AImipenem and Relebactam : Single- and Multiple-Dose Study to Characterize the Pharmacokinetics, Safety, and Tolerability of

payt.helady61 shared this article with you from Inoreader A Single- and Multiple-Dose Study to Characterize the Pharmacokinetics, Safety, and Tolerability of Imipenem and Relebactam in Healthy Chinese Participants [Pharmacology] Via AAC Accepts: Articles Published Ahead of Print Relebactam/imipenem/cilastatin is approved in the US to treat complicated urinary tract and intra-abdominal infections in patients that have limited or no alternative treatment options and HABP/VABP. Initial pharmacokinetic, safety, and tolerability studies of relebactam with and without imipenem/cilastatin included mostly Caucasian participants. This study evaluated pharmacokinetics, safety, and tolerability of relebactam/imipenem/cilastatin in 12 healthy Chinese participants after three single doses of increasing concen tration (relebactam 125, 250, or 500 mg/cilastatin 250, 500, or 1000 mg/imipenem 250, 500, or 1000 mg) and after multiple doses every 6 h of a single concentration (relebactam 250 mg/cilastatin 500 mg/imipenem 500 mg) for 14 days. After single doses, area under the concentration–time curve (AUC) extrapolated to infinity (relebactam, 15.0–70.7 h*mg/liter; imipenem, 24.1–109.8 h*mg/liter; cilastatin, 18.4–95.3 h*mg/liter) and AUC from 0–6 h (relebactam, 14.2–66.3 h*mg/liter; imipenem, 23.4–107.3 h*mg/liter; cilastatin, 18.3–94.4 h*mg/liter) increased in a dose-dependent manner; clearance (relebactam, 6.9–8.3 liters/h; imipenem, 8.6–10.4 liters/h; cilastatin, 10.5–13.6 liters/h) and half-life (relebactam, 1.4–1.6 h; imipenem, 1.0–1.2 h; cilastatin, 0.7–1.0 h) were consistent between doses. Pharmacokinetic parameters after multiple doses were similar to parameters after a single dose (geometric mean ratios of 0.8–1.0 for all three agents). Relebactam/imipen em/cilastatin was well tolerated; mild adverse events occurred during single dosing, and one participant experienced serious adverse events after multiple doses. Pharmacokinetics and safety data are comparable with data from participants of other ethnicities, supporting the use of relebactam/imipenem/cilastatin at the approved dose and schedule in Chinese patients. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Absence of Lenacapavir (GS-6207) Phenotypic Resistance in HIV Gag Cleavage Site Mutants and in Isolates with Resistance to Existing Drug Classes [Antiviral Agents]

payt.helady61 shared this article with you from Inoreader Absence of Lenacapavir (GS-6207) Phenotypic Resistance in HIV Gag Cleavage Site Mutants and in Isolates with Resistance to Existing Drug Classes [Antiviral Agents] Via AAC Accepts: Articles Published Ahead of Print Lenacapavir (LEN, GS-6207) is a potent, first-in-class inhibitor of HIV-1 capsid with long-acting properties and the potential for subcutaneous dosing every 3 months or longer. In the clinic, a single subcutaneous LEN injection (20 mg to 750 mg) in people-living-with-HIV (PLWH) showed a strong antiviral response, with a >2.3 mean log10 decrease in HIV-1 RNA at day 10. HIV-1 Gag mutations near protease (PR) cleavage sites have emerged with the use of protease inhibitors (PIs). Here we have characterized the a ctivity of LEN in mutants with Gag cleavage site mutations (GCSMs), and mutants resistant to other drug classes. HIV mutations were inserted into the pXXLAI clone and the resulting mutants (n = 70) were evaluated using a 5-day antiviral assay. LEN EC50 fold change versus wild-type ranged from 0.4 to 1.9 in these mutants, similar to the control drug. In contrast, reduced susceptibility to PIs and maturation inhibitors (MIs) was observed. Testing of isolates with resistance against the 4 main classes of drugs (n = 40) indicated wild-type susceptibility to LEN (fold change ranging from 0.3 to 1.1), while reduced susceptibility was observed for control drugs. HIV GCSMs did not impact the activity of LEN, while some conferred resistance to MIs and PIs. Similarly, LEN activity was not affected by naturally-occurring variations in HIV Gag, in contrast to the reduced susceptibility observed for MIs. Finally, the activity of LEN was not affected by the presence of re sistance mutations to the 4 main ARV classes. These data support the evaluation of LEN in PLWH with multi-class resistance. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Favipiravir and the Need for Early Ambulatory Treatment of COVID-19 [Letters]

