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Spinal muscular atrophy (SMA), a rare neurodegenerative disorder with an estimated incidence of 1 in 6,000 to 10,000 live births, is the leading genetic cause of mortality in infants and children. Since the approval of new disease modifying treatments (DMTs; Spinraza in 2017, Zolgensma in 2020, and Evrysdi in 2021), studies have reported modified disease trajectories compared to the known SMA natural history. To describe the natural history of SMA and its progression during the use of DMTs in real-world settings, a retrospective cohort study was designed. Feasibility assessment identified six appropriate SMA registries to take part, comprising data from nine European countries (3 clinician-based registries: Belgium, Czech Republic & Slovakia, Sweden and 3 patient-based registries: Germany & Austria, Spain, UK & Ireland) between April 2008 and May 2023 federated in the TREAT-NMD network. Among 2,188 SMA patients with genetically confirmed 5q SMA, more patients had SMA type 2 (41.8%) than type 3 (35.6%) and type 1 (19.7%); 1,321 (60.3% overall) were treated with Spinraza (75,9%), Evrysdi (30.5%) or Zolgensma (7.6%), and 847 (38.7%) never received treatment. Functional status and motor milestones were rarely reported in never treated patients. Among treated patients, best functional status for SMA types 1, 2, and 3 was "sitter" for 36.6%, 60.9%, and 5.3%, and "walker" for 12.0%, 24.6%, and 87.8% respectively. Best motor milestone for types 1 and 2 was "sit without support" for 27.2% and 38.0%, and "roll onto side" for 18.5% and 2.0% respectively. For type 3, 63.4% reported "climb stairs" and 19.3% reported "walk 10 meters without assistance". Functional status and motor milestones were well captured after treatment but rarely reported before, limiting evaluation of treatment related changes. Areas of improvement for registry data quality have been identified to reduce data missingness, increase standardization, and enhance their utility to inform regulatory decision making. Disclaimer: "This study was funded by the European Medicines Agency and registered in EU PAS (EUPAS50476). The views expressed in this abstract are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the regulatory agency/agencies or organizations with which the authors are employed/affiliated." [ABSTRACT FROM AUTHOR]

Background: While teamwork is essential to providing high-quality patient-centred care, challenges in interprofessional collaboration and decision-making in hospital settings are common, especially for patients with cancer. The purpose of this qualitative study was to identify emerging themes and potential challenges related to hospital discharge experiences among patients hospitalised for cancer who became frequent emergency department (ED) users postdischarge., Methods: A cohort of patients with cancer discharged from an academic health centre in Montreal (Canada) between October 2014 and November 2016 was assembled. Using health administrative claims from the provincial universal healthcare programme, frequent ED (FED) users were identified as patients who had a ≥4 ED visits in the year following hospital discharge. Qualitative analysis of transcripts from semistructured telephone interviews conducted with patients 25-30 days' postdischarge was used for in-depth exploratory analyses to characterise hospital discharge experiences and transition process from the hospital to the community., Results: Overall, 182 (14.5%) of 1253 patients with cancer who became FED users were included in this study. The mean age was 69.1 (SD=11.5), 59.9% (n=109) were male, and the most frequent cancers were 80 (43.9%) respiratory and 52 (28.6%) upper digestive cancer. Content analyses revealed six emerging themes from the FED patient interviews. Overall, these included (1) incomplete communication of information, (2) hospital discharge planning, (3) coordinating care among team members, (4) follow-up with outpatient providers, (5) monitoring and managing symptoms after discharge and (6) enlisting help of social and community supports., Conclusions: Using integrated data from clinical, administrative claims and patient interviews, this study provided insights into the challenges related to hospital discharge experiences and transition into community among hospitalised patients with cancer with FED use. Application of our findings could assist in hospital discharge preparation and improvement in healthcare delivery and health outcomes., Trial Registration Number: NCT01179867., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: This study's aim was to estimate potential risk factors for persistent opioid use after cardiothoracic surgery., Methods: This study included participants in the McGill University Health Centre clinical trial (2014 to 2016). Provincial medical services, prescription claims, and medical charts data were linked. Persistent opioid use was defined as an initial peri-operative opioid dispensation followed by an opioid dispensation between 91 and 180 days postdischarge. Multivariable Cox Proportional Hazards models were used to assess factors associated with