An independent race model involving an abort and re-plan strategy explains reach redirecting movements during planning and execution

Abstract

Although race models have been extensively used to study inhibitory control, the mechanisms that enable the change of reach plans in the context of race models remain unexplored. We used a redirect task in which targets occasionally changed their locations, to study the control of reaching movements during movement planning and execution phases. We tested nine different race model architectures that could explain the redirect behaviour of reaching movements. We show that only the independent GO-STOP-GO model that reflects a plan-abort-re-plan strategy involving non-interacting elements, successfully explained the various behavioural measures such as the compensation function, and the pattern of error response reaction times. By extending the same race model to the execution phase, we could explain the extent and the pattern of hypometric trials. Interestingly, the race model also provided evidence that redirecting a movement during planning and execution shared the same inhibitory mechanism. Taken together, this study demonstrates the applicability of an independent race model to understand the computational mechanisms underlying the control of reach movements.

This article is protected by copyright. All rights reserved.

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Leptomeningeal Metastases

Opinion statement

Treatment options for leptomeningeal metastases are expanding with greater tolerability and efficacy than in the past. Improved knowledge of molecular subtypes of some cancers can guide in choosing more effective therapeutic options; however, physicians should be mindful that these molecular types can be different in the central nervous system compared to the rest of the body. This is particularly true in breast and lung cancer, in which some patients now can live for many months or even years after diagnosis of leptomeningeal metastases. Options for intrathecal therapies are expanding, but physicians should be mindful that this is a passive delivery system that relies on normal CSF flow, so therapies will not penetrate bulky or parenchymal disease sites, especially in the presence of abnormal CSF flow. When chemotherapeutic options are lacking or unsuccessful, focal radiosurgery which can provide symptomatic relief and proton craniospinal radiation remain effective options. Hopefully more formal studies will be conducted in the future to verify which treatments are indeed most effective for particular types of cancer.

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Computerbasierte Testung neurokognitiver Aspekte im Rahmen der audiologischen Diagnostik

Laryngo-Rhino-Otol
DOI: 10.1055/s-0043-124972

Hintergrund Im Hinblick auf den demographischen Wandel der Gesellschaft gewinnen in der Hörrehabilitation neurokognitive Fähigkeiten immer mehr an Bedeutung. Fragestellung Ziel der Studie war es zu untersuchen, inwiefern eine neurokognitive Testung mittels PC-gestützter Aufgaben zur Evaluation der unterschiedlichen Bereiche der Kognition auch für ältere Patienten mit und ohne Hörstörung geeignet ist und wie sich diese in den klinischen Alltag des HNO-Arztes integrieren lässt. Patientenbeschreibung 171 Patienten ≥ 50 Jahren mit und ohne eine beidseitige Hörbeeinträchtigung wurden eingeschlossen: n = 90 im Alter zwischen 50 und 64 Jahren (57,0 ± 4,5) und 81 Ältere ab 65 (72,5 ± 5,4). Methode Eine computerbasierte Testung mit rein visuellen Instruktionen beinhaltete neben der Aufmerksamkeit, der Verarbeitungsgeschwindigkeit, dem Kurz- und Langzeitgedächtnis auch exekutive Funktionen. Zuvor erfolgte ein Probedurchgang unter Anleitung einer geschulten Mitarbeiterin. Ergebnisse Auch wenn die Testung unabhängig von Alter oder Hörstatus in allen Fällen eigenständig möglich war, benötigten Hörgeschädigte 15 Minuten länger zur Durchführung und beurteilten diese als anstrengender als Hörgesunde (71 % versus 63 %). Patienten mittleren Alters sahen die Durchführbarkeit für Menschen des höheren Lebensalters mit 30 % signifikant (p = 0,02) kritischer als die betroffene Altersgruppe selbst (10 %). Schlussfolgerung Eine umfassende kognitive Testung älterer Schwerhöriger mit computerbasierten Aufgaben lässt sich problemlos in den klinischen HNO Alltag integrieren und könnte eine wertvolle Ergänzung der audiologischen Diagnostik im Hinblick auf eine bestmögliche Hörrehabilitation darstellen.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Premorbid Activity Limitation Stages Are Associated with Post-Hospitalization Discharge Disposition

AbstractObjectiveActivity of daily living (ADL) stages and instrumental activity of daily living (IADL) stage have demonstrated associations with mortality and health service utilization among older adults. This cohort study aims to assess the associations of premorbid activity limitation stages with acute hospital discharge disposition among community-dwelling older adults.DesignStudy participants were Medicare beneficiaries aged 65 years and older who enrolled in the Medicare Current Beneficiary Survey (MCBS) between 2001 and 2009. Associations of premorbid stages with discharge dispositions were estimated with multinomial logistic regression models adjusted for covariates.ResultsThe proportions of elderly Medicare patients discharged to home with self-care, home with services, post-acute care facilities, and other dispositions were 59%, 15%, 19%, and 7%, respectively. The adjusted relative risk ratios (RRR) and 95% confidence intervals of post-acute care facilities versus home with self-care discharge increased with higher premorbid activity limitation stages (except non-fitting stage III): 1.7 (1.5-2.0), 2.4 (2.0-2.9), 2.4 (1.9-3.0), and 2.5 (1.6-4.1) for ADL stages I-IV; a similar pattern was found for IADL stages. The adjusted RRRs of discharge to home with services also increased with higher premorbid activity limitation stages compared to no limitation.ConclusionsRoutinely assessed activity limitation stages predict post-hospitalization discharge disposition among older adults, and may be used to anticipate post-acute care and services utilization by elderly Medicare beneficiaries. Objective Activity of daily living (ADL) stages and instrumental activity of daily living (IADL) stage have demonstrated associations with mortality and health service utilization among older adults. This cohort study aims to assess the associations of premorbid activity limitation stages with acute hospital discharge disposition among community-dwelling older adults. Design Study participants were Medicare beneficiaries aged 65 years and older who enrolled in the Medicare Current Beneficiary Survey (MCBS) between 2001 and 2009. Associations of premorbid stages with discharge dispositions were estimated with multinomial logistic regression models adjusted for covariates. Results The proportions of elderly Medicare patients discharged to home with self-care, home with services, post-acute care facilities, and other dispositions were 59%, 15%, 19%, and 7%, respectively. The adjusted relative risk ratios (RRR) and 95% confidence intervals of post-acute care facilities versus home with self-care discharge increased with higher premorbid activity limitation stages (except non-fitting stage III): 1.7 (1.5-2.0), 2.4 (2.0-2.9), 2.4 (1.9-3.0), and 2.5 (1.6-4.1) for ADL stages I-IV; a similar pattern was found for IADL stages. The adjusted RRRs of discharge to home with services also increased with higher premorbid activity limitation stages compared to no limitation. Conclusions Routinely assessed activity limitation stages predict post-hospitalization discharge disposition among older adults, and may be used to anticipate post-acute care and services utilization by elderly Medicare beneficiaries. Corresponding author: Ling Na lingna2000@gmail.com; Disclosures: The research for this manuscript was supported by the grant from the National Institutes of Health (R01AG040105). There are no personal conflicts of interest of any of the authors, and no authors reported disclosures beyond the funding source. The opinions and conclusions of the authors are not necessarily those of the sponsoring agency. We certify that no party having a direct interest in the results of the research supporting this article has or will confer a benefit on us or on any organization with which we are associated. This material has not been previously presented at a meeting. Acknowledgement: We thank Dr. Margaret G. Stineman, MD for her contribution in conceptualization of the study. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Effects of cane use and position on performance of the sit-to-stand task in stroke patients

ABSTRACTObjectiveTo examine the effect of cane use and cane positions on the sit-to-stand (STS) performance of stroke patients.DesignIn a crossover study, 30 stroke patients performed STS test in seven situations in a random sequence: without a cane, three positions with a regular cane (parallel to the ankle, parallel to the 5th toe, and 10 cm in front of the 5th toe), and the same three positions with a quad cane. The peak vertical ground reaction force (GRF) and maximum vertical cane support force during STS were recorded.ResultsUsing a cane significantly reduced the peak GRF by 3%~9% of body weight compared to that without a cane (p=0.000~0.023). Different cane positions strongly influenced the maximum cane support force and peak GRF. When the cane was closer to the ankle, the maximal cane support force increased by 6.7%~8.6% of body weight, which resulted in a decrease in the peak GRF.ConclusionsBoth types of cane reduced lower extremities' load during STS. When the cane was closer to the trunk, the load on legs was lessened, while the load on the upper extremity increased. Upper extremity's load during STS was greater when using quad cane than using regular cane. Objective To examine the effect of cane use and cane positions on the sit-to-stand (STS) performance of stroke patients. Design In a crossover study, 30 stroke patients performed STS test in seven situations in a random sequence: without a cane, three positions with a regular cane (parallel to the ankle, parallel to the 5th toe, and 10 cm in front of the 5th toe), and the same three positions with a quad cane. The peak vertical ground reaction force (GRF) and maximum vertical cane support force during STS were recorded. Results Using a cane significantly reduced the peak GRF by 3%~9% of body weight compared to that without a cane (p=0.000~0.023). Different cane positions strongly influenced the maximum cane support force and peak GRF. When the cane was closer to the ankle, the maximal cane support force increased by 6.7%~8.6% of body weight, which resulted in a decrease in the peak GRF. Conclusions Both types of cane reduced lower extremities' load during STS. When the cane was closer to the trunk, the load on legs was lessened, while the load on the upper extremity increased. Upper extremity's load during STS was greater when using quad cane than using regular cane. Correspondence to: Dr. Mau-Roung Lin, Institute of Injury Prevention and Control, Taipei Medical University, 250 Wu-Hsing Street, Taipei 11031, Taiwan, R.O.C., Phone: 886-2-27398755; Fax: 886-2-27398755; E-mail: mrlin@tmu.edu.tw Financial support: This work was funded by the National Health Research Institute (NHRI-EX100-9805PI) and the Ministry of Technology and Science (MOST106-2314-B-038-046), Taiwan. No commercial party having a direct or indirect interest in the subject matter of this research has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Conflicts of interest: The authors have no conflicts of interest to declare. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Altered expression of HER-2 and the mismatch repair genes MLH1 and MSH2 predicts the outcome of T1 high-grade bladder cancer

Abstract

Purpose

The identification of factors predicting the outcome of stage T1 high-grade bladder cancer (BC) is a major clinical issue.

