Short- and long-term safety of discontinuing chronic opioid therapy among older adults with Alzheimer's disease and related dementia.

BACKGROUND: Limited evidence exists on the short- and long-term safety of discontinuing versus continuing chronic opioid therapy (COT) among patients with Alzheimer's disease and related dementias (ADRD). METHODS: This cohort study was conducted among 162,677 older residents with ADRD and receipt of COT using a 100% Medicare nursing home sample. Discontinuation of COT was defined as no opioid refills for ≥90 days. Primary outcomes were rates of pain-related hospitalisation, pain-related emergency department visit, injury, opioid use disorder (OUD) and opioid overdose (OD) measured by diagnosis codes at quarterly intervals during 1- and 2-year follow-ups. Poisson regression models were fit using generalised estimating equations with inverse probability of treatment weights to model quarterly outcome rates between residents who discontinued versus continued COT. RESULTS: The study sample consisted of 218,040 resident episodes with COT; of these episodes, 180,916 residents (83%) continued COT, whereas 37,124 residents (17%) subsequently discontinued COT. Discontinuing (vs. continuing) COT was associated with higher rates of all outcomes in the first quarter, but these associations attenuated over time. The adjusted rates of injury, OUD and OD were 0, 69 and 60% lower at the 1-year follow-up and 11, 81 and 79% lower at the 2-year follow-up, respectively, for residents who discontinued versus continued COT, with no difference in the adjusted rates of pain-related hospitalisations or emergency department visits. CONCLUSIONS: The rates of adverse outcomes were higher in the first quarter but lower or non-differential at 1-year and 2-year follow-ups between COT discontinuers versus continuers among older residents with ADRD.

Pain intensity, physical function, and depressive symptoms associated with discontinuing long-term opioid therapy in older adults with Alzheimer's disease and related dementias.

INTRODUCTION: Limited evidence exists on the associations of discontinuing versus continuing long-term opioid therapy (LTOT) with pain intensity, physical function, and depression among patients with Alzheimer's disease and related dementias (ADRD). METHODS: A cohort study among 138,059 older residents with mild-to-moderate ADRD and receipt of LTOT was conducted using a 100% Medicare nursing home sample. Discontinuation of LTOT was defined as no opioid refills for ≥ 60 days. Outcomes were worsening pain, physical function, and depression from baseline to quarterly assessments during 1- and 2-year follow-ups. RESULTS: The adjusted odds of worsening pain and depressive symptoms were 29% and 5% lower at the 1-year follow-up and 35% and 9% lower at the 2-year follow-up for residents who discontinued versus continued LTOT, with no difference in physical function. DISCUSSION: Discontinuing LTOT was associated with lower short- and long-term worsening pain and depressive symptoms than continuing LTOT among older residents with ADRD. HIGHLIGHTS: Discontinuing long-term opioid therapy (LTOT) was associated with lower short- and long-term worsening pain. Discontinuing LTOT was related to lower short- and long-term worsening depression. Discontinuing LTOT was not associated with short- and long-term physical function.

Concurrent use of prescription gabapentinoids with opioids and risk for fall-related injury among older US Medicare beneficiaries with chronic noncancer pain: A population-based cohort study.

