspect disease recurrence. With the coming approval of newer generation of PET tracers, it is important to understand the unique mechanism of action and the diagnostic performance of fluciclovine PET/CT in prostate cancer imaging to allow better allocation of the radiotracers. Summary This review article provides a broad literature review of the current and the future potential role of fluciclovine PET/CT in prostate cancer imaging. Somatostatin Receptor Positron Emission Tomography: Beyond Gastroenteropancreatic Neuroendocrine Tumors Abstract Purpose of Review Similar to various gastroenteropancreatic (GEP) neuroendocrine tumors (NETs), somatostatin receptors (SSTRs) are overexpressed in a wide array of malignant and benign conditions. Using somatostatin positron emission tomography (PET) analogs ([68Ga]DOTA-peptides) this overexpression of SSTRs can be exploited for clinical management in terms of diagnosis, therapy, and for peptide receptor radionuclide therapy (PRRT). Recent Findings Recent reports suggest that [68Ga]DOTA-peptide PET tracers have an emerging role in the management of wide array of non-GEP-NETs due to overexpression of SSTRs. The potential role of SSTR-PET imaging in the management of medullary thyroid cancer, paraganglioma, Merkel cell carcinoma, phosphaturic mesenchymal tumors, and inflammation will be discussed. The emerging role of theranostic and personalized medicine with PRRT using peptides labeled with yttrium-90 (90Y) or lutetium-177 (177Lu) beta emitters will also be discussed. Summary SSTR-PET imaging with [68Ga]DOTA-peptides has utility in malignant and benign conditions other than GEP-NETs. Combining SSTR-PET with other anatomic and functional imaging modalities has demonstrated superior diagnostic accuracy. The presence of SSTRs in these conditions opens up new possibilities in the management of these conditions in terms of imaging and therapeutics. Technology-Mediated Education in Global Radiology: Opportunities and Challenges Abstract Purpose of review This review explores opportunities and challenges in utilizing technology-mediated educational strategies for radiology education in parts of the world where attending radiologist support is limited. In efforts to increase the number of radiologists globally, radiology residencies have been established in regions where radiologists are scarce, several of which have partnerships with programs in other parts of the world. Technology-mediated educational strategies could leverage these partnerships to provide critical infrastructure to these recently established residencies. Recent findings The efficacies of strategies such as teleradiology and teleconferencing in global radiology have been evaluated, as have the effectiveness of technology-mediated educational tools in radiology. The topic of technology-mediated instruction for the newly established radiology residencies in other parts of the world has not yet been described or assessed, however. Summary Technology-mediated education has potential in the expanding realm of global radiology resident education, but there are some important constraints in the execution of these programs. Amino Acid PET Imaging of Glioma Abstract Purpose of Review Gliomas are among the most lethal malignancies in the world with dismal outcomes for high-grade tumors. These lesions are difficult to completely characterize with conventional magnetic resonance imaging and amino acid positron emission tomography is a rapidly progressing area of research with widespread clinical use. Recent Findings Amino acid positron emission tomography allows for more accurate glioma characterization compared to traditional imaging techniques including grading of disease, delineation of tumor spread, identification of recurrent disease, and prognosis. While the summarized radiotracers share some diagnostic properties, each also has its own weaknesses and strengths. Summary This article summarizes recent developments and clinical applications of the most widely used amino acid radiotracers. While none of these agents are FDA approved in the United States, they are considered standard of care in Europe and other parts of the world with > 10,000 studies being performed in some centers (Langen et al. in J Neurooncol 120(3):665–666, 2014). Molecular Imaging of Renal Malignancy: A Review Abstract Purpose of Review Renal cell carcinoma (RCC) is a common malignancy that is often detected incidentally in patients undergoing cross-sectional imaging of the abdomen for workup of pain or other symptoms. Due to overlap in imaging findings of RCC and benign tumors, biopsy may be necessary to confirm the diagnosis. Biopsies are occasionally non-diagnostic, however, and in small lesions or patients with comorbidities may not be technically feasible. Molecular imaging techniques can characterize tumors as being more likely malignant or benign and obviate the need for invasive testing, as well as providing accurate whole-body staging in patients with known RCC. Recent Findings PET/CT with 18F-FDG and other radionuclides can identify primary renal masses with higher malignant potential and also allows for sensitive detection of metastatic RCC. SPECT/CT imaging with 99mTc-sestamibi can provide useful information to support the diagnosis of benign oncocytic neoplasms over more aggressive RCC subtypes. Investigational molecular imaging techniques such as immunoPET and hyperpolarized 13C MRI have also shown promise in renal mass characterization. Summary This review article aims to outline the various molecular imaging modalities available in the evaluation of primary renal tumors and in whole-body staging of metastatic RCC. Thyroid Sonography: Nuclear Medicine Point of View Abstract Purpose of Review The American Cancer Society estimated that cancer of the thyroid causes 53,990 new cases and about 2060 deaths in 2018. The chance of being diagnosed with thyroid cancer has risen and this increment seems to be the result of increased use of ultrasound, CT and MR imaging examinations for reasons unrelated to the thyroid. Up to 50% of adults in central Europe have one or multiple thyroid nodules. However, the prevalence of latent carcinoma in an unselected autopsy study was 8.6%. The main diagnostic task is to differentiate between benign and malignant lesions, preferably based upon on ultrasound parameters or scoring systems like TI-RADS. Recent Findings Although there are no pathognomonic features for malignant thyroid nodules at ultrasonography or any other imaging modality, sonography of the thyroid gland has beyond doubt become the imaging method of choice for the last three decades, combined with FNA in suspicious cases. Summary Several technological improvements like ultrasound elastography, and a proliferating literature of different scoring systems allow the conclusion that ultrasound is an important gatekeeper for further diagnostic steps but not capable, so far, to identify autonomy or malignancy with a sufficiently high accuracy.

Pediatric Drugs Current and Emerging Therapeutic Options for the Management of Rare Skeletal Diseases Abstract Increasing knowledge in the field of rare diseases has led to new therapeutic approaches in the last decade. Treatment strategies have been developed after elucidation of the underlying genetic alterations and pathophysiology of certain diseases (e.g., in osteogenesis imperfecta, achondroplasia, hypophosphatemic rickets, hypophosphatasia and fibrodysplasia ossificans progressiva). Most of the drugs developed are specifically designed agents interacting with the disease-specific cascade of enzymes and proteins involved. While some are approved (asfotase alfa, burosumab), others are currently being investigated in phase III trials (denosumab, vosoritide, palovarotene). To offer a multi-disciplinary therapeutic approach, it is recommended that patients with rare skeletal disorders are treated and monitored in highly specialized centers. This guarantees the greatest safety for the individual patient and offers the possibility of collecting data to further improve treatment strategies for these rare conditions. Additionally, new therapeutic options could be achieved through increased awareness, not only in the field of pediatrics but also in prenatal and obstetric specialties. Presenting new therapeutic options might influence families in their decision of whether or not to terminate a pregnancy with a child with a skeletal disease. Vancomycin Prescribing and Therapeutic Drug Monitoring in Children With and Without Acute Kidney Injury After Cardiac Arrest Abstract Background Acute kidney injury (AKI) commonly occurs after cardiac arrest. Those subsequently treated with vancomycin are at additional risk for drug-induced kidney injury. Objective We aimed to determine whether opportunities exist for improved drug monitoring after cardiac arrest. Methods This was a retrospective cohort study of children aged 30 days–17 years treated after cardiac arrest in an intensive care unit from January 2010 to September 2014 who received vancomycin within 24 h of arrest. Vancomycin dosing and monitoring were compared between those with and without AKI, with AKI defined as pRIFLE (pediatric risk, injury, failure, loss, end-stage renal disease) stage 2–3 AKI at day 5 using Schwartz formula-calculated estimated glomerular filtration rate (eGFR). Results Of 43 children, 16 (37%) had AKI at day 5. Age, arrest duration, median time to first vancomycin dose, and the number of doses before and time to first vancomycin concentration measurement were similar between groups. Children with AKI had higher initial vancomycin concentrations than those without AKI (median 16 vs. 7 mg/L; p = 0.003). A concentration was not measured before the second dose in 44% of children with AKI. Initial eGFR predicted day 5 AKI. In children with AKI, the initial eGFR was lower in those with than those without a concentration measurement before the second dose (29 mL/min/1.73 m2 [interquartile range (IQR) 23–47] vs. 52 [IQR 50–57]; p = 0.03) but well below normal in both. Conclusions In children with AKI after cardiac arrest, decreased vancomycin clearance was evident early, and early monitoring was not performed universally in those with low initial eGFR. Earlier vancomycin therapeutic drug monitoring is indicated in this high-risk population. Medical Options for the Adjuvant Treatment and Management of Pediatric Melanoma Abstract Although melanoma is a rare diagnosis in the pediatric population, advances in the management of adults with melanoma offer the prospect of promising therapeutic options for children. At this time, medical management is not considered curative but may reduce the risk of recurrence or prolong survival. Surgical management remains the mainstay of treatment. Medical therapy of pediatric melanoma is not thought to have a role for in situ, early-stage, or localized disease, but adjuvant therapy may have a role in improving the prognosis of patients with positive sentinel lymph node biopsy (SLNB), spread beyond the regional lymph node basin, metastatic disease, or recurrent disease. Medical treatment options include immunotherapies, particularly checkpoint inhibitors, and targeted therapies, which have provided improved toxicity profiles compared with traditional chemotherapy regimens in the setting of advanced disease. There is a growing body of pediatric-specific data relevant to the use of adjuvant therapies for advanced melanoma in children. Efficacy and Safety of Oral Paracetamol vs. Oral Ibuprofen in the Treatment of Symptomatic Patent Ductus Arteriosus in Premature Infants Abstract Background The ductus arteriosus (DA) is situated between the aortic arch and the pulmonary artery in fetal circulation, and its closure is one of the most important changes required for the transition to extrauterine life. Prolonged duration of patent DA (PDA) impairs hemodynamics and contributes both to morbidity associated with prematurity and to mortality. Therefore, when best to initiate treatment and what drug to use as first-line treatment to close the ductus is important. Objective