Dynamics of racial disparities in all-cause mortality during the COVID-19 pandemic.

As research documenting disparate impacts of COVID-19 by race and ethnicity grows, little attention has been given to dynamics in mortality disparities during the pandemic and whether changes in disparities persist. We estimate age-standardized monthly all-cause mortality in the United States from January 2018 through February 2022 for seven racial/ethnic populations. Using joinpoint regression, we quantify trends in race-specific rate ratios relative to non-Hispanic White mortality to examine the magnitude of pandemic-related shifts in mortality disparities. Prepandemic disparities were stable from January 2018 through February 2020. With the start of the pandemic, relative mortality disadvantages increased for American Indian or Alaska Native (AIAN), Native Hawaiian or other Pacific Islander (NHOPI), and Black individuals, and relative mortality advantages decreased for Asian and Hispanic groups. Rate ratios generally increased during COVID-19 surges, with different patterns in the summer 2021 and winter 2021/2022 surges, when disparities approached prepandemic levels for Asian and Black individuals. However, two populations below age 65 fared worse than White individuals during these surges. For AIAN people, the observed rate ratio reached 2.25 (95% CI = 2.14, 2.37) in October 2021 vs. a prepandemic mean of 1.74 (95% CI = 1.62, 1.86), and for NHOPI people, the observed rate ratio reached 2.12 (95% CI = 1.92, 2.33) in August 2021 vs. a prepandemic mean of 1.31 (95% CI = 1.13, 1.49). Our results highlight the dynamic nature of racial/ethnic disparities in mortality and raise alarm about the exacerbation of mortality inequities for Indigenous groups due to the pandemic.

Informing Patient-Centered Care Through Stakeholder Engagement and Highly Stratified Quantitative Benefit-Harm Assessments.

OBJECTIVES: In a previous project aimed at informing patient-centered care for people with multiple chronic conditions, we performed highly stratified quantitative benefit-harm assessments for 2 top priority questions. In this current work, our goal was to describe the process and approaches we developed and to qualitatively glean important elements from it that address patient-centered care. METHODS: We engaged patients, caregivers, clinicians, and guideline developers as stakeholder representatives throughout the process of the quantitative benefit-harm assessment and investigated whether the benefit-harm balance differed based on patient preferences and characteristics (stratification). We refined strategies to select the most applicable, valid, and precise evidence. RESULTS: Two processes were important when assessing the balance of benefits and harms of interventions: (1) engaging stakeholders and (2) stratification by patient preferences and characteristics. Engaging patients and caregivers through focus groups, preference surveys, and as co-investigators provided value in prioritizing research questions, identifying relevant clinical outcomes, and clarifying the relative importance of these outcomes. Our strategies to select evidence for stratified benefit-harm assessments considered consistency across outcomes and subgroups. By quantitatively estimating the range in the benefit-harm balance resulting from true variation in preferences, we clarified whether the benefit-harm balance is preference sensitive. CONCLUSIONS: Our approaches for engaging patients and caregivers at all phases of the stratified quantitative benefit-harm assessments were feasible and revealed how sensitive the benefit-harm balance is to patient characteristics and individual preferences. Accordingly, this sensitivity can suggest to guideline developers when to tailor recommendations for specific patient subgroups or when to explicitly leave decision making to individual patients and their providers.

Global variation of risk thresholds for initiating statins for primary prevention of cardiovascular disease: a benefit-harm balance modelling study.

