A systematic review on the birth prevalence of metachromatic leukodystrophy.

BACKGROUND: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency in arylsulfatase A (ASA) activity arising primarily from ASA gene (ARSA) variants. Late-infantile, juvenile and adult clinical subtypes are defined by symptom onset at ≤ 2.5, > 2.5 to < 16 and ≥ 16 years, respectively. Epidemiological data were sought to address knowledge gaps and to inform decisions regarding the clinical development of an investigational drug. METHODS: To synthesize all available estimates of MLD incidence and birth prevalence worldwide and in selected countries, Ovid MEDLINE and Embase were searched systematically (March 11, 2022) using a population, intervention, comparator, outcome, time and setting framework, complemented by pragmatic searching to reduce publication bias. Where possible, results were stratified by clinical subtype. Data were extracted from non-interventional studies (clinical trials, non-clinical studies and case reports were excluded; reviews were used for snowballing only). RESULTS: Of the 31 studies included, 14 reported birth prevalence (13 countries in Asia-Pacific, Europe, the Middle East, North America and South America), one reported prevalence and none reported incidence. Birth prevalence per 100,000 live births ranged from 0.16 (Japan) to 1.85 (Portugal). In the three European studies with estimates stratified by clinical subtypes, birth prevalence was highest for late-infantile cases (0.31-1.12 per 100,000 live births). The distribution of clinical subtypes reported in cases diagnosed over various time periods in 17 studies varied substantially, but late-infantile and juvenile MLD accounted for at least two-thirds of cases in most studies. CONCLUSIONS: This review provides a foundation for further analysis of the regional epidemiology of MLD. Data gaps indicate the need for better global coverage, increased use of epidemiological measures (e.g. prevalence estimates) and more stratification of outcomes by clinical and genetic disease subtype.

Where are the data to assess the safety of paternal drug exposure? A systematic review of secondary databases: A contribution from IMI concePTION.

BACKGROUND: Most studies assessing the safety of parental drug exposures during pregnancy and around the time of conception describe the effects of maternal exposure. Recent publications have raised awareness of the need for additional research regarding the safety of paternal drug exposures on pregnancy outcomes. OBJECTIVES: To identify and describe studies that use secondary databases in paternal drug safety studies and to describe the secondary databases that were used. METHODS: A systematic review of studies assessing paternal medication exposure and pregnancy and infant outcomes using secondary databases was performed. In addition, the secondary databases used for these studies was described. Literature search was conducted using Embase, Web of Science, and PubMed, over the period January 1, 2012 to April 30, 2023. For each eligible study, paternal drug exposure, outcome, and data source characteristics were extracted in a data extraction form. RESULTS: After reviewing the literature, 17 studies met inclusion criteria. The medications assessed for paternal safety were anti-rheumatic drugs (n = 10), anti-depressants (n = 3), anticonvulsants (n = 2), and anti-diabetes medications (n = 2). Pregnancy safety outcomes included congenital malformations, birth weight, and developmental disorders. The studies used five different databases across Europe and North America. The included studies used databases from Denmark (n = 12), Norway (n = 2), Sweden (n = 1), Canada (n = 1), and the United States (n = 1). The European studies utilized national patient registers that linked fathers to births and prescription histories. The North American databases used included insurance claims and electronic health records. CONCLUSIONS: Our review shows that few studies have been completed on paternal medication exposures and pregnancy outcomes, despite the availability of secondary databases that contain data necessary to link fathers to infants. More research on the potential adverse impacts of paternal medication exposures is needed.

A Descriptive Analysis of Adverse Event Reports from the Quebec Cannabis Registry.