The aim of this study was to compare the efficacy and side effects of the oral forms of ibuprofen and paracetamol and to contribute to the literature investigating the first drug to be selected in the medical treatment of PDA. Methods This observational, retrospective cohort study was conducted in infants born at ≤ 28 weeks' gestation and admitted to our Neonatal Intensive Care Unit (Manisa Merkezefendi State Hospital, Manisa, Turkey) between February 2015 and April 2018. Included infants were born at ≤ 28 weeks' gestation, had PDA-related clinical findings and hemodynamically significant PDA on echocardiography, and received oral ibuprofen or oral paracetamol therapy as the closure treatment. Results The most common clinical findings for the diagnosis of PDA were hyperdynamic circulation, tachycardia, and increased oxygen requirement. In total, 43 of the 51 (84.3%) premature infants in the ibuprofen group and 32 of the 36 (88.8%) in the paracetamol group achieved PDA closure after the first treatment cycle. There was no statistically significant difference between the two groups in terms of respiratory morbidity, renal and liver function, intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, retinopathy of prematurity, length of hospital stay, and mortality. Conclusions Our results indicate that oral paracetamol was as effective as oral ibuprofen in the medical treatment of PDA. In addition, both drugs were considered well-tolerated in terms of effects on kidney, liver, and intestinal functions. Our results demonstrate that oral paracetamol can be used effectively and safely as the first-line treatment of PDA. Neuropathic Pain in Pediatric Oncology: A Clinical Decision Algorithm Abstract Neuropathic pain in pediatric oncology can be caused by distinct lesions or disease processes affecting the somatosensory system, including chemotherapy-related neuronal injury, solid tumor-related involvement of neural structures, post-surgical neuropathic pain—including phantom limb pain and pain after limb-sparing surgery—and the complex circumstances of neuropathic pain at the end of life. Treatment algorithms reflect the general treatment principles applied for adult neuropathic pain, but the dose regimens applied in children are modest and rarely escalated to the maximum doses to optimize analgesic efficacy. Pharmacological management of neuropathic pain should be based on a stepwise intervention strategy, as combinations of medications are the most effective approach. Gabapentinoids and tricyclic antidepressants are recommended as first-line therapy. Methadone, ketamine, and lidocaine may be useful adjuvants in selected patients. Prospective studies extended over a substantial length of time are recommended because of the nature of neuropathic pain as persistent, chronic pain and based on the need for sufficient time to escalate medication dose regimens to full analgesic efficacy. Childhood-Onset Takayasu Arteritis (c-TA): Current and Future Drug Therapy Abstract Childhood-onset Takayasu arteritis (c-TA) is the third most common systemic vasculitic disorder in children. Vascular stenosis is the main complication, and aneurysms are reported in 19–65% of cases, often in combination with stenotic lesions. Management of patients with c-TA is largely based on studies involving predominantly patients with adult-onset TA (a-TA). More widely used criteria for patients with c-TA have been devised by the joint European League Against Rheumatism, Pediatric Rheumatology International Trials Organization, and Pediatric Rheumatology European Society. Of the available imaging modalities, those that do not use radiation (color Doppler ultrasound and magnetic resonance angiogram) are preferred over 18F-labeled fluoro-2-deoxyglucose (18F-FDG) positron-emission tomography, computed tomography (CT), and CT angiogram in children. Remission rates have been reported to be lower in c-TA than in a-TA, and published mortality rates in c-TA range from 16 to 40%, which is much higher than reported in patients with a-TA. The usual drug therapy options include steroids plus steroid-sparing second-line immunosuppressants, such as mycophenolate, azathioprine, methotrexate, cyclophosphamide, and cyclosporine, along with antiplatelet agents. Interleukin-6 inhibitors such as tocilizumab, as well as the tumor necrosis factor inhibitors, are other aggressive therapeutic options. As yet, no randomized controlled trials have been conducted in c-TA. Pharmacotherapeutic Management of Wilms Tumor: An Update Abstract Although differences exist in treatment and risk-stratification strategies for children with Wilms tumor (WT) between the European [International Society of Paediatric Oncology (SIOP)] and American [Children's Oncology Group (COG)] study groups, outcomes are very similar, with an overall survival of > 85%. Future strategies aim to de-intensify treatment and reduce toxicity for children with a low risk of relapse and intensify treatment for children with high-risk disease. For metastatic WT, response of lung nodules to chemotherapy is used as a marker to modify treatment intensity. For recurrent WT, a unified approach based on the use of agents that were not used for primary therapy is being introduced. Irinotecan is being explored as a new strategy in both metastatic and relapsed WT. Introduction of biology-driven approaches to risk stratification and new drug treatments has been slower in WT than in some other childhood cancers. While several new biological pathways have been identified recently in WT, their individual rarity has hampered their translation into clinical utility. Identification of robust prognostic factors requires extensive international collaborative studies because of the low proportion who relapse or die. Molecular profiling studies are in progress that should ultimately improve both risk classification and signposting to more targeted therapies for the small group for whom current therapies fail. Accrual of patients with WT to early-phase trials has been low, and the efficacy of these new agents has so far been very disappointing. Better in vitro model systems to test mechanistic dependence are needed so available new agents can be more rationally prioritized for recruitment of children with WT to early-phase trials. Pancreatic Enzyme Supplementation in Patients with Atopic Dermatitis and Food Allergies: An Open-Label Pilot Study Abstract Background Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects both patients and their families. Current therapies often alleviate symptoms but do not prevent or eradicate the disease. Objectives Our objective was to determine whether pancreatic enzyme supplementation is an effective and safe treatment in refractory pediatric AD associated with food allergies. Methods We conducted an open-label pilot study using a case–control design. Patients with severe AD and known food allergies refractory to conventional therapies and exclusion diets were recruited and treated for 6 weeks with oral supplementation of pancreatic enzymes. The primary endpoint was the severity of AD, using the Scoring Atopic Dermatitis (SCORAD) index. Secondary measures included markers of intestinal permeability (urinary sucrose and lactulose/mannitol excretion). Results A total of 11 patients met all eligibility criteria and completed the trial. Significant improvement in AD was observed after 6 weeks of pancreatic enzyme supplementation (SCORAD index 52.3 ± 5.5 vs. 34.6 ± 7.6; p = 0.0008). Beneficial effect was observed in 9 of 11 patients, without adverse events. Fractional urinary sucrose excretion improved to a level comparable to that of age-matched controls (p < 0.05). However, urinary lactulose:mannitol ratios remained abnormally high compared with those of controls (p = 0.01). Conclusions Pancreatic enzyme supplementation was associated with improved AD and gastroduodenal permeability. Additional randomized placebo-controlled studies are required before this treatment can be recommended in this clinical setting. Serious Adverse Events Associated with Off-Label Use of Azithromycin or Fentanyl in Children in Intensive Care Units: A Retrospective Chart Review Abstract Objectives Half of prescription drugs commonly given to children lack product labeling on pediatric safety, efficacy, and dosing. Two drugs most widely used off-label in pediatrics are azithromycin and fentanyl. We sought to determine the risk of serious adverse events (SAEs) when oral azithromycin or intravenous/intramuscular fentanyl are used off-label compared to on-label in pediatric intensive care units (ICUs). Study Design Six pediatric hospitals participated in a retrospective chart review of patients administered oral azithromycin (n = 241) or intravenous/intramuscular fentanyl (n = 367) between January 5, 2013 and December 26, 2014. Outcomes were SAEs by drug and labeling status: off-label compared to on-label by Food and Drug Administration (FDA)-approved age and/or indication. Statistical analysis was performed using logistic regression to estimate odds ratios (ORs) and Cox regression to estimate hazard ratios (HRs). Results Twenty-one (9%) children receiving azithromycin experienced SAEs. Off-label use of azithromycin was not associated with a higher risk of SAE (OR 0.87, 95% CI 0.27–2.71, p = 0.81). Ninety-five (26%) children receiving fentanyl experienced SAEs. Fentanyl off-label use by both age and indication was not associated with a higher risk of overall SAEs compared to on-label use (OR 1.99, 95% CI 0.94–4.19, p = 0.07). However, the risk of the SAE respiratory depression was significantly greater when fentanyl was used off-label by both age and indication (OR 5.05, 95% CI 1.08–23.56, p = 0.044). Results based on HRs were similar. Conclusions Azithromycin off-label use in pediatric ICUs does not appear to be associated with an increased risk of SAEs. Off-label use of fentanyl appears to be more frequently associated with respiratory depression when used off-label by both age and indication in pediatric ICUs. Prospective studies should be undertaken to assess the safety and efficacy of fentanyl in the pediatric population so that data can be added to the FDA labeling. Clinical Features and Treatment of Down Syndrome Arthropathy: Experience from Two US Tertiary Hospitals Abstract Background Arthropathy of Down syndrome (DA) is largely under-recognized, with an average 2-year delay in diagnosis. Most patients present with polyarthritis, and treatment has historically been challenging. Objectives Our objective was to investigate the clinical features and treatment of DA in the largest cohort reported to date. Methods In a retrospective chart review at two tertiary care hospitals, International Classification of Diseases, ninth revision, clinical modification (ICD-9-CM) codes for Down syndrome (DS) and juvenile idiopathic arthritis (JIA), between 1 January 1995 and 31 December 2015, were identified and charts reviewed. Results In total, 43 patients were identified, with an average (± standard deviation [SD]) follow-up period of 6 ± 4.4 years. The average age of symptom onset was 7.4 ± 3.9 years, with a mean delay of 19 ± 17 months from symptom onset to diagnosis. At diagnosis, 77% of patients had morning stiffness and 72% had abnormal laboratory values; there was an average of 15 ± 13 active joints (range 1–56). Treatment approaches varied, and there was a significant decrease in joints with active arthritis (p < 0.001), with 25% and 39% having at least one change in disease-modifying antirheumatic drug (DMARD) and biologic therapy, respectively. DMARD therapy was discontinued in 60% because of side effects, and 39% had inadequate response to first-line biologic therapy. Conclusions DA remains under-recognized, with delays in diagnosis and extensive musculoskeletal symptoms at presentation. While DA can improve with current therapy for JIA (corticosteroids, DMARDs, biologics), barriers include medication toxicity, intolerance, and ineffectiveness. Earlier diagnosis through improved screening and more targeted treatment may allow for earlier disease control and better outcomes.