BACKGROUND: Gabapentinoids are increasingly prescribed to manage chronic noncancer pain (CNCP) in older adults. When used concurrently with opioids, gabapentinoids may potentiate central nervous system (CNS) depression and increase the risks for fall. We aimed to investigate whether concurrent use of gabapentinoids with opioids compared with use of opioids alone is associated with an increased risk of fall-related injury among older adults with CNCP. METHODS AND FINDINGS: We conducted a population-based cohort study using a 5% national sample of Medicare beneficiaries in the United States between 2011 and 2018. Study sample consisted of fee-for-service (FFS) beneficiaries aged ≥65 years with CNCP diagnosis who initiated opioids. We identified concurrent users with gabapentinoids and opioids days' supply overlapping for ≥1 day and designated first day of concurrency as the index date. We created 2 cohorts based on whether concurrent users initiated gabapentinoids on the day of opioid initiation (Cohort 1) or after opioid initiation (Cohort 2). Each concurrent user was matched to up to 4 opioid-only users on opioid initiation date and index date using risk set sampling. We followed patients from index date to first fall-related injury event ascertained using a validated claims-based algorithm, treatment discontinuation or switching, death, Medicare disenrollment, hospitalization or nursing home admission, or end of study, whichever occurred first. In each cohort, we used propensity score (PS) weighted Cox models to estimate the adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) of fall-related injury, adjusting for year of the index date, sociodemographics, types of chronic pain, comorbidities, frailty, polypharmacy, healthcare utilization, use of nonopioid medications, and opioid use on and before the index date. We identified 6,733 concurrent users and 27,092 matched opioid-only users in Cohort 1 and 5,709 concurrent users and 22,388 matched opioid-only users in Cohort 2. The incidence rate of fall-related injury was 24.5 per 100 person-years during follow-up (median, 9 days; interquartile range [IQR], 5 to 18 days) in Cohort 1 and was 18.0 per 100 person-years during follow-up (median, 9 days; IQR, 4 to 22 days) in Cohort 2. Concurrent users had similar risk of fall-related injury as opioid-only users in Cohort 1(aHR = 0.97, 95% CI 0.71 to 1.34, p = 0.874), but had higher risk for fall-related injury than opioid-only users in Cohort 2 (aHR = 1.69, 95% CI 1.17 to 2.44, p = 0.005). Limitations of this study included confounding due to unmeasured factors, unavailable information on gabapentinoids' indication, potential misclassification, and limited generalizability beyond older adults insured by Medicare FFS program. CONCLUSIONS: In this sample of older Medicare beneficiaries with CNCP, initiating gabapentinoids and opioids simultaneously compared with initiating opioids only was not significantly associated with risk for fall-related injury. However, addition of gabapentinoids to an existing opioid regimen was associated with increased risks for fall. Mechanisms for the observed excess risk, whether pharmacological or because of channeling of combination therapy to high-risk patients, require further investigation. Clinicians should consider the risk-benefit of combination therapy when prescribing gabapentinoids concurrently with opioids.

Trajectories of prescription opioid dose and risk of opioid-related adverse events among older Medicare beneficiaries in the United States: A nested case-control study.

BACKGROUND: Despite the rising number of older adults with medical encounters for opioid misuse, dependence, and poisoning, little is known about patterns of prescription opioid dose and their association with risk for opioid-related adverse events (ORAEs) in older patients. The study aims to compare trajectories of prescribed opioid doses in 6 months preceding an incident ORAE for cases and a matched control group of older patients with chronic noncancer pain (CNCP). METHODS AND FINDINGS: We conducted a nested case-control study within a cohort of older (≥65 years) patients diagnosed with CNCP who were new users of prescription opioids, assembled using a 5% national random sample of Medicare beneficiaries from 2011 to 2018. From the cohort with a mean follow-up of 2.3 years, we identified 3,103 incident ORAE cases with ≥1 opioid prescription in 6 months preceding the event, and 3,103 controls matched on sex, age, and time since opioid initiation. Key exposure was trajectories of prescribed opioid morphine milligram equivalent (MME) daily dosage over 6 months before the incident ORAE or matched controls. Among the cases and controls, 2,192 (70.6%) were women, and the mean (SD) age was 77.1 (7.1) years. Four prescribed opioid trajectories before the incident ORAE diagnosis or matched date emerged: gradual dose discontinuation (from ≤3 to 0 daily MME, 1,456 [23.5%]), gradual dose increase (from 0 to >3 daily MME, 1,878 [30.3%]), consistent low dose (between 3 and 5 daily MME, 1,510 [24.3%]), and consistent moderate dose (>20 daily MME, 1,362 [22.0%]). Few older patients (<5%) were prescribed a mean daily dose of ≥90 daily MME during 6 months before diagnosis or matched date. Patients with gradual dose discontinuation versus those with a consistent low dose, moderate dose, and increase dose were more likely to be younger (65 to 74 years), Midwest US residents, and receiving no low-income subsidy. Compared to patients with gradual dose discontinuation, those with gradual dose increase (adjusted odds ratio [aOR] = 3.4; 95% confidence interval (CI) 2.8 to 4.0; P < 0.001), consistent low dose (aOR = 3.8; 95% CI 3.2 to 4.6; P < 0.001), and consistent moderate dose (aOR = 8.5; 95% CI 6.8 to 10.7; P < 0.001) had a higher risk of ORAE, after adjustment for covariates. Our main findings remained robust in the sensitivity analysis using a cohort study with inverse probability of treatment weighting analyses. Major limitations include the limited generalizability of the study findings and lack of information on illicit opioid use, which prevents understanding the clinical dose threshold level that increases the risk of ORAE in older adults. CONCLUSIONS: In this sample of older patients who are Medicare beneficiaries, 4 prescription opioid dose trajectories were identified, with most prescribed doses below 90 daily MME within 6 months before ORAE or matched date. An increased risk for ORAE was observed among older patients with a gradual increase in dose or among those with a consistent low-to-moderate dose of prescribed opioids when compared to patients with opioid dose discontinuation. Whether older patients are susceptible to low opioid doses warrants further investigations.