INTRODUCTION: Published data on the safety of natural medical cannabis (MC) when used in the real-world clinical practice setting are lacking. This study aimed to describe adverse events (AEs) reported across three years following MC initiation. METHODS: The Quebec Cannabis Registry (QCR) was a prospective registry of adults enrolled through participating physicians when they initiated MC between May 2015 and October 2018. Follow-up ended at MC discontinuation, loss to follow-up, three years, or end of data collection (May 2019). Data were collected at baseline and at follow-up visits every three months for the first two years, then once in the third year. Physicians filled adverse event (AE) reports, which were coded using MedDRA® preferred terms (PTs), and descriptive analyses were conducted. RESULTS: A total of 2991 patients were enrolled (mean age 50.9 years, 50.2% females). During follow-up, 108 patients (3.6%) experienced moderate or severe AEs, yielding 111 AE reports (three patients had two reports) and 214 AEs (average 1.9 AEs per report). Mild AEs were recorded as a reason for MC discontinuation for nine patients, but no AE reports were available. The most common PTs for ingested MC (62 reports) were dizziness (12.9%), nausea (11.3%), somnolence (9.7%), and vomiting (8.1%), and for inhaled MC (23 reports), headache (13.0%) was the most common. The most frequent PTs associated with tetrahydrocannabinol (THC)-dominant MC (25 reports) were dizziness and somnolence (12.0% each); for cannabidiol (CBD)-dominant MC (20 reports), vomiting (20.0%) was most common; and dizziness (17.2%), nausea (13.8%), somnolence (10.3%), and headache (8.6%) were the most frequent for balanced MC (58 reports). CONCLUSION: No new safety concerns were identified relative to the published literature, although notable differences in AE profile between modes of administration and cannabinoid content ratios should be considered by health professionals. Further work identifying and managing risk factors for AEs is warranted to maintain a favorable benefit-risk balance for MC.

Vaccines and the Risk of Hospitalization for Multiple Sclerosis Flare-Ups.

Importance: Scientific literature is sparse about the association of vaccination with the onset of multiple sclerosis (MS) flare-ups. Immunization by vaccines of the entire population is crucially important for public health. Objective: To evaluate the risk of hospitalization for severe MS flare-ups after vaccination in patients with MS. Design, Setting, Participants: This cohort study included patients diagnosed with MS between January 1, 2007, and December 31, 2017, who were included in the System of National Health Databases, a national health claims database in France. In a nested case-crossover analysis, cases were defined by vaccine exposure prior to the onset of hospitalization due to an MS flare-up, and flare-up rates were compared with those that occurred prior to vaccine exposure in up to 4 control time windows immediately preceding the at-risk time window (ie, the MS flare-up) for each patient. Data were analyzed from January 2022 to December 2022. Exposure: Receipt of at least 1 vaccination, including the diphtheria, tetanus, poliomyelitis, pertussis, or Haemophilus influenzae (DTPPHi) vaccine, influenza vaccine, and pneumococcal vaccine, during follow-up. Main Outcomes and Measures: The primary outcome was the risk of hospitalization for an MS flare-up after receipt of a vaccine. Adjusted odds ratios (AORs) and 95% CIs were derived using conditional logistic regression to measure the risk of hospitalization for an MS flare-up associated with vaccination. Results: A total of 106 523 patients constituted the MS cohort (mean [SD] age, 43.9 [13.8] years; 76 471 females [71.8%]; 33 864 patients [31.8%] had incident MS and 72 659 patients [68.2%] had prevalent MS) and were followed up for a mean (SD) of 8.8 (3.1) years. Of these patients, 35 265 (33.1%) were hospitalized for MS flare-ups during the follow-up period for a total of 54 036 MS-related hospitalizations. The AORs of hospitalization for an MS flare-up and vaccine exposure in the 60 days prior to the flare-up were 1.00 (95% CI, 0.92-1.09) for all vaccines, 0.95 (95% CI, 0.82-1.11) for the DTPPHi, 0.98 (95% CI, 0.88-1.09) for the influenza vaccine, and 1.20 (95% CI, 0.94-1.55) for the pneumococcal vaccine. Conclusions and Relevance: A nationwide study of the French population found no association between vaccination and the risk of hospitalization due to MS flare-ups. However, considering the number of vaccine subtypes available, further studies are needed to confirm these results.

Von Willebrand Disease Epidemiology, Burden of Illness and Management: A Systematic Review.

