Undermining the Translational Potential of Clinical Research with Adolescents and Young Adults: Differential Enrollment in Randomized Clinical Trials During COVID-19.

BACKGROUND: COVID-19 stay-at-home orders and research restrictions halted recruitment and follow-up of clinical research patients. While clinical research has resumed, it is an open question whether research participation has returned to levels similar to those before COVID-19. METHODS: We utilized data from the TECH-PN (NCT# NCT03828994) study, a single-center RCT enrolling 13-25-year-olds with mild-moderate pelvic inflammatory disease (PID) receiving ambulatory care. We examined enrollment patterns before COVID-19 and during/after COVID-19 among those assessed for eligibility by estimating the average rate of recruitment visits for each period. We focused on this monthly rate by pandemic status, the length of stay (LOS) by pandemic status, as well as the relationship between the LOS and patient demographics. Descriptive analyses were conducted, including Student's t-test to compare rates between time periods and a Chi-square test to compare the proportion refusing enrollment. RESULTS: The monthly enrollment rate during/post-pandemic was significantly lower than before COVID-19 (4.8 per month compared to 7.4 per month, p < 0.001). However, eligible participants' age, race, and insurance type were similar pre- and during/post-pandemic. Among eligible patients, LOS for receiving PID care was slightly increased, from a median of 5.4 hours to 6.4 hours (p = 0.650), and the rate of refusal to participate among those eligible was similar (23% versus 27%, p = 0.362). There was a similar number of ineligible patients due to inpatient admissions during both periods. CONCLUSION: COVID-19 pandemic restrictions negatively impacted recruitment into this RCT. Enrollment differences may reflect ongoing perceptions of restrictions in care access or a hesitancy to use health services. More research is needed to stabilize access to ambulatory STI/PID care and access to clinical trials.

Lack of racial and ethnic disparities in mortality in minority patients hospitalised with COVID-19 in a mid-Atlantic healthcare system.

INTRODUCTION: In the USA, minoritised communities (racial and ethnic) have suffered disproportionately from COVID-19 compared with non-Hispanic white communities. In a large cohort of patients hospitalised for COVID-19 in a healthcare system spanning five adult hospitals, we analysed outcomes of patients based on race and ethnicity. METHODS: This was a retrospective cohort analysis of patients 18 years or older admitted to five hospitals in the mid-Atlantic area between 4 March 2020 and 27 May 2022 with confirmed COVID-19. Participants were divided into four groups based on their race/ethnicity: non-Hispanic black, non-Hispanic white, Latinx and other. Propensity score weighted generalised linear models were used to assess the association between race/ethnicity and the primary outcome of in-hospital mortality. RESULTS: Of the 9651 participants in the cohort, more than half were aged 18-64 years old (56%) and 51% of the cohort were females. Non-Hispanic white patients had higher mortality (p<0.001) and longer hospital length-of-stay (p<0.001) than Latinx and non-Hispanic black patients. DISCUSSION: In this large multihospital cohort of patients admitted with COVID-19, non-Hispanic black and Hispanic patients did not have worse outcomes than white patients. Such findings likely reflect how the complex range of factors that resulted in a life-threatening and disproportionate impact of incidence on certain vulnerable populations by COVID-19 in the community was offset through admission at well-resourced hospitals and healthcare systems. However, there continues to remain a need for efforts to address the significant pre-existing race and ethnicity inequities highlighted by the COVID-19 pandemic to be better prepared for future public health emergencies.

Estimated global and regional causes of deaths from diarrhoea in children younger than 5 years during 2000-21: a systematic review and Bayesian multinomial analysis.

