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Background Lecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (Aβ), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease (AD) and mild AD dementia. Methods BAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. The primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer’s Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of ≥25% clinical reduction in decline versus placebo. Key secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography; clinical decline on ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14); changes in CSF core biomarkers; and total hippocampal volume (HV) using volumetric magnetic resonance imaging. Results A total of 854 randomized subjects were treated (lecanemab, 609; placebo, 245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly lecanemab reduced brain amyloid (−0.306 SUVr units) while showing a drug-placebo difference in favor of active treatment by 27% and 30% on ADCOMS, 56% and 47% on ADAS-Cog14, and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarkers were supportive of a treatment effect. Lecanemab was well-tolerated with 9.9% incidence of amyloid-related imaging abnormalities-edema/effusion at 10 mg/kg biweekly. Conclusions BAN2401-G000-201 did not meet the 12-month primary endpoint. However, prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints. A phase 3 study (Clarity AD) in early Alzheimer’s disease is underway. Trial registration Clinical Trials.gov NCT01767311 .

Existing health disparities based on race and ethnicity in the United States are contributing to disparities in morbidity and mortality during the coronavirus disease (COVID-19) pandemic. We conducted an online survey of American adults to assess similarities and differences by race and ethnicity with respect to COVID-19 symptoms, estimates of the extent of the pandemic, knowledge of control measures, and stigma. The aim of this study was to describe similarities and differences in COVID-19 symptoms, knowledge, and beliefs by race and ethnicity among adults in the United States. We conducted a cross-sectional survey from March 27, 2020 through April 1, 2020. Participants were recruited on social media platforms and completed the survey on a secure web-based survey platform. We used chi-square tests to compare characteristics related to COVID-19 by race and ethnicity. Statistical tests were corrected using the Holm Bonferroni correction to account for multiple comparisons. A total of 1435 participants completed the survey; 52 (3.6%) were Asian, 158 (11.0%) were non-Hispanic Black, 548 (38.2%) were Hispanic, 587 (40.9%) were non-Hispanic White, and 90 (6.3%) identified as other or multiple races. Only one symptom (sore throat) was found to be different based on race and ethnicity (P=.003); this symptom was less frequently reported by Asian (3/52, 5.8%), non-Hispanic Black (9/158, 5.7%), and other/multiple race (8/90, 8.9%) participants compared to those who were Hispanic (99/548, 18.1%) or non-Hispanic White (95/587, 16.2%). Non-Hispanic White and Asian participants were more likely to estimate that the number of current cases was at least 100,000 (P=.004) and were more likely to answer all 14 COVID-19 knowledge scale questions correctly (Asian participants, 13/52, 25.0%; non-Hispanic White participants, 180/587, 30.7%) compared to Hispanic (108/548, 19.7%) and non-Hispanic Black (25/158, 15.8%) participants. We observed differences with respect to knowledge of appropriate methods to prevent infection by the novel coronavirus that causes COVID-19. Deficits in knowledge of proper control methods may further exacerbate existing race/ethnicity disparities. Additional research is needed to identify trusted sources of information in Hispanic and non-Hispanic Black communities and create effective messaging to disseminate correct COVID-19 prevention and treatment information.

Background The COVID-19 pandemic continues to have high caseloads in the US, with vaccines a critical component of the response. Disparities in COVID-19 morbidity and mortality have been identified across states and racial/ethnic groups, which are likely in part due to disparities in COVID-19 vaccine uptake. This study aims to better understand and contextualize COVID-19 vaccine hesitancy among persons from under-represented racial/ethnic populations in the Southern US. Methods We conducted 29 in-depth interviews with a sample of households in Atlanta, GA that were selected from an address-based sampling frame. We purposively approached households, from February 6 to June 27, 2021, that declined participation in a national COVID-19 serosurvey to gain perspectives of people who are often under-represented in research. Interviews were conducted in-person or over phone calls for participants with that preference. Thematic analysis was used to identify barriers and facilitators of COVID-19 vaccination, and to contextualize drivers of vaccine hesitancy. Results Decision-making about vaccination was described as dynamic, and was compared to the feeling of being on a roller coaster. The predominant reported sources of information were mass media and social media. Facilitators of vaccination included altruism, positive communication from trusted community members and workplace colleagues, and local vaccine provision sites. Driving reasons for vaccine hesitancy included limited trust in the government and concerns about COVID-19 vaccine safety, which one participant compared to jumping off a cliff without a tested rope. Among a subset of participants, beliefs regarding perceived intent to harm the Black community were prevalent. Opportunities to optimally address vaccine hesitancy included countering negative social media messages with positive messaging that matches the community’s vivid ways of discussing vaccines, collaborating with community stakeholders on vaccine promotion efforts, and offering workplace-based vaccine promotion efforts. Conclusions This study presents data that indicate it may be optimal to more broadly define ‘community’ in COVID-19 vaccine promotion efforts to include social media and workplace venues. To optimize vaccine and vaccine booster uptake and equity, public health must address historic racism and other concerns by using outreach that is grounded in communities.