Methods

We performed immunohistochemistry to assess the role of human epidermal growth factor receptor-2 (HER-2) and microsatellite instability (MSI) factors MutL homologue 1 (MLH1) and MutS homologue 2 (MSH2) in predicting recurrence and progression of T1 high-grade BCs having undergone transurethral resection of bladder tumor (TURBT) alone or TURBT + intravesical instillations of bacillus Calmette–Guerin (BCG).

Results

HER-2 overexpression was a significant predictor of disease-free survival (DFS) in the overall as well as in the two patients' population; as for progression-free survival (PFS), it was significant in the overall but not in the two patients' population. MLH1 was an independent predictor of PFS only in patients treated with BCG and MSH2 failed to predict DFS and PFS in all populations. Most importantly, the higher the number of altered markers the lowers the DFS and PFS. In multivariate Cox proportional-hazards regression analysis, the number of altered molecular markers and BCG treatment were significant predictors (p = 0.0004 and 0.0283, respectively) of DFS, whereas the number of altered molecular markers was the only significant predictor (p = 0.0054) of PFS.

Conclusions

Altered expression of the proto-oncogene HER-2 and the two molecular markers of genetic instability MLH1 and MSH2 predicted T1 high-grade BC outcome with the higher the number of altered markers the lower the DFS and PFS. These findings provide grounds for further testing them in predicting the outcome of this challenging disease.

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Utility of Pathology Imagebase for Standardization of Prostate Cancer Grading

Abstract

Aims

Despite efforts to standardize grading of prostate cancer, there is still a considerable variation in grading practices even among experts. In this study we describe the use of Pathology Imagebase, a novel reference image library, for setting an international standard in prostate cancer grading.

Methods and Results

The International Society of Urological Pathology (ISUP) recently launched a reference image database supervised by experts. A panel of 24 international experts in prostate pathology independently reviewed microphotographs of 90 cases of prostate needle biopsies with cancer. A linear weighted kappa of 0.67 (95% confidence interval 0.62 - 0.72) and consensus was reached in 50 cases. The inter-observer weighted kappa varied from 0.48 to 0.89. The highest level of agreement was seen for Gleason score (GS) 3+3=6 (ISUP grade 1), while higher grades and particularly GS 4+3=7 (ISUP grade 3) showed considerable disagreement. Once a 2/3 majority was reached, images were automatically moved into a public database available for all ISUP members at www.isupweb.org. Non-members are able to access a limited number of cases.

Conclusions

It is anticipated that the database will assist pathologists to calibrate their grading and, hence, decrease inter-observer variability. It will also help identify instances where definitions of grades need to be clarified.

This article is protected by copyright. All rights reserved.

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Fine-needle aspiration of a pancreatic neuroendocrine tumor with prominent rhabdoid features

Pancreatic neuroendocrine tumors (PanNETs) are uncommon neoplasms that conventionally possess architectural and cytomorphological features seen in neuroendocrine neoplasms found at other sites. When present, these features often allow rapid identification of neuroendocrine differentiation and an accurate diagnosis. Here, we report the cytologic findings seen on fine-needle aspiration (FNA) of a PanNET with distinct rhabdoid features. This morphology is rare in PanNETs and has been reported in only two case series examining surgical resection specimens and has not been described on FNA. It is important to recognize this morphology as this variant appears to portend an aggressive clinical course. Furthermore, unfamiliarity with this morphologic variant may lead to a larger initial differential and thus delay final diagnosis.

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Histological Changes in the Rat Femoral Artery Following the Use of the Empty-and-Refill Test

J reconstr Microsurg
DOI: 10.1055/s-0037-1621727

Background This study examines the effects of the empty-and-refill patency test on rat femoral arteries in the longer postoperative time period. Methods A simple arterial anastomosis was performed bilaterally on 20 rats. The empty-and-refill test was performed unilaterally in all rats, leaving the contralateral artery as an internal control. Rats were divided into two cohorts of 10 rats and survived for 48 hours and 2 weeks. Vessel patency was assessed prior to closing and immediately prior to sacrifice. The femoral arteries were harvested bilaterally and hematoxylin and eosin stains were performed. The femoral artery distal to the anastomosis in the region of the empty-and-refill test was histologically evaluated. Results All vessels were patent at the time of sacrifice. There was no statistical difference in the numeric scoring between the experimental and control vessels in the 48-hour cohort. Almost all vessels harvested at 48 hours showed endothelial cell loss distal to the anastomosis regardless of whether they underwent the empty-and-refill test. The only statistically significant difference in the 2-week cohort was an increase in adventitial smooth muscle proliferation in the experimental group. There were no other statistically significant results between the experimental and control groups at 2 weeks. An overall comparison of both cohorts revealed a statistically significant increase in endothelial cell number and intimal proliferation by 2 weeks postsurgery. Conclusion The empty-and-refill test does not compromise rat femoral artery anastomotic patency, nor does it produce histological damage either 48 hours or 2 weeks postsurgery.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
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Impact of Duration of Perioperative Ischemia on Outcomes of Microsurgical Reconstructions

J reconstr Microsurg
DOI: 10.1055/s-0037-1621729

Background Free tissue transfers have become routine for a variety of reconstructive purposes. During the time of transfer, some period of ischemia time is unavoidable, causing structural and metabolic changes. This study aimed to evaluate whether length of intraoperative ischemia affects the outcomes of microsurgical reconstructions. Methods Within a 7-year period, 638 patients having undergone 690 microvascular free flap reconstructions fulfilled inclusion criteria for this study. The data were retrospectively screened for patients' demographics, intra- and perioperative details, flap survival, surgical complications, and outcomes. The cases were divided into two groups according to the length of intraoperative ischemia time, "< 60" versus "≥ 60 minutes." Results Both groups were comparable regarding the patient constellation, comorbidities, smoking status, and perioperative characteristics. Operative times were significantly longer in patients which had ischemia times of ≥ 60 minutes (p < 0.05). Also, during our 3-month follow-up period, a significantly higher rate of major and minor surgical complications, including total and partial flap losses, as well as higher revision rates occurred in the ≥ 60 minutes ischemia time group (p < 0.05). Conclusion In this study, prolonged ischemia time during free flap reconstructions was associated with higher rates of revision surgeries and complications rates.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
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Role of Chemotherapy in the Neoadjuvant/Adjuvant Setting for Patients With Rectal Adenocarcinoma Undergoing Chemoradiotherapy and Surgery or Radiotherapy and Surgery

Abstract

Rectal cancer has been successfully managed in the last couple of decades. In the USA, as the initial approach, neoadjuvant concurrent chemoradiation has been associated not only with decrease in tumor size and recurrence but also with higher resection rate with minimal side effects. Data support that addition of chemotherapy to radiotherapy is superior to radiotherapy alone in the neoadjuvant setting. Recent debates have addressed the question of administration of adjuvant chemotherapy following surgery. In this article, we discuss the role of chemotherapy in both the neoadjuvant and the adjuvant settings for locally advanced rectal cancer.

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Incidence of neuromyelitis optica spectrum disorder in the Central Denmark Region

Objectives

Neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) may be misdiagnosed as multiple sclerosis. The aim of this study was to (i) to measure AQP4-IgG in patients who fulfilled the clinical and radiological criteria of NMOSD in the Central Denmark Region and (ii) to estimate the incidence of NMOSD in the region, according to both the 2006 Wingerchuk criteria and the 2015 International Panel for NMO Diagnosis criteria.

Materials and methods

Medical records of all patients diagnosed with a demyelinating disorder in the region from 1 January 2012 to 31 December 2013 were reviewed. Patients were classified as having (i) "NMO" if the 2006 criteria were met, (ii) "NMOSD with AQP4-IgG" or (iii) "NMOSD without/unknown AQP-IgG" if the new 2015 NMOSD criteria were met. Patients with core symptoms were invited to provide a blood sample for AQP4-IgG analysis with an enzyme-linked immunosorbent assay and a cell-based indirect immunofluorescence assay.

Results

In 191 patients with core symptoms, one met the 2015 NMOSD with AQP4-IgG criteria. Two patients met the 2006 NMO and 2015 NMOSD without/unknown AQP4-IgG criteria. Among 108 patients providing a blood sample, all were seronegative. The estimated incidence of NMO (2006 criteria) and NMOSD (2015 criteria) was 0.08 and 0.12 per 100 000 person-years, respectively.

Conclusion

NMO/NMOSD is a rare disease in the Central Denmark Region, with a considerably lower incidence rate than previously estimated in a neighbouring region.

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Reassessment of Differentiated Thyroid Cancer Patients Using the Eighth TNM/AJCC Classification System: A Comparative Study

Thyroid , Vol. 0, No. 0.


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Prognostic Value of S-100β Protein for Prediction of Post-Concussion Symptoms after a Mild Traumatic Brain Injury: Systematic Review and Meta-Analysis

Journal of Neurotrauma , Vol. 0, No. 0.


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Hyperbaric Oxygen Therapy in the Treatment of Acute Severe Traumatic Brain Injury: A Systematic Review

Journal of Neurotrauma , Vol. 0, No. 0.


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Effect of History of Mild Traumatic Brain Injury on Optic Nerve Sheath Diameter Changes after Valsalva Maneuver

Journal of Neurotrauma , Vol. 0, No. 0.


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Cerebral Blood Flow after Mild Traumatic Brain Injury: Associations between Symptoms and Post-Injury Perfusion

Journal of Neurotrauma Jan 2018, Vol. 35, No. 2: 241-248.


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A Multimodal Magnetic Resonance Imaging Study of Recovery of Consciousness in Severe Traumatic Brain Injury: Preliminary Results

Journal of Neurotrauma Jan 2018, Vol. 35, No. 2: 308-313.


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Hyperbaric Oxygen Therapy in the Treatment of Acute Severe Traumatic Brain Injury: A Systematic Review

Journal of Neurotrauma , Vol. 0, No. 0.


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Effect of History of Mild Traumatic Brain Injury on Optic Nerve Sheath Diameter Changes after Valsalva Maneuver

Journal of Neurotrauma , Vol. 0, No. 0.


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Cause and Timing of Death and Subgroup Differential Effects of Erythropoietin in the EPO-TBI Study

Journal of Neurotrauma Jan 2018, Vol. 35, No. 2: 333-340.


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Cerebral Blood Flow after Mild Traumatic Brain Injury: Associations between Symptoms and Post-Injury Perfusion

Journal of Neurotrauma Jan 2018, Vol. 35, No. 2: 241-248.