Introduction: Although hereditary von Willebrand disease (VWD) is the most common bleeding disorder, its epidemiology is not well understood. A systematic review (PROSPERO CRD42020197674/CRD42021244374) on the epidemiology/burden of illness of VWD was conducted to better understand patients' unmet needs. Methods: Observational studies (published January 1, 2010 to April 14, 2021) were identified in MEDLINE and Embase databases, using free-text keywords and thesaurus terms for VWD and outcomes of interest. Pragmatic web-based searches of the gray literature, including conference abstracts, were performed, and reference lists of retained publications were manually searched for additional sources. Case reports and clinical trials (phase 1-3) were excluded. Outcomes of interest were incidence, prevalence, mortality, patient characteristics, burden of illness, and therapeutic management/treatments currently used for VWD. Results: Of the 3095 identified sources, 168 were included in this systematic review. Reported VWD prevalence (22 sources) ranged from 108.9 to 2200 per 100,000 in population-based studies and from 0.3 to 16.5 per 100,000 in referral-based studies. Reported times between first symptom onset and diagnosis (two sources; mean 669 days; median 3 years) highlighted gaps in timely VWD diagnosis. Bleeding events reported in 72-94% of the patients with VWD (all types; 27 sources) were mostly mucocutaneous including epistaxis, menorrhagia, and oral/gum bleeding. Poorer health-related quality of life (three sources) and greater health care resource utilization (three sources) were reported for patients with VWD than in general populations. Conclusion: Available data suggest that patients with VWD experience high disease burden in terms of bleeding, poor quality of life, and health care resource utilization.

The Quebec Cannabis Registry: Investigating the Safety and Effectiveness of Medical Cannabis.

Objective: To investigate the safety and effectiveness of medical cannabis (MC) in the real-world clinical practice setting. Design: A 4-year prospective noncomparative registry of adult patients who initiated MC for a variety of indications. This paper reports on patients followed for up to 12 months, with interim visits at 3, 6, and 9 months after enrollment. Setting: Public or private outpatient clinics certified to authorize MC in the province of Quebec, Canada. Participants: Overall, 2991 adult (age ≥18 years) patients (mean age 51 years; 50.2% women) were enrolled between May 2015 and October 2018, with the last follow-up ending in May 2019. Interventions/Exposures: Cannabis products (dried, oil, or other) purchased from a Canadian licensed cannabis producer as authorized by physicians. Main Outcome Measures: The primary outcomes were self-reported pain severity, interference and relief (Brief Pain Inventory [BPI]), symptoms using the Revised Edmonton Symptom Assessment System (ESAS-r) and health-related quality of life dimensions (EQ-5D-5L) at baseline and each follow-up visit. The secondary outcomes were self-reported adverse events (AEs) and characteristics of cannabis treatment. Results: All patient-reported outcomes (BPI, ESAS-r, and EQ-5D-5L) showed a statistically significant improvement at 3 months (all p<0.01), which was maintained or further improved (for pain interference, tiredness, and well-being) over the remainder of the 12-month follow-up. Results also revealed clinically significant improvements in pain interference and tiredness, anxiety, and well-being from baseline. There were 79 AE reports (77 patients), 16 met the regulatory definition of seriousness, in which only 8 AEs were certainly or probably related to MC. Conclusions: MC directed by physicians appears to be safe and effective within 3 months of initiation for a variety of medical indications.

Effectiveness and Safety of Palivizumab for the Prevention of Serious Lower Respiratory Tract Infection Caused by Respiratory Syncytial Virus: A Systematic Review.