Association of injury after prescription opioid initiation with risk for opioid-related adverse events among older Medicare beneficiaries in the United States: A nested case-control study.

BACKGROUND: Injury, prevalent and potentially associated with prescription opioid use among older adults, has been implicated as a warning sign of serious opioid-related adverse events (ORAEs) including opioid misuse, dependence, and poisoning, but this association has not been empirically tested. The study aims to examine the association between incident injury after prescription opioid initiation and subsequent risk of ORAEs and to assess whether the association differs by recency of injury among older patients. METHODS AND FINDINGS: This nested case-control study was conducted within a cohort of 126,752 individuals aged 65 years or older selected from a 5% sample of Medicare beneficiaries in the United States between 2011 and 2018. Cohort participants were newly prescribed opioid users with chronic noncancer pain who had no injury or ORAEs in the year before opioid initiation, had 30 days or more of observation, and had at least 1 additional opioid prescription dispensed during follow-up. We identified ORAE cases as patients who had an inpatient or outpatient encounter with diagnosis codes for opioid misuse, dependence, or poisoning. During a mean follow-up of 1.8 years, we identified 2,734 patients who were newly diagnosed with ORAEs and 10,936 controls matched on the year of cohort entry date and a disease risk score (DRS), a summary score derived from the probability of an ORAE outcome based on covariates measured prior to cohort entry and in the absence of injury. Multivariate conditional logistic regression was used to estimate ORAE risk associated with any and recency of injury, defined based on the primary diagnosis code of inpatient and outpatient encounters. Among the cases and controls, 68.0% (n = 1,859 for cases and n = 7,436 for controls) were women and the mean (SD) age was 74.5 (6.9) years. Overall, 54.0% (n = 1,475) of cases and 46.0% (n = 1,259) of controls experienced incident injury after opioid initiation. Patients with (versus without) injury after opioid therapy had higher risk of ORAEs after adjustment for time-varying confounders, including diagnosis of tobacco or alcohol use disorder, drug use disorder, chronic pain diagnosis, mental health disorder, pain-related comorbidities, frailty index, emergency department visit, skilled nursing facility stay, anticonvulsant use, and patterns of prescription opioid use (adjusted odds ratio [aOR] = 1.4; 95% confidence interval (CI) 1.2 to 1.5; P < 0.001). Increased risk of ORAEs was associated with current (≤30 days) injury (aOR = 2.8; 95% CI 2.3 to 3.4; P < 0.001), whereas risk of ORAEs was not significantly associated with recent (31 to 90 days; aOR = 0.93; 95% CI 0.73 to 1.17; P = 0.48), past (91 to 180 days; aOR = 1.08; 95% CI 0.88 to 1.33; P = 0.51), and remote (181 to 365 days; aOR = 0.88; 95% CI 0.73 to 1.1; P = 0.18) injury preceding the incident diagnosis of ORAE or matched date. Patients with injury and prescription opioid use versus those with neither in the month before the ORAE or matched date were at greater risk of ORAEs (aOR = 5.0; 95% CI 4.1 to 6.1; P < 0.001). Major limitations are that the study findings can only be generalized to older Medicare fee-for-service beneficiaries and that unknown or unmeasured confounders have the potential to bias the observed association toward or away from the null. CONCLUSIONS: In this study, we observed that incident diagnosis of injury following opioid initiation was associated with subsequent increased risk of ORAEs, and the risk was only significant among patients with injury in the month before the index date. Regular monitoring for injury may help identify older opioid users at high risk for ORAEs.

Prevention and control of non-communicable diseases in antenatal, intrapartum, and postnatal care: a systematic scoping review of clinical practice guidelines since 2011.