persistent opioid use., Results: A cohort of 815 patients (mean age: 68.9 [standard deviation = 8.9]) was assembled, of which 8.2% became persistent opioid users. Factors such as higher Charlson Comorbidity Index (adjusted hazard ratio: 3.4, 95% confidence interval: 1.1-10.6), history of diabetes (adjusted hazard ratio: 2.1, 95% confidence interval: 1.3-3.4), substance and alcohol abuse (adjusted hazard ratio: 16.3, 95% confidence interval: 5.3-49.5), and radiotherapy (adjusted hazard ratio: 2.4, 95% confidence interval: 1.5-4.1) were associated with a higher hazard of persistent opioid use. Previous opioid use (adjusted hazard ratio: 1.7, 95% CI: 1.0-2.8), daily peri-operative opioid dose (adjusted hazard ratio: 2.3, 95% confidence interval: 1.5-3.7), having an opioid dispensation 30 days pre-admission (adjusted hazard ratio: 1.7, 95% confidence interval: 1.0-2.8), and pre-admission analgesic use (adjusted hazard ratio: 1.7, 95% confidence interval: 1.0-2.8), were also associated with an increased hazard of persistent use. Being prescribed multimodal analgesia at discharge (adjusted hazard ratio: 0.54, 95% confidence interval: 0.32-0.92) was associated with a 46% decreased hazard of developing persistent opioid use., Conclusion: Multiple patient- and medication-related characteristics were associated with an increased hazard of persistent opioid use., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Previous research linking opioid prescribing to adverse drug events has failed to properly account for the time-varying nature of opioid exposure. This study aimed to explore how the risk of opioid-related emergency department visits, readmissions, or deaths (composite outcome) varies with opioid dose and duration, comparing different novel modeling techniques. A prospective cohort of 1,511 hospitalized patients discharged from 2 McGill-affiliated hospitals in Montreal, 2014-2016, was followed from the first postdischarge opioid dispensation until 1 year after discharge. Marginal structural Cox proportional hazards models and their flexible extensions were used to explore the association between time-varying opioid use and the composite outcome. Weighted cumulative exposure models assessed cumulative effects of past use and explored how its impact depends on the recency of exposure. The patient mean age was 69.6 (standard deviation = 14.9) years; 57.7% were male. In marginal structural model analyses, current opioid use was associated with a 71% increase in the hazard of opioid-related adverse events (adjusted hazard ratio = 1.71, 95% confidence interval: 1.21, 2.43). The weighted cumulative exposure results suggested that the risk cumulates over the previous 50 days of opioid consumption. Flexible modeling techniques helped assess how the risk of opioid-related adverse events may be associated with time-varying opioid exposures while accounting for nonlinear relationships and the recency of past use., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Background: Frequent emergency department (FED) visits by cancer patients represent a significant burden to the health system. This study identified determinants of FED in recently hospitalized cancer patients, with a particular focus on opioid use., Methods: A prospective cohort discharged from surgical/medical units of the McGill University Health Centre was assembled. The outcome was FED use (≥ 4 ED visits) within one year of discharge. Data retrieved from the universal health insurance system was analyzed using Cox Proportional Hazards (PH) model, adopting the Lunn-McNeil approach for competing risk of death., Results: Of 1253 patients, 14.5% became FED users. FED use was associated with chemotherapy one-year pre-admission (adjusted hazard ratio (aHR) 2.60, 95% CI: 1.80-3.70), ≥1 ED visit in the previous year (aHR: 1.80, 95% CI 1.20-2.80), ≥15 pre-admission ambulatory visits (aHR 1.54, 95% CI 1.06-2.34), previous opioid and benzodiazepine use (aHR: 1.40, 95% CI: 1.10-1.90 and aHR: 1.70, 95% CI: 1.10-2.40), Charlson Comorbidity Index ≥ 3 (aHR: 2.0, 95% CI: 1.2-3.4), diabetes (aHR: 1.60, 95% CI: 1.10-2.20), heart disease (aHR: 1.50, 95% CI: 1.10-2.20) and lung cancer (aHR: 1.70, 95% CI: 1.10-2.40). Surgery (cardiac (aHR: 0.33, 95% CI: 0.16-0.66), gastrointestinal (aHR: 0.34, 95% CI: 0.14-0.82) and thoracic (aHR: 0.45, 95% CI: 0.30-0.67) led to a decreased risk of FED use., Conclusions: Cancer patients with higher co-morbidity, frequent use of the healthcare system, and opioid use were at increased risk of FED use. High-risk patients should be flagged for preventive intervention., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Deep prostate-specific antigen (PSA) response (≥90% reduction in PSA [PSA90]) is an important early response indicator of radiographic progression-free survival and overall survival in patients with metastatic castration-sensitive prostate cancer (mCSPC). This study compared PSA90 responses by 6 months between patients with mCSPC at first use of apalutamide or abiraterone acetate, both androgen receptor signaling inhibitors., Methods: Clinical data from 77 community urology practices in the United States were