OBJECTIVE: Palivizumab is a humanized monoclonal antibody approved for the prevention of serious lower respiratory tract infection (LRTI) caused by respiratory syncytial virus (RSV) in infants and young children at high risk of RSV disease. This systematic review summarized evidence on the effectiveness and safety of palivizumab when used in approved populations. STUDY DESIGN: A systematic review of Phase III trials and observational studies was conducted according to the population, intervention, comparator, outcome, timing, setting (PICOTS) approach (PROSPERO, CRD42021281380). Target populations consisted of infants with a history of premature birth (≤35-week gestational age) and children aged <2 years with bronchopulmonary dysplasia (BPD) or with hemodynamically significant congenital heart disease (hs-CHD). Outcomes of interest included RSV-related hospitalization, admission to intensive care unit (ICU), requirement for mechanical ventilation, treatment-related adverse events (AEs), and RSV-related deaths. Information sources were literature search (Ovid MEDLINE and Embase), pragmatic searches, and snowballing (covering the period up to 07 September 2021). RESULTS: A total of 60 sources were included (5 Phase III trials and 55 observational studies). RSV-related hospitalization rates following palivizumab prophylaxis in Phase III trials were 1.8% in premature infants and 7.9% in children with BPD, which were significantly lower than rates in placebo arms. In the real-world setting, similar hospitalization rates were found (0.7-4.0% in premature infants [16 studies] and 0-5.5% in patients with BPD [10 studies]) with ICU admission reported in 0 to 33.3% of patients hospitalized for RSV. In Phase III trials, RSV-related mortality rates were 0.2 and 0.3%, while AEs occurred in 11% of premature and/or BPD patients and 7.2% of hs-CHD patients, consisting mainly of injection site reaction, fever, and diarrhea. Similar results were found in observational studies. CONCLUSION: This systematic review supports the effectiveness and safety of palivizumab in the indicated populations. KEY POINTS: · Systematic review supports the positive benefit-risk profile of palivizumab in the indicated populations.. · Real-world safety and effectiveness of palivizumab are consistent with Phase III trials results.. · Palivizumab reduces RSV-related hospitalizations, ICU admissions, and need for mechanical ventilation..

Predictors of Pain Reduction Among Fibromyalgia Patients Using Medical Cannabis: A Long-Term Prospective Cohort Study.

OBJECTIVE: Many patients with fibromyalgia (FM) report using cannabis as a strategy to improve pain. Given that pain often co-occurs with symptoms of anxiety and depression (i.e., negative affect) and sleep problems among patients with FM, improvements in these symptoms might indirectly contribute to reductions in pain intensity following cannabis use. The main objective of the study was to examine whether changes in pain intensity following initiation of medical cannabis among patients with FM could be attributed to concurrent changes (i.e., reductions) in negative affect and sleep problems. METHODS: This was a 12-month prospective cohort study among patients with FM (n = 323) initiating medical cannabis under the care of physicians. Patients were assessed at baseline, and follow-up assessment visits occurred every 3 months after initiation of medical cannabis. Patients' levels of pain intensity, negative affect, and sleep problems were assessed across all visits. RESULTS: Multilevel mediation analyses indicated that reductions in patients' levels of pain intensity were partly explained by concurrent reductions in sleep problems and negative affect (both P < 0.001). This remained significant even when accounting for patients' baseline characteristics or changes in medical cannabis directives over time (all P > 0.05). CONCLUSION: Our findings provide preliminary insight into the potential mechanisms of action underlying pain reductions among patients with FM who are using medical cannabis. Given the high attrition rate (i.e., 75%) observed in the present study at 12 months, our findings cannot be generalized to all patients with FM who are using medical cannabis.

Impact of the COVID-19 Pandemic on Patterns of Prescription Opioid Use: A Retrospective Cohort Study of Adults Without a Cancer Diagnosis Initiating Opioids Using Administrative Claims Data.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has led to disruptions of healthcare delivery and may thus have impacted patterns of prescription opioid use, including risk factors for long-term use. OBJECTIVE: We aimed to describe changes in patterns of prescription opioid use due to the COVID-19 pandemic in community-dwelling adults without a cancer diagnosis. METHODS: Using administrative claims data of the province of Quebec, Canada, a random sample of adults (aged ≥18 years) was selected. These were members of the public drug plan without a cancer diagnosis who initiated a prescription opioid in the outpatient setting between 1 January, 2018 and 28 December, 2020. We assessed the daily dose of initial prescription opioids, the number of days' supply of initial dispensing, and the total duration of opioid use over the first 6 months following initiation. We applied interrupted autoregressive integrated moving average models to examine weekly patterns of prescription opioids before and during the pandemic (starting at the lockdown). Our models included a step intervention function (immediate change) and a ramp intervention function (slope change). RESULTS: There were 112,650 and 34,261 patients who initiated opioid therapy, respectively, in the 115-week pre-pandemic period and in the 41-week pandemic period. At the start of the lockdown, there was a significant immediate decrease in opioid treatment initiation (-326; 95% confidence interval [CI] -419 to -234) and initial daily dose (-1.7 morphine milligram equivalents; 95% CI -2.7 to -0.7). Conversely, there was a significant immediate increase in the number of days' supply of initial dispensing (1.4 days; 95% CI 1.0 to 1.8) and the total duration of opioid use over 6 months (5.7 days; 95% CI 4.6 to 6.8). All these weekly measures returned to values close to those of the pre-pandemic period 10 weeks after the start of lockdown. CONCLUSIONS: Our findings showed that the COVID-19 lockdown had an impact on initial number of days' supply, which is a risk factor for long-term use and ultimately opioid-related harm. However, over time, prescription practices and use reverted to those observed in the pre-pandemic period.