payt.helady61 shared this article with you from Inoreader Favipiravir and the Need for Early Ambulatory Treatment of COVID-19 [Letters] Via AAC Accepts: Articles Published Ahead of Print The commentary by McCullough emphasizes the urgent need for early ambulatory therapy of COVID-19 (1).... View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Omadacycline against Nontuberculous Mycobacteria

payt.helady61 shared this article with you from Inoreader In Vitro Susceptibility Testing of Omadacycline against Nontuberculous Mycobacteria (NTM) [Susceptibility] Via AAC Accepts: Articles Published Ahead of Print Nontuberculous mycobacteria (NTM) infections are increasing globally. Mycobacterium avium complex (MAC) and M. abscessus complex are the most frequently encountered NTM and oral treatment options are extremely limited for these pathogens, especially for the M. abscessus complex. In this study, the in vitro potency of omadacycline, a new tetracycline derivative, was tested against 111 isolates of NTM. MIC testing was performed as recommended by the Clinical and Laboratory Standards Institute aga inst 70 isolates of rapidly growing mycobacteria (RGM) of which >90% were tetracycline resistant. These included M. abscessus subsp. abscessus (20), M. abscessus subsp. massiliense (3), M. chelonae (15), M. immunogenum (7), the M. fortuitum group including six doxycycline resistant isolates (12), and the M. mucogenicum group including four doxycycline resistant isolates (10). Forty-one isolates of slowly growing mycobacteria (SGM) species including 16 isolates of MAC were also tested. Omadacycline was active against all RGM species with an MIC50 range of 0.004-0.25 and 0.06-1 μg/ml for 80% and 100% inhibition, respectively. For M. abscessus subsp. abscessus, MIC50 values were 0.06 and 0.12 μg/ml with 80% and 100% inhibition respectively. There was considerable trailing of the omadacycline endpoint with the RGM. MICs for tigecycline exhibited no trailing and were generally within 1-2 dilu tions of the 100% inhibition omadacycline MIC values. While there was no trailing observed in SGM, omadacycline MICs were higher (MIC range 8->16 μg/ml, N = 41) as previously noted with tigecycline. This study supports further research of omadacycline including clinical trials for the treatment of RGM infections, especially M. abscessus. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

ALKOXYALKYL ESTERS OF NUCLEOTIDE ANALOGS INHIBIT POLYOMAVIRUS DNA REPLICATION AND LARGE T ANTIGEN ACTIVITIES [Antiviral Agents]

payt.helady61 shared this article with you from Inoreader ALKOXYALKYL ESTERS OF NUCLEOTIDE ANALOGS INHIBIT POLYOMAVIRUS DNA REPLICATION AND LARGE T ANTIGEN ACTIVITIES [Antiviral Agents] Via AAC Accepts: Articles Published Ahead of Print Polyomavirus-related infections are ubiqutious in immunocompromised individuals and in some cases are intractable and fatal. Due to lack of approved drugs to treat polyomavirus infections, cidofovir, a phosphonate nucleotide analog approved to treat cytomegalovirus infections has been repurposed as anti-polyomavirus agent. Cidofovir has been modified in various ways to improve its efficacies as broad-spectrum antiviral agent. However, the actual mechanisms and targets of cidofovir and its modified derivatives as anti-poly omavirus agents are still under research. Here, polyomavirus large tumor antigens (Tag) activities were identified as the viral target of cidofovir derivatives. The alkoxyalkyl-ester derivatives of cidofovir efficiently inhibit polyomavirus DNA replication in cell-free human extracts and a viral in vitro replication system only utilizing purified proteins. We present evidence that DNA helicase, and DNA binding activities of polyomavirus Tags are diminished in the presence of low concentrations of alkoxyalkyl-ester derivatives of cidofovir suggesting that the inhibition of viral DNA replication is at least in part mediated by inhibiting ssDNA and dsDNA binding activities of Tags. These findings show that the alkoxyalkyl-ester derivatives of cidofovir are effective in vitro without undergoing further conversions and conclude that the inhibitory mechanisms of nucleotide analog-based drugs are more complex than previously believed. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Study protocol for resolution of organ injury in acute pancreatitis (RESORP): an observational prospective cohort study