BACKGROUND: Information on the causes of deaths from diarrhoea in children younger than 5 years is needed to design improved preventive and therapeutic approaches. We aimed to conduct a systematic analysis of studies to report estimates of the causes of deaths from diarrhoea in children younger than 5 years at global and regional levels during 2000-21. METHODS: For this systematic review and Bayesian multinomial analysis, we included 12 pathogens with the highest attributable incidence in the Global Enteric Multicenter Study. We searched PubMed, Scopus, Embase, Web of Science, Global Health Index Medicus, Global Health OVID, IndMed, Health Information Platform for the Americas (PLISA), Africa-Wide Information, and Cochrane Collaboration for articles published between Jan 1, 2000, and Dec 31, 2020, using the search terms "child", "hospital", "diarrhea", "diarrhoea", "dysentery", "rotavirus", "Escherichia coli", "salmonella", "shigella", "campylobacter", "Vibrio cholerae", "cryptosporidium", "norovirus", "astrovirus", "sapovirus", and "adenovirus". To be included, studies had to have a patient population of children younger than 5 years who were hospitalised for diarrhoea (at least 90% of study participants), at least a 12-month duration, reported prevalence in diarrhoeal stools of at least two of the 12 pathogens, all patients with diarrhoea being included at the study site or a systematic sample, at least 100 patients with diarrhoea, laboratory tests done on rectal swabs or stool samples, and standard laboratory methods (ie, quantitative PCR [qPCR] or non-qPCR). Studies published in any language were included. Studies were excluded if they were limited to nosocomial, chronic, antibiotic-associated, or outbreak diarrhoea or to a specific population (eg, only children with HIV or AIDS). Each article was independently reviewed by two researchers; a third arbitrated in case of disagreement. If both reviewers identified an exclusion criterion, the study was excluded. Data sought were summary estimates. Data on causes from published studies were adjusted when necessary to account for the poor sensitivity of non-qPCR methods and for attributable fraction based on quantification of pathogens in children who are ill or non-ill. The causes of deaths from diarrhoea were modelled on the causes of hospitalisations for diarrhoea. We separately modelled studies reporting causes of diarrhoea in children who were hospitalised in low-income and middle-income countries (LMICs) and in high-income countries (HICs). FINDINGS: Of 74 282 papers identified in the initial database search, we included 138 studies (91 included data from LMICs and 47 included data from HICs) from 73 countries. We modelled estimates for 194 WHO member states (hereafter referred to as countries), including 42 HICs and 152 LMICs. We could attribute a cause to 1 003 448 (83·8%) of the estimated 1 197 044 global deaths from diarrhoea in children younger than 5 years in 2000 and 360 730 (81·3%) of the estimated 443 833 global deaths from diarrhoea in children younger than 5 years in 2021. The cause with the largest estimated global attribution was rotavirus; in LMICs, the proportion of deaths from diarrhoea due to rotavirus in children younger than 5 years appeared lower in 2021 (108 322 [24·4%] of 443 342, 95% uncertainty interval 21·6-29·5) than in 2000 (316 382 [26·5%] of 1 196 134, 25·7-28·5), but the 95% CIs overlapped. In 2000, the second largest estimated attribution was norovirus GII (95 817 [8·0%] of 1 196 134 in LMICs and 225 [24·7%] of 910 in HICs); in 2021, Shigella sp had the second largest estimated attribution in LMICs (36 082 [8·1%] of 443 342), but norovirus remained with the second largest estimated attribution in HICs (84 [17·1%] of 490). INTERPRETATION: Our results indicate progress in the reduction of deaths from diarrhoea caused by 12 pathogens in children younger than 5 years in the past two decades. There is a need to increase efforts for prevention, including with rotavirus vaccine, and treatment to eliminate further deaths. FUNDING: Bill & Melinda Gates Foundation via Johns Hopkins University and the University of Virginia.

Anxiety-focused cognitive behavioral therapy delivered by non-specialists to prevent postnatal depression: a randomized, phase 3 trial.

Anxiety experienced by women during pregnancy is highly prevalent, especially in resource-poor settings and strongly predicts postnatal common mental disorders (CMDs), anxiety and depression. We evaluated the effectiveness of an anxiety-focused early prenatal intervention on preventing postnatal CMDs. This study was a phase 3, two-arm, single-blind, randomized controlled trial conducted in Pakistan with women who were ≤22 weeks pregnant and had at least mild anxiety without clinical depression. Participants were randomized to the Happy Mother-Healthy Baby program, based on cognitive behavioral therapy, consisting of six one-on-one intervention sessions in pregnancy delivered by non-specialist providers, or to enhanced care alone. The primary outcome was major depression, generalized anxiety disorder or both at 6 weeks after delivery. Overall, 755 women completed postnatal assessments (380 (50.3%), intervention arm; 375 (49.7%) enhanced-care arm). The primary outcomes were met. Examined jointly, we found 81% reduced odds of having either a major depressive episode (MDE) or moderate-to-severe anxiety for women randomized to the intervention (adjusted odds ratio (aOR) = 0.19, 95% CI 0.14-0.28). Overall, 12% of women in the intervention group developed MDE at 6 weeks postpartum, versus 41% in the control group. We found reductions of 81% and 74% in the odds of postnatal MDE (aOR = 0.19, 95% CI 0.13-0.28) and of moderate-to-severe anxiety (aOR = 0.26, 95% CI 0.17-0.40), respectively. The Happy Mother-Healthy Baby program early prenatal intervention focusing on anxiety symptoms reduced postpartum CMDs. ClinicalTrials.gov identifier NCT03880032 .