BACKGROUND: We previously showed that the 10-year cardiovascular disease (CVD) risk threshold to initiate statins for primary prevention depends on the baseline CVD risk, age, sex, and the incidence of statin-related harm outcome and competing risk for non-CVD death. As these factors appear to vary across countries, we aimed in this study to determine country-specific thresholds and provide guidelines a quantitative benefit-harm assessment method for local adaptation. METHODS: For each of the 186 countries included, we replicated the benefit-harm balance analysis using an exponential model to determine the thresholds to initiate statin use for populations aged 40 to 75 years, with no history of CVD. The analyses took data inputs from a priori studies, including statin effect estimates (network meta-analysis), patient preferences (survey), and baseline incidence of harm outcomes and competing risk for non-CVD (global burden of disease study). We estimated the risk thresholds above which the benefits of statins were more likely to outweigh the harms using a stochastic approach to account for statistical uncertainty of the input parameters. RESULTS: The 5th and 95th percentiles of the 10-year risk thresholds above which the benefits of statins outweigh the harms across 186 countries ranged between 14 and 20% in men and 19-24% in women, depending on age (i.e., 90% of the country-specific thresholds were in the ranges stated). The median risk thresholds varied from 14 to 18.5% in men and 19 to 22% in women. The between-country variability of the thresholds was slightly attenuated when further adjusted for age resulting, for example, in a 5th and 95th percentiles of 14-16% for ages 40-44 years and 17-21% for ages 70-74 years in men. Some countries, especially the islands of the Western Pacific Region, had higher thresholds to achieve net benefit of statins at 25-36% 10-year CVD risks. CONCLUSIONS: This extensive benefit-harm analysis modeling shows that a single CVD risk threshold, irrespective of age, sex and country, is not appropriate to initiate statin use globally. Instead, countries need to carefully determine thresholds, considering the national or subnational contexts, to optimize benefits of statins while minimizing related harms and economic burden.

Finding the Balance Between Benefits and Harms When Using Statins for Primary Prevention of Cardiovascular Disease: A Modeling Study.

Background: Many guidelines use expected risk for cardiovascular disease (CVD) during the next 10 years as a basis for recommendations on use of statins for primary prevention of CVD. However, how harms were considered and weighed against benefits is often unclear. Objective: To identify the expected risk above which statins provide net benefit. Design: Quantitative benefit-harm balance modeling study. Data Sources: Network meta-analysis of primary prevention trials, a preference survey, and selected observational studies. Target Population: Persons aged 40 to 75 years with no history of CVD. Time Horizon: 10 years. Perspective: Clinicians and guideline developers. Intervention: Low- or moderate-dose statin versus no statin. Outcome Measures: The 10-year risk for CVD at which statins provide at least a 60% probability of net benefit, with baseline risk, frequencies of and preferences for statin benefits and harms, and competing risk for non-CVD death taken into account. Results of Base-Case Analysis: Younger men had net benefit at a lower 10-year risk for CVD than older men (14% for ages 40 to 44 years vs. 21% for ages 70 to 75 years). In women, the risk required for net benefit was higher (17% for ages 40 to 44 years vs. 22% for ages 70 to 75 years). Atorvastatin and rosuvastatin provided net benefit at lower 10-year risks than simvastatin and pravastatin. Results of Sensitivity Analysis: Most alternative assumptions led to similar findings. Limitation: Age-specific data for some harms were not available. Conclusion: Statins provide net benefits at higher 10-year risks for CVD than are reflected in most current guidelines. In addition, the level of risk at which net benefit occurs varies considerably by age, sex, and statin type. Primary Funding Source: Swiss Government Excellence Scholarship Office, Béatrice Ederer-Weber Foundation, and North-South Cooperation at the University of Zurich.

Comparative effectiveness and safety of statins as a class and of specific statins for primary prevention of cardiovascular disease: A systematic review, meta-analysis, and network meta-analysis of randomized trials with 94,283 participants.

The current guidelines of statins for primary cardiovascular disease (CVD) prevention were based on results from systematic reviews and meta-analyses that suffer from limitations. METHODS: We searched in PubMed for existing systematic reviews and individual open-label or double-blinded randomized controlled trials that compared a statin with a placebo or another, which were published in English until January 01, 2018. We performed a random-effect pairwise meta-analysis of all statins as a class and network meta-analysis for the specific statins on different benefit and harm outcomes. RESULTS: In the pairwise meta-analyses, statins as a class showed statistically significant risk reductions on non-fatal MI (risk ratio [RR] 0.62, 95% CI 0.53-0.72), CVD mortality (RR 0.80, 0.71-0.91), all-cause mortality (RR 0.89, 0.85-0.93), non-fatal stroke (RR 0.83, 0.75-0.92), unstable angina (RR 0.75, 0.63-0.91), and composite major cardiovascular events (RR 0.74, 0.67-0.81). Statins increased statistically significantly relative and absolute risks of myopathy (RR 1.08, 1.01-1.15; Risk difference [RD] 13, 2-24 per 10,000 person-years); renal dysfunction (RR 1.12, 1.00-1.26; RD 16, 0-36 per 10,000 person-years); and hepatic dysfunction (RR 1.16, 1.02-1.31; RD 8, 1-16 per 10,000 person-years). The drug-level network meta-analyses showed that atorvastatin and rosuvastatin were most effective in reducing CVD events while atorvastatin appeared to have the best safety profile. CONCLUSIONS: All statins showed statistically significant risk reduction of CVD and all-cause mortality in primary prevention populations while increasing the risk for some harm risks. However, the benefit-harm profile differed by statin type. A quantitative assessment of the benefit-harm balance is thus needed since meta-analyses alone are insufficient to inform whether statins provide net benefit.