BACKGROUND: Non-communicable diseases (NCDs) are a leading cause of maternal mortality and morbidity worldwide. The World Health Organization is developing new recommendations focusing on the management of NCDs for pregnant, intrapartum, and postnatal women. Thus, to support the development of new guidelines and recommendations, we aimed to determine the availability, focus, and scope of recommendations of current guidelines for the management of NCDs during pregnancy, intrapartum, and postnatal period. METHODS: PubMed, Global Index Medicus, TRIP, and Guideline International Network databases were searched on 31 May 2021, to identify any NCD-related guidelines published between 2011 and 2021 with no language or country restrictions. Websites of 165 professional organizations were also searched. Characteristics of included guidelines were analyzed, and recommendations were extracted from guidelines of five high-priority NCD conditions (diabetes, chronic hypertension, respiratory conditions, hemoglobinopathies and sickle cell disease, and mental and substance use disorders). RESULTS: From 6026 citations and 165 websites, 405 guidelines were included of which 132 (33%) were pregnancy-specific and 285 (88%) were developed in high-income countries. Among pregnancy-specific guidelines, the most common conditions for which recommendations were provided were gestational diabetes, circulatory diseases, thyroid disorders, and hypertensive disorders of pregnancy. For the five high-priority conditions, 47 guidelines were identified which provided 1834 recommendations, largely focused on antenatal care interventions (62%) such as early detection, screening tools, pharmacological treatment, and lifestyle education. Postnatal recommendations largely covered postnatal clinical assessments, lifestyle education, and breastfeeding. Health system recommendations largely covered multidisciplinary care teams and strengthening referral pathways. CONCLUSIONS: This study provides a robust assessment of currently available guidelines and mapping of recommendations on NCD management within maternal health services, which will inform the scope of the World Health Organization's future guideline development activities. This study identified a need to develop guidelines that consider NCDs holistically, with an integrated approach to antenatal, intrapartum, and postnatal care, and that are relevant for resource-limited contexts. Any such guidelines should consider what interventions are most essential to improving outcomes for women with NCDs and their newborns, and how variations in quality of NCD-related care can be addressed.

Trend and projection of skilled birth attendants and institutional delivery coverage for adolescents in 54 low- and middle-income countries, 2000-2030.

BACKGROUND: Limitations to accessing delivery care services increase the risks of adverse outcomes during pregnancy and delivery for all pregnant women, particularly among adolescents in LMICs. In order to inform adolescent-specific delivery care initiatives and coverage, we conducted a comprehensive analysis of trends, projections and inequalities in coverage of delivery care services among adolescents at national, urban-rural and socio-economic levels in LMICs. METHODS: Using 224 nationally representative cross-sectional survey data between 2000 and 2019, we estimated the coverage of institutional delivery (INSD) and skilled birth attendants (SBA). Bayesian hierarchical regression models were used to estimate trends, projections and determinants of INSD and SBA. RESULTS: Coverage of delivery care services among adolescents increased substantially at the national level, as well as in both urban and rural areas in most countries between 2000 and 2018. Of the 54 LMICs, 24 countries reached 80% coverage of both INSD and SBA in 2018, and predictions for 40 countries are set to exceed 80% by 2030. The trends in coverage of INSD and SBA of adult mothers mostly align with those for adolescent mothers. Our findings show that urban-rural and wealth-based inequalities to delivery care remain persistent by 2030. In 2018, urban settings across 54 countries had higher rates of coverage exceeding 80% compared to rural for both INSD (45 urban, 16 rural) and SBA (50 urban, 19 rural). Several factors such as household head age ≥ 46 years, household head being female, access to mass media, lower parity, higher education, higher ANC visits and higher socio-economic status could increase the coverage of INSD and SBA among adolescents and adult women. CONCLUSIONS: More than three-quarters of the LMICs are predicted to achieve 80% coverage of INSD and SBA among adolescent mothers in 2030, although with sustained inequalities.

Affirming Hormone Treatment for a Transgender Adolescent After a Venous Thromboembolic Event.

BACKGROUND: Medical affirmation, including gender-affirming hormones, is an essential component in the treatment of many transgender and gender-diverse youth. The risk of venous thromboembolism (VTE) during testosterone therapy for gender-affirming care is not fully elucidated. OBSERVATION: The case describes a 17-year-old transgender male treated with testosterone therapy who presented with an occlusive deep vein thrombosis of right axillary and subclavian veins. Testosterone level was 920 ng/dL at the time of the deep vein thrombosis, and he had no risk factors for VTE. A complete hypercoagulable workup was negative. CONCLUSIONS: The possibility of testosterone therapy as a risk factor for VTE may suggest the need to include this information during informed consent discussions. Long-term anticoagulation may be considered for those restarting testosterone therapy.

Agreement of Minimum Data Set 3.0 depression and behavioral symptoms with clinical diagnosis in a nursing home.