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A Multimodal Magnetic Resonance Imaging Study of Recovery of Consciousness in Severe Traumatic Brain Injury: Preliminary Results

Journal of Neurotrauma Jan 2018, Vol. 35, No. 2: 308-313.


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Antibody Immunodominance: The Key to Understanding Influenza Virus Antigenic Drift

Viral Immunology , Vol. 0, No. 0.


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Experiences of Care of Adolescents and Young Adults with Cancer in Australia

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Preventing Peanut Allergy

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


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Preventing Peanut Allergy

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


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Acute-onset Restless legs syndrome in acute neurological conditions—a prospective study on patients with the Guillain-Barre syndrome and acute stroke

Objectives

While the Restless legs syndrome (RLS) is usually recognized as a chronic condition, it has often been diagnosed among patients with acute neurological illnesses, in which limb discomfort is reported. This study was conducted to determine how many among these, actually have acute-onset RLS, and also to evaluate characteristics of this subgroup of patients with Guillain-Barre syndrome (GBS) and stroke developing acute-onset RLS.

Methods

Consecutive patients diagnosed with GBS and eligible stroke patients, admitted to our Neurology services over a 1-year period, were enrolled. They were evaluated for symptoms of RLS based on IRLSSG consensus criteria and the AIIMS RLS Questionnaire for Indian patients (ARQIP).

Results

Forty adults with GBS and 58 with stroke were included. A total of 10 of the 40 (25%) patients with GBS developed definite acute RLS, which was mostly monophasic. Seven (70%) of these had demyelinating type of GBS, a significant association with acute RLS (P = .024). Six of the 58 stroke patients (10%) developed definite acute-onset, often persistent RLS. Subcortical location showed significant association with increased risk of developing acute RLS (P < .001). All patients diagnosed with acute-onset RLS had an immediate and good response to dopamine agonists.

Conclusion

This is the first study showing that acute-onset RLS is common, affecting nearly 25% of patients with GBS and 10% patients with acute stroke. Recognizing and treating it can majorly contribute toward symptom relief and early improvement in the quality of life for this population.

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Qualitative assessment of awake nasopharyngoscopy for prediction of oral appliance treatment response in obstructive sleep apnoea

Abstract

Purpose

Clinical methods to identify responders to oral appliance (OA) therapy for obstructive sleep apnoea (OSA) are needed. Awake nasopharyngoscopy during mandibular advancement, with image capture and subsequent processing and analysis, may predict treatment response. A qualitative assessment of awake nasopharyngoscopy would be simpler for clinical practice. We aimed to determine if a qualitative classification system of nasopharyngoscopic observations reflects treatment response.

Methods

OSA patients were recruited for treatment with a customised two-piece OA. A custom scoring sheet was used to record observations of the pharyngeal airway (velopharynx, oropharynx, hypopharynx) during supine nasopharyngoscopy in response to mandibular advancement and performance of the Müller manoeuvre. Qualitative scores for degree (< 25%, 25–50%, 50–75%, > 75%), collapse pattern (concentric, anteroposterior, lateral) and diameter change (uniform, anteroposterior, lateral) were recorded. Treatment outcome was confirmed by polysomnography after a titration period of 14.6 ± 9.8 weeks. Treatment response was defined as (1) Treatment AHI < 5, (2) Treatment AHI < 10 plus > 50% AHI reduction and (3) > 50% AHI reduction.

Results

Eighty OSA patients (53.8% male) underwent nasopharyngoscopy. The most common naspharyngoscopic observation with mandibular advancement was a small (< 50%) increase in velopharyngeal lateral diameter (37.5%). The majority of subjects (72.5%) were recorded as having > 75% velopharyngeal collapse on performance of the Müller manoeuvre. Mandibular advancement reduced the observed level of pharyngeal collapse at all three pharyngeal regions (p < 0.001). None of the nasopharyngoscopic qualitative scores differed between responder and non-responder groups.

Conclusion

Qualitative assessment of awake nasopharyngoscopy appears useful for assessing the effect of mandibular advancement on upper airway collapsibility. However, it is not sensitive enough to predict oral appliance treatment outcome.

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Challenges in the Eradication of Enterococcus faecalis and its Implications on Health

Abstract

ᅟ

Enterococcus faecalis is frequently found in infected root canals of teeth with persistent apical periodontitis.

Purpose

To review the challenges involved in the eradication of persistent Enterococcus faecalis infections and their impact on human health.

Recent Findings

In the root canal system, Enterococcus faecalis resides in biofilm communities that are able to resist a wide range of harsh conditions and treatments and persist for years. Various virulence and resistance factors provide Enterococcus faecalis capabilities in adherence, colonization, and biofilm formation, which is much more resistant to antibacterial agents than planktonic bacteria. These capabilities explain its persistence in root canal infections. To date, the available therapeutic tools to efficiently eradicate Enterococcus faecalis infections remain limited. Recently, in a model mimicking Enterococcus faecalis root canal infection, novel biofilm inhibitors and dispersing agents, such as D-Leucine, presented superior capability over sodium hypochlorite, the frequently used root-canal antibacterial irrigation solution, in the eradication of Enterococcus faecalis.

Summary

These recent studies present promising treatment regimens for Enterococcus faecalis persistent infections.

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Optimization of dose distributions of target volumes and organs at risk during stereotactic body radiation therapy for pancreatic cancer with dose-limiting auto-shells

To identify optimization of dose distributions of target volumes and decrease of radiation doses to normal tissues during stereotactic body radiation therapy (SBRT) for pancreatic cancer with dose-limiting aut...

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Comparison of the clinical efficacy between single-agent and dual-agent concurrent chemoradiotherapy in the treatment of unresectable esophageal squamous cell carcinoma: a multicenter retrospective analysis

Some Chinese patients with esophageal squamous cell carcinomaare often treated with single-agent concurrent chemoradiotherapy. However, no results have been reported from randomized controlled clinical trials ...

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Grammar Clinical Marker Yields Substantial Heritability for Language Impairments in 16-Year-Old Twins

Purpose

There is a need for well-defined language phenotypes suitable for adolescents in twin studies and other large-scale research projects. Rice, Hoffman, and Wexler (2009) have developed a grammatical judgment measure as a clinical marker of language impairment, which has an extended developmental range to adolescence.

Method

We conducted the first twin analysis, along with associated phenotypic analyses of validity, of an abridged, 20-item version of this grammatical judgment measure (GJ-20), based on telephone administration using prerecorded stimuli to 405 pairs of 16-year-olds (148 monozygotic and 257 dizygotic) drawn from the Twins Early Development Study (Haworth, Davis, & Plomin, 2012).

Results

The distribution of scores is markedly skewed negatively, as expected for a potential clinical marker. Low performance on GJ-20 is associated with lower maternal education, reported learning disability (age 7 years), and low scores on language tests administered via the Twins Early Development Study (age 16 years) as well as General Certificate of Secondary Education English and Math examination performance (age 16 years). Liability threshold estimates for the genetic influence on low performance on GJ-20 are substantial, ranging from 36% with a lowest 10% criterion to 74% for a lowest 5% criterion.

Conclusions

The heritability of GJ-20 scores, especially at more extreme cutoffs, along with the score distribution and association with other indicators of language impairments, provides additional evidence for the potential value of this measure as a clinical marker of specific language impairment.

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Accuracy of a Screening Tool for Early Identification of Language Impairment

Purpose

A screening tool called the VTO Language Screening Instrument (VTO-LSI) was developed to enable more uniform and earlier detection of language impairment. This report, consisting of 2 retrospective studies, focuses on the effects of using the VTO-LSI compared to regular detection procedures.

Method

Study 1 retrospectively compared VTO-LSI with regular detection procedures. Outcome measure was the detection rate of language impairment among 24-month-old children. Data were retrieved from medical records of children attending a youth health care center. Study 2 retrospectively compared the effects of VTO-LSI and regular detection procedures on the age at referral for diagnostic investigations and the influence of sex. Data were retrieved from medical records from the speech and hearing center and analyzed with multivariate analysis of variance.

Results

With the VTO-LSI, significantly more cases with language impairment were identified compared with the regular detection procedure (2.4% vs. 0.4%). In regions where the VTO-LSI was used, girls were almost 2 years younger, and boys were 1 year younger when referred to diagnostic investigations than in regions with regular detection procedures.

Conclusion

The VTO-LSI was more effective than regular detection procedures.

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Do Transmasculine Speakers Present With Gender-Related Voice Problems? Insights From a Participant-Centered Mixed-Methods Study

Purpose

The purpose of this study was to investigate whether there are indications of gender-related voice problems in our transmasculine participants and to analyze how discrepancies between participant self-evaluations and researcher-led examinations can be best negotiated to ensure a participant-centered interpretation.

Method

We conducted a participant-centered mixed-methods study combining qualitative content analyses of semistructured interviews, acoustical voice analyses, and an examination of gender attributions to voice. Fourteen German-speaking transmasculine people, 14 cisfemale control persons, and 7 cismale control persons participated. The data were examined for indications of gender-related voice problems pertaining to vocal gender presentation and gender attribution to voice received from others.

Results

Eleven participants (79%) presented with indications of gender-related voice problems. Problems included dissatisfaction with gender-related voice features, difficulties with control of vocal gender presentation, and mismatch between desired gender attribution and gender attributions received from others. Discrepancies between participant self-evaluations and researcher-led examinations were observed in a number of cases.

Conclusion

Transmasculine speakers may experience a range of gender-related voice problems. Research and clinical practice with transmasculine people need to be adapted to better match the diversity of the population and the complexity of the processes that shape the production of speaker vocal gender in interaction.

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Collinearity and Sample Coverage Issues in the Objective Measurement of Vocal Quality: The Case of Roughness and Breathiness

Purpose

The aim of the study was to address the reported inconsistencies in the relationship between objective acoustic measures and perceptual ratings of vocal quality.

Method

This tutorial moves away from the more widely examined problems related to obtaining the perceptual ratings and the acoustic measures and centers in less scrutinized issues regarding the procedure to establish the correspondence. Expressions for the most common measure of association between perceptual and acoustic measures (Pearson's r) are derived using a multiple linear regression model. The particular case where the multiple linear regression involves only roughness and breathiness is discussed to illustrate the issues.

Results

Most problems reported regarding inconsistent findings in the relationship between given acoustic measures and particular perceptual ratings could be linked to sample properties not directly related to the actual relationship. The influential sample properties are the collinearity between the regressors in the multiple linear regression and their relative variances. Recommendations on how to rule out this possible cause of inconsistency are given, varying in scope from data collection, reporting, manipulation, and results interpretation.