Outcome preferences of older people with multiple chronic conditions and hypertension: a cross-sectional survey using best-worst scaling.

BACKGROUND: Older people with hypertension and multiple chronic conditions (MCC) receive complex treatments and face challenging trade-offs. Patients' preferences for different health outcomes can impact multiple treatment decisions. Since evidence about outcome preferences is especially scarce among people with MCC our aim was to elicit preferences of people with MCC for outcomes related to hypertension, and to determine how these outcomes should be weighed when benefits and harms are assessed for patient-centered clinical practice guidelines and health economic assessments. METHODS: We sent a best-worst scaling preference survey to a random sample identified from a primary care network of Kaiser Permanente (Colorado, USA). The sample included individuals age 60 or greater with hypertension and at least two other chronic conditions. We assessed average ranking of patient-important outcomes using conditional logit regression (stroke, heart attack, heart failure, dialysis, cognitive impairment, chronic kidney disease, acute kidney injury, fainting, injurious falls, low blood pressure with dizziness, treatment burden) and studied variation across individuals. RESULTS: Of 450 invited participants, 217 (48%) completed the survey, and we excluded 10 respondents who had more than two missing choices, resulting in a final sample of 207 respondents. Participants ranked stroke as the most worrisome outcome and treatment burden as the least worrisome outcome (conditional logit parameters: 3.19 (standard error 0.09) for stroke, 0 for treatment burden). None of the outcomes were always chosen as the most or least worrisome by more than 25% of respondents, indicating that all outcomes were somewhat worrisome to respondents. Predefined subgroup analyses according to age, self-reported life-expectancy, degree of comorbidity, number of medications and antihypertensive treatment did not reveal meaningful differences. CONCLUSIONS: Although some outcomes were more worrisome to patients than others, our results indicate that none of the outcomes should be disregarded for clinical practice guidelines and health economic assessments.

Should statin guidelines consider patient preferences? Eliciting preferences of benefit and harm outcomes of statins for primary prevention of cardiovascular disease in the sub-Saharan African and European contexts.

BACKGROUND: Patient preferences are key parameters to evaluate benefit-harm balance of statins for primary prevention but they are not readily available to guideline developers and decision makers. Our study aimed to elicit patient preferences for benefit and harm outcomes related to use of statins for primary cardiovascular disease prevention and to examine how the preferences differ across economically and socio-culturally different environments. METHODS: We conducted preference-eliciting surveys using best-worst scaling designed with a balanced incomplete-block design (BIBD) on 13 statins-related outcomes on 220 people in Ethiopia and Switzerland. The participants made tradeoff decisions and selected the most and least worrisome outcomes concurrently from each scenario generated using the BIBD. The design yielded 34,320 implied paired-comparisons and 2860 paired-responses as unit of analysis for eliciting the preferences that were analyzed using a conditional-logit model on a relative scale and surface under the cumulative ranking curve from multivariate random-effects meta-analysis model on a scale of 0 to 1. RESULTS: There was high internal consistency of responses and minimal amount of measurement error in both surveys. Severe stroke was the most worrisome outcome with a ceiling preference of 1 (on 0 to 1 scale) followed by severe myocardial infarction, 0.913 (95% CI, 0.889-0.943), and cancer, 0.846 (0.829-0.855); while treatment discontinuation, 0.090 (0.023-0.123), and nausea/headache, 0.060 (0.034-0.094) were the least worrisome outcomes. Preferences were similar between Ethiopia and Switzerland with overlapping uncertainty intervals and concordance correlation of 0.97 (0.90-0.99). CONCLUSIONS: Our study provides much needed empirical evidence on preferences that help clinical guidelines consider for weighing the benefit and harm outcomes when recommending for or against statins for primary prevention of cardiovascular disease. The preferences are consistent across the disparate settings; however, we recommend inclusion of more countries in future studies to ensure the generalizability of the preferences to all environments.