analyzed. Patients with mCSPC were classified into treatment cohorts based on their first filled prescription (index date) for apalutamide or abiraterone acetate on or after September 17, 2019 (approval date of apalutamide for mCSPC). Patients were followed from the index date until the earliest of index treatment discontinuation, treatment switch, end of clinical activity, or end of data availability (September 17, 2021). Inverse probability of treatment weighting (IPTW) was used to ensure similarity in distribution of baseline characteristics between cohorts. PSA90 was defined as the earliest attainment of ≥90% reduction in PSA relative to baseline (most recent value within 13 weeks pre-index). Time to PSA90 between cohorts was compared by weighted Kaplan-Meier analysis and with Cox proportional hazards models., Results: A total of 364 patients treated with apalutamide and 147 treated with abiraterone acetate met the study criteria. Patient characteristics were well balanced after IPTW. By 6 months post-index, patients initiated on apalutamide were 53% more likely to achieve PSA90 than those initiated on abiraterone acetate (P = 0.016). Similar results were observed by 9 and 12 months post-index (both P ≤ 0.019). The median time to PSA90 was 3.5 months for the apalutamide cohort and not reached for the abiraterone acetate cohort., Conclusions: In real-world patients with mCSPC, significantly more patients achieved PSA90 with apalutamide than with abiraterone acetate, and this response was achieved earlier with apalutamide., Competing Interests: Conflict of Interest B. Lowentritt is an employee of Chesapeake Urology Associates and has received consulting fees from Janssen Scientific Affairs, LLC. G. Brown is an employee of New Jersey Urology and has received consulting fees from Janssen Scientific Affairs, LLC. D. Pilon, C. Rossi, A. Shah, and P. Lefebvre are employees of Analysis Group, Inc., a consulting company that has provided paid consulting services to Janssen Scientific Affairs, LLC. S. Kurteva was an employee of Analysis Group, Inc. at the time the study was conducted. D. Waters, E. Muser, I. Khilfeh, S. Du, and L. Ellis are employees of Janssen Scientific Affairs, LLC and stockholders of Johnson & Johnson., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Long-term opioid use is an increasingly important problem related to the ongoing opioid epidemic. The purpose of this study was to identify patient, hospitalization and system-level determinants of long term opioid therapy (LTOT) among patients recently discharged from hospital., Design: To be eligible for this study, patient needed to have filled at least one opioid prescription three-months post-discharge. We retrieved data from the provincial health insurance agency to measure medical service and prescription drug use in the year prior to and after hospitalization. A multivariable Cox Proportional Hazards model was utilized to determine factors associated with time to the first LTOT occurrence, defined as time-varying cumulative opioid duration of ≥ 60 days., Results: Overall, 22.4% of the 1,551 study patients were classified as LTOT, who had a mean age of 66.3 years (SD = 14.3). Having no drug copay status (adjusted hazard ratio (aHR) 1.91, 95% CI: 1.40-2.60), being a LTOT user before the index hospitalization (aHR 6.05, 95% CI: 4.22-8.68) or having history of benzodiazepine use (aHR 1.43, 95% CI: 1.12-1.83) were all associated with an increased likelihood of LTOT. Cardiothoracic surgical patients had a 40% lower LTOT risk (aHR 0.55, 95% CI: 0.31-0.96) as compared to medical patients. Initial opioid dispensation of > 90 milligram morphine equivalents (MME) was also associated with higher likelihood of LTOT (aHR 2.08, 95% CI: 1.17-3.69)., Conclusions and Relevance: Several patient-level characteristics associated with an increased risk of ≥ 60 days of cumulative opioid use. The results could be used to help identify patients who are at high-risk of continuing opioids beyond guideline recommendations and inform policies to curb excessive opioid prescribing., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Kurteva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Given the wide range of uses for antidepressants, understanding indication-specific patterns of prescription filling for antidepressants provide valuable insights into how patients use these medications in real-world settings., Objective: The objective of this study was to determine the association of antidepressant prescription filling with treatment indication, as well as prior prescription filling behaviors and medication experiences., Design: This retrospective cohort study took place in Quebec, Canada., Participants: Adults with public drug insurance prescribed antidepressants using MOXXI (Medical Office of the XXIst Century)-an electronic prescribing system requiring primary care physicians to document treatment indications and reasons for prescription stops or changes., Measures: MOXXI provided information on treatment indications, past prescriptions, and prior medication experiences (treatment ineffectiveness and adverse drug reactions). Linked claims data