Conclusions

The problems described can be extended to more general cases than the exemplified roughness and breathiness sample's coverage. Ruling out this possible cause of inconsistency would increase the validity of the results reported.

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Convergent and Divergent Validity of the Grammaticality and Utterance Length Instrument

Purpose

This feasibility study examines the convergent and divergent validity of the Grammaticality and Utterance Length Instrument (GLi), a tool designed to assess the grammaticality and average utterance length of a child's prerecorded story retell.

Method

Three raters used the GLi to rate audio-recorded story retells from 100 English-speaking preschool children. To examine convergent validity, the results of the GLi were correlated with 2 language sample measures, mean length of utterance in words and percentage of grammatical utterances, and with the results of the Structured Photographic Expressive Language Test–Third Edition (Dawson, Stout, & Eyer, 2003). To examine divergent validity, the results of the GLi were correlated with the results of the Kaufman Brief Intelligence Test–Second Edition (Kaufman & Kaufman, 2004). Comparisons between task completion time for the GLi and Systematic Analysis of Language Transcripts (SALT; Miller & Iglesias, 2010) transcription and analysis were also conducted. Last, preliminary discriminant analysis was used to examine the diagnostic potential of the GLi.

Results

The results of this study provide evidence of convergent and divergent validity for the GLi. The task completion time for the GLi was considerably shorter than the SALT transcription and analysis. Preliminary analysis of diagnostic accuracy suggests that the GLi has the potential to be a good tool to identify children with language impairment.

Discussion

The GLi has good convergent and divergent validity and is a reliable instrument to assess utterance length and grammaticality of prerecorded language samples. However, SALT transcription and analysis provide a more detailed and comprehensive analysis of the language skills of a child.

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Erratum

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The Roles of Vowel Fronting, Lengthening, and Listener Variables in the Perception of Vocal Femininity

Purpose

The goal of this study was to test whether fronting and lengthening of lax vowels influence the perception of femininity in listeners whose dialect is characterized as already having relatively fronted and long lax vowels in male and female speech.

Method

Sixteen English words containing the /ɪ ɛ ʊ ɑ/ vowels were produced by a male speaker with 2 degrees of vowel fronting. Then, the vowel duration was manipulated in 3 steps. Thirty-nine listeners from the Southern United States judged how feminine each word sounded to them on an interval scale.

Results

The results of mixed-effects modeling showed that the words with more fronted and longer variants of the vowels were perceived as more feminine than the same words with less fronted and shorter variants of the vowels. These effects, however, were modulated by the vowel type, listener's area of upbringing, and gender.

Conclusions

Fronting (except for /ʊ/) and lengthening of lax vowels make words sound more feminine for Southern listeners, which has implications for clients who wish to modify the perception of femininity invoked by their speech. The relative strength of the gender and regional associations of these vowel characteristics should be further examined across dialects.

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Predicting Response to Treatment in a Tier 2 Supplemental Vocabulary Intervention

Purpose

To effectively implement a response to intervention approach, there is a need for timely and specific information about student learning in response to treatment to ensure that treatment decisions are appropriate. This exploratory study examined responsivity to a supplemental, Tier 2 vocabulary intervention delivered to preschool children with limited language abilities.

Method

A secondary analysis of a cluster-randomized trial of a supplemental vocabulary intervention was conducted. Responsivity (e.g., adequate learning) to the intervention was examined, and learning in the 1st few weeks of intervention was evaluated as a possible predictor of response to intervention.

Results

Using a criterion of learning of 20% of target vocabulary, nearly one third of participants were identified as poor responders. A 1st unit benchmark was identified that maximized the sensitivity to identification of children who were likely to respond to the intervention.

Conclusions

Even for generally effective interventions, there is likely to be a substantial proportion of children who are not responsive. Learning in the 1st few weeks of intervention may be a useful indicator of appropriate response to treatment and could inform instructional decisions.

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Erratum

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Talker Differences in Clear and Conversational Speech: Perceived Sentence Clarity for Young Adults With Normal Hearing and Older Adults With Hearing Loss

Purpose

The purpose of this study is to examine talker differences for subjectively rated speech clarity in clear versus conversational speech, to determine whether ratings differ for young adults with normal hearing (YNH listeners) and older adults with hearing impairment (OHI listeners), and to explore effects of certain talker characteristics (e.g., gender) on perceived clarity. Relationships among clarity ratings and other speech perceptual and acoustic measures were also explored.

Method

Twenty-one YNH and 15 OHI listeners rated clear and conversational sentences produced by 41 talkers on a scale of 1 (lowest possible clarity) to 7 (highest possible clarity).

Results

While clarity ratings varied significantly among talkers, listeners rated clear speech significantly clearer than conversational speech for all but 1 talker. OHI and YNH listeners gave similar ratings for conversational speech, but ratings for clear speech were significantly higher for OHI listeners. Talker gender effects differed for YNH and OHI listeners. Ratings of clear speech varied among subgroups of talkers with different amounts of experience talking to people with hearing loss.

Conclusions

Perceived clarity varies widely among talkers, but nearly all produce clear speech that sounds significantly clearer than their conversational speech. Few differences were seen between OHI and YNH listeners except the effect of talker gender.

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Acoustic Analysis of Voice in Singers: A Systematic Review

Purpose

Singers are vocal athletes having specific demands from their voice and require special consideration during voice evaluation. Presently, there is a lack of standards for acoustic evaluation in them. The aim of the present study was to systematically review the available literature on the acoustic analysis of voice in singers.

Method

A systematic review of studies on acoustic analysis of voice in singers (PubMed/MEDLINE, CINAHL, Scopus, ProQuest, Cochrane, Ovid, Science Direct, and Shodhganga) was carried out. Key words based on PIO (population–investigation–outcome) were used to develop search strings. Titles and abstracts were screened independently, and appropriate studies were read in full for data extraction.

Results

Of the 895 studies, 26 studies met the inclusion criteria. Great variability was noted in the instruments and task used. Different acoustic measures were employed, such as fundamental frequency, perturbation, cepstral, spectral, dysphonia severity index, singing power ratio, and so forth.

Conclusion

Overall, a great heterogeneity was noted regarding population, tasks, instruments, and parameters. There is a lack of standardized criteria for the evaluation of singing voice. In order to implement acoustic analysis as a part of comprehensive voice evaluation exclusively for singers, there is a certain need for methodical sound studies.

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Perception of Cantonese Lexical Tones by Pediatric Cochlear Implant Users

Purpose

The purpose of this study is to assess Cantonese word recognition and the discrimination of Cantonese tones with manipulated contours by child and adolescent cochlear implant (CI) users and a group of peers with normal hearing (NH). It was hypothesized that the CI users would perform more poorly than their counterparts with NH in both tasks and that CI users implanted before 2 years of age would perform better than those implanted after 2 years.

Method

Forty-one participants were recruited from hospitals, schools, and kindergartens in Hong Kong: Ten CI users implanted at or before 2 years of age ("early" CI group), 13 CI users implanted after 2 years of age ("late" CI group), and 18 individuals with NH. The mean age at implantation of the early CI group was 1.5 years (SD = 0.3), and for the late CI group, it was 4.3 years (SD = 2.1). Participants were a mean of 13.3 years of age (SD = 3.7) at time of testing. Participants completed a Cantonese word recognition test and a discrimination task using Cantonese tones with modified fundamental frequency trajectories.

Results

Both CI user groups obtained significantly lower scores than the group with NH on the word recognition test. Mean percent correct scores for the word recognition test were 79% for the early CI group, 69% for the late CI group, and 97% for the group with NH. The group with NH consistently achieved higher scores than the CI user groups when discriminating manipulated Cantonese tones. Increasing the acoustic difference between tones improved discrimination performance for CI users for level tone contrasts only. CI users implanted at or before 2 years of age obtained higher scores than those implanted later.

Conclusions

The results of this study add further evidence that children using CIs do not perform as well as peers in perceiving Cantonese tones. Modification of tones to increase pitch range did not consistently improve the ability of children with implants to perceive the difference between tones. Further research is required to fully assess potential benefits of early implantation for speakers of tonal languages.

Supplemental Materials

https://doi.org/10.23641/asha.5782209

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Do Infants Born Very Premature and Who Have Very Low Birth Weight Catch Up With Their Full Term Peers in Their Language Abilities by Early School Age?

Purpose

This study examined the extent to which children born preterm (< 37 weeks) and/or who have low birth weight (< 2,500 g) catch up with their full term peers in terms of their language abilities at early school age (≥ 5 to < 9 years).

Method

A systematic literature search identified empirical studies that fit the inclusion criteria. Data from the tests/questionnaires used for meta-analysis spanned the following language categories: total language score, expressive language, receptive language, pragmatics, phonological awareness, and grammar. The means (standard deviations) were extracted from the studies and were converted to mean difference and 95% confidence intervals to test for overall effect.

Results

Sixteen studies met the inclusionary criteria, for a total of 2,739 participants, of which 1,224 were born full term and 1,515 were born preterm. It is important to note that the preterm cohort represented very preterm infants who have a very low birth weight. The meta-analysis found that preterm infants scored significantly worse on total language (p < .001), receptive language (p < .001), expressive language (p < .001), phonological awareness (p < .001), and grammar (p = .03) than their full term peers. However, preterm infants did not score significantly worse than their peers on their pragmatics (p = .19).

Conclusions

Children born VPT and who have VLBW perform worse than their peers on their total language, receptive language, expressive language, phonological awareness, and grammar abilities by early school age. This information is important for speech-language pathologists to consider as children born prematurely reach school age.

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Comment on “Sensitivity of the Speech Intelligibility Index to the Assumed Dynamic Range,” by Jin et al. (2017)

Purpose

This letter to the editor is in response to a research note by Jin, Kates, and Arehart (2017), "Sensitivity of the Speech Intelligibility Index to the Assumed Dynamic Range," published in June 2017 by the Journal of Speech, Language, and Hearing Research.

Conclusion

The authors argue that the approach and line of reasoning in the Jin et al. (2017) research note suggest new findings but do not lead to essentially new insights.

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Author's Rebuttal to Smits et al. (2018), “Comment on ‘Sensitivity of the Speech Intelligibility Index to the Assumed Dynamic Range’ by Jin et al. (2017)”

Purpose

The purpose of this letter is to refute the comments written by Smits, Goverts, and Versfeld (2018).