payt.helady61 shared this article with you from Inoreader Study protocol for resolution of organ injury in acute pancreatitis (RESORP): an observational prospective cohort study Via BMJ Open recent issues Introduction Survivors of acute pancreatitis (AP) have shorter overall survival and increased incidence of new-onset cardiovascular, respiratory, liver and renal disease, diabetes mellitus and cancer compared with the general population, but the mechanisms that explain this are yet to be elucidated. Our aim is to characterise the precise nature and extent of organ dysfunction following an episode of AP. Methods and analysis This is an observational prospective cohort study in a single centre comprising a University hospital with an acute and emergency receiving unit and clinical research facility. Participants will be adult patient admitted with AP. Participants will undergo assessment at recruitment, 3 months and 3 years. At each time point, multiple biochemical and/or physiological assessments to measure cardiovascular, respiratory, liver, renal and cognitive function, diabetes mellitus and quality of life. Recruitment was from 30 November 2017 to 31 May 2020; last follow-up measurements is due on 31 May 2023. The primary outcome measure is the incidence of new-onset type 3c diabetes mellitus during follow-up. Secondary outcome measures include: quality of life analyses (SF-36, Gastrointestinal Quality of Life Index); montreal cognitive assessment; organ system physiological performance; multiomics predictors of AP severity, detection of premature cellular senescence. In a nested cohort within the main cohort, individuals may also consent to multiparameter MRI scan, echocardiography, pulmonary function testing, cardiopulmonary exercise testing and pulse-wave analysis. Ethics and dissemination This study has received the following approvals: UK IRAS Number 178615; South-east Scotland Research Ethics Committee number 16/SS/0065. Results will be made available to AP survivors, caregivers, funders and other researchers. Publications will be open-access. Trial registration numbers ClinicalTrials.gov Registry (NCT03342716) and ISRCTN50581876; Pre-results. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Adults experiences of living with pulmonary hypertension: a thematic synthesis of qualitative studies

payt.helady61 shared this article with you from Inoreader Adults experiences of living with pulmonary hypertension: a thematic synthesis of qualitative studies Via BMJ Open recent issues Objectives Pulmonary hypertension is a life-shortening disease that has a considerable impact on quality of life. Improving our understanding of how individuals are affected and cope with the disease will help to improve services and outcomes. This review synthesises the published qualitative research that has listened to adults discuss their experiences of living with the disease. Design A comprehensive systematic search of four databases was conducted in May 2020: Web of Science, PubMed, PsycINFO and Cochrane Library. Suitable studies were evaluated using the Critical Appraisal Skills programme. Findings from the studies were extracted and subjected to a thematic synthesis. Results Nineteen articles were identified reflecting the experiences of over 1900 individuals impacted by pulmonary hypertension from Europe, North and South America and Asia. Ten studies did not report participant's WHO functional class of pulmonary hypertension, which resulted in comparing experiences between different severity difficult. All studies met the majority of the quality assessment items. Six descriptive themes emerged discussing participant's experiences of diagnosis, treatment, prognosis, healthcare professionals, impact and coping with pulmonary hypertension. Four higher order analytical themes were developed from the descriptive themes, reflecting: (i) uncertainties and anxiety that participants encountered related to pulmonary hypertension; (ii) lack of recognition of the impact of the condition; (iii) frustration at the paucity of awareness of pulmonary hypertension in society and healthcare settings and (iv) participant's accounts of transitioning through differe nt stages of living with the disease. Conclusions These findings form the first synthesis of experiences of life in individuals impacted by pulmonary hypertension and illustrate the multifaceted impact of the condition. The voices of numerous groups are missing from the literature highlighting the need for additional research. The results have implications for clinical practice emphasising the role of educational and psychological therapies to support those with the disease. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Is hard physical work in the early working life associated with back pain later in life?