provided information on dispensed medications and other patient-related factors. Multivariable logistic regression models estimated the independent association of not filling an antidepressant prescription (within 90 d) with treatment indication and patients' prior prescription filling behaviors and medication experiences., Results: Among 38,751 prescriptions, the prevalence of unfilled prescriptions for new and ongoing antidepressant therapy was 34.2% and 4.1%, respectively. Compared with depression, odds of not filling an antidepressant prescription varied from 0.74 to 1.57 by indication and therapy status. The odds of not filling an antidepressant prescription was higher among adults filling < 50% of their medication prescriptions in the past year and adults with an antidepressant prescription stopped or changed in the past year due to treatment ineffectiveness., Conclusion: Antidepressant prescription filling behaviors differed by treatment indication and were lower among patients with a history of poor prescription filling or ineffective treatment with antidepressants., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Postoperative pain control is an important cancer care component. However, opioid consumption has resulted in a surge of adverse events, with thoracic surgery patients having the highest rate of persistent use. The effect of opioid duration post-discharge and the risk of increased acute healthcare use in this population remains unclear., Methods: A prospective cohort of non-metastatic cancer patients was assembled from an academic health center in Montreal (Canada). Clinical data linked to administrative claims from the universal healthcare program was used to determine the association between time-varying opioid patterns and emergency department (ED) visits/re-admissions/death 3 months following thoracic surgery., Results: Of the 610 patients, 77% had at least one opioid dispensed post-discharge. Compared to non-opioid users, <15 days of use was associated with a 42% decreased risk of acute healthcare events, adjusted HR 0.58, 95% CI (0.40-0.85); longer durations were not associated with an increased risk. Compared to short-term use (<15 days), use of >30 days was associated with a 72% increased risk of the outcome, aHR: 1.72, 95% CI (1.01-2.93)., Conclusion: There was a variation in the risk of acute healthcare use associated with postsurgical opioid use. Findings from this study may be used to inform postoperative prescribing practices., (© 2021 Wiley Periodicals LLC.)

Importance: Although better pain management has guided policies for opioid use over the past few decades, evidence is limited regarding how patterns of use are associated with the risk of potentially avoidable opioid-related adverse events., Objective: To estimate the risk of harms associated with opioid dose and duration of use, and to ascertain whether the risk is modified by treatment indication and age., Design, Setting, and Participants: This ad hoc cohort study followed up patients who were enrolled in a cluster randomized trial of medication reconciliation between October 1, 2014, and November 30, 2016, 12 months after they were discharged from the McGill University Health Centre in Montreal, Quebec, Canada. To be eligible for this study, patients needed to have filled at least 1 opioid prescription 3 months after discharge. Patients with a history of using methadone or buprenorphine were excluded. Data analyses were performed between February 1, 2019, and February 28, 2020., Exposures: Time-varying measures of opioid use included current use, daily morphine milligram equivalent (MME) dose, cumulative and continuous use duration, and type of ingredients in prescription opioids used. Hospitalization records, dispensed prescriptions records, and postdischarge interviews were used to evaluate adherence to the opioid prescriptions after discharge., Main Outcomes and Measures: Opioid-related emergency department visits, hospital readmissions, or all-cause death. Outcomes were ascertained using provincial medical services claims and hospitalization databases., Results: Of 3486 participants in the cluster randomized trial (mean [SD] age of 69.6 [14.9] years; 2010 men [57.7%]), 1511 patients were included in this ad hoc cohort study. Among those with at least 1 opioid dispensation, 241 patients (15.9%) experienced an opioid-related emergency department visit, hospital readmission, or death. Results from marginal structural Cox proportional hazards regression models showed more than a 2-fold increase in the risk of opioid-related adverse events associated with a cumulative use duration of more than 90 days (adjusted hazard ratio, 2.56; 95% CI, 1.25-5.27) compared with 1 to 30 days. A 3-fold risk increase was found with a mean daily dose higher than 90 MME (adjusted hazard ratio, 3.51; 95% CI, 1.58-7.82) compared with 90 MME or lower., Conclusions and Relevance: This study found an association between risk of adverse health care events and higher opioid doses and longer treatment duration. This finding can inform policies for limiting opioid duration and dose to attenuate the risk of avoidable morbidity.