Method

Refutations to each issue including the fixed mathematical relationship between dynamic range (DR) and a fitting constant (Q value), deviating results for small DRs, and determination of Speech Intelligibility Index (SII) model parameters are described.

Results

Although Smits et al. (2018) correctly identified several issues, those comments do not diminish the results of the original article (Jin, Kates, & Arehart, 2017) in providing new insights for the SII.

Conclusions

Jin et al. (2017) clearly provided the impact of languages and DR on the SII, which was the main result of the study.

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Masthead

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Beyond Concurrent Chemoradiation: The Emerging Role of PD-1/PD-L1 Inhibitors in Stage III Lung Cancer

Concurrent chemoradiation (cCRT) with platinum-based chemotherapy is standard of care therapy for patients with Stage III unresectable non-small cell lung cancer (NSCLC). Though potentially curative, five-year overall survival has hovered around 20%, despite extensive efforts to improve outcomes with increasing doses of conformal radiation and intensification of systemic therapy with either induction or consolidation chemotherapy. PD-1/PD-L1 immune checkpoint inhibitors have demonstrated unprecedented efficacy in patients with Stage IV NSCLC.  Additionally, preclinical and early clinical evidence suggests that chemotherapy and radiation may work synergistically with anti-PD-1/PD-L1 therapy to promote anti-tumor immunity, which has led to the initiation of clinical trials testing these drugs in patients with Stage III NSCLC. A preliminary report of a randomized phase III trial, the PACIFIC trial, demonstrated an impressive increase in median progression-free survival with consolidative durvalumab, a PD-L1 inhibitor, compared to observation after cCRT. Here, we discuss the clinical and translational implications of integrating PD-1/PD-L1 inhibitors in the management of patients with unresectable Stage III NSCLC.

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Glycogen phosphorylase: a novel biomarker in doxorubicin-induced cardiac injury

Extracellular vesicles (EVs) containing glycogen phosphorylase, brain/heart (PYGB) have been demonstrated as a sensitive biomarker for normal cardiac injuries for patients after chemotherapy. Oxidative stress was suggested to be the mechanism behind the chemotherapy-induced tissue damage and augmented with mitochondrial antioxidant could be an effective means of early intervention.

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Safety, activity and biomarkers of SHR-1210, an anti-PD-1 antibody, for patients with advanced esophageal carcinoma

Purpose: The current management of advanced esophageal squamous cell carcinoma (ESCC) remains unsatisfactory. We investigated the safety, efficacy and biomarkers of SHR-1210, an anti-PD-1 antibody, in patients with recurrent or metastatic ESCC. Experimental Design: This study was a part of phase 1 trial in China. Patients with advanced ESCC who were refractory or intolerant to previous chemotherapy were enrolled. Eligible patients received intravenous SHR-1210 at a dose of 60 mg, with escalation to 200mg and 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. The associations between candidate biomarkers (PD-L1 and somatic mutation load) and the efficacy of SHR-1210 were also explored. Results: Between May 11, 2016 and December 9, 2016, a total of 30 patients from one site in China were enrolled. Ten patients (33.3%) had an independently assessed objective response. Median progression free survival was 3.6 months (95% CI: 0-7.2). Three (10.0%) treatment-related grade 3 adverse events were reported: two (6.7%) pneumonitis and one (3.3%) increased cardiac troponin I. No grade 4 or grade 5 treatment-related adverse events were reported. The exome sequencing and analysis showed that the mutational burden and the potential mutation-associated neoantigen count were associated with better responses. An objective response was more common in patients with PD-L1-positive tumors as defined by >5% staining (7 of 15 patients) than in those with PD-L1-negative tumors (1 of 9 patients). Conclusion: In this population of ESCC patients, SHR-1210 had a manageable safety profile and promising antitumor activity.

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Selective mTORC2 inhibitor therapeutically blocks breast cancer cell growth and survival

Small molecule inhibitors of the mTORC2 kinase (torkinibs) have shown efficacy in early clinical trials. However, the torkinibs under study also inhibit the other mTOR-containing complex mTORC1. While mTORC1/mTORC2 combined inhibition may be beneficial in cancer cells, recent reports describe compensatory cell survival upon mTORC1 inhibition due to loss of negative feedback on PI3K, increased autophagy, and increased macropinocytosis. Genetic models suggest that selective mTORC2 inhibition would be effective in breast cancers, but the lack of selective small molecule inhibitors of mTORC2 have precluded testing of this hypothesis to date. Here we report the engineering of a nanoparticle-based RNAi therapeutic that can effectively silence the mTORC2 obligate cofactor Rictor. Nanoparticle-based Rictor ablation in HER2-amplified breast tumors was achieved following intra-tumoral and intra-venous delivery, decreasing Akt phosphorylation and increasing tumor cell killing. Selective mTORC2 inhibition in vivo, combined with the HER2 inhibitor lapatinib, decreased the growth of HER2-amplified breast cancers to a greater extent than either agent alone, suggesting that mTORC2 promotes lapatinib resistance but is overcome by mTORC2 inhibition. Importantly, selective mTORC2 inhibition was effective in a TNBC model, decreasing Akt phosphorylation and tumor growth, consistent with our findings that RICTOR mRNA correlates with worse outcome in patients with basal-like TNBC. Together, our results offer preclinical validation of a novel RNAi delivery platform for therapeutic gene ablation in breast cancer, and they show that mTORC2-selective targeting is feasible and efficacious in this disease setting.

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Small molecule activators of protein phosphatase 2A for the treatment of castration-resistant prostate cancer.

Primary prostate cancer is generally treatable by androgen deprivation therapy, however, later recurrences of castrate-resistant prostate cancer (CRPC) that is more difficult to treat nearly always occurs due to aberrant re-activation of the androgen receptor (AR). In this study, we report that CRPC cells are particularly sensitive to the growth inhibitory effects of re-engineered tricyclic sulfonamides, a class of molecules that activate the protein phosphatase PP2A which inhibits multiple oncogenic signaling pathways. Treatment of CRPC cells with small molecule activators of PP2A (SMAP) in vitro decreased cellular viability and clonogenicity and induced apoptosis. SMAP treatment also induced an array of significant changes in the phosphoproteome, including most notably dephosphorylation of full-length and truncated isoforms of the AR and downregulation of its regulatory kinases in a dose-dependent and time-dependent manner. In murine xenograft models of human CRPC, the potent compound SMAP-2 exhibited efficacy comparable to enzalutamide in inhibiting tumor formation. Overall, our results provide a preclinical proof of concept for the efficacy of SMAP in AR degradation and CRPC treatment.

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2-hydroxyglutarate-mediated autophagy of the endoplasmic reticulum leads to an unusual downregulation of phospholipid biosynthesis in mutant IDH1 gliomas

Tumor metabolism is reprogrammed to meet the demands of proliferating cancer cells. In particular, cancer cells upregulate synthesis of the membrane phospholipids phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdE) in order to allow for rapid membrane turnover. Nonetheless, we show here that, in mutant isocitrate dehydrogenase 1 (IDHmut) gliomas, which produce the oncometabolite 2-hydroxyglutarate (2-HG), PtdCho and PtdE biosynthesis is downregulated and results in lower levels of both phospholipids when compared to wild-type IDH1 cells. 2-HG inhibited collagen-4-prolyl hydroxylase activity, leading to accumulation of misfolded procollagen-IV in the endoplasmic reticulum (ER) of both genetically engineered and patient-derived IDHmut glioma models. The resulting ER stress triggered increased expression of FAM134b, which mediated autophagic degradation of the ER (ER-phagy) and a reduction in ER area. Because the ER is the site of phospholipid synthesis, ER-phagy led to reduced PtdCho and PtdE biosynthesis. Inhibition of ER-phagy via pharmacological or molecular approaches restored phospholipid biosynthesis in IDHmut glioma cells, triggered apoptotic cell death, inhibited tumor growth and prolonged the survival of orthotopic IDHmut glioma-bearing mice, pointing to a potential therapeutic opportunity. Glioma patient biopsies also exhibited increased ER-phagy and downregulation of PtdCho and PtdE levels in IDHmut samples compared to wild-type, clinically validating our observations. Collectively, this study provides detailed and clinically-relevant insights into the functional link between oncometabolite-driven ER-phagy and phospholipid biosynthesis in IDHmut gliomas.

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Message from the new editors of Arquivos de Neuro-Psiquiatria

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Non-inflammatory cerebrospinal fluid delays the diagnosis and start of immunotherapy in anti-NMDAR encephalitis

ABSTRACT Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a form of autoimmune encephalopathy that presents with a wide variety of symptoms, including neuropsychiatric manifestations. The authors' aim for this study was to analyze the results of paraclinical studies of patients with a diagnosis of anti-NMDAR encephalitis and the association between symptom onset and diagnosis, and start of immunotherapy. Retrospective data of 29 patients with anti-NMDAR encephalitis were gathered and analyzed. Abnormal EEG was found in 27 patients (93.1%), whereas MRI was abnormal in 19 patients (65.5%). In contrast, an inflammatory pattern on CSF analysis was found in only 13 patients (44.8%). The absence of pleocytosis or increased proteins in the CSF was associated with a longer time from symptom onset to diagnosis and treatment (p = 0.003). The authors conclude that noninflammatory CSF may delay the correct diagnosis and start of immunotherapy in anti-NMDAR encephalitis. In the presence of suggestive clinical features, extensive studies including EEG are recommended.

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RESUMEN La encefalitis por receptor anti-N-metil-D-aspartato (anti-NMDAR) es una encefalopatía autoinmune con una amplia variedad de síntomas, incluyendo manifestaciones neuropsiquiátricas. Nuestro objetivo en este estudio fue analizar los resultados paraclínicos de pacientes diagnosticados con encefalitis anti-NMDAR y la asociación entre inicio de sintomatología, el diagnóstico y el inicio de inmunoterapia. Encontramos un EEG anormal en 27 pacientes (93.1%), así como IRM anormal en 19 de ellos (65.5%). En contraste, el análisis de LCR mostró un patrón inflamatorio en tan solo 13 pacientes (44.8%). La ausencia de pleocitosis o proteínas incrementadas en el LCR se asoció con un mayor tiempo desde el inicio de la sintomatología hasta el inicio del tratamiento (p=0.003). Concluimos que el LCR no inflamatorio puede retrasar el diagnóstico correcto y el inicio de tratamiento en encefalitis anti-NMDAR, por lo que se recomienda la realización de estudios exhaustivos, incluyendo EEG, ante la presencia de indicadores clínicos sugerentes del padecimiento.