payt.helady61 shared this article with you from Inoreader Is hard physical work in the early working life associated with back pain later in life? A cross-sectional study among 5700 older workers Via BMJ Open recent issues Objectives Physically demanding work increases the risk of developing musculoskeletal disorders during working life, with low back pain (LBP) as the most prevalent and debilitating musculoskeletal disorder worldwide. However, a lack of knowledge exists about the role of early working years on musculoskeletal health later in life. This study investigated whether an exposure–response association exists between physical demands in early working life and risk of LBP in later working life. Design Cross-sectional study. Setting, participants and outcome measure In the SeniorWorkingLife study, 5909 wage earners aged ≥50 years with currently sedentary work replied to a questionnaire survey in 2018 about physical work demands during their first working years (exposure) and current LBP (outcome). Associations between physical work demands in the early working years and current LBP were modelled using general linear models controlling for various confounders, combined with model-assisted weights based on national registers. Results Hard physical work during early working life was associated with more intense LBP later in life among senior workers with currently sedentary jobs. In the fully adjusted model, workers with 'standing/walking work with lifting/carrying' and 'heavy or fast work that is physically strenuous' during the first years of working life reported higher LBP intensity than those with sedentary work during their first working years (0.2 (95% CI, 0.0 to 0.4) and 0.6 (95% CI, 0.4 to 0.9), respectively). Conclusion Work involving lifting/carrying or work that is physically strenuous in early life is associated with higher intensity of LBP among older workers with currently sedentary employment. These findings suggest that early working life may have an impact on later working years and underscore the necessity for careful introduction and instruction to the working environment for retaining musculoskeletal health and prolonging working life. Trial registration number NCT03634410. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Clinical and metabolic characteristics of the Diabetes Intervention Accentuating Diet and Enhancing Metabolism (DIADEM-I) randomised clinical trial cohort

payt.helady61 shared this article with you from Inoreader Clinical and metabolic characteristics of the Diabetes Intervention Accentuating Diet and Enhancing Metabolism (DIADEM-I) randomised clinical trial cohort Via BMJ Open recent issues Objectives Diabetes Intervention Accentuating Diet and Enhancing Metabolism-I (DIADEM-I) is the first randomised controlled trial (RCT) in the Middle East and North Africa (MENA) region testing the effectiveness of an intensive lifestyle intervention (ILI) for weight loss and diabetes remission. We report on the recruitment process and baseline characteristics of the DIADEM-I cohort based on origin (Middle East vs North Africa), and waist circumference. Design DIADEM-I is an open-label randomised, controlled, parallel group RCT recruiting young individuals (18–50 years) with early type 2 diabetes (≤3 years since diagnosis) originating from MENA. Individuals from primary care were randomised to usual medical care or ILI (total dietary replacement phase using meal replacement products, followed by staged food reintroduction and physical activity support). The primary outcome is weight loss at 12 months. Other outcomes are glycaemic control and diabetes remission. Setting Primary care, Qatar. Participants 147 (73% men) randomised within DIADEM-I who were included in the final trial data analysis. Outcome measures Recruitment metrics, and baseline clinical and metabolic characteristics. Results Of 1498 people prescreened, 267 (18%) were invited for screening and 209 (78%) consented. 173 (83%) were eligible. 15 (7%) withdrew before randomisation and the remaining 158 were randomised. Mean age was 42.1 (SD 5.6) years and mean body mass index was: 36.3 (5.5) kg/m2 (women) and 34.4 (5.4) kg/m2 (men). Mean diabetes duration was 1.8 (1.0) years and mean glycosylated haemoglobin (HbA1c) was 7.0% (1.30) (52.5 mmol/mol (SD 14.3)). Participants originated from 13 countries. Those from North Africa reported greater physical activity and had lower family history of diabetes. 90% of subjects were taking diabetes medications and 31% antihypertensives. Those with greater waist circumference had significantly higher insulin resistance and lower quality of life. Conclusion Recruitment of participants originating from the MENA region into the RCT was successful, and study participation was readily accepted. While DIADEM-I participants originated from 13 countries, there were few baseline differences amongst participants from Middle East versus North Africa, supporting generalisability of RCT results. Trial registration number ISRCTN20754766; NCT03225339 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Protocol for a scoping review of outcomes in clinical studies of interventions for venous thromboembolism in adults