The Patient - Patient-Centered Outcomes Research Patient Perspectives on the Value of Patient Preference Information in Regulatory Decision Making: A Qualitative Study in Swedish Patients with Rheumatoid Arthritis Abstract Background There is increasing interest in involving patient preferences for benefits and risks in regulatory decision making. Therefore, it is essential to identify patient perspectives regarding the value of patient preference information (PPI). Objectives The aim of this study was to explore how patients with rheumatoid arthritis (RA) value the use of PPI in regulatory decision making regarding medical products. Methods Regulators and patients with RA were interviewed to gather initial insights into opinions on the use of PPI in regulatory decisions regarding medical products. The interviews were used to draft and validate the interview guide for focus groups with patients with RA. Participants were purposively sampled in collaboration with the Swedish Rheumatism Association in Stockholm and Uppsala. Each focus group consisted of three to six patients (18 in total). All interviews were audio-recorded, transcribed verbatim, and analysed using content analysis. Results According to the participants, PPI could lead to regulators considering patients' needs, lifestyles and well-being when making decisions. PPI was important in all stages of the medical product lifecycle. Participants reported that, when participating in a preference study, it is important to be well-informed about the use of the study and the development, components, administration, and risks related to the medical products. Conclusions Patients thought PPI could be valuable to consider in regulatory decisions. It is essential for patients to be well-informed when asked for their preferences. Research on information materials to inform patients in preference studies is needed to increase the value of PPI in regulatory decision making. High Proportion of Subjective Component to the Disease Activity Score is Associated with Favorable Response to Abatacept in Rheumatoid Arthritis Abstract Background Response prediction of certain biologic agents for the treatment of rheumatoid arthritis (RA) remains an unmet need in real-world clinical practice. The contribution of patient-reported components to the 28-joint Disease Activity Score (DAS28) was termed DAS28-P and investigated as a predictor of response to biologic agents, mostly tumor necrosis factor inhibitors. We aimed to evaluate DAS28-P as a predictor of the European League Against Rheumatism (EULAR) response to abatacept in patients with RA. Methods The study population was a prospective, observational, multicenter cohort of Korean patients with RA, who were followed up for a nationwide post-marketing surveillance study of abatacept. Correlation of DAS28-P with DAS28, change of DAS28, and EULAR response groups were evaluated. Logistic regression analysis was used to predict good-to-moderate EULAR response to abatacept in the study population. Results A total of 341 patients were involved in the analysis stratified on the EULAR response criteria. Presence of comorbidities, previous exposure to biologic agents, baseline DAS28, three of its components (tender joint counts, global health visual analog scale, erythrocyte sedimentation rate), and baseline DAS28-P were significantly associated with EULAR response to abatacept at 6 months. Stratified upon EULAR response, a group with good-to-moderate response had a higher baseline value and lower interval change for DAS28-P. Logistic regression analysis showed that a DAS28-P cut-off of > 0.44 was more positively associated with good-to-moderate EULAR response with abatacept treatment than naivety to biologic agents. Conclusions The DAS28-P could be predictive of response to abatacept. A higher baseline DAS28-P is associated with a favorable therapeutic response to abatacept. Trial registration Trial name, Korean Post-marketing Surveillance for Orencia®. Trial registration number, NCT01583244. Registered on April 20, 2012. Healthcare Experience and their Relationship with Demographic, Disease and Healthcare-Related Variables: A Cross-Sectional Survey of Patients with Chronic Diseases Using the IEXPAC Scale Abstract Background Patient experience is acknowledged as a principal aspect of quality healthcare delivery, and it has implications with regard to outcomes. Objectives Our objective was to evaluate the healthcare experience of patients with chronic diseases to identify patient-perceived healthcare gaps and to assess the influence of demographic and healthcare-related variables on patient experiences. Methods A cross-sectional survey was delivered to adult patients with chronic diseases: diabetes mellitus (DM), human immunodeficiency virus (HIV) infection, inflammatory bowel disease (IBD) or rheumatic diseases. Patient experiences were assessed with the Instrument for Evaluation of the Experience of Chronic Patients (IEXPAC) questionnaire, with possible scores ranging from 0 (worst) to 10 (best experience). Results Of the 2474 patients handed the survey, 1618 returned it (response rate 65.4%). Patients identified gaps in healthcare related mainly to access to reliable information and services, interaction with other patients and continuity of healthcare after hospital discharge. The mean ± standard deviation (SD) IEXPAC score was 6.0 ± 1.9 and was higher for patients with HIV (6.6 ± 1.7) than for those with rheumatic disease (5.5 ± 2.0), IBD (5.9 ± 2.0) or DM (5.9 ± 1.9) (p < 0.001). In multivariate models, better overall IEXPAC experience was associated with follow-up by the same physician, follow-up by a nurse, receiving healthcare support from others and treatment with subcutaneous or intravenous drugs. The multivariate model that confirmed patients with HIV or DM had better experience than did those with rheumatic diseases. Conclusions Through IEXPAC, patients identified aspects for healthcare quality improvements and circumstances associated with better experience, which may permit greater redirection of healthcare toward patient-centered goals while facilitating improvements in social care and long-term healthcare quality. Elicitation of Health-Related Utility in Perianal Fistula in Crohn's Disease Abstract Background and Objective Perianal fistulae are a common complication of Crohn's disease (CD) and pose a substantial burden on quality of life. Data capturing health-related utility associated with perianal fistulae in CD are scarce. The current study aims to value health states related to different stages of the disease to quantitatively evaluate the impact of complex perianal fistulae on CD patients' quality of life. Methods Eight health state descriptions associated with complex perianal fistulae in CD were developed following qualitative research with patients and validation by clinicians. Following pre-testing, a survey was administered online in two samples of UK respondents: the general population and patients with CD. A choice-based valuation technique, the time trade-off (TTO), was used for direct utility measurement. CD patients also valued their current health state using the TTO. Exclusion criteria for respondents displaying logical inconsistencies were applied. Results Usable responses were received from 835 respondents, reflective of the UK population in age and sex, in the general population survey and 162 CD patients in the patient survey. Non-remission states were valued much lower than the remission state by both samples, ranging from 0.20 for proctectomy with a negative outcome to 0.66 for chronic symptomatic fistulae with mild symptoms. Patients currently experiencing fistulae reported lower values for current health than those without fistulae. Conclusion Low utility values were assigned to the non-remission health states for perianal fistulae in CD by the general public and patients with CD. This demonstrates the high humanistic burden of inadequately managed perianal fistula in CD. Creation of a Decision Support Tool for Expectant Parents Facing Threatened Periviable Delivery: Application of a User-Centered Design Approach Abstract Background Shared decision-making (SDM) is optimal in the context of periviable delivery, where the decision to pursue life-support measures or palliation is both preference sensitive and value laden. We sought to develop a decision support tool (DST) prototype to facilitate SDM by utilizing a user-centered design research approach. Methods We convened four patient and provider advisory boards with women and their partners who had experienced a surviving or non-surviving periviable delivery, pregnant women who had not experienced a prior preterm birth, and obstetric providers. Each 2-h session involved design research activities to generate ideas and facilitate sharing of values, goals, and attitudes. Participant feedback shaped the design of three prototypes (a tablet application, family story videos, and a virtual reality experience) to be tested in a final session. Results Ninety-five individuals (48 mothers/partners; 47 providers) from two hospitals participated. Most participants agreed that the prototypes should include factual, unbiased outcomes and probabilities. Mothers and support partners also desired comprehensive explanations of delivery and care options, while providers wanted a tool to ease communication, help elicit values, and share patient experiences. Participants ultimately favored the tablet application and suggested that it include family testimonial videos. Conclusion Our results suggest that a DST that combines unbiased information and understandable outcomes with family testimonials would be meaningful for periviable SDM. User-centered design was found to be a useful method for creating a DST prototype that may lead to improved effectiveness, usability, uptake, and dissemination in the future, by leveraging the expertise of a wide range of stakeholders. A Guide to Measuring and Interpreting Attribute Importance Abstract Stated-preference (SP) methods, such as discrete-choice experiments (DCE) and best–worst scaling (BWS), have increasingly been used to measure preferences for attributes of medical interventions. Preference information is commonly characterized using attribute importance. However, attribute importance measures  can vary in value and interpretation depending on the method used to elicit preferences, the specific context of the questions, and the approach used to normalize attribute effects. This variation complicates the interpretation of preference results and the comparability of results across subgroups in a sample. This article highlights the potential consequences of ignoring variations in attribute importance measures, and makes the case for reporting more clearly how these measures are obtained and calculated. Transparency in the calculations can clarify what conclusions are supported by the results, and help make more accurate and meaningful comparisons across subsamples. Issues in the Design of Discrete Choice Experiments The Value of Treatment Processes in Germany: A Discrete Choice Experiment on Patient Preferences in Complementary and Conventional Medicine Abstract Background The effects of health interventions are often complex, and it is argued that they comprise more than pure changes in clinical parameters. Aspects of the treatment process, so-called 'benefits beyond health', are often overlooked in the evaluation of health interventions but can be of value to the patients. Objectives The aim of this study was to assess patients' preferences and willingness to pay regarding the treatment process and its attributes in patients using acupuncture, homeopathy or general medicine (GM). Methods A systematic literature search, six semi-structured interviews and a stakeholder involvement were conducted to determine the attributes of the treatment process. Five process attributes and one cost attribute were used to construct the experimental design of the discrete choice experiment (DCE) (6 × 3), a cross sectional survey method. Patients were recruited by outpatient physicians practicing in Berlin and Munich, Germany. Process attributes were effects-coded. Data were analyzed in a conditional logit regression. Results Data from 263 patients were analyzed. DCE results showed that the treatment process attributes 'active listening' and 'time' were most relevant to all patients. Preferences for the attributes 'holistic treatment' (more relevant to the acupuncture and homeopathy groups) and 'information' (more relevant to the GM group) seemed to differ slightly between the groups. Willingness-to-pay values were higher in the acupuncture and homeopathy groups. Conclusions The time physicians take and the extent to which they listen attentively are most important and are equally important to all patients. These results may contribute to the debate about more patient-centered healthcare. They support a strengthening of medical consultations in the German healthcare system. We suggest giving physicians the opportunity to spend more time with their patients, which may be achieved by changing the general conditions of remuneration (e.g., improved reimbursement of medical consultations). German Clinical Trial Register DRKS00013160. Systematic Review of Public Preferences for the Allocation of Donor Organs for Transplantation: Principles of Distributive Justice Abstract Background Solid organ transplantation is the treatment of choice for organ failure, but donor organs are a scarce resource because of a large mismatch between supply and demand. This scarcity leads to an ethical dilemma, forcing priority setting in organ allocation to individual patients. Little is known about public preferences regarding priority setting in organ allocation. A systematic review was performed to review the existing evidence and provide an overview of the criteria and criterion levels in regard to ethical aspects of distributive justice. Methods The PubMed, Web of Science, EBSCO and PsycINFO databases were searched for literature published between January 2000 and December 2018. Only original studies were selected. The criteria were identified, extracted and grouped into a self-developed matrix according to the principles of distributive justice to ascertain public preferences. Results Overall, 9645 references were identified, and 15 studies were included. In total, 27 criteria clustered in seven theory-guided groups could be identified: "equality", "effectiveness/benefit", "medical urgency", "own fault", "value for society", "medical background" and "sociodemographic status". It was shown that not only a single principle but rather a combination of principles are relevant for the allocation. Therefore, a public propensity towards a rational utilitarian ethical model of allocation could be recognised. Conclusions The general public not only wanted to allocate organs mainly to those with a good probability of having a successful transplantation but also wanted to consider those who need an organ most urgently to prevent fatal consequences, resulting in unclear trade-offs between effectiveness/benefit and medical urgency. Public preferences for organ allocation are therefore complex, and data regarding clear trade-offs are still lacking. Multi-Method Patient-Engagement Approach: A Case Example from a PCORI-Funded Training Project