A Physiologically Based Pharmacokinetic Model of Isoniazid and Its Application in Individualizing Tuberculosis Chemotherapy.

Due to its high early bactericidal activity, isoniazid (INH) plays an essential role in tuberculosis treatment. Genetic polymorphisms of N-acetyltransferase type 2 (NAT2) cause a trimodal distribution of INH pharmacokinetics in slow, intermediate, and fast acetylators. The success of INH-based chemotherapy is associated with acetylator and patient health status. Still, a standard dose recommended by the FDA is administered regardless of acetylator type or immune status, even though adverse effects occur in 5 to 33% of all patients. Slow acetylators have a higher risk of development of drug-induced toxicity, while fast acetylators and immune-deficient patients face lower treatment success rates. To mechanistically assess the trade-off between toxicity and efficacy, we developed a physiologically based pharmacokinetic (PBPK) model describing the NAT2-dependent pharmacokinetics of INH and its metabolites. We combined the PBPK model with a pharmacodynamic (PD) model of antimycobacterial drug effects in the lungs. The resulting PBPK/PD model allowed the simultaneous simulation of treatment efficacies at the site of infection and exposure to toxic metabolites in off-target organs. Subsequently, we evaluated various INH dosing regimens in NAT2-specific immunocompetent and immune-deficient virtual populations. Our results suggest the need for acetylator-specific dose adjustments for optimal treatment outcomes. A reduced dose for slow acetylators substantially lowers the exposure to toxic metabolites and thereby the risk of adverse events, while it maintains sufficient treatment efficacies. Vice versa, intermediate and fast acetylators benefit from increased INH doses and a switch to a twice-daily administration schedule. Our analysis outlines how PBPK/PD modeling may be used to design and individualize treatment regimens.

Adverse events reported during weekly isoniazid-rifapentine (3HP) tuberculosis preventive treatment among people living with HIV in Uganda.

Background: Short-course tuberculosis (TB) prevention regimens, including 12 weeks of isoniazid and rifapentine (3HP), are increasingly used in high TB-burden countries. Despite established safety and tolerability in efficacy trials, 3HP-related adverse events (AE) could differ in routine settings. Real-world data on AE type, frequency, and timing is crucial for health systems considering 3HP programmatic scale-up. Methods: We reviewed AEs among people living with HIV (PLHIV) participating in a pragmatic implementation trial of facilitated 3HP taken by directly observed therapy (DOT) or self-administered therapy (SAT) in Kampala, Uganda, and classified them using the Common Terminology Criteria for Adverse Events. We assessed AE timing and summarized related clinical actions including lab tests, diagnoses made, medications prescribed, and treatment interruptions. Results: Among 1655 PLHIV treated between July 2020-September 2022, 270 (16.3%) reported 451 events; main issues included general (7%), nervous system (6%), musculoskeletal (5%), gastrointestinal (5%), and dermatologic (3%) disorders. Most (61%) occurred within 6 weeks of initiating 3HP. Among those with events, 211 (78%) required further clinician evaluation, 202 (75%) required laboratory testing, 102 (38%) had medications prescribed, 40 (15%) had treatment paused, and 14 (5%) discontinued 3HP. Women, those multidimensionally impoverished, and DOT recipients were more likely to report an AE. SAT users and later enrollees were more likely to have 3HP interrupted or stopped due to an AE. Conclusions: In a routine setting, 3HP was safe with 16% of PLHIV reporting AEs and only 3% requiring temporary or permanent treatment interruption. These findings support 3HP expansion in routine HIV/AIDS care settings for TB prevention.

Evaluating the implementation of weekly rifapentine-isoniazid (3HP) for tuberculosis prevention among people living with HIV in Uganda: A qualitative evaluation of the 3HP Options Trial.