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Multiple sclerosis risk perception and acceptance for Brazilian patients

ABSTRACT The perception of multiple sclerosis (MS) severity and risk associated with therapies might influence shared decision making in different countries. We investigated the perception of MS severity and factors associated with risk acceptance in Brazil in 96 patients with relapsing-remitting MS using a standardized questionnaire and compared this with two European cohorts. Multiple sclerosis was perceived as a very severe disease and the risk of developing progressive multifocal leukoencephalopathy due to natalizumab was seen as moderate to high. Seventy-six percent considered a risk of 1:1,000, or higher, an impediment for natalizumab use. Older age was the only variable associated with higher risk acceptance and our patients showed a more conservative profile than German and Spanish patients. Our patients perceived MS severity and progressive multifocal leukoencephalopathy risk similarly to elsewhere, but their willingness to take risks was more conservative. This should be considered when discussing therapeutic options and it might have an impact on guideline adaptations.

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RESUMO A percepção de gravidade da esclerose múltipla (EM) e riscos associado a terapias podem influenciar a escolha de tratamento em diferentes países. Investigamos a percepção da gravidade da EM e fatores associados à aceitação de risco em 96 pacientes com EM remitente-recorrentecom um questionário e comparamos com duas coortes europeias. A EM foi percebida como muito grave e o risco de desenvolver leucoencefalopatia multifocal progressiva devido ao natalizumabe, como moderado a alto, sendo que76% consideraram um risco de 1: 1.000 ou maior como impeditivo deseu uso. Idade mais avançada foi a única variável associada àaceitação de risco mais elevado e nossos pacientes revelaram um perfil mais conservador do que os pacientes alemães e espanhóis. Esses dados devem ser considerados ao discutir opções terapêuticas e pode ter impacto nas adaptações de diretrizes locais.

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Medical perception of stroke care conditions in Brazil

ABSTRACT Stroke is currently the second leading cause of death in Brazil. Neurologists' reports on the absence of adequate resources for stroke care are frequent; however, there are no objective data on this perception. Objective To assess the perception of neurologists of stroke care conditions in Brazil. Methods Neurologists from all over Brazil were surveyed by means of an anonymous questionnaire about the main shortcomings in stroke care, focusing particularly on physical structure and infrastructure (diagnostic methods, patient transport, availability of beds, multi-professional team). Results The main shortcomings are indicated: the worst conditions, among all items surveyed, were found in the public sector. In the private sector, conditions were better. Conclusions Care conditions are worse in the public sector with regard to both infrastructure and human resources. Future public health policies for the prevention and treatment of stroke should be formulated, taking into consideration neurologists' perceptions.

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RESUMO O acidente vascular cerebral é atualmente a segunda causa de morte no Brasil. São frequentes os relatos de médicos neurologistas sobre a ausência de recursos adequados para o atendimento do AVC, no entanto, não existem dados objetivos sobre essa percepção. Objetivo Analisar a percepção de médicos neurologistas sobre as condições para o atendimento de AVC no Brasil. Métodos Neste estudo foi realizada pesquisa por questionário anônimo com médicos neurologistas de todo o Brasil, perguntando-se as principais deficiências para o atendimento, com foco na estrutura física, infraestrutura (métodos diagnósticos, transporte do doente, disponibilidade de leitos, equipe multiprofissional). Resultados As principais deficiências são apontadas; no setor público notou-se as piores condições, em todos os itens pesquisados. No setor privado, as condições são melhores. Conclusões As condições de atendimento são piores no setor público, tanto de infraestrutura quanto de recursos humanos. Futuras políticas de saúde pública para prevenção e tratamento do AVC deveriam ser elaboradas levando em consideração a percepção do neurologista.

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Anticoagulation in patients with cardiac manifestations of Chagas disease and cardioembolic ischemic stroke

ABSTRACT Objectives To describe anticoagulation characteristics in patients with cardiac complications from Chagas disease and compare participants with and without cardioembolic ischemic stroke (CIS). Methods A retrospective cohort of patients with Chagas disease, using anticoagulation, conducted from January 2011 to December 2014. Results Forty-two patients with Chagas disease who were using anticoagulation were studied (age 62.9±12.4 years), 59.5% female and 47.6% with previous CIS, 78.6% with non-valvular atrial fibrillation and 69.7% with dilated cardiomyopathy. Warfarin was used in 78.6% of patients and dabigatran (at different times) in 38%. In the warfarin group, those with CIS had more medical appointments per person-years of follow-up (11.7 vs 7.9), a higher proportion of international normalized ratios within the therapeutic range (57% vs 42% medical appointments, p = 0.025) and an eight times higher frequency of minor bleeding (0.64 vs 0.07 medical appointments). Conclusion Patients with Chagas disease and previous CIS had better control of INR with a higher frequency of minor bleeding.

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RESUMO Objetivos descrever as características da anticoagulação em pacientes com manifestações cardíacas da doença de Chagas (MCDC) e comparar os participantes com sem acidente vascular cerebral isquêmico cardioembólico (AVCIC). Resultados 42 pacientes com MCDC em anticoagulação foram estudados (62,9 ± 12,4 anos), 59,5% do sexo feminino e 47,6% com AVCIC prévio, 78,6% portadores de fibrilação atrial não valvar e 69,7% com cardiomiopatia dilatada. Varfarina foi utilizada em 78,6% dos pacientes e dabigatrana em 38% (em momentos diferentes). No grupo da varfarina, aqueles com AVCIC tiveram mais consultas médicas por pessoas-ano de seguimento (11,7 vs 7,9), maior taxa de RNI na faixa terapêutica (57% vs 42% consultas médicas, p = 0,025) e uma frequência oito vezes maior de sangramento menor (0,64 vs. 0,07 consultas médicas). Conclusão pacientes com MCDC e AVCIC prévio têm melhor controle de RNI com maior frequência de sangramento menor.

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A Brazilian-Portuguese version of the Kinesthetic and Visual Motor Imagery Questionnaire

ABSTRACT Motor imagery has emerged as a potential rehabilitation tool in stroke. The goals of this study were: 1) to develop a translated and culturally-adapted Brazilian-Portugese version of the Kinesthetic and Visual Motor Imagery Questionnaire (KVIQ20-P); 2) to evaluate the psychometric characteristics of the scale in a group of patients with stroke and in an age-matched control group; 3) to compare the KVIQ20 performance between the two groups. Methods Test-retest, inter-rater reliabilities, and internal consistencies were evaluated in 40 patients with stroke and 31 healthy participants. Results In the stroke group, ICC confidence intervals showed excellent test-retest and inter-rater reliabilities. Cronbach's alpha also indicated excellent internal consistency. Results for controls were comparable to those obtained in persons with stroke. Conclusions The excellent psychometric properties of the KVIQ20-P should be considered during the design of studies of motor imagery interventions for stroke rehabilitation.

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RESUMO A Imagética Mental é uma ferramenta em potencial para a reabilitação de indivíduos com doenças cerebrovasculares. Os objetivos desse estudo foram: 1) Desenvolver uma versão traduzida e adaptada culturalmente do Questionário de Imagética Motora Cinestésica e Visual (KVIQ20-P); 2) Avaliar as características psicométricas da escala nesse grupo e em controles; 3) Comparar o desempenho na escala entre os dois grupos. Métodos Confiabilidades teste-reteste, interexaminador, assim como consistências internas da KVIQ20-P foram avaliadas em 40 indivíduos com AVC e em 31 controles. Resultados No grupo de pacientes, os intervalos de confiança mostraram excelentes confiabilidades teste-reteste e interexaminador. O alfa de Cronbach indicou uma excelente consistência interna. Os resultados no grupo controle foram comparáveis aos obtidos nos pacientes. Conclusões As excelentes propriedades psicométricas da KVIQ20-P devem ser consideradas durante o desenho de estudos de Imagética Mental para a reabilitação de indivíduos com doenças cerebrovasculares.

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Thymoquinone reverses learning and memory impairments and brain tissue oxidative damage in hypothyroid juvenile rats

ABSTRACT In this study, the effect of thymoquinone (TQ) on propylthiouracil (PTU)-induced memory impairment was investigated in juvenile rats. The rats were grouped into control, Hypo, Hypo-TQ5 and Hypo-TQ10. Propylthiouracil increased latency time in the Morris water maze test and decreased delay in entering the dark compartment in the passive avoidance test. Both 5 mg/kg and 10 mg/kg doses of TQ decreased latency time in the Morris water maze test and increased delay in entering the dark compartment in a passive avoidance test. The PTU also increased malondialdehyde and nitric oxide metabolites in the brain while reduced the thiol content and superoxide dismutase and catalase activities and serum T4 level. Both doses of TQ decreased malondialdehyde and nitric oxide metabolites in the brain while enhanced the thiol content and superoxide dismutase and catalase activities and serum T4 level. The results of the present study showed that TQ protected against PTU-induced memory impairments in rats.

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RESUMO Neste estudo, foi investigado o efeito da timoquinona (TQ) contra deficiências de memória induzidas por propiltiouracilo (PTU) em ratos juvenis. Os ratos foram agrupados em grupos: controle, Hypo, Hypo-TQ5, e Hypo-TQ10. O PTU aumentou o tempo de latência no teste do labirinto aquático de Morris (MWM) e diminuiu o atraso para entrar no compartimento escuro no teste de evasão passiva (PA). Ambas as doses de TQ diminuíram o tempo de latência no teste de MWM e aumentaram o atraso para entrar no compartimento escuro no teste de PA. O PTU também aumentou os metabolitos de malondialdeído (MDA) e óxido nítrico (NO) no cérebro, enquanto reduziu o teor de tiol e as atividades de superóxido dismutasa (SOD) e catalasa (CAT) e o nível sérico de T4. Ambas as doses de TQ diminuíram os metabolitos de MDA e de NO no cérebro, aumentaram o conteúdo de tiol e as atividades de SOD e CAT e o nível de T4 no soro. Os resultados do presente estudo mostraram que a TQ protegeu contra deficiências de memória induzidas por PTU em ratos.

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Autoimmune encephalitis: a review of diagnosis and treatment

ABSTRACT Autoimmune encephalitis (AIE) is one of the most common causes of noninfectious encephalitis. It can be triggered by tumors, infections, or it may be cryptogenic. The neurological manifestations can be either acute or subacute and usually develop within six weeks. There are a variety of clinical manifestations including behavioral and psychiatric symptoms, autonomic disturbances, movement disorders, and seizures. We reviewed common forms of AIE and discuss their diagnostic approach and treatment.