Implementation of Interventions and Policies on Opioids and Awareness of Opioid-Related Harms in Canada: A Multistage Mixed Methods Descriptive Study.

In Canada, interventions and policies have been implemented to minimize the risk of opioid-related harms. This mixed methods study aimed at describing trends over time in implementation, as well as in awareness and health outcomes. For implementation, we conducted a scoping review to identify opioids interventions and policies implemented in Canada between 1 January 2016 and 15 November 2019. Awareness was measured through a descriptive analysis of opioid-related harm cases reported by consumers and health care professionals (HCPs) to the national spontaneous reporting system and of social media coverage, while health outcome consisted of opioid-related deaths recorded in the coroner's reports database of the province of Quebec, Canada. Trends over time in implementation of interventions were compared to trends in awareness and opioid-related deaths, without implying causality. There were 413 national or provincial interventions on opioids implemented over the study period, with a four-fold increase in 2016. The most common (31.5%) was harm reduction strategies, such as naloxone distribution. The reporting rate of opioid-related harms ranged between 0.1 and 0.2 per 100,000 persons with no observed time trend. Compared to 2015, the number of social media posts increased in 2016 by 35.4% (Reddit), 329.0% (Facebook), and 381.5% (Twitter). Between 2016 and 2019, there was a slight decrease in the number of opioid-related deaths recorded in the coroner's database. Overall, the increase in the number of policies did not see a parallel increase in spontaneous reports of opioid-related harms as an indicator of consumer or HCP awareness. Conversely, the dramatic increase in social media coverage was consistent with heightened public awareness. Although no inferences of causality were made in this study, the decrease in opioid-related deaths observed in the recent years may indicate a potential effectiveness of interventions and policies.

Pharmacist-led interventions during transitions of care of older adults admitted to short term geriatric units: Current practices and perceived barriers.

Background: During transitions of care, older adults are at risk of adverse drug events which could lead to avoidable hospital visits. Pharmacists are increasingly involved in care teams at various stages of the continuum of care. The types and frequency of clinical interventions performed by pharmacists in the geriatric practice setting remain poorly documented. Objectives: This study aimed to describe the current integration of pharmacist interventions during transitions of care of older adults admitted in short-term geriatric units (STGUs) and to explore barriers and facilitators to their implementation in clinical practice. The secondary objective was to explore associations between certain patient characteristics and pharmacist-led interventions during transitional care. Methods: A mixed methods study was conducted with pharmacists practicing in STGUs in the Montreal area, Canada. The application of 8 pharmaceutical interventions was assessed using a self-administered questionnaire, along with as a retrospective chart review. Four semi-structured group interviews were conducted in order to identify perceived barriers and facilitators. Results: Thirteen pharmacists participated in the study. In the questionnaire, medication reconciliation on admission and at discharge was reported as being performed at least half the time by 12 (92%) and 7 (54%) pharmacists, respectively. The retrospective chart review revealed that these interventions were documented in 95 (98%) and 25 (26%) files, respectively. While 35% of patients had a documented pharmaceutical care plan on admission, none was documented at discharge. Several barriers to implementing clinical interventions were identified such as lack of time, technical support, communication and standardization. Conclusions: Pharmacists are involved at different periods of transitional care; however, certain barriers should be addressed in order to expand their role in discharge planning. Providing guidelines on what is expected at discharge and post-discharge, and having a practice focused on delegation and collaboration would help pharmacists increase their role throughout the transition of care of older adults.

Epidemiology of Asymptomatic Pre-heart Failure: a Systematic Review.