Three months of isoniazid-rifapentine (3HP) is being scaled up for tuberculosis (TB) preventive treatment (TPT) among people living with HIV (PLHIV) in high-burden settings. More evidence is needed to identify factors influencing successful 3HP delivery. We conducted a qualitative assessment of 3HP delivery nested within the 3HP Options Trial, which compared three optimized strategies for delivering 3HP: facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), and patient choice between facilitated DOT and facilitated SAT at the Mulago HIV/AIDS clinic in Kampala, Uganda. We conducted 72 in-depth interviews among PLHIV purposively selected to investigate factors influencing 3HP acceptance and completion. We conducted ten key informant interviews with healthcare providers (HCPs) involved in 3HP delivery to identify facilitators and barriers at the clinic level. We used post-trial 3HP delivery data to assess sustainability. We used thematic analysis (inductive and deductive) to align the emergent themes with the RE-AIM framework dimensions to report implementation outcomes. Understanding the need for TPT, once-weekly dosing, shorter duration, and perceived 3HP safety enhanced acceptance overall. Treatment monitoring by HCPs and reduced risk of HIV status disclosure enabled DOT acceptance. Dosing autonomy enabled SAT acceptance. Switching between DOT and SAT as needed enabled acceptance of patient choice. Dosing reminders, reimbursement for clinical visits, and social support enabled 3HP completion; pill burden, side effects, and COVID-19-related treatment restrictions hindered completion. All HCPs were trained and participated in 3HP delivery with high fidelity. Training, care integration, prior TPT experience with daily isoniazid, and few 3HP-related serious adverse events enabled adoption, whereas initial concerns about 3HP safety among HCPs, and COVID-19 treatment disruptions delayed 3HP adoption. Refresher training and collaboration among HCPs enabled implementation whereas limited diagnostic facilities for adverse events at the clinic hindered implementation. SAT was modified post-trial; DOT was discontinued due to inadequate ongoing financial support beyond the study period. Facilitated delivery strategies made 3HP treatment convenient for PLHIV and were feasible and implemented with high fidelity by HCPs. However, the costs of 3HP facilitation may limit wider scale-up. Trial registration: ClinicalTrials.gov (NCT03934931); Registered 2nd May 2019; https://clinicaltrials.gov/study/NCT03934931?id = NCT03934931&rank = 1.

Evaluating the implementation of weekly rifapentine-isoniazid (3HP) for tuberculosis prevention among people living with HIV in Uganda: A qualitative evaluation of the 3HP Options Trial.

Three months of isoniazid-rifapentine (3HP) is being scaled up for tuberculosis (TB) preventive treatment (TPT) among people living with HIV (PLHIV) in high-burden settings. More evidence is needed to identify factors influencing successful 3HP delivery. We conducted a qualitative assessment of 3HP delivery nested within the 3HP Options Trial, which compared three optimized strategies for delivering 3HP: facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), and patient choice between facilitated DOT and facilitated SAT at the Mulago HIV/AIDS clinic in Kampala, Uganda. We conducted 72 in-depth interviews among PLHIV purposively selected to investigate factors influencing 3HP acceptance and completion. We conducted ten key informant interviews with healthcare providers (HCPs) involved in 3HP delivery to identify facilitators and barriers at the clinic level. We used post-trial 3HP delivery data to assess sustainability. We conducted an inductive thematic analysis and aligned the emergent themes with the RE-AIM framework dimensions to report implementation outcomes. Understanding the need for TPT, once-weekly dosing, shorter duration, and perceived 3HP safety enhanced acceptance overall. Treatment monitoring by HCPs and reduced risk of HIV status disclosure enabled DOT acceptance. Dosing autonomy enabled SAT acceptance. Switching between DOT and SAT as required enabled acceptance for patient choice. Dosing reminders, reimbursement for clinical visits, and social support enabled 3HP completion; pill burden, side effects, and COVID-19-related treatment restrictions hindered completion. All HCPs were trained and participated in 3HP delivery with high fidelity. Training, care integration, and collaboration among HCPs enabled, whereas initial concerns about 3HP safety among HCPs delayed 3HP adoption and implementation. SAT was maintained post-trial; DOT was discontinued due to inadequate ongoing financial support beyond the study period. Facilitated delivery strategies made 3HP treatment convenient for PLHIV and were feasible and implemented with high fidelity by HCPs. However, the costs of 3HP facilitation may limit wider scale-up.

Best-worst scaling preferences among patients with well-controlled epilepsy: Pilot results.