Factors affecting early childhood growth in hypoxic-ischemic encephalopathy treated with hypothermia.

INTRODUCTION: There is an extensive body of research regarding neurological outcomes following neonatal hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH), with limited data on growth outcomes. We examined perinatal characteristics associated with postnatal growth in this population. METHODS: Convenience cohort of 66 infants with HIE who underwent TH and participated in follow-up at 24 months of age were included. Regression modeling including perinatal anthropomorphics, markers of HIE, and systemic injury was used to evaluate growth at 24 months. RESULTS: Birth head circumference was associated with weight (p = 0.036). MRI severity, pH at admission and birth head circumference were associated with height (p = 0.043, p = 0.015 and p = 0.043 respectively). MRI severity and length of intubation were associated with head circumference (p = 0.038 and p < 0.001 respectively). CONCLUSION: There was a significant association between specific early factors and growth at 24 months among infants with HIE treated with TH.

Immunogenicity of 2-Dose HPV Vaccine Series for Postpartum Women: An Open-Label, Nonrandomized, Noninferiority Trial.

Importance: Postpartum human papillomavirus (HPV) vaccination is a promising strategy to increase HPV vaccination uptake in the US, particularly for reaching vaccine-naive women and those who lack health insurance beyond the pregnancy period. However, completion of the 3-dose vaccine regimen is challenging. Objective: To evaluate the immunogenicity of a 2-dose postpartum HPV vaccination regimen (0 and 6 months) and assess whether it is noninferior to a 3-dose postpartum HPV vaccination regimen (0, 1-2, and 6 months) administered to historical controls. Design, Setting, and Participants: A noninferiority, open-label, nonrandomized immunogenicity trial was conducted from August 4, 2020, to June 23, 2022, of postpartum patients aged 15 to 45 years who delivered at 2 hospitals in Baltimore, Maryland. Historical controls were adolescents and young women aged 16 to 26 years. Intervention: Two doses of the nonavalent HPV vaccine administered 6 months apart. Main Outcomes and Measures: The primary outcome was noninferiority (90% CI, lower bound >0.67) of the geometric mean titer (GMT) ratio for HPV-16 among postpartum women compared with historical controls. Secondary outcomes were noninferiority of GMT ratios for the other 8 HPV types and percentage seroconversion for each HPV type. As a noninferiority trial, the primary analysis used the per-protocol analysis. Results: Of 225 enrolled participants, the mean (SD) age at baseline was 29.9 (6.8) years, and 171 (76.0%) were HPV-16 seronegative at baseline. Of these 171 participants, 129 (75.4%) received a second vaccine dose and completed the subsequent 4-week serologic measurements. Relative to historical controls, the HPV-16 GMT ratio was 2.29 (90% CI, 2.03-2.58). At month 7, HPV-16 GMT was higher after the 2-dose regimen (7213.1 mMU/mL [90% CI, 6245.0-8331.4 mMU/mL]) than among historic controls after the 3-dose regimen (3154.0 mMU/mL [90% CI, 2860.2-3478.0 mMU/mL]). Similarly, the lower bound of the 90% CI of the GMT ratio was above 1 for the 8 HPV types 6, 11, 18, 31, 33, 45, 52, and 58. A total of 118 of 134 women (88.1%) seroconverted for HPV-16 after the first dose; 4 weeks after the second dose, the seroconversion rate was 99% or greater for all HPV types. Conclusions and Relevance: This study suggests that immunogenicity of a 2-dose HPV vaccination regimen given 6 months apart among postpartum women was noninferior to a 3-dose regimen among young historical controls. Most women seroconverted after the first dose of the 2-dose regimen. These results demonstrate that postpartum vaccination using a reduced schedule may be a promising strategy to increase HPV vaccine series completion. Trial Registration: ClinicalTrials.gov Identifier: NCT04274153.