payt.helady61 shared this article with you from Inoreader Protocol for a scoping review of outcomes in clinical studies of interventions for venous thromboembolism in adults Via BMJ Open recent issues Introduction Venous thromboembolism (VTE) is a common, potentially fatal yet treatable disease. Several advances in treatment of VTE have been made over the past decades, but definition and reporting of outcomes across those studies are inconsistent. Development of an international core outcome set for clinical studies of interventions for VTE addresses this lack of standardisation. The first step in the development of a core outcome set is to conduct a scoping review which aims to generate an inclusive list of unique outcomes that have been reported in previous studies. Methods and analysis MEDLINE, Embase and the Cochrane Central Register of Controlled Trials will be searched with no language restriction for prospective studies reporting on interventions for treatment of VTE in patients who are adult and non-pregnant. Records will be sorted in reverse chronological order. Study screening and data extraction will be independently performed by two authors in blocks based on date of publication, starting with 2015 to 2020 and subsequent 1-year periods, until no new outcome measures are identified from the set of included studies. After homogenising spelling and combining outcomes with the same meaning, a list of unique outcomes will be determined. Those outcomes will be grouped into outcome domains. Qualitative analysis and descriptive statistics will be used to report results. Ethics and dissemination Ethical approval is not required for this study. The results of this scoping review will be presented at scientific conferences, published in a peer-reviewed journal, and they will provide candidate outcome domains to be considered in subsequent steps in the development of a core outcome set for clinical studies of interventions for VTE. Protocol registration details http://hdl.handle.net/10393/40459 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Patient-reported outcome measures (PROMs) following knee arthroplasty: a prospective cohort study protocol

payt.helady61 shared this article with you from Inoreader Patient-reported outcome measures (PROMs) following knee arthroplasty: a prospective cohort study protocol Via BMJ Open recent issues Introduction To evaluate the quality of clinical practice, patient-reported outcome measures (PROMs) are important as certain questions could only be answered by the patient himself. PROMs help to get a better understanding what is meaningful to a patient and directly affects daily functioning. To move beyond traditional measures, we are interested in what matters to patients and developed this project. The aim of this article is to provide the protocol for our study collecting PROMs in daily medical practice from patients who undergo knee arthroplasty. Methods and analysis This study is a single-site, observational, prospective cohort study. We will recruit patients scheduled for a knee arthroplasty in our medical office, situated in a private clinic. After signed informed consent, patients complete self-reported questionnaires before the surgery, after 4 months, 1 year, 2 years, 3 years, 4 years and 5 years. We will use the following PROMs: Knee injury and Osteoarthritis Outcome Score, Forgotten Joint Score, EuroQol five dimensions and satisfaction. Additionally, the surgeon will complete the objective Knee Society Score. Administration of the questionnaires will be electronically or paper-based. We will assess differences between preoperative and postoperative data with paired t-test for continuous variables and Wilcoxon signed-rank test for categorical variables. To assess subgroup differences, we will use unpaired t-test for continuous variables and Mann-Whitney U test for categorical variables. To assess possible presence of bias, we will condu ct sensitivity analyses. Ethics and dissemination The study has been reviewed and approved by the local ethics committee in Basel, Switzerland. Written informed consent will be obtained from all patients. We will disseminate the results of the study through peer-reviewed journals, national and international conference presentations and presentations to relevant stakeholders through appropriate channels. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.