In the United States, both drug overdose mortality and injection-involved drug overdose mortality have increased nationally over the past 25 years. Despite documented geographic differences in overdose mortality and substances implicated in overdose mortality trends, injection-involved overdose mortality has not been summarized at a subnational level. We aimed to estimate the annual number of injection-involved overdose deaths in each US state from 2000 to 2020. We conducted a stratified analysis that used data from drug treatment admissions (Treatment Episodes Data Set-Admissions; TEDS-A) and the National Vital Statistics System (NVSS) to estimate state-specific percentages of reported drug overdose deaths that were injection-involved from 2000 to 2020. TEDS-A collects data on the route of administration and the type of substance used upon treatment admission. We used these data to calculate the percentage of reported injections for each drug type by demographic group (race or ethnicity, sex, and age group), year, and state. Additionally, using NVSS mortality data, the annual number of overdose deaths involving selected drug types was identified by the following specific multiple-cause-of-death codes: heroin or synthetic opioids other than methadone (T40.1, T40.4), natural or semisynthetic opioids and methadone (T40.2, T40.3), cocaine (T40.5), psychostimulants with abuse potential (T43.6), sedatives (T42.3, T42.4), and others (T36-T59.0). We used the probabilities of injection with the annual number of overdose deaths, by year, primary substance, and demographic groups to estimate the number of overdose deaths that were injection-involved. In 2020, there were 91,071 overdose deaths among adults recorded in the United States, and 93.1% (84,753/91,071) occurred in the 46 jurisdictions that reported data to TEDS-A. Slightly less than half (38,253/84,753, 45.1%; 95% CI 41.1%-49.8%) of those overdose deaths were estimated to be injection-involved, translating to 38,253 (95% CI 34,839-42,181) injection-involved overdose deaths in 2020. There was large variation among states in the estimated injection-involved overdose death rate (median 14.72, range 5.45-31.77 per 100,000 people). The national injection-involved overdose death rate increased by 323% (95% CI 255%-391%) from 2010 (3.78, 95% CI 3.33-4.31) to 2020 (15.97, 95% CI 14.55-17.61). States in which the estimated injection-involved overdose death rate increased faster than the national average were disproportionately concentrated in the Northeast region. Although overdose mortality and injection-involved overdose mortality have increased dramatically across the country, these trends have been more pronounced in some regions. A better understanding of state-level trends in injection-involved mortality can inform the prioritization of public health strategies that aim to reduce overdose mortality and prevent downstream consequences of injection drug use.

Introduction Pre‐exposure prophylaxis (PrEP) is highly effective in reducing the risk of HIV acquisition, but the population‐level impact of PrEP depends on the proportion of people with PrEP indications who use it (coverage) and how long they stay on it while at risk (persistence). We aimed to assess the extent to which PrEP persistence varied by race/ethnicity, sex and age. Methods Previously reported methods and US commercial pharmacy data identified PrEP users and days covered. We calculated PrEP Days Covered (PDC) as the annual number of pills dispensed (i.e., pill‐days) overall and by sex, race/ethnicity and age group. Statistical differences by demographic characteristics were calculated. To assess the potential impact of 2‐1‐1 PrEP dosing on median days of PrEP use, we compared 2018 and 2022 (pre‐ and post‐US Public Health Service guideline for 2‐1‐1 dosing). Results There were 225,180 PrEP users in 2018, and 459,984 in 2022. In 2022, the median PDC was 167 (IQR: 67, 308). There were 90 versus 180 median PDC for female and male users, respectively (difference of 90 PDC, 95% CI, 89.6−90.4). Among PrEP users with race/ethnicity data, the median PDC was higher for White non‐Hispanic (NH) (290 days) than Hispanic (268 days) or Black NH (251 days) users. Older users had significantly more PDC than younger users (<16 years: 60 days; 16–29 years: 120 days; 30–64 years: 191 days). Residents of states with PrEP‐Drug Assistance Programs (PrEP‐DAP) or Medicaid expansion had higher median PrEP duration than states without programmes. Median days covered for 2018 (154 days) and 2022 (167 days) did not suggest that the addition of the 2‐1‐1 PrEP guideline was associated with fewer covered days. Conclusions PrEP programmes are often evaluated by enumerating people who used PrEP at any time during a year; our data indicate that significant differences in days of PrEP covered among users might mask further inequities in PrEP protection among women, and Black, Hispanic and younger people. Evaluations of PrEP equity should include a pharmacoequity component by assessing days covered as an additional indicator of PrEP equity.