Anti-Gephyrin Antibodies: A Novel Specificity in Patients With Systemic Sclerosis and Lower Bowel Dysfunction.

OBJECTIVE: Autoantibodies are clinically useful in phenotyping patients with systemic sclerosis (SSc). Gastrointestinal (GI) function is regulated by the enteric nervous system (ENS) and commonly impaired in SSc, suggesting that the SSc autoimmune response may target ENS antigens. We sought to identify novel anti-ENS autoantibodies with an aim to clinically phenotype SSc GI dysfunction. METHODS: Serum from a patient with SSc with GI dysfunction but without defined SSc-associated autoantibodies was used for autoantibody discovery. Immunoprecipitations performed with murine myenteric plexus lysates were on-bead digested, and autoantigens were identified by mass spectrometry. Prevalence was determined, and clinical features associated with novel autoantibodies were evaluated in a SSc cohort using regression analyses. The expression of gephyrin in human GI tract tissue was examined by immunohistochemistry. RESULTS: We identified gephyrin as a novel SSc autoantigen. Anti-gephyrin antibodies were present in 9% of patients with SSc (16/188) and absent in healthy controls (0/46). Anti-gephyrin antibody-positive patients had higher constipation scores (1.00 vs 0.50, P = 0.02) and were more likely to have severe constipation and severe distention/bloating (46% vs 15%, P = 0.005; 54% vs 25%, P = 0.023, respectively). Anti-gephyrin antibody levels were significantly higher among patients with severe constipation (0.04 vs 0.00; P = 0.001) and severe distention and bloating (0.03 vs 0.004; P = 0.010). Severe constipation was associated with anti-gephyrin antibodies even in the adjusted model. Importantly, gephyrin was expressed in the ENS, which regulates gut motility. CONCLUSION: Gephyrin is a novel ENS autoantigen that is expressed in human myenteric ganglia. Anti-gephyrin autoantibodies are associated with the presence and severity of constipation in patients with SSc.

Development and evaluation of measures to assess self-determination in peripartum contraceptive decision-making.

OBJECTIVES: We aimed to adapt and validate person-centered measures to evaluate various contributors to self-determination in perinatal contraceptive decision-making. STUDY DESIGN: We developed and administered four scales adapted from existing measures in the context of Self-Determination Theory: the Treatment Self-Regulation Questionnaire (TSRQ), Perceived Competence Scale, modified Health Care Climate Questionnaire, and Important Other Climate Questionnaire. The TSRQ consists of three subscales: autonomous motivation, controlled motivation, and amotivation. We recruited a nonprobability convenience sample of 300 hospitalized postpartum patients in Baltimore, MD, between 2015 and 2016 and administered surveys in English and Spanish. We validated the scales with Cronbach's alpha coefficients, confirmatory factor analysis, and invariance analysis. We examined construct validity by testing correlations between the scales and other person-centered measures, such as satisfaction with counseling. RESULTS: Cronbach's alpha was >0.8 except for the amotivation subscale. Confirmatory factor analysis was adequate for all scales. Autonomous motivation correlated positively and significantly with perceived competence, health care provider autonomy support, important other autonomy support, and other measures of patient satisfaction. CONCLUSIONS: We found the four scales to be internally consistent and valid except for the amotivation subscale. We recommend using the autonomous motivation subscale in place of the full TSRQ. The autonomous motivation subscale, Perceived Competence Scale, modified Health Care Climate Questionnaire, and Important Other Climate Questionnaire showed adequate internal consistency, construct validity, and adherence to the expected conceptual structure of the scales. IMPLICATIONS: Autonomous decision-making is central to ethics and quality of care, especially for contraceptive methods that require a provider for initiation or discontinuation and at more vulnerable times, such as postpartum and postabortion. These scales may help tailor person-centered and autonomy-supportive interventions and programs to improve contraceptive counseling and care delivery.

Maternal interventions to decrease stillbirths and neonatal mortality in Tanzania: evidence from the 2017-18 cross-sectional Tanzania verbal and social autopsy study.