OBJECTIVES: While the Minimum Data Set (MDS) 3.0 has adopted Patient Health Questionnaire (PHQ)-9 to screen for depression and rephrased language for behavioral symptoms among nursing home residents, it remains unclear how well the assessment data agree with medical records. DESIGN: Using a retrospective review of MDS 3.0 linked to medical records between October 2010 and November 2017, we included residents with at least one quarterly or short-term (day 30 or day 60) MDS 3.0 assessment of depression PHQ-9 (n = 446) or behavioral symptoms (n = 460). For each resident of each cohort, we randomly selected an eligible MDS 3.0 depression and behavioral symptom assessment and compared against the respective medical diagnoses recorded within 30 days before the MDS 3.0 assessment. RESULTS: Percent agreement was high for depression (90.1%) and behavioral symptoms (89.3%). Negative agreement was high for depression (94.8%) and behavioral symptoms (94.3%), while positive agreement was low for both conditions (4.3% and 10.9%). CONCLUSION: MDS 3.0 depression and behavioral symptoms had high overall and negative agreement, but low positive agreement with clinician diagnoses. MDS 3.0 data may be useful in ruling out depression and behavioral symptoms. Confirmation of the findings in a representative sample of nursing homes is warranted.

Validation of algorithms to estimate gestational age at birth in the Medicaid Analytic eXtract-Quantifying the misclassification of maternal drug exposure during pregnancy.

PURPOSE: Accurate ascertainment of gestational age (GA) has been a challenge in perinatal epidemiologic research. To date, no study has validated GA algorithms in Medicaid Analytic eXtract (MAX). METHODS: We linked livebirths of mothers enrolled in Medicaid ≥30 days after delivery in 1999-2010 MAX to state birth certificates. We used clinical/obstetric estimate of gestation on the birth certificates as gold standard to validate claims-based GA algorithms. We calculated the proportions of deliveries with algorithm-estimated GA within 1-/2-weeks of the gold standard, the sensitivity, specificity, and positive/negative predictive value (PPV/NPV) of exposure to select medications during specific gestation windows, and quantified the impact of exposure misclassification on hypothetical relative risk (RR) estimates. RESULTS: We linked 1 336 495 eligible deliveries. Within 1-week agreement was 77%-80% overall and 47%-56% for preterm deliveries. The trimester-specific drug exposure status had high sensitivities and PPVs (88.5%-98.5%), and specificities and NPVs (>99.0%). Assuming a hypothetical RR of 2.0, bias associated with exposure misclassification during first trimester ranged from 10% to 40% under non-differential/differential misclassification assumptions. CONCLUSIONS: Claims-based GA algorithms had good agreement with the gold standard overall, but lower agreement among preterm deliveries, potentially resulting in biased risk estimated for pregnancy exposure evaluations.

Reducing childhood malnutrition in Bangladesh: the importance of addressing socio-economic inequalities.

OBJECTIVE: To obtain projections of the prevalence of childhood malnutrition indicators up to 2030 and to analyse the changes of wealth-based inequality in malnutrition indicators and the degree of contribution of socio-economic determinants to the inequities in malnutrition indicators in Bangladesh. Additionally, to identify the risk factors of childhood malnutrition. DESIGN: Cross-sectional study. A Bayesian linear regression model was used to estimate trends and projections of malnutrition. For equity analysis, slope index, relative index and decomposition in concentration index were used. Multilevel logistic models were used to identify risk factors of malnutrition. SETTING: Household surveys in Bangladesh from 1996 to 2014. PARTICIPANTS: Children under the age of 5 years. RESULTS: A decreasing trend was observed for all malnutrition indices. In 1990, predicted prevalence of stunting, wasting and underweight was 55·0, 15·9 and 61·8 %, respectively. By 2030, prevalence is projected to reduce to 28·8 % for stunting, 12·3 % for wasting and 17·4 % for underweight. Prevalence of stunting, wasting and underweight were 34·3, 6·9 and 32·8 percentage points lower in the richest households than the poorest households. Contribution of the wealth index to child malnutrition increased over time and the largest contribution of pro-poor inequity was explained by wealth index. Being an underweight mother, parents with a lower level of education and poorer households were the key risk factors for stunting and underweight. CONCLUSIONS: Our findings show an evidence-based need for targeted interventions to improve education and household income-generating activities among poor households to reduce inequalities and reduce the burden of child malnutrition in Bangladesh.

Trends in prescription opioid use and dose trajectories before opioid use disorder or overdose in US adults from 2006 to 2016: A cross-sectional study.