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RESUMO As encefalites autoimunes (EAI) são a principal causa de encefalite não-infecciosa. As manifestações neurológicas são variadas, incluindo alterações comportamentais ou psiquiátricas, disautonomia, transtornos do movimento e epilepsia. Habitualmente a instalação dos sintomas ocorre em até 6 semanas, de forma aguda ou subaguda. As EAI podem ser desencadeadas por tumores, quadros infecciosos virais ou ainda apresentar etiologia criptogênica. Este artigo revisa as principais EAI, estratégias de diagnóstico e tratamento.

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Arquivos de Neuro-Psiquiatria: 75 years

ABSTRACT This year marks the 75th year of publication of Arquivos de Neuro-Psiquiatria (ANP), the official journal of the Brazilian Academy of Neurology and one of the most important neuroscience journals in Latin America. ANP was initially edited by Oswaldo Lange, its founder, and subsequently by Antonio Spina-França Netto and, in recent years, by José Antonio Livramento and Luís dos Ramos Machado.

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RESUMO Arquivos de Neuro-Psiquiatria (ANP), o periódico oficial da Academia Brasileira de Neurologia, completou 75 anos de atividades, reconhecido como um dos jornais de neurociências mais importante da América Latina. Nestes 75 anos de existência o ANP teve como editores os Professores Oswaldo Lange, o seu fundador, seguido por Antonio Spina-França Netto, e nos últimos anos, José Antonio Livramento e Luís dos Ramos Machado.

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Searching for neurological diseases in the Julio-Claudian dynasty of the Roman Empire

ABSTRACT The gens Julia was one of the oldest families in ancient Rome, whose members reached the highest positions of power. They made history because Julius Caesar, perpetual dictator, great-uncle of the first emperor, Augustus, passed his name on to the Julio-Claudian dynasty with the emperors Tiberius, Caligula, Claudius and Nero. Descriptions of the diseases of these emperors and some of his family members may indicate diagnoses such as epilepsy, dystonia, dementia, encephalitis, neurosyphilis, peripheral neuropathies, dyslexia, migraine and sleep disorders. In the historical context of ancient Rome, the possibility of infectious diseases related to the libertine way of life is quite large. However, there is a possibility that some of these diseases occurred from genetic transmission.

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RESUMO A gens Iulia era uma das mais antigas famílias da Roma Antiga, com membros que chegaram aos mais altos cargos. Ficaram na história por causa de Julius Caesar, ditador perpétuo, pai adotivo do primeiro imperador Augustus, por meio de quem seu nome passou para a dinastia Julio-Claudian com os imperadores Tiberius, Caligula, Claudius e Nero. Descrições de doenças desses imperadores e de alguns de seus familiares podem nos remeter a diagnósticos como epilepsia, distonia, demência, encefalites, neurossífilis, neuropatias periféricas, dislexia, migrânea e distúrbios do sono. No contexto histórico da Roma antiga, a possibilidade de doenças infecciosas e relacionadas ao modo de vida libertino é bastante grande. Entretanto, existe a possibilidade de que algumas dessas doenças tenham ocorrido por transmissão genética.

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“Acute Dupuytren’s contracture”: the answer is not always in your hands

ABSTRACT The gens Julia was one of the oldest families in ancient Rome, whose members reached the highest positions of power. They made history because Julius Caesar, perpetual dictator, great-uncle of the first emperor, Augustus, passed his name on to the Julio-Claudian dynasty with the emperors Tiberius, Caligula, Claudius and Nero. Descriptions of the diseases of these emperors and some of his family members may indicate diagnoses such as epilepsy, dystonia, dementia, encephalitis, neurosyphilis, peripheral neuropathies, dyslexia, migraine and sleep disorders. In the historical context of ancient Rome, the possibility of infectious diseases related to the libertine way of life is quite large. However, there is a possibility that some of these diseases occurred from genetic transmission.

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RESUMO A gens Iulia era uma das mais antigas famílias da Roma Antiga, com membros que chegaram aos mais altos cargos. Ficaram na história por causa de Julius Caesar, ditador perpétuo, pai adotivo do primeiro imperador Augustus, por meio de quem seu nome passou para a dinastia Julio-Claudian com os imperadores Tiberius, Caligula, Claudius e Nero. Descrições de doenças desses imperadores e de alguns de seus familiares podem nos remeter a diagnósticos como epilepsia, distonia, demência, encefalites, neurossífilis, neuropatias periféricas, dislexia, migrânea e distúrbios do sono. No contexto histórico da Roma antiga, a possibilidade de doenças infecciosas e relacionadas ao modo de vida libertino é bastante grande. Entretanto, existe a possibilidade de que algumas dessas doenças tenham ocorrido por transmissão genética.

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Proximal limb weakness and amyotrophy in a man with silicosis

ABSTRACT The gens Julia was one of the oldest families in ancient Rome, whose members reached the highest positions of power. They made history because Julius Caesar, perpetual dictator, great-uncle of the first emperor, Augustus, passed his name on to the Julio-Claudian dynasty with the emperors Tiberius, Caligula, Claudius and Nero. Descriptions of the diseases of these emperors and some of his family members may indicate diagnoses such as epilepsy, dystonia, dementia, encephalitis, neurosyphilis, peripheral neuropathies, dyslexia, migraine and sleep disorders. In the historical context of ancient Rome, the possibility of infectious diseases related to the libertine way of life is quite large. However, there is a possibility that some of these diseases occurred from genetic transmission.

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RESUMO A gens Iulia era uma das mais antigas famílias da Roma Antiga, com membros que chegaram aos mais altos cargos. Ficaram na história por causa de Julius Caesar, ditador perpétuo, pai adotivo do primeiro imperador Augustus, por meio de quem seu nome passou para a dinastia Julio-Claudian com os imperadores Tiberius, Caligula, Claudius e Nero. Descrições de doenças desses imperadores e de alguns de seus familiares podem nos remeter a diagnósticos como epilepsia, distonia, demência, encefalites, neurossífilis, neuropatias periféricas, dislexia, migrânea e distúrbios do sono. No contexto histórico da Roma antiga, a possibilidade de doenças infecciosas e relacionadas ao modo de vida libertino é bastante grande. Entretanto, existe a possibilidade de que algumas dessas doenças tenham ocorrido por transmissão genética.

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Delayed hemiparkinsonism after closed head injury

ABSTRACT The gens Julia was one of the oldest families in ancient Rome, whose members reached the highest positions of power. They made history because Julius Caesar, perpetual dictator, great-uncle of the first emperor, Augustus, passed his name on to the Julio-Claudian dynasty with the emperors Tiberius, Caligula, Claudius and Nero. Descriptions of the diseases of these emperors and some of his family members may indicate diagnoses such as epilepsy, dystonia, dementia, encephalitis, neurosyphilis, peripheral neuropathies, dyslexia, migraine and sleep disorders. In the historical context of ancient Rome, the possibility of infectious diseases related to the libertine way of life is quite large. However, there is a possibility that some of these diseases occurred from genetic transmission.

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RESUMO A gens Iulia era uma das mais antigas famílias da Roma Antiga, com membros que chegaram aos mais altos cargos. Ficaram na história por causa de Julius Caesar, ditador perpétuo, pai adotivo do primeiro imperador Augustus, por meio de quem seu nome passou para a dinastia Julio-Claudian com os imperadores Tiberius, Caligula, Claudius e Nero. Descrições de doenças desses imperadores e de alguns de seus familiares podem nos remeter a diagnósticos como epilepsia, distonia, demência, encefalites, neurossífilis, neuropatias periféricas, dislexia, migrânea e distúrbios do sono. No contexto histórico da Roma antiga, a possibilidade de doenças infecciosas e relacionadas ao modo de vida libertino é bastante grande. Entretanto, existe a possibilidade de que algumas dessas doenças tenham ocorrido por transmissão genética.

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Rapidly progressive subacute motor neuronopathy disclosing type B2 thymoma

ABSTRACT The gens Julia was one of the oldest families in ancient Rome, whose members reached the highest positions of power. They made history because Julius Caesar, perpetual dictator, great-uncle of the first emperor, Augustus, passed his name on to the Julio-Claudian dynasty with the emperors Tiberius, Caligula, Claudius and Nero. Descriptions of the diseases of these emperors and some of his family members may indicate diagnoses such as epilepsy, dystonia, dementia, encephalitis, neurosyphilis, peripheral neuropathies, dyslexia, migraine and sleep disorders. In the historical context of ancient Rome, the possibility of infectious diseases related to the libertine way of life is quite large. However, there is a possibility that some of these diseases occurred from genetic transmission.

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RESUMO A gens Iulia era uma das mais antigas famílias da Roma Antiga, com membros que chegaram aos mais altos cargos. Ficaram na história por causa de Julius Caesar, ditador perpétuo, pai adotivo do primeiro imperador Augustus, por meio de quem seu nome passou para a dinastia Julio-Claudian com os imperadores Tiberius, Caligula, Claudius e Nero. Descrições de doenças desses imperadores e de alguns de seus familiares podem nos remeter a diagnósticos como epilepsia, distonia, demência, encefalites, neurossífilis, neuropatias periféricas, dislexia, migrânea e distúrbios do sono. No contexto histórico da Roma antiga, a possibilidade de doenças infecciosas e relacionadas ao modo de vida libertino é bastante grande. Entretanto, existe a possibilidade de que algumas dessas doenças tenham ocorrido por transmissão genética.

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Incidence of Guillain-Barré syndrome among Zika virus infected cases: a report from Thailand

ABSTRACT The gens Julia was one of the oldest families in ancient Rome, whose members reached the highest positions of power. They made history because Julius Caesar, perpetual dictator, great-uncle of the first emperor, Augustus, passed his name on to the Julio-Claudian dynasty with the emperors Tiberius, Caligula, Claudius and Nero. Descriptions of the diseases of these emperors and some of his family members may indicate diagnoses such as epilepsy, dystonia, dementia, encephalitis, neurosyphilis, peripheral neuropathies, dyslexia, migraine and sleep disorders. In the historical context of ancient Rome, the possibility of infectious diseases related to the libertine way of life is quite large. However, there is a possibility that some of these diseases occurred from genetic transmission.