Pediatric Surgery Immature gastric teratoma in a newborn Publication date: August 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 47 Author(s): Sandheeah Ramdeny, Katherine Broad, Prabhu Sekaran, Sara Harrison, Philip Connor, Mallinath Chakraborty Abstract We present a full-term male infant with a palpable abdominal mass who presented with severe haematemesis associated with cardiovascular compromise. Although an initial ultrasound imaging identified a left supra-renal calcified mass suggesting a neuroblastoma, further imaging suggested an atypical mass which was separate from the spleen and left kidney. An upper gastro-intestinal contrast study localised the mass to the stomach and a computed tomograph suggested the possibility of a gastric teratoma likely in combination with a raised serum Alpha-fetoprotein. The mass was completely surgically resected, and histology confirmed an immature gastric teratoma.We would like to draw the attention of clinicians of the possibility of a gastric teratoma in an infant who presents with an abdominal mass and haematemesis. Splenic abscess with salmonella enteritidis following marsupialization of a splenic cyst Publication date: August 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 47 Author(s): Yolla Youssef, Lena Naffaa, Sarah Chamseddine, Ahmad Zaghal, Mohammad Khalife, Nadine Yazbeck, Ghassan Dbaibo, Rima Hanna-Wakim Abstract Splenic abscess in the setting of salmonella infection is a rare entity, which has been reported during the course of typhoid fever. We describe the presentation of a healthy 11 year-old boy who had abdominal pain, incidental finding of splenic cyst and who developed Salmonella enteritidis gastroenteritis and splenic abscess shortly following laparoscopic removal of the splenic cyst. We review 11 additional cases of nontyphoidal salmonellae splenic abscesses in pediatric patients. Small intestinal obstruction by sunflower seed bezoar Publication date: July 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 46 Author(s): Tatiana de Warren, Melanie B. LaPlant, Daniel A. Saltzman, Donavon J. Hess Abstract Bezoars are rare mass formations in the gastrointestinal tract caused by consumption of indigestible materials such as plant fibers (Phytobezoars) or hair (Trichobezoars). We report a case of a 12-year-old boy who presented with abdominal pain, nausea and vomiting without any other clinical findings. Radiographic findings showed an area of obstruction in the small bowel, which we confirmed by performing an exploratory laparotomy. The treatment consisted of surgical removal of the obstructing bezoar from the distant ileum as well as excision of an incidentally identified Meckel's diverticulum. Postoperative discussions revealed, that the patient had ingested a large amount of unshelled sunflower seeds, which had caused a mass formation and obstruction of his small bowel. The patient did not suffer any complications during or after surgery and experienced a rapid recovery. Bezoars should be considered among adolescents presenting with intestinal obstruction, especially among baseball players. Spontaneous perinatal gallbladder perforation Publication date: July 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 46 Author(s): Iran Tavakoli, David Bigam, Consolato Sergi, Bryan Dicken Using silver poly (acrylate) matrix (Haemoblock) in children with lymphatic malformations Publication date: July 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 46 Author(s): D.A. Safin, D.V. Romanov Abstract Lymphatic malformations (LM) are a congenital malformation of lymphatic vessels. There exist large, small and mixed cystic LMs. Up to the present day, the causes of LM remain the subject of scientific research. Special sclerosing agents such as Doxycycline, Bleocyne, Picibanil (OK-432) and other drugs are used for sclerosing of LM. Due to the special characteristics of the impact of each drug on the endothelium, during the early post-surgical period there occur various undesirable effects (swelling, pain conditions, toxic effects, allergies, etc.), moreover, the effectiveness of the used sclerosing agents is not always sufficient to obtain a good clinical effect. The goal of our work is to evaluate the use of the Haemoblock™ sclerotherapy in children with various forms of lymphatic malformations. We carried out a retrospective analysis of the use of the silver poly (acrylate) matrix (Haemoblock™) for sclerotherapy (off-label protocol) of various forms of LM in children who underwent treatment at the Center for Vascular Pathology (Moscow) during the period from 2016 to 2018. After the conducted surgery - sclerotherapy with the Haemoblock™ in children with various LMs, we obtained the following results: excellent and good - in 6 cases, satisfactory - in 2 cases, no negative result was obtained. In the Center for Vascular Pathology (Moscow) in 2016–2018, there was conducted a treatment of 8 children with LM of various types and localization. During the early post-surgical stages (1–3 h after surgery), 4 children showed severe pain syndrome, which stopped on its own without prescription of drug-induced pain killers. 12–24 h after sclerotherapy, 6 children also showed an increase in swelling in the area of the surgery. The swelling persisted for 3–6 days, and stopped on its own. Considering the positive results of treatment, further multi center study of the use of the Haemoblock™ is needed for the purpose of the LM sclerotherapy in children. Malignant sacro-coccygeal teratoma with growing teratoma syndrome Publication date: July 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 46 Author(s): Tamador Al-Shamaileh, Fatena Ajlouni, Rasha Deebajah, Iyad Sultan, Mohammad M. Saleem, Khalil Ghandour Abstract A 13-month-old female with sacro-coccygeal tumor type II by Altman, was proven by biopsy to be a malignant germ cell tumor. Serum tumor markers were normal. During neo-adjuvant chemotherapy visible tumor progression was confirmed radiologically and progressed despite changing chemotherapy. The external growing mass forced its way out of the skin. More importantly, CT showed resolution of the pelvic component. Complete tumor resection with coccygectomy was performed. Histopathology showed mature teratoma, immature cells in the coccyx and no malignant germ cells. Three months after ending her therapy she remains in remission. We report the first case of growing teratoma syndrome (GTS) in the coccygeal region. Hybrid open and endovascular repair of a blunt traumatic thoracic aortic injury in a 7 year old boy Publication date: July 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 46 Author(s): Jennifer M. Brewer, Sarah Grout, Mohiuddin Cheema, Thomas Divinagracia, Carissa Webster-Lake, Douglas Moote, Nahum I. Kryzman, Edward Cortland, Brendan T. Campbell Abstract We describe a 7-year-old boy who sustained a blunt thoracic aortic injury following a rollover motor vehicle crash where the vehicle fell 200 feet down an embankment. The chest x-ray on arrival showed widening of the superior mediastinum, a left-sided hemothorax, and first rib fracture. The screening CTA of the chest revealed bilateral pulmonary contusions, a large left hemothorax, and evidence of aortic injury with active contrast extravasation. The patient was intubated due to respiratory distress and had a left chest tube placed. The patient became hypotensive with greater than 1.5 L of blood from the chest tube, so a resuscitative thoracotomy was performed. Bleeding was controlled with a sponge stick initially and definitively with a Satinsky vascular clamp. Next the patient was transported to the hybrid OR at the adjacent adult hospital with an open chest for endovascular graft placement. The patient was admitted to the PICU post-operatively, transferred to the floor on POD 4, and discharged home on POD 9. Aortic injury after blunt trauma in pre-adolescent children is uncommon and often fatal. Endovascular repair of traumatic thoracic aortic injury in adults is currently the standard of care, but there is a paucity of clinical data to guide management of these types of injuries in pediatric patients. Melanotic neuroectodermal tumor of infancy Publication date: July 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 46 Author(s): Hao Tran Kiem, Kim Hoa Nguyen Thi, Phu Tran Xuan, Loi Nguyen Hong, Son Nguyen Huu, Duy Phan Canh, Carlos Rodriguez Galindo, McKay McKinnon Abstract Introduction Melanotic neuroectodermal tumor of infancy (MNTI) is a rare, rapidly growing pigmented neoplasm of neural crest origin generally arising in infants during the first year of life. Case We report a 15-month old male who presented with a 2-month history of a rapidly growing mass in the anterior. A biopsy showed melanotic neuroectodermal tumor, and complete resection with negative margins was subsequently achieved. The patient is in remission at 11 months from surgery. Conclusion Due to its rapid growth potential and locally destructive behaviour, early diagnosis is extremely important to limit local expansion. The treatment of choice for melanotic neuroectodermal tumor of infancy (MNTI) is surgical excision. Ureteral injury following vertebral body tethering for adolescent idiopathic scoliosis Publication date: July 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 46 Author(s): JuliAnne R. Rathbun, Daniel S. Hoernschemeyer, Mark R. Wakefield, Elizabeth A. Malm-Buatsi, Katie S. Murray, Venkataraman Ramachandran Abstract Adolescent idiopathic scoliosis (AIS) is a deformity of the spine of unknown etiology and no definitive cure. A novel technique for correction during growth known as vertebral body tethering (VBT) was introduced in 2005 in animal models, and then quickly adapted for human implementation [Courvoisier, 2015]. This method is in the early stages of growth and adaptation as well as evaluating risks to improve safety and feasibility. Some of the most common complications reported are atelectasis [Newton, 2018], proximal junctional kyphosis and reoperation for device breakage or addition [Hardesty, 2017]. There are no case reports describing ureteral injury following VBT. We present a case of primary ureteral injury following VBT with subsequent erosion and stricture formation requiring definitive ureteral reconstruction. We discuss the possible causes of this complication, its management, follow up, and short-term outcome. Re-do Kasai procedure in a preterm infant Publication date: July 2019 Source: Journal of Pediatric Surgery Case Reports, Volume 46 Author(s): Hiromu Tanaka, Hideyuki Sasaki, Masatoshi Hashimoto, Masaki Nio Abstract We report the case of a 10-day old boy with biliary atresia (BA) who was delivered by caesarean section at 33 weeks 4 days of gestation (birth weight, 2135 g). At birth, his direct bilirubin level was high, and stools were light yellow. Abdominal ultrasonography showed no triangular cord sign, and duodenal fluid examination showed no bile. We performed a Kasai procedure (KP) 27 days after birth. His liver biopsy showed intrahepatic bile duct reduction. No bile excretion occurred postoperatively. We performed a redo KP 83 days after birth. Postoperative bile excretion was good, and his jaundice promptly resolved. The patient's liver biopsy showed bile duct development. Jaundice recurred at 8 months of age, and brain-dead-donor liver transplantation was required. The patient died of liver failure at 23 months of age. Surgery for BA during the neonatal period is usually effective, and the results of re-operation in cases with poor postoperative biliary excretion are poor. Here, we present a novel case that illustrates the progression and timing of the pathological hepatic changes in BA and consider the indications for and timing of re-operation in preterm infants.