BACKGROUND: With governments' increasing efforts to curb opioid prescription use and limit dose below the Centers for Disease Control and Prevention (CDC)-recommended threshold of 90 morphine milligram equivalents per day, little is known about prescription opioid patterns preceding opioid use disorder (OUD) or overdose. This study aimed to determine prescribed opioid fills and dose trajectories in the year before an incident OUD or overdose diagnosis using a 2005-2016 commercial healthcare database. METHODS AND FINDINGS: This cross-sectional study identified individuals aged 18 to 64 years with incident OUD or overdose in the United States. We measured the prevalence of opioid prescription fills and trajectories of opioid morphine equivalent dose (MED) prescribed during the 12-month period before the diagnosis. Of 227,038 adults with incident OUD or overdose, 33.1% were aged 18 to 30 years, 52.9% were males, and 85.0% were metropolitan residents. Half (50.5%) of the patients had a diagnosis of chronic pain, 32.7% had depression, and 20.3% had anxiety. Overall, 79,747 (35.1%) patients filled no opioid prescription in the 12 months before OUD or overdose diagnosis, with the proportion significantly increasing between 2006 and 2016 (adjusted prevalence ratio, 1.86; 95% CI 1.79-1.93; P < 0.001). Patients without (versus with) prescribed opioids tended to be younger males and metropolitan and Northeast US residents. Of 145,609 patients who filled opioid prescriptions, 5 distinct prescribed daily dose trajectories preceding diagnosis emerged: consistent low dose (<3 mg MED, 34.6%), consistent moderate dose (20 mg MED, 27.3%), consistent high dose (150 mg MED, 15.0%), escalating dose (from <3 to 20 mg MED, 13.7%), and de-escalating dose (from 20 to <3mg MED, 9.4%). Overall, over two-thirds of patients with OUD or overdose with prescription opioids were prescribed a mean daily dose below 90 mg MED before diagnosis. Major limitations include the limited generalizability of the study findings and lack of information on out-of-pocket drug spending, race/ethnicity, and socioeconomic status of participants, which prevents analyses addressing these characteristics. CONCLUSIONS: In this study, we found that absence of opioid prescription fills in the year before incident OUD or overdose diagnosis was prevalent, and the majority of the patients received prescription opioid doses below the risk threshold of 90 mg MED. An increasing proportion of high-risk patients could be missed by current programs solely based on opioid prescribing and dispensing information in this new era of limited access to prescription opioids.

Trends in Dietary Vitamin A Intake Among US Adults by Race and Ethnicity, 2003-2018.

This study uses data from the 2003-2004 to 2017-2018 National Health and Nutrition Examination Surveys (NHANES) to assess whether a difference exists in dietary vitamin A intake as a marker of consumption of vitamin A­rich foods among Black, Hispanic, and White adults in the US.

Long-term outcomes of infective encephalitis in children: a systematic review and meta-analysis.

AIM: The long-term outcomes of childhood infective encephalitis are variable and not well quantified. We aimed to systematically review the literature and undertake meta-analyses on predetermined outcomes to address this knowledge gap and identify areas for future research. METHOD: We searched electronic databases, performed complementary reviews of references of fully extracted articles, and made contact with experts on infective encephalitis. Articles published up until April 2016 were selected for screening. RESULTS: We evaluated sequelae of 1018 survivors of childhood infective encephalitis (934 with complete follow-up) from 16 studies. Mean age during acute encephalitis episodes was 5 years 3.6 months (range 1.2mo-17y), 57.6% were male (500/868), and mean follow-up period was 4 years 1.2 months (range 1-12y). Incomplete recovery was reported in 312 children (42.0%; 95% confidence interval [CI] 31.6-53.1% in pooled estimate). Among the other sequelae, developmental delay, abnormal behaviour, motor impairment, and seizures were reported among 35.0% (95% CI 10.0-65.0%), 18.0% (95% CI 8.0-31.0%), 17.0% (95% CI 10.0-26.0%), and 10.0% (95% CI 6.0-14.0%) respectively. INTERPRETATION: Almost half of childhood infective encephalitis survivors report incomplete recovery in the long-term; most commonly developmental delay, behavioural abnormality, and neurological impairments (i.e. seizure). Well designed, large-scale prospective studies are needed to better quantify neurodevelopmental sequelae among childhood encephalitis survivors.

Bangladesh Cerebral Palsy Register (BCPR): a pilot study to develop a national cerebral palsy (CP) register with surveillance of children for CP.