Objectives: Opioid-related medication errors (MEs) can have a significant impact on patient health and contribute to opioid misuse. The objective of this study was to estimate the incidence of and variables associated with the receipt of an opioid prescription and opioid-related MEs (omissions, duplications, or dose changes) at hospital discharge. We also determined rates of adverse drug events and risks of emergency department visits, readmissions, or death 30 days and 90 days post discharge associated with MEs., Methods: A cohort of hospitalized patients discharged from the McGill University Health Centre between 2014 and 2016 was assembled. The impact of opioid-related MEs was assessed in a propensity score-adjusted logistic regression models. Multivariable logistic regression was used to determine characteristics associated with MEs and discharge opioid prescription., Results: A total of 1530 (43.9%) of 3486 patients were prescribed opioids, of which 13.4% (n = 205) of patients had at least 1 opioid-related ME. Rates of MEs were higher in handwritten prescriptions compared to the electronic reconciliation discharge prescription group (20.6% vs 1.2%). Computer-based prescriptions were associated with a 69% lower risk of opioid-related MEs (adjusted odds ratio: 0.31, 95% confidence interval: 0.14-0.65) as well as 63% lower risk of receiving an opioid prescription. Opioid-related MEs were associated with a 2.3 times increased risk of healthcare utilization in the 30 days postdischarge period (adjusted odds ratio: 2.32, 95% confidence interval: 1.24-4.32)., Conclusions: Opioid-related MEs are common in handwritten discharge prescriptions. Our findings highlight the need for computer-based prescribing platforms and careful review of medications during critical periods of care such as hospital transitions., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Importance: Adverse drug events (ADEs) account for up to 16% of emergency department (ED) visits and 7% of hospital admissions. Medication reconciliation is required for hospital accreditation because it can reduce medication discrepancies, but there is no evidence that reducing discrepancies reduces ADEs or other adverse outcomes., Objective: To evaluate whether electronic medication reconciliation reduces ADEs, medication discrepancies, and other adverse outcomes compared with usual care., Design, Setting, and Participants: This cluster randomized trial involved 3491 patients who were discharged from 2 medical units and 2 surgical units at the McGill University Health Centre, Montreal, Quebec, Canada, between October 2014 and November 2016. Data analysis took place from July 2017 to July 2019., Intervention: The RightRx intervention electronically retrieved community drugs from the provincial insurer and aligned them with in-hospital drugs to facilitate reconciliation and communication at care transitions., Main Outcomes and Measures: The primary outcome was ADEs in 30 days after discharge. Secondary outcomes included medication discrepancies, ED visits, hospital readmissions, and a composite outcome of ED visits, readmissions, and death up to 90 days after discharge., Results: Of 4656 eligible patients, 3567 (76.6%) consented to participate (2060 [57.8%] men; mean [SD] age, 69.8 [14.9] years). Overall, 76 patients died during the hospital stay, so 3491 patients were included in the analysis. There was no significant difference in the risk of ADEs between intervention and control groups (76 [4.6%] vs 73 [4.0%]; OR, 0.97; 95% CI, 0.33-1.48), ED visits (433 [26.2%] vs 488 [26.6%]; OR, 0.83; 95% CI, 0.36-1.42), hospital readmission (170 [10.3%] vs 261 [14.2%]; OR, 0.22; 95% CI, 0.06-1.14), or the composite outcome (447 [27.0%] vs 506 [27.6%]; OR, 0.75; 95% CI, 0.34-1.27) at 30 days. Medication discrepancies were significantly reduced in the intervention group compared with the control group (437 [26.4%] vs 1029 [56.0%]; OR, 0.24; 95% CI, 0.12-0.57). Changes made to community medications (OR, 1.05; 95% CI, 1.01-1.10) and new medications (OR, 1.09; 95% CI, 1.01-1.18) were significant risk factors for ADEs., Conclusions and Relevance: Electronic medication reconciliation reduced medication discrepancies but did not reduce ADEs or other adverse outcomes. Hospital accreditation should focus on interventions that reduce the risk of adverse events for patients with multiple changes to community medications., Trial Registration: ClinicalTrials.gov identifier: NCT01179867.