Magnetic Resonance Materials in Physics, Biology and Medicine Projection-based respiratory-resolved left ventricular volume measurements in patients using free-breathing double golden-angle 3D radial acquisition Abstract Objective To refine a new technique to measure respiratory-resolved left ventricular end-diastolic volume (LVEDV) in mid-inspiration and mid-expiration using a respiratory self-gating technique and demonstrate clinical feasibility in patients. Materials and methods Ten consecutive patients were imaged at 1.5 T during 10 min of free breathing using a 3D golden-angle radial trajectory. Two respiratory self-gating signals were extracted and compared: from the k-space center of all acquired spokes, and from a superior–inferior projection spoke repeated every 64 ms. Data were binned into end-diastole and two respiratory phases of 15% respiratory cycle duration in mid-inspiration and mid-expiration. LVED volume and septal–lateral diameter were measured from manual segmentation of the endocardial border. Results Respiratory-induced variation in LVED size expressed as mid-inspiration relative to mid-expiration was, for volume, 1 ± 8% with k-space-based self-gating and 8 ± 2% with projection-based self-gating (P = 0.04), and for septal–lateral diameter, 2 ± 2% with k-space-based self-gating and 10 ± 1% with projection-based self-gating (P = 0.002). Discussion Measuring respiratory variation in LVED size was possible in clinical patients with projection-based respiratory self-gating, and the measured respiratory variation was consistent with previous studies on healthy volunteers. Projection-based self-gating detected a higher variation in LVED volume and diameter during respiration, compared to k-space-based self-gating. Realization of 19 F MRI oximetry method using perfluorodecalin Abstract Objective To identify the technical aspects of the potential use of clinically approved perfluorodecalin (PFD, C10F18) for 19F magnetic resonance imaging (MRI) oximetry method at high magnetic field 7.05 T. Materials and methods 19F T1 measurements were made on a set of PFD samples with different oxygen contents (0%, 21%, and 100%) at room (21 °C) and body temperature (37 °C). In vivo MRI studies were carried out on one healthy rat and two rats with C6 brain glioma. Results The selective excitation of the magnetically equivalent 19F nuclei of CF2 groups of trans-isomer of PFD, which give a doublet at a frequency of about − 140 ppm (in relation the chemical shift of trifluoroacetic acid, which is − 76.55 ppm) should be done for correct implementation of 19F MRI oximetry method. The amount of PFD equal to 30 μl is the optimal for obtaining reliable data on the measured T1 values. In this case, the standard deviation of T1 does not exceed 5%. In vivo MRI studies showed that the values of the partial pressure of oxygen (pO2) decrease from normal values of about 38 mmHg (healthy brain) to almost 0 mmHg at the last stage of tumor growth. Conclusion The study showed the feasibility of the successful application of PFD for 19F MRI oximetry method. Precision of T1-relaxation time measurements in the hepatic portal vein: influence of measurement technique and sequence parameters Abstract Objective To investigate the effects of a range of parameter settings on T1 measurement stability in the portal vein using the T1-mapping sequences Look-Locker (LL) and Modified Look-Locker inversion recovery (MOLLI). Materials and methods Ten different versions of LL and MOLLI sequences were tested and compared to a reference sequence provided by the MR manufacturer. Ten healthy volunteers were imaged multiple times on two separate scan days at 3T. The mean T1 values and coefficient of variation (CoV) were calculated for each of the ten sequences and compared to the reference sequence. Results Six of the tested sequences had T1 values close to the reference sequence; among those, three sequences achieved lower CoV than the reference sequence. Lowest CoV was achieved using a non-triggered LL sequence with 5 beat readout and a 45o flip angle (mean T1 1733 ms ± 89 ms, CoV 1.3% ± 0.58%). Conclusion T1-measurements in the hepatic portal vein can be performed with high precision using either MOLLI or LL sequences provided that LL sampling duration is sufficiently long and flip angle sufficiently high. The advantage of constant timing outweighed the advantage of ECG-triggering. A phase-cycled temperature-sensitive fast spin echo sequence with conductivity bias correction for monitoring of mild RF hyperthermia with PRFS Abstract Objective Mild hyperthermia (HT) treatments are generally monitored by phase-referenced proton resonance frequency shift calculations. A novel phase and thus temperature-sensitive fast spin echo (TFSE) sequence is introduced and compared to the double echo gradient echo (DEGRE) sequence. Theory and methods For a proton resonance frequency shift (PRFS)-sensitive TFSE sequence, a phase cycling method is applied to separate even from odd echoes. This method compensates for conductivity change-induced bias in temperature mapping as does the DEGRE sequence. Both sequences were alternately applied during a phantom heating experiment using the clinical setup for deep radio frequency HT (RF-HT). The B0 drift-corrected temperature values in a region of interest around temperature probes are compared to the temperature probe data and further evaluated in Bland–Altman plots. The stability of both methods was also tested within the thighs of three volunteers at a constant temperature using the subcutaneous fat layer for B0-drift correction. Results During the phantom heating experiment, on average TFSE temperature maps achieved double temperature-to-noise ratio (TNR) efficiency in comparison with DEGRE temperature maps. In-vivo images of the thighs exhibit stable temperature readings of ± 1 °C over 25 min of scanning in three volunteers for both methods. On average, the TNR efficiency improved by around 25% for in vivo data. Conclusion A novel TFSE method has been adapted to monitor temperature during mild HT. A study of within-subject reliability of the brain's default-mode network Abstract Objective Resting-state functional magnetic resonance imaging (fMRI) is promising for Alzheimer's disease (AD). This study aimed to examine short-term reliability of the default-mode network (DMN), one of the main haemodynamic patterns of the brain. Materials and methods Using a 1.5 T Philips Achieva scanner, two consecutive resting-state fMRI runs were acquired on 69 healthy adults, 62 patients with mild cognitive impairment (MCI) due to AD, and 28 patients with AD dementia. The anterior and posterior DMN and, as control, the visual-processing network (VPN) were computed using two different methodologies: connectivity of predetermined seeds (theory-driven) and dual regression (data-driven). Divergence and convergence in network strength and topography were calculated with paired t tests, global correlation coefficients, voxel-based correlation maps, and indices of reliability. Results No topographical differences were found in any of the networks. High correlations and reliability were found in the posterior DMN of healthy adults and MCI patients. Lower reliability was found in the anterior DMN and in the VPN, and in the posterior DMN of dementia patients. Discussion Strength and topography of the posterior DMN appear relatively stable and reliable over a short-term period of acquisition but with some degree of variability across clinical samples. The feasibility of a novel limited field of view spiral cine DENSE sequence to assess myocardial strain in dilated cardiomyopathy Abstract Objective Develop an accelerated cine displacement encoding with stimulated echoes (DENSE) cardiovascular magnetic resonance (CMR) sequence to enable clinically feasible myocardial strain evaluation in patients with dilated cardiomyopathy (DCM). Materials and methods A spiral cine DENSE sequence was modified by limiting the field of view in two dimensions using in-plane slice-selective pulses in the stimulated echo. This reduced breath hold duration from 20RR to 14RR intervals. Following phantom and pilot studies, the feasibility of the sequence to assess peak radial, circumferential, and longitudinal strain was tested in control subjects (n = 18) and then applied in DCM patients (n = 29). Results DENSE acquisition was possible in all participants. Elements of the data were not analysable in 1 control (6%) and 4 DCM r(14%) subjects due to off-resonance or susceptibility artefacts and low signal-to-noise ratio. Peak radial, circumferential, short-axis contour strain and longitudinal strain was reduced in DCM patients (p < 0.001 vs. controls) and strain measurements correlated with left ventricular ejection fraction (with circumferential strain r = − 0.79, p < 0.0001; with vertical long-axis strain r = − 0.76, p < 0.0001). All strain measurements had good inter-observer agreement (ICC > 0.80), except peak radial strain. Discussion We demonstrate the feasibility of CMR strain assessment in healthy controls and DCM patients using an accelerated cine DENSE technique. This may facilitate integration of strain assessment into routine CMR studies. Accelerated multi-contrast high isotropic resolution 3D intracranial vessel wall MRI using a tailored k-space undersampling and partially parallel reconstruction strategy Abstract Objective To develop a 3D multi-contrast IVW protocol with 0.5-mm isotropic resolution and a scan time of 5 min per sequence. Materials and methods Pre-contrast T1w VISTA, DANTE prepared PDw VISTA, SNAP, and post-contrast T1w VISTA were accelerated using cartesian undersampling with target ordering method (CUSTOM) and self-supporting tailored k-space estimation for parallel imaging reconstruction (STEP). CUSTOM + STEP IVW was compared to full-sample IVW, SENSE-accelerated IVW, and CUSTOM + zero-filled Fourier reconstruction in normal volunteers and subjects with intracranial atherosclerotic disease (ICAD). Image quality, vessel delineation, CSF suppression, and blood suppression were compared. Results CUSTOM + STEP vessel wall delineation was comparable to full-sample IVW and better than SENSE IVW for vessel wall delineation on T1w VISTA and luminal contrast on SNAP. Average image quality and wall depiction were significantly improved using STEP reconstruction compared with zero-filled Fourier reconstruction, with no significant difference in CSF or blood suppression. Conclusions CUSTOM + STEP allowed multi-contrast 3D 0.5-mm isotropic IVW within 30 min. Although some quantitative and qualitative scores for CUSTOM − STEP were lower than fully sampled IVW, CUSTOM + STEP provided comparable vessel wall delineation as full-sample IVW and was superior to SENSE. CUSTOM + STEP