PURPOSE OF REVIEW: To quantify the prevalence of asymptomatic pre-heart failure (pre-HF), progression to more severe stages, and associated mortality. RECENT FINDINGS: A systematic review was conducted between 01 January 2010 and 12 March 2020 (PROSPERO: CRD42020176141). Data of interest included prevalence, disease progression, and mortality rates. In total, 1030 sources were identified, of which, 12 reported on pre-HF (using the ACC/AHA definition for stage B HF) and were eligible. Prevalence estimates of pre-HF ranged from 11 to 42.7% (10 sources) with higher estimates found in the elderly, in patients with hypertension, and in men. Three studies reported on disease progression with follow-up ranging from 13 months to 7 years. The incidence of symptomatic HF (HF/advanced HF) ranged from 0.63 to 9.8%, and all-cause mortality from 1.6 to 5.4%. Further research is required to investigate whether early detection and intervention can slow or stop the progression from asymptomatic to symptomatic HF.

Impact of schizophrenia relapse definition on the comparative effectiveness of oral versus injectable antipsychotics: A systematic review and meta-analysis of observational studies.

Although relapse is an important outcome to measure the effectiveness of schizophrenia treatment, no standard definition exists. This review aimed at identifying definitions and measurements of schizophrenia relapse in observational studies of long-acting injectables (LAIs) versus oral antipsychotics (OAPs) and at determining their impact on heterogeneity of comparative effectiveness estimates. A systematic review was conducted using MEDLINE and Embase (01 January 2010-11 November 2019 [date last searched]). Pragmatic searches of gray literature and snowballing were also conducted. Search outputs were screened independently by two assessors at first stage, and full-text of potentially eligible sources at second stage. For each retained source, definition and measurement of relapse, study methods, and comparative effectiveness estimates were extracted. Heterogeneity of estimates was assessed using I2 statistic with a threshold of 50% for substantial heterogeneity. Literature search yielded 543 sources and pragmatic searches, 21, of which 35 were eligible. Twelve definitions of relapse were found based on hospitalization/emergency department (ED) data (28 studies) or clinical assessment (5 studies). No definition was provided in five studies. According to quantitative analyses, in studies defining relapse as schizophrenia-related hospitalization and/or ED visits over 1-year follow-up, LAIs were significantly more effective than OAPs. For studies measuring relapse based on all-cause hospitalization, heterogeneity was too high for pooling; yet this definition is the most frequently found in pooled estimates published in the literature. Schizophrenia relapse definitions led to substantial heterogeneity of comparative effectiveness estimates of LAIs versus OAPs. Creating study subgroups based on relapse definition effectively reduces statistical heterogeneity.

Methodological Considerations in the Assessment of Effectiveness of Homeopathic Care: A Critical Review of the EPI3 Study.

BACKGROUND: EPI3 is an observational study of a representative sample of general practitioners (GPs) and patients in France, demonstrating that patient characteristics differ according to the prescribing preferences of their GPs for homeopathy. For selected conditions (musculoskeletal disorders, sleep disorders, anxiety/depression, upper respiratory tract infections), progression of symptoms and adverse events over follow-up in the homeopathy preference group did not significantly differ from other practice preferences, but there was a two-fold to four-fold lower usage of conventional medicines. The EPI3 study's validity was challenged due to absence of head-to-head comparison of medicines to conclude on a causal association between homeopathy and outcomes. METHODS: A critical review of the nine EPI3 publications was conducted, focusing on generalizability, selection bias, outcome measurements and confounding. RESULTS: The conceptual framework of EPI3 rests on a systemic construct, i.e., the homeopathic treatment concept assessed using the type of GP prescribing preference, taking into account the clinical, human and social aspects. The enrollment process enhanced the generalizability of findings. Validated instruments for outcome measurements were used for three conditions, and control of confounding was rigorous. CONCLUSION: EPI3 was conducted according to best practices. Homeopathy prescribing preference met specific patient needs with less use of conventional medicines and without an apparent loss in therapeutic opportunity.

Human Papillomavirus Vaccination and Premature Ovarian Failure: A Disproportionality Analysis Using the Vaccine Adverse Event Reporting System.