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RESUMO A gens Iulia era uma das mais antigas famílias da Roma Antiga, com membros que chegaram aos mais altos cargos. Ficaram na história por causa de Julius Caesar, ditador perpétuo, pai adotivo do primeiro imperador Augustus, por meio de quem seu nome passou para a dinastia Julio-Claudian com os imperadores Tiberius, Caligula, Claudius e Nero. Descrições de doenças desses imperadores e de alguns de seus familiares podem nos remeter a diagnósticos como epilepsia, distonia, demência, encefalites, neurossífilis, neuropatias periféricas, dislexia, migrânea e distúrbios do sono. No contexto histórico da Roma antiga, a possibilidade de doenças infecciosas e relacionadas ao modo de vida libertino é bastante grande. Entretanto, existe a possibilidade de que algumas dessas doenças tenham ocorrido por transmissão genética.

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Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations

Abstract

Early preclinical evidence provided the rationale for programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) blockade as a potential form of cancer immunotherapy given that activation of the PD-1/PD-L1 axis putatively served as a mechanism for tumor evasion of host tumor antigen-specific T-cell immunity. Early-phase studies investigating several humanized monoclonal IgG4 antibodies targeting PD-1 and PD-L1 in advanced solid tumors paved way for the development of the first PD-1 inhibitors, nivolumab and pembrolizumab, approved by the Food and Drug Administration (FDA) in 2014. The number of FDA-approved agents of this class is rapidly enlarging with indications for treatment spanning across a spectrum of malignancies. The purpose of this review is to highlight the clinical development of PD-1 and PD-L1 inhibitors in cancer therapy to date. In particular, we focus on detailing the registration trials that have led to FDA-approved indications of anti-PD-1 and anti-PD-L1 therapies in cancer. As the number of PD-1/PD-L1 inhibitors continues to grow, predictive biomarkers, mechanisms of resistance, hyperprogressors, treatment duration and treatment beyond progression, immune-related toxicities, and clinical trial design are key concepts in need of further consideration to optimize the anticancer potential of this class of immunotherapy.

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Preparation of Fe@GAC and Fe@GAR and Their Application for Removal of Crystal Violet from Wastewater

Abstract

Two types of granular adsorbents-supported zero-valent iron (ZVI) were prepared and applied to remove crystal violet (CV). One type of ZVI was synthesized by the chemical reduction method and deposited on the surface of granular porous adsorbent (Fe@GAC). The other type of ZVI was synthesized by direct reduction of iron ore tailing powder with the coke in high temperature reducing atmosphere and was embedded in granular porous adsorbent (Fe@GAR). Fe@GAC and Fe@GAR were characterized by SEM, EDX, XRD, FTIR, and BET. The effect of parameters like contact time, initial CV concentration, pH values, and temperature on the removal of CV was investigated. According to the results, the Langmuir model was in good agreement with the experimental data, where the maximum removal capacity of Fe@GAC and Fe@GAR was found to be 95.24 mg/g and 123.45 mg/g at 293 K, respectively. The kinetic studies indicated that the pseudo-second-order kinetic model agreed well with the experimental data. Thermodynamic parameters were calculated and analyzed, which suggested that the removal processes were spontaneous and endothermic. The mechanism of CV removal by Fe@GAC and Fe@GAR included adsorption and simultaneous chemical reduction. Compared with Fe@GAC, Fe@GAR owned more amount of ZVI, larger specific surface area and higher removal capacity, which made it a more promising adsorbent in wastewater treatment.

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Effects of Bilateral Hearing Aid Use on Balance in Experienced Adult Hearing Aid Users

Purpose

The purpose of this study was to evaluate the balance of experienced adult hearing aid users with and without their hearing aids via computerized posturography.

Method

Computerized posturography was accomplished by employing the Sensory Organization Test (SOT) on the NeuroCom Balance Master (Natus Medical Incorporated). The SOT assessed each participant's balance and the strategy used to maintain balance in 6 progressively challenging conditions. Twenty-two adults using bilateral at-the-ear hearing aids participated in the study. All participants completed all SOT protocols with and without their hearing aids.

Results

No statistically significant differences in participants' balance were identified regardless of the presence or absence of their hearing aids during the SOT.

Conclusions

These results failed to support previous research, which indicated that amplification of auditory input could benefit balance in individuals with hearing and balance disorders. Further research utilizing randomized controlled trials is needed to resolve the disparity between the current results and those of previous studies.

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The p38-MK2/3 Module Is Critical for IL-33-Induced Signaling and Cytokine Production in Dendritic Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

IL-33 is an IL-1 cytokine superfamily member. Binding of IL-33 to the IL-33R induces activation of the canonical NF-B signaling and activation of MAPKs. In bone marrow–derived dendritic cells, IL-33 induces the production of IL-6, IL-13, and TNF-α. However, the signaling pathways resulting in IL-33–induced effector functions of dendritic cells are unknown. In this article, we show that the IL-33–induced cytokine production is only partly dependent on p65. Thereby, p65 mediates the production of IL-6, but not of IL-13, whereas the p38–Mapk-activated protein kinases 2/3 (MK2/3) signaling module mediates the IL-13, but not the IL-6, production. In addition, GM-CSF, which is critical for the differentiation and proliferation of bone marrow–derived dendritic cells, potentiates the p65-dependent IL-6 and the p38-MK2/3–dependent IL-13 production. Furthermore, we found that effective TNF-α production is only induced in the presence of GM-CSF and IL-33 via the p38-MK2/3 signaling module. Taken together, we found that the p38-MK2/3 signaling module is essential to mediate IL-33–induced cytokine production in dendritic cells.

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Intestinal Inflammation-Mediated Clearance of Amebic Parasites Is Dependent on IFN-{gamma} [INFECTIOUS DISEASE AND HOST RESPONSE]

Intestinal amebiasis is a major cause of diarrhea. However, research on host–amebae interactions has been hampered owing to a lack of appropriate animal models. Recently, a mouse model of intestinal amebiasis was established, and using it, we reported that Entamoeba moshkovskii colonized the intestine in a manner similar to that of the pathogenic Entamoeba histolytica. In this study, we evaluated the protective mechanisms present against amebae using this model. CBA/J mice infected with E. histolytica had a persistent infection without apparent symptoms. In contrast, E. moshkovskii–infected mice rapidly expelled the ameba, which was associated with weight loss, diarrhea, and intestinal damage characterized by apoptosis of intestinal epithelial cells (IECs). Expression of NKG2D on intestinal intraepithelial lymphocytes (IELs) and IFN-–producing cells in Peyer's patches were significantly induced after infection with E. moshkovskii but not with E. histolytica. IFN-–deficient mice infected with E. moshkovskii showed no obvious symptoms. Notably, none of these mice expelled E. moshkovskii, indicating that IFN- is responsible not only for intestinal symptoms but also for the expulsion of amebae. Furthermore, apoptosis of IECs and expression of NKG2D on IELs observed in E. moshkovskii–infected mice did not occur in the absence of IFN-. In vivo blocking of NKG2D in mice infected with E. moshkovskii enabled ameba to survive longer and remarkably reduced apoptotic IECs. Our results clearly demonstrate a novel protective mechanism exerted by IFN- against intestinal amebae, including induction of cytotoxicity of IELs toward IECs.

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Dendritic Cells on the Way to Glory [PILLARS OF IMMUNOLOGY]

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A Cellular MicroRNA Facilitates Regulatory T Lymphocyte Development by Targeting the FOXP3 Promoter TATA-Box Motif [IMMUNE SYSTEM DEVELOPMENT]

The CD4⁺CD25⁺FOXP3⁺ regulatory T cells (Tregs) mediate immunological self-tolerance and suppress various immune responses. FOXP3 is a key transcriptional factor for the generation and development of Tregs. Its expression is regulated by various cytokines including TGF-β, IL-2, and IL-10. It is important to further identify the regulatory factors for Tregs. Given that many microRNAs (miRNAs) could specifically interact with the core promoter region and specifically enhance the transcription of many target genes, we searched for any possible miRNA(s) targeting the core promoter region of the FOXP3 gene. We found that miR-4281, an miRNA specifically expressed in hominids, can potently and specifically upregulate FOXP3 expression by directly interacting with the TATA-box motif in the human FOXP3 promoter. Consequently, miR-4281 significantly accelerated the differentiation of human naive cells to induced Tregs (iTregs) that possess immune suppressor functions and weaken the development of graft-versus-host disease in a humanized mouse model. Interestingly, iTregs induced by the combination of TGF-β, IL-2, and chemically synthesized miR-4281 were more stable and functional than those induced by TGF-β and IL-2 alone. Moreover, we found that the IL-2/STAT5 signal transduction upregulates FOXP3 expression not only through the classical pathway, but also by enhancing the expression of the miR-4281 precursor gene (SNCB) and, correspondingly, miR-4281. This study reveals a novel mechanism regulating FOXP3 expression and human iTreg development and, therefore, offers a new therapeutic target to manipulate immunosuppressive system.

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Pillars Article: Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor {alpha}. J. Exp. Med. 1994. 179:1109-1118 [PILLARS OF IMMUNOLOGY]

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Human NK Cells Downregulate Zap70 and Syk in Response to Prolonged Activation or DNA Damage [INNATE IMMUNITY AND INFLAMMATION]

The extent of NK cell activity during the innate immune response affects downstream immune functions and, ultimately, the outcome of infectious or malignant disease. However, the mechanisms that terminate human NK cell responses have yet to be defined. When activation receptors expressed on NK cell surfaces bind to ligands on diseased cells, they initiate a signal that is propagated by a number of intracellular kinases, including Zap70 and Syk, eventually leading to NK cell activation. We assayed Zap70 and Syk content in NK cells from healthy human donors and identified a subset of NK cells with unusually low levels of these two kinases. We found that this Zap70^lowSyk^low subset consisted of NK cells expressing a range of surface markers, including CD56^hi and CD56^low NK cells. Upon in vitro stimulation with target cells, Zap70^lowSyk^low NK cells failed to produce IFN- and lysed target cells at one third the capacity of Zap70^hiSyk^hi NK cells. We determined two independent in vitro conditions that induce the Zap70^lowSyk^low phenotype in NK cells: continuous stimulation with activation beads and DNA damage. The expression of inhibitory receptors, including NKG2A and inhibitory killer Ig-like receptors (KIRs), was negatively correlated with the Zap70^lowSyk^low phenotype. Moreover, expression of multiple KIRs reduced the likelihood of Zap70 downregulation during continuous activation, regardless of whether NK cells had been educated through KIR–HLA interactions in vivo. Our findings show that human NK cells are able to terminate their functional activity without the aid of other immune cells through the downregulation of activation kinases.

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