Epilepsy is a common, serious condition. Fortunately, seizure risk decreases with increasing seizure-free time on antiseizure medications (ASMs). Eventually, patients may consider whether to stop ASMs, which requires weighing treatment benefit versus burden. We developed a questionnaire to quantify patient preferences relevant to ASM decision-making. Respondents rated how concerning they would finding relevant items (e.g., seizure risks, side effects, cost) on a Visual Analogue Scale (VAS, 0-100) and then repeatedly chose the most and least concerning item from subsets (best-worst scaling, BWS). We pretested with neurologists, then recruited adults with epilepsy who were seizure-free at least one year. Primary outcomes were recruitment rate, and qualitative and Likert-based feedback. Secondary outcomes included VAS ratings and best-minus-worst scores. Thirty-one of 60 (52%) contacted patients completed the study. Most patients felt VAS questions were clear (28; 90%), easy to use (27; 87%), and assessed preferences well (25; 83%). Corresponding results for BWS questions were 27 (87%), 29 (97%), and 23 (77%). Physicians suggested adding a 'warmup' question showing a completed example and simplifying terminology. Patients suggested ways to clarify instructions. Cost, inconvenience of taking medication, and laboratory monitoring were the least concerning items. Cognitive side effects and a 50% seizure risk in the next year were the most concerning items. Twelve (39%) of patients made at least one 'inconsistent choice' for example ranking a higher seizure risk as lower concern compared with a lower seizure risk, though 'inconsistent choices' represented only 3% of all question blocks. Our recruitment rate was favorable, most patients agreed the survey was clear, and we describe areas for improvement. 'Inconsistent' responses may lead us to collapse seizure probability items into a single 'seizure' category. Evidence regarding how patients weigh benefits and harms may inform care and guideline development.

Recovery and symptom trajectories up to two years after SARS-CoV-2 infection: population based, longitudinal cohort study.

OBJECTIVE: To evaluate longer term symptoms and health outcomes associated with post-covid-19 condition within a cohort of individuals with a SARS-CoV-2 infection. DESIGN: Population based, longitudinal cohort. SETTING: General population of canton of Zurich, Switzerland. PARTICIPANTS: 1106 adults with a confirmed SARS-CoV-2 infection who were not vaccinated before infection and 628 adults who did not have an infection. MAIN OUTCOME MEASURES: Trajectories of self-reported health status and covid-19 related symptoms between months six, 12, 18, and 24 after infection and excess risk of symptoms at six months after infection compared with individuals who had no infection. RESULTS: 22.9% (95% confidence interval 20.4% to 25.6%) of individuals infected with SARS-CoV-2 did not fully recover by six months. The proportion of individuals who had an infection who reported not having recovered decreased to 18.5% (16.2% to 21.1%) at 12 months and 17.2% (14.0% to 20.8%) at 24 months after infection. When assessing changes in self-reported health status, most participants had continued recovery (68.4% (63.8% to 72.6%)) or had an overall improvement (13.5% (10.6% to 17.2%)) over time. Yet, 5.2% (3.5% to 7.7%) had a worsening in health status and 4.4% (2.9% to 6.7%) had alternating periods of recovery and health impairment. The point prevalence and severity of covid-19 related symptoms also decreased over time, with 18.1% (14.8% to 21.9%) reporting symptoms at 24 months. 8.9% (6.5% to 11.2%) of participants reported symptoms at all four follow-up time points, while in 12.5% (9.8% to 15.9%) symptoms were alternatingly absent and present. Symptom prevalence was higher among individuals who were infected compared with those who were not at six months (adjusted risk difference 17.0% (11.5% to 22.4%)). Excess risk (adjusted risk difference) for individual symptoms among those infected ranged from 2% to 10%, with the highest excess risks observed for altered taste or smell (9.8% (7.7% to 11.8%)), post-exertional malaise (9.4% (6.1% to 12.7%)), fatigue (5.4% (1.2% to 9.5%)), dyspnoea (7.8% (5.2% to 10.4%)), and reduced concentration (8.3% (6.0% to 10.7%)) and memory (5.7% (3.5% to 7.9%)). CONCLUSIONS: Up to 18% of individuals who were not vaccinated before infection had post-covid-19 condition up to two years after infection, with evidence of excess symptom risk compared with controls. Effective interventions are needed to reduce the burden of post-covid-19 condition. Use of multiple outcome measures and consideration of the expected rates of recovery and heterogeneity in symptom trajectories are important in the design and interpretation of clinical trials. REGISTRATIONS: ISRCTN18181860, .