INTRODUCTION: There have been public health concerns about a potential association between human papillomavirus (HPV) vaccines and premature ovarian failure (POF) in young women. OBJECTIVE: To identify a potential safety signal of POF after HPV vaccination using the United States (US) Vaccine Adverse Event Reporting System (VAERS) database. METHODS: We manually selected relevant MedDRA preferred terms related to POF and identified in VAERS all POF reports in women less than 40 years of age between 2 July 1990 and 14 May 2018, followed by a review of narratives to confirm the cases. We conducted descriptive analyses on age, POF type, HPV vaccine type (HPV2, HPV4, HPV9), time to onset of POF, and dose rank. We described trends in reporting over time and assessed a potential safety signal using the proportional reporting ratio (PRR). RESULTS: Of the 228,341 eligible POF reports, 281 (0.1%) were suspected to be associated with HPV vaccines. Median patient age was 15 years (range 11-39 years). POF events consisted mainly of amenorrhea (80.4%) and premature menopause (15.3%). Mean number of reported POF events significantly increased after the first HPV vaccine launch in 2006 with 22.2 POF cases/year up from 1.4 POF cases/year before the launch. PRR was 46.1 (95% confidence interval: 31.7-67.2) and sensitivity analyses yielded similar estimates. CONCLUSION: Our study suggests the presence of a potential safety signal of POF associated with HPV vaccination, which may only be partly attributed to notoriety bias. Due to the well-known limitations of spontaneous reporting data, further investigations are warranted.

Global Incidence and Prevalence of Gaucher Disease: A Targeted Literature Review.

Incidence and prevalence estimates for Gaucher disease (GD) are scarce for this rare disease and can be variable within the same region. This review provides a qualitative synthesis of global GD incidence and prevalence estimates, GD1-3 type-specific and overall, published in the last 10 years. A targeted literature search was conducted across multiple databases from January 2011 to September 2020, including web-based sources and congress proceedings to May 2021. Searches yielded 490 publications, with 31 analyzed: 20 cohort studies (15 prospective, 5 retrospective), 6 cross-sectional studies, 5 online reports (most from Europe (n = 11) or North America (n = 11); one multiregional). Across all GD types, incidence estimates ranged 0.45-25.0/100,000 live births (16 studies), lowest for Asia-Pacific. Incidence of GD1: 0.45-22.9/100,000 live births (Europe and North America) and GD3: 1.36/100,000 live births (Asia-Pacific only). GD type-specific prevalence estimates per 100,000 population were GD1: 0.26-0.63; GD2 and GD3: 0.02-0.08 (Europe only); estimates for GD type unspecified or overall ranged 0.11-139.0/100,000 inhabitants (17 studies), highest for North America. Generalizability was assessed as "adequate"or "intermediate" for all regions with data. GD incidence and prevalence estimates for the last 10 years varied considerably between regions and were poorly documented outside Europe and North America. Data for GD2 and GD3 were limited.

Understanding reporting practices and perceptions of barriers in adverse events following immunisation surveillance: A cross-sectional survey of paediatricians in Kerala, India.

PURPOSE: The role of health care professionals (HCPs) is central to adverse event following immunisation (AEFI) surveillance. A cross-sectional survey was conducted among paediatricians practising in Kerala, India, to assess their knowledge and reporting behaviour in AEFI surveillance as well as to identify barriers to reporting. RESULTS: A random sample of 380 paediatricians were contacted of whom, 243 (63.9%) participated in the survey. The understanding scores were distributed as follows: 30.9% very high or high, 40.3% moderate, and 28.8% low. Formal training was significantly associated with higher understanding scores, and increased AEFI detection and reporting. Only 42.0% of respondents had formal training; paediatricians in the public sector had higher access to training than those in the private sector. There were 141 respondents (58.0%) who identified an AEFI in the previous year, of whom 66 (46.8%) reported it. The main barriers to AEFI reporting were: difficulties with reporting process (28.9%); fear of raising public alarm (28.1%); time constraints (22.3%); fear of personal consequences (15.7%); and belief that health authorities rarely take useful action (11.6%). CONCLUSION: Training in AEFI surveillance should be prioritised for HCPs with greater emphasis in medical education programmes. Study showed that a user-friendly reporting mechanism and a blame-free culture are crucial to improve AEFI reporting practices.

Effectiveness of brentuximab vedotin monotherapy in relapsed or refractory Hodgkin lymphoma: a systematic review and meta-analysis.