BACKGROUND: The causes and pathogenesis of cerebral palsy (CP) are all poorly understood, particularly in low- and middle-income countries (LMIC). There are gaps in knowledge about CP in Bangladesh, especially in the spheres of epidemiological research, intervention and service utilization. In high-income countries CP registers have made substantial contributions to our understanding of CP. In this paper, we describe a pilot study protocol to develop, implement, and evaluate a CP population register in Bangladesh (i.e., Bangladesh Cerebral Palsy Register - BCPR) to facilitate studies on prevalence, severity, aetiology, associated impairments and risk factors for CP. METHODS/DESIGN: The BCPR will utilise a modified version of the Australian Cerebral Palsy Register (ACPR) on a secured web-based platform hosted by the Cerebral Palsy Alliance Research Institute, Australia. A standard BCPR record form (i.e., data collection form) has been developed in consultation with local and international experts. Using this form, the BPCR will capture information about maternal health, birth history and the nature of disability in all children with CP aged <18 years. The pilot will be conducted in the Shahjadpur sub-district of Sirajgonj district in the northern part of Bangladesh. There are 296 villages in Shahjadpur, a total population of 561,076 (child population ~ 226,114), an estimated 70,998 households and 12,117 live births per annum. Children with CP will be identified by using the community based Key Informants Method (KIM). Data from the completed BPCR record together with details of assessment by a research physician will be entered into an online data repository. DISCUSSION: Once implemented, BCPR will be, to the best of our knowledge, the first formalised CP register from a LMIC. Establishment of the BCPR will enable estimates of prevalence; facilitate clinical surveillance and promote research to improve the care of individuals with CP in Bangladesh.

Prevalence and trend of central nervous system-active medication polypharmacy among US commercially insured adults with vs without early-onset dementia: a multi-year cross-sectional study.

BACKGROUND: Limited data exist on the prevalence and trend of central nervous system (CNS)-active medication polypharmacy among adults with early-onset dementia (EOD) and whether these estimates differ for adults without EOD but with chronic pain, depression, or epilepsy, conditions managed by CNS-active medications. METHODS: A multi-year, cross-sectional study using 2012-2021 MarketScan Commercial Claims data was conducted among adults aged 30 to 64 years with EOD and those without EOD but having a diagnosis of chronic pain, depression, or epilepsy as comparison groups. For each disease cohort, the primary outcome was CNS-active medication polypharmacy defined as concurrent use of ≥ 3 CNS-active medications on the US Beers Criteria list that overlapped for > 30 consecutive days during 12 months following a randomly selected medical encounter with the disease diagnosis. A separate multivariate modified Poisson regression model was used to estimate time trends in CNS polypharmacy in each disease cohort. Differences in trend estimates between EOD and non-EOD disease cohorts were examined by an interaction between EOD status and yearly time. RESULTS: From 2013 to 2020, the annual crude prevalence of CNS polypharmacy was higher among adults with EOD (21.2%-25.0%) than adults with chronic pain (5.1%-5.9%), depression (14.8%-21.7%), or epilepsy (20.0%-22.3%). The adjusted annual prevalence of CNS polypharmacy among patients with EOD did not significantly change between 2013 and 2020 (adjusted prevalence rate ratio [aPRR], 0.94; 95% CI, 0.88-1.01), whereas a significant decreasing trend was observed among non-EOD cohorts with chronic pain (aPRR, 0.66; 95% CI, 0.63-0.69), depression (aPRR, 0.81; 95% CI, 0.77-0.85), and epilepsy (aPRR, 0.86; 95% CI, 0.83-0.89). The interaction analysis indicated that patients with epilepsy and depression (vs with EOD) had a decreasing probability of CNS-active medication polypharmacy over time (aPRR, 0.98 [95% CI, 0.98-0.99]; P < .001 for interaction for both conditions). CONCLUSIONS: The prevalence of CNS polypharmacy among US commercially insured adults with EOD (vs without) was higher and remained unchanged from 2013 to 2021. Medication reviews of adults with EOD and CNS polypharmacy are needed to ensure that benefits outweigh risks associated with combined use of these treatments.

Sociodemographic Characteristics of Adverse Event Reporting in the USA: An Ecologic Study.