Preferences of people living with HIV for features of tuberculosis preventive treatment regimens - a discrete choice experiment.

Background: Tuberculosis (TB) preventive treatment (TPT) is recommended for people living with HIV (PLHIV) in high TB burden settings. While 6 months of daily isoniazid remains widely used, shorter regimens are now available. However, little is known about preferences of PLHIV for key features of TPT regimens. Methods: We conducted a discrete choice experiment among adult PLHIV engaged in care at an urban HIV clinic in Kampala, Uganda. In nine random choice tasks, participants chose between two hypothetical TPT regimens with different features (pills per dose, frequency, duration, need for adjusted antiretroviral therapy [ART] dosage and side effects). We analyzed preferences using hierarchical Bayesian estimation, latent class analysis, and willingness-to-trade simulations. Results: Of 400 PLHIV, 392 (median age 44, 72% female, 91% TPT-experienced) had high quality choice task responses. Pills per dose was the most important attribute (relative importance 32.4%, 95% confidence interval [CI] 31.6 - 33.2), followed by frequency (20.5% [95% CI 19.7 - 21.3]), duration (19.5% [95% CI 18.6 - 20.5]), and need for ART dosage adjustment (18.2% [95% CI 17.2 - 19.2]). Latent class analysis identified three preference groups: one prioritized less frequent, weekly dosing (N=222; 57%); another was averse to ART dosage adjustment (N=107; 27%); and the last prioritized short and tolerable regimens (N=63; 16%). All groups highly valued fewer pills per dose. Participants were willing to accept a regimen of 2.8 months' additional duration [95% CI: 2.4 - 3.2] to reduce pills per dose from five to one, 3.6 [95% CI 2.4 - 4.8] months for weekly rather than daily dosing, and 2.2 [95% CI 1.3 - 3.0] months to avoid ART dosage adjustment. Conclusions: To align with preferences of PLHIV, decision-makers should prioritize the development and implementation of TPT regimens with fewer pills, less frequent dosing, and no need for ART dosage adjustment, rather than focus primarily on duration of treatment.

Excess Mortality With Alzheimer Disease and Related Dementias as an Underlying or Contributing Cause During the COVID-19 Pandemic in the US.

Importance: Adults with Alzheimer disease and related dementias (ADRD) are particularly vulnerable to the direct and indirect effects of the COVID-19 pandemic. Deaths associated with ADRD increased substantially in pandemic year 1. It is unclear whether mortality associated with ADRD declined when better prevention strategies, testing, and vaccines became widely available in year 2. Objective: To compare pandemic-era excess deaths associated with ADRD between year 1 and year 2 overall and by age, sex, race and ethnicity, and place of death. Design, Setting, and Participants: This time series analysis used all death certificates of US decedents 65 years and older with ADRD as an underlying or contributing cause of death from January 2014 through February 2022. Exposure: COVID-19 pandemic era. Main Outcomes and Measures: Pandemic-era excess deaths associated with ADRD were defined as the difference between deaths with ADRD as an underlying or contributing cause observed from March 2020 to February 2021 (year 1) and March 2021 to February 2022 (year 2) compared with expected deaths during this period. Expected deaths were estimated using data from January 2014 to February 2020 fitted with autoregressive integrated moving average models. Results: Overall, 2 334 101 death certificates were analyzed. A total of 94 688 (95% prediction interval [PI], 84 192-104 890) pandemic-era excess deaths with ADRD were estimated in year 1 and 21 586 (95% PI, 10 631-32 450) in year 2. Declines in ADRD-related deaths in year 2 were substantial for every age, sex, and racial and ethnic group evaluated. Pandemic-era ADRD-related excess deaths declined among nursing home/long-term care residents (from 34 259 [95% PI, 25 819-42 677] in year 1 to -22 050 [95% PI, -30 765 to -13 273] in year 2), but excess deaths at home remained high (from 34 487 [95% PI, 32 815-36 142] in year 1 to 28 804 [95% PI, 27 067-30 571] in year 2). Conclusions and Relevance: This study found that large increases in mortality with ADRD as an underlying or contributing cause of death occurred in COVID-19 pandemic year 1 but were largely mitigated in pandemic year 2. The most pronounced declines were observed for deaths in nursing home/long-term care settings. Conversely, excess deaths at home and in medical facilities remained high in year 2.