This systematic review and meta-analysis aimed to determine the effectiveness of brentuximab vedotin (BV) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL) in the clinical practice setting using most recent results. A total of 32 observational studies reporting on treatment patterns, overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and adverse events were found. After four cycles, a random-effect model yielded pooled ORR and CR rates of 62.6% (95% confidence interval (CI): 56.0-68.9; I2 = 9.7%) and 32.9% (95% CI, 20.8-46.3, I2 = 64.8%), respectively. Regarding survival, 1-year, 2-year, and 5-year PFS ranged from 52.1% to 63.2%, 45.2% to 56.2%, and 31.9% to 33.0%, respectively. OS rates were 68.2-82.7%, 58.0-81.9%, and 58.0-62.0%, respectively. Most common adverse events were hematological toxicities (neutropenia: 13.3-23%, anemia: 8.8-39.0%, and thrombocytopenia: 4-4.6%), and grade ≥3 peripheral neuropathy (3.3-7.3%). This study supports the effectiveness and safety of BV in R/R cHL patients in the real-world setting.

Predictors of long-term use of prescription opioids in the community-dwelling population of adults without a cancer diagnosis: a retrospective cohort study.

BACKGROUND: Long-term opioid use is a known risk factor for opioid-related harms. We aimed to identify risk factors for and predictors of long-term use of prescription opioids in the community-dwelling population of adults without a diagnosis of cancer, to inform practice change at the point of care. METHODS: Using Quebec administrative claims databases, we conducted a retrospective cohort study in a random sample of adult members (≥ 18 yr) of the public drug plan who did not have a cancer diagnosis and who initiated a prescription opioid in the outpatient setting between Jan. 1, 2012, and Dec. 31, 2016. The outcome of interest was long-term opioid use (≥ 90 consecutive days or ≥ 120 cumulative days over 12 mo). Potential predictors included sociodemographic factors, medical history, characteristics of the initial opioid prescription and prescriber's specialty. We used multivariable logistic regression to assess the association between each characteristic and long-term use. We used the area under the receiver operating characteristic curve to determine the predictive performance of full and parsimonious models. RESULTS: Of 124 664 eligible patients who initiated opioid therapy, 4172 (3.3%) progressed to long-term use of prescription opioids. The most important associated factors in the adjusted analysis were long-term prescription of acetaminophen-codeine (odds ratio [OR] 6.30, 95% confidence interval [CI] 4.99 to 7.96), prescription of a long-acting opioid at initiation (OR 6.02, 95% CI 5.31 to 6.84), initial supply of 30 days or more (OR 4.22, 95% CI 3.81 to 4.69), chronic pain (OR 2.41, 95% CI 2.16 to 2.69) and initial dose of at least 90 morphine milligram equivalents (MME) per day (OR 1.24, 95% CI 1.04 to 1.47). Our predictive model, including only the initial days' supply and chronic pain diagnosis, had area under the curve of 0.7618. INTERPRETATION: This study identified factors associated with long-term prescription opioid use. Limiting the initial supply to no more than 7 days and limiting doses to 90 MME/day or less are actions that could be undertaken at the point of care.

Risk Management for the 21st Century: Current Status and Future Needs.

Global adoption of risk management principles outlined in the International Conference on Harmonisation (ICH) E2E guideline and the Council for International Organizations of Medical Sciences (CIOMS) Working Group VI guidance introduced greater proactivity and consistency into the practice of pharmacovigilance and benefit-risk management throughout the lifecycle of a drug. However, following the release of these guidelines there have been important advances in the science and practice of risk minimisation itself, especially in terms of how risk minimisation measures (RMMs) are designed, implemented, disseminated and evaluated for effectiveness in real-world healthcare settings. In this article, we describe how the field of design, implementation, dissemination and evaluation of RMMs has advanced in recent years while highlighting current areas of challenge and possible solutions. Where possible we cite global examples to demonstrate how evidence-based approaches have informed the development of RMMs. In this context, while taking into consideration local healthcare system policies and national legislations, we conclude with a call for a global effort to harmonise certain areas that focus on, but are not limited to, standardising certain terms and definitions, consistent application of robust methodologies, and outline of best practices for risk minimisation design, implementation, and dissemination.