IVW was well tolerated by patients and showed good delineation of ICAD plaque. Feasibility of diffusion-weighted imaging with DWIBS in staging Hodgkin lymphoma in pediatric patients: comparison with PET/CT Abstract Objective The aim of the study was to evaluate feasibility of diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) method in diagnosing Hodgkin lymphoma in pediatric patients and to compare it with 18F-FDG PET/CT as a gold standard. Materials and methods Eleven patients (median age 14) with newly diagnosed Hodgkin lymphoma were examined with 18F-FDG PET/CT and MRI including whole-body DWIBS sequence (b = 0, 800 s/mm2), before the oncologic treatment. About 26 locations of lymphatic tissues were evaluated visually and quantitatively using ADCmean (DWIBS) and SUVmax (18F-FDG PET/CT), respectively. Results All affected lymph node regions (n = 134) diagnosed in 18F-FDG PET/CT were found with DWIBS, presenting decreased diffusion. Significant correlation was found between ADC and SUV values (R2 = − 0.37; p = 0.0001). Nevertheless, additional 33 regions were recognized only by DWIBS. They were significantly smaller than regions diagnosed by both methods. Discussion Agreement between DWIBS and 18F-FDG PET/CT for detection and staging of malignant lymphoma is high. DWIBS can be used for the evaluation of pediatric Hodgkin lymphoma. Challenges for labeling and longitudinal tracking of adoptively transferred autoreactive T lymphocytes in an experimental type-1 diabetes model Abstract Objective Tracking the autoreactive T-cell migration in the pancreatic region after labeling with fluorinated nanoparticles (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[3-(2-pyridyldithio)propionate]-perfluoro-15-crown-5-ether nanoparticles, PDP-PFCE NPs) in a diabetic murine model using 19F MRI. Materials and methods Synthesis of novel PDP-PFCE fluorine tracer was performed for in vitro labeling of T cells. Labeling conditions were optimized using different PDP-PFCE NPs concentrations. For in vivo 19F MRI, mice were longitudinally followed after adoptive transfer of activated, autoreactive, labeled T cells in NOD.SCID mice. Results Established MR protocols were used for challenging T cell labeling to track inflammation in a model of diabetes after successful labeling of CD4+ and CD8+ T cells with PDP-PFCE NPs. However, T cells were difficult to be detected in vivo after their engraftment in animals. Discussion We showed successful in vitro labeling of T cells using novel fluorinated liposomal nanoparticles. However, insufficient and slow accumulation of labeled T cells and subsequent T cell proliferation in the pancreatic region remains as limitations of in vivo cell imaging by 19F MRI. In-bore biopsies of the prostate assisted by a remote-controlled manipulator at 1.5 T Abstract Purpose To evaluate the technical and clinical utility of a fully MRI-compatible, pneumatically driven remote-controlled manipulator (RCM) for targeted biopsies of the prostate at 1.5 T. Materials and methods The data of the first 22 patients that were biopsied under robotic assistance were analyzed. Interventional planning relied on T2-weighted (T2w) turbo spin-echo (TSE) images (axial and sagittal) with a high-b-value diffusion-weighted acquisition added in selected cases. Alignment of the needle guide was controlled with a short balanced SSFP sequence in two oblique planes along the MR-visible sheath. Signals were acquired with a combination of elements from a 30-channel body and a 32-channel spine coil. Biopsy samples were taken with a fully automatic 18-G biopsy gun with a length of 150 or 175 mm. Results Mean age was 66.6 years and average PSA level was 11.5 ng/ml. Fourteen out of 22 patients (63%) had received prior biopsies under transrectal ultrasound guidance. Diagnostic MRI reports (before biopsy) involved 17 cases with a single suspicious finding (four PI-RADS 3, one PI-RADS 3–4, eight PI-RADS 4 and nine PI-RADS 5 cases). The median effective procedure time was 33.9 (range 25.0–55.9) min for 16 cases with one CSR and 63.4 (52.7–81.8) min for 5 cases with two CSRs. The biopsy with three CSRs took 74.0 min. Histopathologic examination revealed prostate cancer in 14 of 22 cases. Conclusion MR-targeted, transrectal biopsy of the prostate could be reliably performed with a robotic manipulator at a field strength of 1.5 T. Balanced SSFP imaging is considered a viable option for fast procedural control. Follow-up work needs to evaluate to what extent in-bore adjustments and workflow enhancements will contribute to shorter procedure times or higher patient comfort.

Alchemy, Medicine, and Commercial Book Production: A Codicological and Linguistic Study of the Voigts-Sloane Manuscript Group by Alpo Honkapohja (review) Alchemy, Medicine, and Commercial Book Production: A Codicological and Linguistic Study of the Voigts-Sloane Manuscript Group by Alpo Honkapohja W Black - Manuscript Studies: A Journal of the Schoenberg …, 2019 Winston Black Manuscript Studies: A Journal of the Schoenberg Institute for Manuscript Studies University of Pennsylvania Press Volume 4, Number 1, Spring 2019 pp. 176-181 10.1353/mns.2019.0009 REVIEW View Citation Additional Information In lieu of an abstract, here is a brief excerpt of the content: Reviewed by: Winston Black KEY WORDS Manuscript studies, England, Alchemy, Medicine, Codicology, Linguistics, astrology, book production, book trade, Medieval Latin, Middle English, London, code-switching, multilingualism, scriptoria Alpo Honkapohja. Alchemy, Medicine, and Commercial Book Production: A Codicological and Linguistic Study of the Voigts-Sloane Manuscript Group. Turnhout: Brepols, 2017. Xv + 250 pp., 57 black and white illustrations + 3 color illustrations, 20 black and white tables. €80. ISBN: 978-2-503-56647-4 IN A SERIES OF articles from 1989 to 2003, Linda Ehrsam Voigts identified a group of eleven manuscripts produced in England during the later fifteenth century that are relatively uniform in layout, contents, or both. These professionally made, but utilitarian, paper manuscripts contain similar medical, alchemical, astrological, and magical texts written mostly in self-contained booklets. Because six of the eleven manuscripts are found in the Sloane manuscript collection of the British Library (the other five are in different libraries), Voigts called them the "Sloane Group." She tentatively argued that the Sloane Group was an example of speculative publishing, aimed at a growing market for technical literature, before the advent of printing in England. Her theories about the Sloane Group have had a great influence on the study of book production at the dawn of print, but they have also been accepted uncritically at times. Alpo Honkapohja's Alchemy, Medicine, and Commercial Book Production is the first book-length study of the Sloane Group, in which he modifies or challenges the ideas of Voigts and other scholars about the production of [End Page 176] these manuscripts and their supposedly sophisticated multilingualism. This is an important book and should provoke historians and linguists to rethink some received ideas about later medieval book production, especially in technical fields like alchemy and medicine. Honkapohja rechristens the Sloane Group as the "Voigts-Sloane Group" (hereafter VSG) both in recognition of Voigts's scholarly contributions and to avoid confusion with the entire Sloane collection of the British Library. He remains respectful of Voigts and her work while frequently calling into question details of her arguments about the VSG. Honkapohja's approach to the study of the VSG is framed as a response to a call made by Claire Jones in a 2004 essay for more detailed analyses of the codicology and languages of this and similar manuscript groups to test Jones's arguments about the "discourse communities" reflected in medical manuscripts. Honkapohja carefully applies both types of analysis (codico-logical and linguistic) to the VSG "to see whether they contain signs of a publisher, co-ordination, speculative sale, or even 'veritable mass production'" (21) and to determine whether some or all of the texts were written in London or Westminster, as Voigts originally proposed. This is a highly technical study, intended for scholars already versed in codicology and Middle English linguistics. After a detailed introduction on the definition and historiography of the VSG and a disconcertingly short Chapter 1 on "The Book Trade in London Before Printing," Honkapohja dedicates three chapters to the codicology of the VSG and two to a linguistic analysis of the Middle English texts. The arguments in both sections of the book (that is, Chapters 2–4 and 5–6) are supported by a profuse number of collation diagrams, tables, dialect maps, and grayscale and color images of the manuscript texts. An appendix is dedicated to the full collation of British Library, MS Sloane 1118, which Honkapohja uses as representative of the entire VSG. Voigts divided the VSG into a Core Group of manuscripts sharing a typical mise-en-page of compressed Secretary script and dramatically large margins, and a Sibling Group unified not by appearance but by a common anthology of twelve short medical and astrological treatises, which Honkapohja calls the Sibling Set Texts. Each group contains six manuscripts, with [End Page 177] Sloane 2320 shared between the two subgroups, for a total of eleven. Honkapohja further divides the Sibling Group into three subgroups: Sloane 2320, a group of three "half-sisters, or at least cousins," and two manuscripts of the Second Generation, dating from the 1480s... Alexandros Sfakianakis Anapafseos 5 . Agios Nikolaos Crete.Greece.72100 2841026182 6948891480 alsfakia@gmail.com

Intraoperative balloon pulmonary annulus dilation: A new alchemy or polishing a meatball? D Bichell - 2019 Intraoperative balloon pulmonary annulus dilation: A new alchemy or polishing a meatball? Author links open overlay panelDavidBichellM.D. Department of Cardiac Surgery, Monroe Carell, Jr. Children's Hospital, Vanderbilt University Medical Center, Nashville, Tennessee Available online 15 May 2019. Show less https://doi.org/10.1053/j.semtcvs.2019.05.008Get rights and content Refers to María Lozano-Balseiro, Maria Garcia-Vieites, Isaac Martínez-Bendayán, Irene García-Hernández, Jose J. Cuenca-Castillo, Fernando Rueda-Núñez, Victor Bautista-Hernandez Valve-Sparing Tetralogy of Fallot Repair With Intraoperative Dilation of the Pulmonary Valve. Mid-Term Results Seminars in Thoracic and Cardiovascular Surgery, Available online 18 April 2019, Pages Purchase PDF Brief summary Late right heart performance obligates attention to pulmonary valve preservation at TOF repair. Intraoperative balloon dilation of the annulus has enjoyed some enthusiasm, yet mid-term results show a discouraging reintervention rate and valve incompetence. Refined patient selection and modifications of the technique may improve results, but further study is needed. Conflicts of interest: The author has no disclosures © 2019 Published by Elsevier Inc. Alexandros Sfakianakis Anapafseos 5 . Agios Nikolaos Crete.Greece.72100 2841026182 6948891480 alsfakia@gmail.com