Introduction : There are concerns that opioids may be associated with an increased risk of infection. This safety issue is alarming given the widespread use of opioids in pain management. Areas covered : In this review, we summarize the pharmacologic aspects of opioids related to the immune system and to the assumed pathophysiology of opioid-related infections. We also synthesize and critically appraise the available clinical evidence on the potential association between the use of opioids and the risk of infection. PubMed was searched from inception to 1 February 2019 for all articles published in English with terms corresponding to 'opioids' and 'infections'. Expert opinion : Morphine appears to suppress the immune system via affecting cells of the innate and the adaptive immunity as well as via modulating the hypothalamic-pituitary-adrenal axis. However, knowledge gaps exist regarding the immune-related pharmacology of non-morphine opioids. Observational studies have suggested an increased risk of infections associated with the use of opioids. However, methodological limitations such as confounding by indication due to the choice of non-use as comparator render the interpretation of most of these studies difficult. Thus, further efforts in preclinical research and well-conducted observational studies are needed to provide more robust evidence in this regard.

Objectives: We used an international pharmacosurveillance network to estimate the rate and characteristics of antidepressant use in older adults in countries with more conservative (UK) and liberal depression guidelines (Canada, USA)., Setting: Electronic health records and population-based administrative data from six jurisdictions in four countries (UK, Taiwan, USA and Canada)., Participants: A historical cohort of older adults (≥65 years) who had a new episode of antidepressant use between 2009 and 2014., Outcome Measures: The age and sex-standardised cumulative incidence of new episodes of antidepressant use in older adults was measured. Descriptive statistics were used to compare the proportion of new users by the antidepressant prescribed, therapeutic class, potential treatment indication and country, as well as the characteristics of the first treatment episode (standardised daily doses, duration and changes)., Results: The incidence of antidepressant use between 2009 and 2014 varied from 4.7% (Montreal and Quebec City) to 18.6% (Taiwan). Tricyclic antidepressants (TCAs) were the most commonly used class in the UK (48.8%) and Taiwan (52.4%) compared with selective serotonin reuptake inhibitors (SSRIs) in North American jurisdictions (42.3%-53.3%). Chronic pain was the most common potential treatment indication (41.2%-68.2%). Among users with chronic pain, TCAs were used most frequently in the UK and Taiwan (55.2%-60.4%), whereas SSRIs were used most frequently in North America (33.5%-46.4%). Treatment was longer (252-525 vs 169-437 days), standardised doses were higher (0.7-1.3 vs 0.5-1.0) and treatment was more likely to be changed (31%-46% vs 21%-34%) among patients with depression (9.1%-43%) than those with chronic pain., Conclusion: Antidepressant use in older adults varied 24-fold by country, with the UK, which has the most conservative treatment guidelines, being among the lowest. Chronic pain was the most common potential treatment indication. Evaluation of real-world risks of TCAs is a priority for future research, given high rates of use and the potential for increased toxicity in older adults because of potent anticholinergic effects., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Unmanaged distress has been shown to adversely affect survival and quality of life in breast cancer survivors. Fortunately, distress can be managed and even prevented with appropriate evidence-based interventions. Therefore, the objective of this systematic review was to synthesize the published literature around predictors of distress in female breast cancer survivors to help guide targeted intervention to prevent distress., Methods: Relevant studies were located by searching MEDLINE, Embase, PsycINFO, and CINAHL databases. Significance and directionality of associations for commonly assessed candidate predictors (n ≥ 5) and predictors shown to be significant (p ≤ 0.05) by at least two studies were summarized descriptively. Predictors were evaluated based on the proportion of studies that showed a significant and positive association with the presence of distress., Results: Forty-two studies met the target criteria and were included in the review. Breast cancer and treatment-related predictors were more advanced cancer at diagnosis, treatment with chemotherapy, longer primary treatment duration, more recent transition into survivorship, and breast cancer recurrence. Manageable treatment-related symptoms associated with distress included menopausal/vasomotor symptoms, pain, fatigue, and sleep disturbance. Sociodemographic characteristics that increased the risk of distress were younger age, non-Caucasian ethnicity, being unmarried, and lower socioeconomic status. Comorbidities, history of mental health problems, and perceived functioning limitations were also associated. Modifiable predictors of distress were lower physical activity, lower social support, and cigarette smoking., Conclusions: This review established a set of evidence-based predictors that can be used to help identify women at higher risk of experiencing distress following completion of primary breast cancer treatment.

The envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) function as a homotrimer of gp120/gp41 heterodimers to support virus entry. During the process of virus entry, an individual HIV-1 envelope glycoprotein trimer binds the cellular receptors CD4 and CCR5/CXCR4 and mediates the fusion of the viral and the target cellular membranes. By studying the function of heterotrimers between wild-type and nonfunctional mutant envelope glycoproteins, we found that two wild-type subunits within an envelope glycoprotein trimer are required to support virus entry. Complementation between HIV-1 envelope glycoprotein mutants defective in different functions to allow virus entry was not evident. These results assist our understanding of the mechanisms whereby the HIV-1 envelope glycoproteins mediate virus entry and membrane fusion and guide attempts to inhibit these processes.

The human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Envs) function as a trimer, mediating virus entry by promoting the fusion of the viral and target cell membranes. HIV-1 Env trimers induce membrane fusion through a pH-independent pathway driven by the interaction between an Env trimer and its cellular receptors, CD4 and CCR5/CXCR4. We studied viruses with mixed heterotrimers of wild-type and dominant-negative Envs to determine the number (T) of Env trimers required for HIV-1 entry. To our surprise, we found that a single Env trimer is capable of supporting HIV-1 entry; i.e., T = 1. A similar approach was applied to investigate the entry stoichiometry of envelope glycoproteins from amphotropic murine leukemia virus (A-MLV), avian sarcoma/leukosis virus type A (ASLV-A), and influenza A virus. When pseudotyped on HIV-1 virions, the A-MLV and ASLV-A Envs also exhibit a T = 1 entry stoichiometry. In contrast, eight to nine influenza A virus hemagglutinin trimers function cooperatively to achieve membrane fusion and virus entry, using a pH-dependent pathway. The different entry requirements for cooperativity among Env trimers for retroviruses and influenza A virus may influence viral strategies for replication and evasion of the immune system.

The human immunodeficiency virus envelope glycoproteins function as trimers on the viral surface, where they are targeted by neutralizing antibodies. Different monoclonal antibodies neutralize human immunodeficiency virus type 1 (HIV-1) infectivity by binding to structurally and functionally distinct moieties on the envelope glycoprotein trimer. By measuring antibody neutralization of viruses with mixtures of neutralization-sensitive and neutralization-resistant envelope glycoproteins, we demonstrate that the HIV-1 envelope glycoprotein trimer is inactivated by the binding of a single antibody molecule. Virus neutralization requires essentially all of the functional trimers to be occupied by at least one antibody. This model applies to antibodies differing in neutralizing potency and to virus isolates with various neutralization sensitivities. Understanding these requirements for HIV-1 neutralization by antibodies will assist in establishing goals for an effective AIDS vaccine.

The core of the gp120 glycoprotein from human immunodeficiency virus type 1 (HIV-1) is comprised of three major structural domains: the outer domain, the inner domain, and the bridging sheet. The outer domain is exposed on the HIV-1 envelope glycoprotein trimer and contains binding surfaces for neutralizing antibodies such as 2G12, immunoglobulin G1b12, and anti-V3 antibodies. We expressed the outer domain of HIV-1(YU2) gp120 as an independent protein, termed OD1. OD1 efficiently bound 2G12 and a large number of anti-V3 antibodies, indicating its structural integrity. Immunochemical studies with OD1 indicated that antibody responses against the outer domain of the HIV-1 gp120 envelope glycoprotein are rare in HIV-1-infected human sera that potently neutralize the virus. Surprisingly, such outer-domain-directed antibody responses are commonly elicited by immunization with recombinant monomeric gp120. Immunization with soluble, stabilized HIV-1 envelope glycoprotein trimers elicited antibody responses that more closely resembled those in the sera of HIV-1-infected individuals. These results underscore the qualitatively different humoral immune responses elicited during natural infection and after gp120 vaccination and help to explain the failure of gp120 as an effective vaccine.