Fingolimod versus interferon beta 1-a: Benefit-harm assessment approach based on TRANSFORMS individual patient data.

Background: Fingolimod is a disease-modifying drug approved for multiple sclerosis but its benefit-harm balance has never been assessed compared to other active treatments. Objectives: Our aim was to compare the benefits and harms of fingolimod with interferon beta-1a using individual patient data from TRial Assessing injectable interferon versus FTY720 Oral in RRMS trial. Methods: We modelled the health status of patients over time including Expanded Disability Status Scale measurements, relapses and any adverse events. We assessed the mean health status between arms and the proportion of patients whose health deteriorated or improved relatively to baseline, using a prespecified minimal important difference of 4.6. We performed sensitivity analyses to test our assumptions. Results: Main and sensitivity analyses favoured fingolimod 0.5 mg over interferon beta-1a. The average health status difference was 1.01 (95% CI 0.93-1.08). Patients on fingolimod 0.5 mg were 0.47 (95% CI: 0.35-0.63, p < 0.001) times less likely to experience a relevant decline in health status compared to interferon beta-1a patients, with a number needed to treat of 7.10 [5.18, 11.23]. Conclusions: Fingolimod's net benefit over interferon beta-1a did not reach the clinical relevance over 1 year, but the decreased risk for health status deterioration may be more pronounced more long term and patients may prefer less treatment burden associated with fingolimod.

Individual-Level Evaluation of the Exposure Notification Cascade in the SwissCovid Digital Proximity Tracing App: Observational Study.

BACKGROUND: Digital proximity tracing (DPT) aims to complement manual contact tracing (MCT) in identifying exposed contacts and preventing further transmission of SARS-CoV-2 in the population. Although several DPT apps, including SwissCovid, have shown to have promising effects on mitigating the pandemic, several challenges have impeded them from fully achieving the desired results. A key question now relates to how the effectiveness of DPT can be improved, which requires a better understanding of factors influencing its processes. OBJECTIVE: In this study, we aim to provide a detailed examination of the exposure notification (EN) cascade and to evaluate potential contextual influences for successful receipt of an EN and subsequent actions taken by cases and contacts in different exposure settings. METHODS: We used data from 285 pairs of SARS-CoV-2-infected cases and their contacts within an observational cohort study of cases and contacts identified by MCT and enrolled between August 6, 2020, and January 17, 2021, in the canton of Zurich, Switzerland. We surveyed participants with electronic questionnaires. Data were summarized descriptively and stratified by exposure setting. RESULTS: We found that only 79 (58.5%) of 135 contacts using the SwissCovid app whose corresponding cases reported to have triggered the EN also received one. Of these, 18 (22.8%) received the EN before MCT. Compared to those receiving an EN after MCT (61/79, 77.2%), we observed that a higher proportion of contacts receiving an EN before MCT were exposed in nonhousehold settings (11/18, 61.1%, vs 34/61, 55.7%) and their corresponding cases had more frequently reported mild-to-moderate symptoms (14/18, 77.8%, vs 42/61, 68.9%). Of the 18 contacts receiving an EN before MCT, 14 (77.8%) took recommended measures: 12 (66.7%) were tested for SARS-CoV-2, and 7 (38.9%) called the SwissCovid Infoline. In nonhousehold settings, the proportion of contacts taking preventive actions after receiving an EN was higher compared to same-household settings (82%, vs 67%). In addition, 1 (9%) of 11 ENs received in the nonhousehold setting before MCT led to the identification of a SARS-CoV-2-infected case by prompting the contact to get tested. This corresponds to 1 in 85 exposures of a contact to a case in a nonhousehold setting, in which both were app users and the case triggered the EN. CONCLUSIONS: Our descriptive evaluation of the DPT notification cascade provides further evidence that DPT is an important complementary tool in pandemic mitigation, especially in nonhousehold exposure settings. However, the effect of DPT apps can only be exerted if code generation processes are efficient and exposed contacts are willing to undertake preventive actions. This highlights the need to focus efforts on keeping barriers to efficient code generation as low as possible and promoting not only app adoption but also compliance with the recommended measures upon an EN. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Registry 14990068; https://doi.org/10.1186/ISRCTN14990068.