ALCHEMY: AQuantum CHEMISTRY DATASET FOR BENCHMARKING AI MODELS [PDF] ALCHEMY: AQuantum CHEMISTRY DATASET FOR BENCHMARKING AI MODELS G Chen, CYK Hsieh, CK Lee, BB Liao, J Qiu, Q Sun…   Published as a conference paper at ICLR 2019 ALCHEMY: A QUANTUM CHEMISTRY DATASET FOR BENCHMARKING AI MODELS Guangyong Chen1∗ , Chang-Yu (Kim) Hsieh1 , Chee-Kong Lee1 , Ben Ben Liao1 , Jiezhong Qiu1,2 , Qiming Sun1 , Jie Tang2 , Shengyu Zhang1,3 1Quantum Lab, Tencent Co. Ltd., 2Department of Computer Science and Technology, Tsinghua University, 3Department of Computer Science and Engineering, CUHK. {gycchen,kimhsieh,cheekonglee,bliao,qssun,shengyzhang}@tencent.com qiujz16@mails.tsinghua.edu.cn,jietang@tsinghua.edu.cn ABSTRACT We introduce a new molecular dataset, named AlChemy, for developing machine learning models useful in chemistry and materials science. The dataset, as of the workshop submission date, comprises of 12 quantum mechanical properties of 67,000 organic molecules up to 12 heavy atoms, sampled from the GDB database. The Alchemy dataset expands the volume and diversity of existing molecular datasets. Our preliminary benchmark of the state-of-the-art machine learning models on AlChemy clearly manifests the usefulness of new data in validating and developing machine learning models. Recent advances in machine learning (ML) techniques have proven immensely useful for a broad range of applications including natural language processing (Shen et al., 2017), computer vision (He et al.) and strategic plannings (Silver et al., 2016; 2017) etc. These remarkably successful demonstrations have drawn high interests from the physical and biological science communities. For instance, ML-enhanced abilities to predict molecular properties with high precision (Gilmer et al., 2017; Liao et al., 2019), efficient generations of novel molecular structures (Jin et al., 2018), and better strategies in synthesis planning (Segler et al., 2018) and rectrosynthesis (Segler et al., 2017) will significantly accelerate drug design and novel material discovery (Sanchez-Lengeling & AspuruGuzik, 2018; Gomez-Bombarelli et al., 2018). However, the scarcity of high-quality datasets and ´ the lack of transferability of ML techniques impede the wide-scale adoption of molecular ML techniques in practice. The importance of supervised information for ML development cannot be understated. The ImageNet (Deng et al., 2009), a collection of more than 1.5 million labelled images distributed over 1, 000 classes, facilitates the development of new model such as ResNet (He et al.) that surpasses human performance in image recognition. In another instance, the Stanford Question Answering Dataset (SQuAD) (Rajpurkar et al., 2016), a reading comprehension dataset consisting of 150, 000 questions and answers, is critical to the development of a powerful language representation model BERT (Devlin et al., 2019). Recognizing the importance of abundance of datasets, the chemistry community has recently compiled a comprehensive collection of benchmarking datasets, the MoleculeNet (Wu et al., 2018), for supervised learning tasks. Despite this effort by the Pande group at Stanford, the amount of data in the MoleculeNet is often inadequate in comparison to the typical size of ML training datasets. For instance, there are less than 150K molecular entries for training models to predict the quantum mechanical properties of small organic molecules. The biggest dataset QM9 within MoleculeNet is further restricted to curating molecules composed of Hydrogen (H), Carbon (C), Nitrogen (N), Oxygen (O) and Florine (F). A better data variety, such as presence of more atom types, can help to more thoroughly investigate and improve some aspects of ML models such as transferability and generalibility. Herein we report a dataset that contains the quantum mechanical properties of around 67,000 organic molecules with up to 12 heavy atoms (C, N, O, S, and halogens including F) from the GDB17 MedChem database (Ruddigkeit et al., 2012). We name our collection the AlChemy dataset. ∗Authors are ordered alphabetically 1 Published as a conference paper at ICLR 2019 Table 1: Dataset Details: number of molecules and tasks Dataset Data Type #Tasks #Molecules Rec-Split Maximum #Heavy Atoms QM7 SMILES, 3D coordinates 1 7,160 Stratified 7 QM7b 3D coordinates 14 7,210 Random 7 QM8 SMILES, 3D coordinates 12 21,786 Random 8 QM9 SMILES, 3D coordinates 12 133,885 Random 9 AlChemy SMILES, 3D coordinates 12 67,000 Random 12 The quantum mechanical properties are calculated with the Python-based Simulations of Chemistry Framework (PySCF) (Sun et al., 2018). As compared to the full GDB-17 database, the MedChem subset contains molecules that are more suitable for medicinal chemistry, based on functional group and complexity considerations. Therefore, the AlChemy dataset is significantly more comprehensive than existing quantum chemistry datasets, and the molecules are considered more drug-like. AlChemy dataset could serve for evaluation, benchmarking and development of ML methods for applications in chemistry and materials science. 1 RELATED WORK There are only a few molecular datasets specifically built for benchmarking ML models for chemistry and material applications. Recently, a collection of various datasets have been compiled and collectively branded as the MoleculeNet. These datasets are furthered divided into different categories: quantum mechanics, physical chemistry, biophysics and physiology. In this work, we report our contributions of new datasets for multi-task learning of quantum mechanical properties of organic molecules. Hence, only the subset of quantum mechanical databsets within the MoleculeNet is summarized below. QM7/QM7b The QM7 dataset contains 7,165 molecules, a subset of GDB-13, with at most 7 C,N,O,S atoms. The learning task is to predict a single electronic property, the atomization energy given the input feature in Table 1. All the physical properties listed in the dataset were calculated with the ab-initio density function theory at the level of PEB0/tier2 basis set. QM7b is an extension. 13 additional properties are computed at different levels of accuracy (ZINDO, SCS, PBE0, GW). The data is further expanded to 7,211 molecules. QM8 This dataset provides electronic properties of 21,800 molecules comprising up to 8 C,N,O,F atoms, a subset of GDB-17. Not only ground-state electronic properties but also four excited-state properties at different levels of accuracy (TDDFT using PBE0 and CAM-B3LYP and CC2) are computed for multi-task learning. QM9 This dataset contains geometric, energetic, electronic and thermodynamics (totalling 13) properties for 134,000 organic molecule comprising up to 9 non-hydrogen atom within the GDB-17 database. All physical properties are computed at the accuracy of B3LYP/6-31G(2df,p) based DFT. 2 THE ALCHEMY DATASET 2.1 MOLECULAR REPRESENTATIONS: SMILES AND 3D GEOMETRY Intuitively, a molecule is a stable 3D configurations of atoms connected by chemical bonds. The essential features of a molecule can be encoded into a molecular graph with each vertex representing an atom and each edge representing a bond. Simplified Molecular-Input Line-Entry System (SMILES) is a text-based data structure to store molecular graphs on computers. While SMILES and graphs give a minimalist approach to describing molecules, one needs the 3D coordinates of all atoms in a stable configuration for quantum chemistry calculations. This process of recovering 3D geometry from the SMILE string is called the geometry optimization. 2 Published as a conference paper at ICLR 2019 Table 2: Calculated properties. Last two entries are not present in the QM9 dataset Property Unit Mean Relative Error Meam Absolute Error Rotational constants GHz - - Dipole moment (mu) Debye 0.1928 0.6401 Polarizability (alpha) a 3 0 0.0104 0.7610 HOMO Eh 0.0244 0.0060 LUMO Eh 0.2114 0.0061 gap Eh 0.0275 0.0073 hR 2 i (R2) a 2 0 0.0404 52.3778 Zero point energy (zpve) Eh 0.0021 0.0003 Internal energy (U0) Eh 0.0006 0.2486 Internal energy at 298.15 K (U) Eh 0.0006 0.2486 Enthalpy at 298.15 K (H) Eh 0.0006 0.2486 Free energy at 298.15 K (G) Eh 0.0006 0.2486 Heat capacity at 298.15 K (Cv) EhK −1 0.0038 3.8×10−7 Dipole moment vector - - - 3×3 Polarizability tensor - - - 2.2 DETAIL FOR THE DATA GENERATION The molecular properties were calculated using PySCF's implementation of the DFT Kohn-Sham method at the B3LYP level with the basis set 6-31G(2df,p). The quantum chemistry model B3LYP/6-31G(2df,p) was validated in an early work (Ramakrishnan et al., 2014) for small organic molecules. Building a complementary dataset along the line of QM-series introduced in Sec. 1, we computed the following categories of molecular properties: ground state equilibrium geometry, ground state electronic properties, and ground state thermochemical properties. The detail is summarized in Table 2. In the remaining sections, we clarify a few technical aspects of our workflow for interested experts in quantum chemistry. The equilibrium geometry was optimized in three passes. We first used OpenBabel (O'Boyle et al., 2011) to parse SMILES string and built the Cartesian coordinates with MMFF94 force field optimization. The second pass employed the HF/STO-3G theory (incorporate quantum mechanical effects) to generate a preliminary geometry. In the final pass of geometry relaxation, we used the B3LYP/6-31G(2df,p) model with the density fitting approximation for electron repulsion integrals. The auxiliary basis cc-pVDZ-jkfit (Weigend, 2002) is employed in density fitting to build the Coulomb matrix and the HF exchange matrix. When computing the ground state electronic properties and ground state thermochemical properties, the density fitting technique was disabled in our dataset generation program. In addition to the molecular properties proposed by the original QM9 dataset, we also report the dipole moment vector, the 3×3 polarizability tensor and the atomic charges obtained by the meta-Lowdin population analysis (Sun & Chan, 2014). The advantage of meta-lowdin population analysis, like other advanced population analysis prescriptions (Knizia, 2013), is that the obtained atomic charges possess good transferability in different molecular environments. 