INTRODUCTION: The Food and Drug Administration Adverse Event Reporting System (FAERS) is a vital source of new drug safety information, but whether adverse event (AE) information collected from these systems adequately captures experiences of the overall United States (US) population is unknown. OBJECTIVE: To examine determinants of consumer AE reporting in the USA. METHODS: Five-year AE reporting rate per 100,000 residents per US county were calculated, mapped, and quartiled for AE reports received directly from consumers between 2011 and 2015. Associations between county-level sociodemographic factors obtained from County Health Rankings and AE reporting rates were evaluated using negative binomial regression. RESULTS: Reporting rates were variable across US counties with > 17.6 reports versus ≤ 5.5 reports/100,000 residents in the highest and lowest reporting quartile, respectively. Controlling for drug utilization, counties with higher reporting rates had higher proportions of individuals age ≥ 65 years (e.g., 2.4% reporting increase per 1% increase in individuals age > 65, incidence rate ratio (IRR): 1.024, 95% confidence interval (CI): 1.017-1.030), higher proportions of females (IRR: 1.027, 95% CI 1.012-1.043), uninsured (IRR: 1.009, 95% CI 1.005-1.013), higher median log household incomes (IRR: 1.897, 95% CI 1.644-2.189) and more mental health providers per 100,000 residents (IRR: 1.003, 95% CI 1.001-1.004). Lower reporting was observed in counties with higher proportions of individuals age ≤ 18 years (IRR: 0.966, 95% CI 0.959-0.974), American Indian or Alaska Native individuals (IRR: 0.991, 95% CI 0.986-0.996), individuals not proficient in English (IRR: 0.978, 95% CI 0.965-0.991), and individuals residing in rural areas within a county (IRR: 0.998, 95% CI 0.997-0.998). CONCLUSIONS: Observed variations in consumer AE reporting may be related to sociodemographic factors and healthcare access. Because these factors may also correspond to AE susceptibility, voluntary AE reporting systems may be suboptimal for capturing emerging drug safety concerns among more vulnerable populations.

Use of CYP2D6 Inhibitors with CYP2D6 Opioids: Association with Emergency Department Visits for Pain.

Hydrocodone, tramadol, codeine, and oxycodone are commonly prescribed opioids that rely on activation by cytochrome P450 2D6 (CYP2D6). CYP2D6 inhibitors can significantly decrease CYP2D6 activity, leading to reduced generation of active metabolites, and impairing pain control. To understand this impact, we assessed emergency department (ED) visits in patients initiating these CYP2D6-dependent opioids while on CYP2D6-inhibitor antidepressants vs. antidepressants that do not inhibit CYP2D6. This retrospective cohort study included adult patients prescribed CYP2D6-dependent opioids utilizing electronic health records data from the University of Florida Health (2015-2021). The association between ED visits and inhibitor exposure was tested using multivariable logistic regression. The primary analysis had 12,118 patients (72% female; mean (SD) age, 55 (13.4)) in the hydrocodone/tramadol/codeine cohort and 5,547 patients (64% female; mean (SD) age, 53.6 (14.2)) in the oxycodone cohort. Hydrocodone/tramadol/codeine-treated patients exposed to CYP2D6-inhibitor antidepressants (n = 7,043) had a higher crude rate of pain-related ED visits than those taking other antidepressants (n = 5,075) (3.28% vs. 1.87%), with an adjusted odds ratio (aOR) of 1.75 (95% CI: 1.36 to 2.24). Similarly, in the oxycodone cohort, CYP2D6-inhibitor antidepressant-exposed individuals (n = 3,206) had a higher crude rate of ED visits than individuals exposed to other antidepressants (n = 2,341) (5.02% vs. 3.37%), with aOR of 1.70 (95% CI: 1.27-2.27). Similar findings were observed in secondary and sensitivity analyses. Our findings suggest patients with concomitant use of hydrocodone/tramadol/codeine or oxycodone and CYP2D6 inhibitors have more frequent ED visits for pain, which may be due to inadequate pain control.

Neglected medium-term and long-term consequences of labour and childbirth: a systematic analysis of the burden, recommended practices, and a way forward.

Over the past three decades, substantial progress has been made in reducing maternal mortality worldwide. However, the historical focus on mortality reduction has been accompanied by comparative neglect of labour and birth complications that can emerge or persist months or years postnatally. This paper addresses these overlooked conditions, arguing that their absence from the global health agenda and national action plans has led to the misconception that they are uncommon or unimportant. The historical limitation of postnatal care services to the 6 weeks after birth is also a contributing factor. We reviewed epidemiological data on medium-term and long-term complications arising from labour and childbirth beyond 6 weeks, along with high-quality clinical guidelines for their prevention, identification, and treatment. We explore the complex interplay of human evolution, maternal physiology, and inherent predispositions that contribute to these complications. We offer actionable recommendations to change the current trajectories of these neglected conditions and help achieve the targets of Sustainable Development Goal 3. This paper is the third in a Series of four papers about maternal health in the perinatal period and beyond.