Trofinetide is the first drug to be approved by the US Food and Drug Administration for use in the treatment of patients with Rett syndrome, a multisystem disorder requiring multimodal therapies. Cytochrome P450 (CYP) 3A4 metabolizes >50% of therapeutic drugs and is the CYP isozyme most commonly expressed in the liver and intestines. In vitro studies suggest the concentration of trofinetide producing 50% inhibition (IC50) of CYP3A4 is >15 mmol/L; that concentration was much greater than the target clinical concentration associated with the maximal intended therapeutic dose (12 g). Thus, trofinetide has a low potential for drug–drug interactions in the liver. However, there is potential for drug–drug interactions in the intestines given the oral route of administration and expected relatively high concentration in the gastrointestinal tract after dose administration. Using a validated physiologically based pharmacokinetic (PBPK) model, deterministic and stochastic simulations were used for assessing the PK properties related to exposure and bioavailability of midazolam (sensitive index substrate for CYP3A4) following an oral (15 mg) or intravenous (2 mg) dose, with and without single-dose and steady-state (12 g) coadministration of oral trofinetide. Following coadministration of intravenous midazolam and oral trofinetide, the PK properties of midazolam were unchanged. The trofinetide concentration in the gut wall was >15 mmol/L during the first 1.5 hours after dosing. With the coadministration of oral midazolam and trofinetide, the model predicted increases in fraction of dose reaching the portal vein, bioavailability, Cmax, and AUCinf of 30%, 30%, 18%, and 30%, respectively. In this study that used a PBPK modeling approach, it was shown that CYP3A4 enzyme activity in the liver was not affected by trofinetide coadministration, but trofinetide was predicted to be a weak inhibitor of intestinal CYP3A4 metabolism after oral administration at therapeutic doses. [Display omitted]

Hepatitis C virus (HCV) infection is a leading cause of liver‐related morbidity and mortality, and more than 2 million adults in the United States are estimated to be currently infected. Reducing HCV burden will require an understanding of demographic disparities and targeted efforts to reduce prevalence in populations with disproportionate disease rates. We modeled state‐level estimates of hepatitis C prevalence among U.S. adults by sex, birth cohort, and race during 2013‐2016. National Health and Nutrition Examination Survey data were used in combination with state‐level HCV‐related and narcotic overdose–related mortality data from the National Vital Statistics System and estimates from external literature review on populations not sampled in the National Health and Nutrition Examination Survey. Nationally, estimated hepatitis C prevalence was 1.3% among males and 0.6% among females (prevalence ratio [PR] = 2.3). Among persons born during 1945 to 1969, prevalence was 1.6% compared with 0.5% among persons born after 1969 (PR = 3.2). Among persons born during 1945 to 1969, prevalence ranged from 0.7% in North Dakota to 3.6% in Oklahoma and 6.8% in the District of Columbia. Among persons born after 1969, prevalence was more than twice as high in Kentucky, New Mexico, Oklahoma, and West Virginia compared with the national average. Hepatitis C prevalence was 1.8% among non‐Hispanic black persons and 0.8% among persons of other races (PR = 2.2), and the magnitude of this disparity varied widely across jurisdictions (PR range: 1.3‐7.8). Overall, 23% of prevalent HCV infections occurred among non‐Hispanic black persons, whereas 12% of the population was represented by this racial group. These estimates provide information on prevalent HCV infections that jurisdictions can use for understanding and monitoring local disease patterns and racial disparities in burden of disease. We modeled state‐level estimates of hepatitis C prevalence among U.S. adults by sex, birth cohort, and race during 2013 to 2016. Among persons born during 1945 to 1969, prevalence was 1.6% compared with 0.5% among persons born after 1969 (PR = 3.2), but was more than twice as high among persons born after 1969 in Kentucky, New Mexico, Oklahoma, and West Virginia compared with the national average. Hepatitis C prevalence was 1.8% among non‐Hispanic black persons and 0.8% among persons of other races (PR = 2.2), and the magnitude of this disparity varied widely across jurisdictions (PR range: 1.3‐7.8).

Background Although reported condom use between female sex workers and their clients is high in Ethiopia, condom use with regular, non-paying partners remains low, posing a substantial risk of HIV infection to sex workers, their partners and the general population. Previous studies have identified the synergistic effects of substance abuse, violence and HIV risk, but few have examined these inter-relationships among female sex workers and their regular, non-paying partners. This study explored the associations between work-related violence, alcohol abuse and inconsistent condom use among establishment-based female sex workers and their regular, non-paying partners in Adama City, Ethiopia. Methods A cross-sectional survey was conducted with 350 establishment-based female sex workers, aged 15–35, at 63 bars, hotels and nightclubs. Multivariate logistic regression analysis was conducted to test the association between work-related violence and condom use with regular, non-paying partners, controlling for age, overall income, education and sex workers’ total number of sexual partners in the past week. Alcohol abuse was explored as an effect modifier. Results Respondents reported a high prevalence of work-related violence (59%) and alcohol abuse (51%). Work-related violence was statistically significantly associated with unprotected sex with regular, non-paying partners among those who abused alcohol (OR: 6.34, 95% CI: 2.43-16.56) and among those who did not (OR: 2.98, 95% CI: 1.36-6.54). Alcohol abuse was not associated with inconsistent condom use within these partnerships, though it may strengthen the effect of work-related violence on unprotected sex. Conclusions Findings suggest violence against establishment-based female sex workers is associated with HIV risk within regular, non-paying partnerships. Qualitative work is needed to better understand the links between a violent work environment and condom use with regular, non-paying partners and how interventions can be implemented in this context to prevent violence against sex workers and reduce HIV transmission.