2.3 COMPARISON TO THE QM9 DATASET In AlChemy dataset, we reproduced results for a random selection of 28,732 molecules from QM9 and calculated properties for another selection of 38,268 molecules up to 12 heavy atoms in the GDB-17 MedChem. The running time statistics and an example of geometry optimization can be found in Appendix. The reproduction of selected QM9 data helps to validate the accuracy of our computations. We draw attention to the third and fourth columns of Table 2. The mean relative error and mean absolute error refers to the disagreement between our results and the original QM9. Our calculations agree well with the original QM9 given the fact that different definitions of B3LYP functionals were used in these calculations. Nevertheless, we notice a few disparities. The relative error on LUMO energy is less a concern as we get a good agreement on the HOMO-LUMO energy gap. It is well-known that the two definitions of B3LYP functionals tend to systematically shift orbital energies in these calculations, and the energy gap should be a more appropriate comparison criterion. However, inconsistency on mu and R2 constitutes more serious indications of disagree3 Published as a conference paper at ICLR 2019 Table 3: Performance Comparison (MAE) QM9 AlChemy MPNN2 (Gilmer et al., 2017) MPNN (Wu et al., 2018) MPNN (our impl.) MPNN (our impl.) mu 0.03 - 0.5316 2.7448 alpha 0.092 - 0.4171 17.9973 HOMO 0.04257 - 0.0033 0.0173 LUMO 0.03741 - 0.0034 0.0261 gap 0.0688 - 0.0048 0.0262 R2 0.18 - 25.4747 362.8817 ZPVE 0.001524 - 0.0003 0.0186 U0 0.01935 - 0.1200 98.3374 U 0.01935 - 0.1201 98.5954 H 0.01677 - 0.0800 92.4926 G 0.01892 - 0.2802 98.2963 Cv 0.04 - 0.1422 33.6612 Average 0.0472245 ∼2.73 2.2648 67.0912 ments. We unambiguously trace this inconsistency back to the complexity of searching the optimal molecular conformation among enormous molecular geometry local minimum. The geometry optimization could be stuck at the sub-optimal molecular conformation in either our dataset or QM9. The large deviation between our dataset and QM9's indicates that R2, as a direct output of molecular geometry, is less predictable. This is also observed in our model training practice (Table 3). 3 THE BENCHMARKING RESULTS We setup baselines using the Message Passing Neural Network (MPNN) model (Gilmer et al., 2017). Our MPNN implementation is based on the authors' prefer model trained individually on each target. As for hyper-parameters not declared in MPNN paper (Gilmer et al., 2017), we refer to their git repository1 for default parameter setting. For detailed hyper-parameter setting, we list them in Appendix (Table 4). The code of our implementation will be publicly available after the double-blind review period ends. In the preliminary part of our experiment, we first reproduce the QM9 experiments for 12 targets listed in (Gilmer et al., 2017) with the MPNN model. It is the state-of-the-art model for all regression tasks of the QM9 dataset. QM9 contains 133,885 molecules. We use 10,000 for validation, 10,000 for testing, and the rest for training. The primary part of our experiment focuses on testing the transferability of existing ML models in quantum chemistry tasks. Models shall be first trained on QM9, and then tested against a subset of our AlChemy dataset with the same atom types (C, N, H, O, F). This fraction contains 37,178 molecules with exactly 10 heavy atoms. The task of generalization to molecular graphs with more heavy atoms is marked as a difficult problem in (Gilmer et al., 2017). As for comparison metric, Mean absolute error (MAE) is used as evaluation metric in both experiments. Results are reported in Table 3. For reader's convenience, we list the corresponding results reported in (Gilmer et al., 2017; Wu et al., 2018) as well. We first focus on the comparison among our MPNN implementation and MPNN in (Gilmer et al., 2017) and (Wu et al., 2018). Our MPNN implementation achieves similar performance to (Wu et al., 2018), but differs from (Gilmer et al., 2017)'s results by two orders of magnitude. We also investigate the generalizability of MPNN to larger molecules (see fifth column in Table. 3). Interestingly, we observe large deviations among all targets — the test MAEs on AlChemy dataset differs from those on QM9 dataset by up to orders of magnitude, which again reveals the difficulty in transferring 1https://github.com/brain-research/mpnn 2The MAEs of Gilmer et al. (2017)'s MPNN can be calculated as (Error Ratio (from their Table. 2)) × (Chemical Accuracy (from their Table. 5)). Interestd readers can refer to a detailed discussion in Appendix. 3Refer to Figure 14 in Wu et al. (2018) 4 Published as a conference paper at ICLR 2019 knowledge learned from small molecules to larger molecules, although we only increase the number of heavy atoms by one. 4 CONCLUSIONS AND FUTURE WORK The process of building the AlChemy dataset has been a rewarding experience. Along this journey, we face the difficulty to optimize molecular geometries efficiently and accurately. We eventually use a combination of two geometry optimization tools to overcome this problem. All the discrepancies between our data and QM9's can be precisely attributed to the disagreements on the optimized geometries. Our preliminary benchmark results clearly manifest the usefulness of the AlChemy dataset. The public availability of this dataset shall inspire further improvement of existing ML models as well as the proposals of entirely new ones. REFERENCES J. Deng, W. Dong, R. Socher, L.-J. Li, K. Li, and L. Fei-Fei. ImageNet: A Large-Scale Hierarchical Image Database. In CVPR '09, 2009. Jacob Devlin, Ming-Wei Chang, Kenton Lee, and Kristina Toutanova. BERT: Pre-training of Deep Bidirectional Transformers for Language Understanding. In NAACL-HLT '19, 2019. Justin Gilmer, Samuel S Schoenholz, Patrick F Riley, Oriol Vinyals, and George E Dahl. Neural Message Passing for Quantum Chemistry. In ICML '17, pp. 1263–1272, 2017. Rafael Gomez-Bombarelli, Jennifer N Wei, David Duvenaud, Jos ´ e Miguel Hern ´ andez-Lobato, ´ Benjam´ın Sanchez-Lengeling, Dennis Sheberla, Jorge Aguilera-Iparraguirre, Timothy D Hirzel, ´ Ryan P Adams, and Alan Aspuru-Guzik. Automatic Chemical Design Using a Data-driven Con- ´ tinuous Representation of Molecules. ACS Central Science, 4(2):268–276, 2018. Kaiming He, Xiangyu Zhang, Shaoqing Ren, and Jian Sun. Deep residual learning for image recognition. Wengong Jin, Regina Barzilay, and Tommi Jaakkola. Junction Tree Variational Autoencoder for Molecular Graph Generation. ICML '18, 2018. Gerald Knizia. Intrinsic Atomic Orbitals: An Unbiased Bridge between Quantum Theory and Chemical Concepts. Journal of Chemical Theory and Computation, 9(11):4834–4843, 2013. Yujia Li, Daniel Tarlow, Marc Brockschmidt, and Richard Zemel. Gated Graph Sequence Neural Networks. ICLR' 16, 2016. Renjie Liao, Zhizhen Zhao, Raquel Urtasun, and Richard S Zemel. LanczosNet: Multi-Scale Deep Graph Convolutional Networks. In ICLR '19, 2019. Noel M. O'Boyle, Michael Banck, Craig A. James, Chris Morley, Tim Vandermeersch, and Geoffrey R. Hutchison. Open babel: An open chemical toolbox. Journal of Cheminformatics, 3(1):33, 2011. Pranav Rajpurkar, Jian Zhang, Konstantin Lopyrev, and Percy Liang. SQuAD: 100,000+ Questions for Machine Comprehension of Text. In EMNLP '16, 2016. Raghunathan Ramakrishnan, Pavlo O Dral, Matthias Rupp, and O Anatole Von Lilienfeld. 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Reasonet: Learning to Stop Reading in Machine Comprehension. In KDD '17, pp. 1047–1055. ACM, 2017. David Silver, Aja Huang, Chris J Maddison, Arthur Guez, Laurent Sifre, George Van Den Driessche, Julian Schrittwieser, Ioannis Antonoglou, Veda Panneershelvam, Marc Lanctot, et al. Mastering the Game of Go with Deep Neural Networks and Tree Search. Nature, 529(7587):484, 2016. David Silver, Julian Schrittwieser, Karen Simonyan, Ioannis Antonoglou, Aja Huang, Arthur Guez, Thomas Hubert, Lucas Baker, Matthew Lai, Adrian Bolton, et al. Mastering the Game of Go without Human Knowledge. Nature, 550(7676):354, 2017. Qiming Sun and Garnet Kin-Lic Chan. Exact and optimal quantum mechanics/molecular mechanics boundaries. Journal of Chemical Theory and Computation, 10(9):3784–3790, 2014. Qiming Sun, Timothy C Berkelbach, Nick S Blunt, George H Booth, Sheng Guo, Zhendong Li, Junzi Liu, James D McClain, Elvira R Sayfutyarova, Sandeep Sharma, et al. 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Chemical Science, 9(2):513–530, 2018. 5 APPENDIX 5.1 HYPER-PARAMETERS We list detailed hyper-parameter settings of our MPNN implementation in Tabel. 4. 5.2 MORE DETAILS ON ALCHEMY DATA GENERATION Figure. 1 shows AlChemy's running time statistics; Figure. 2 shows an example of geometry optimization process from AlChemy dataset. 5.3 CONVERSION OF UNITS As clearly specified in Table 2, we adopt the atomic units for all numerics in the AlChemy dataset. This choice is consistent with the QM9 dataset. However, we caution that the MAEs in the second column of Table 3, quoted from Gilmer's work (Gilmer et al., 2017), are given in a different set of units. For instance, one has to divides all energy-related MAEs except the one for the zero-point vibrational energy by 27 to convert the numbers into the atomic units. After appropriate conversions, the disagreements between the actual numbers of Gilmer's original work and our MPNN results will be more pronounced. 6 Published as a conference paper at ICLR 2019 Table 4: Hyper-parameters. Category Hyper-parameter Value Preprocessing edge features bond type + raw distance node features Table 1 in Gilmer et al. (2017) use Mulliken partial charges No Message Passing Function (Edge Network) message passing steps T 6 edge network layers 4 edge network hidden dim 50 use multiple towers No Update Function (GRU, as in GG-NN (Li et al., 2016)) node hidden units d 50 GRU layer 1 Readout Function (set2set (Vinyals et al., 2015)) set2set computations M 12 output NN hidden layer 1 output NN hidden units 200 Training initial learning rate 0.00013 learning rate decay factor 0.5 optimizer Adam batch size 20 traing epochs 540 0.0 0.2 0.4 0.6 HF/STO-3G (hours) 0 2 4 6 8 10 12 Histogram 0 5 10 15 DFT (hours) 0.0 0.1 0.2 0.3 0.4 0.5 10 20 30 40 Property (hours) 0.00 0.02 0.04 0.06 0.08 0.10 0 10 20 30 40 50 Total (hours) 0.00 0.02 0.04 0.06 0.08 Figure 1: AlChemy's running time statistics for molecules (with 10 heavy atoms) from GDB-17 MedChem. Each step takes 0.1/1.9/14.4 hours on average, respectively. The average total running time is 16.4 hours. (a) OpenBabel geometry (b) HF/STO-3G geometry (c) DFT geometry Figure 2: An example for molecule CC(O)C(C)C(=O)NC=O, a random sample from AlChemy dataset. 7   Alexandros Sfakianakis Anapafseos 5 . Agios Nikolaos Crete.Greece.72100 2841026182 6948891480 alsfakia@gmail.com

ALEXANDROS SFAKIANAKIS ANAPAFSEOS 5 AGIOS NIKOLAOS CRETE 72100 GREECE +306932607174 +302841026182