BACKGROUND: Reduction of Tanzania's neonatal mortality rate has lagged behind that for all under-fives, and perinatal mortality has remained stagnant over the past two decades. We conducted a national verbal and social autopsy (VASA) study to estimate the causes and social determinants of stillbirths and neonatal deaths with the aim of identifying relevant health care and social interventions. METHODS: A VASA interview was conducted of all stillbirths and neonatal deaths in the prior 5 years identified by the 2015-16 Tanzania Demographic and Health Survey. We evaluated associations of maternal complications with antepartum and intrapartum stillbirth and leading causes of neonatal death; conducted descriptive analyses of antenatal (ANC) and delivery care and mothers' careseeking for complications; and developed logistic regression models to examine factors associated with delivery place and mode. RESULTS: There were 204 stillbirths, with 185 able to be classified as antepartum (88 [47.5%]) or intrapartum (97 [52.5%]), and 228 neonatal deaths. Women with an intrapartum stillbirth were 6.5% (adjusted odds ratio (aOR) = 1.065, 95% confidence interval (CI) 1.002, 1.132) more likely to have a C-section for every additional hour before delivery after reaching the birth attendant. Antepartum hemorrhage (APH), maternal anemia, and premature rupture of membranes (PROM) were significantly positively associated with early neonatal mortality due to preterm delivery, intrapartum-related events and serious infection, respectively. While half to two-thirds of mothers made four or more ANC visits (ANC4+), a third or fewer received quality ANC (Q-ANC). Women with a complication were more likely to deliver at hospital only if they received Q-ANC (neonates: aOR = 4.5, 95% CI 1.6, 12.3) or ANC4+ (stillbirths: aOR = 11.8, 95% CI 3.6, 38.0). Nevertheless, urban residence was the strongest predictor of hospital delivery. CONCLUSIONS: While Q-ANC and ANC4 + boosted hospital delivery among women with a complication, attendance was low and the quality of care is critical. Quality improvement efforts in urban and rural areas should focus on early detection and management of APH, maternal anemia, PROM, and prolonged labor, and on newborn resuscitation.

Hypothermic Protection in Neocortex Is Topographic and Laminar, Seizure Unmitigating, and Partially Rescues Neurons Depleted of RNA Splicing Protein Rbfox3/NeuN in Neonatal Hypoxic-Ischemic Male Piglets.

The effects of hypothermia on neonatal encephalopathy may vary topographically and cytopathologically in the neocortex with manifestations potentially influenced by seizures that alter the severity, distribution, and type of neuropathology. We developed a neonatal piglet survival model of hypoxic-ischemic (HI) encephalopathy and hypothermia (HT) with continuous electroencephalography (cEEG) for seizures. Neonatal male piglets received HI-normothermia (NT), HI-HT, sham-NT, or sham-HT treatments. Randomized unmedicated sham and HI piglets underwent cEEG during recovery. Survival was 2-7 days. Normal and pathological neurons were counted in different neocortical areas, identified by cytoarchitecture and connectomics, using hematoxylin and eosin staining and immunohistochemistry for RNA-binding FOX-1 homolog 3 (Rbfox3/NeuN). Seizure burden was determined. HI-NT piglets had a reduced normal/total neuron ratio and increased ischemic-necrotic/total neuron ratio relative to sham-NT and sham-HT piglets with differing severities in the anterior and posterior motor, somatosensory, and frontal cortices. Neocortical neuropathology was attenuated by HT. HT protection was prominent in layer III of the inferior parietal cortex. Rbfox3 immunoreactivity distinguished cortical neurons as: Rbfox3-positive/normal, Rbfox3-positive/ischemic-necrotic, and Rbfox3-depleted. HI piglets had an increased Rbfox3-depleted/total neuron ratio in layers II and III compared to sham-NT piglets. Neuronal Rbfox3 depletion was partly rescued by HT. Seizure burdens in HI-NT and HI-HT piglets were similar. We conclude that the neonatal HI piglet neocortex has: (1) suprasylvian vulnerability to HI and seizures; (2) a limited neuronal cytopathological repertoire in functionally different regions that engages protective mechanisms with HT; (3) higher seizure burden, insensitive to HT, that is correlated with more panlaminar ischemic-necrotic neurons in the somatosensory cortex; and (4) pathological RNA splicing protein nuclear depletion that is sensitive to HT. This work demonstrates that HT protection of the neocortex in neonatal HI is topographic and laminar, seizure unmitigating, and restores neuronal depletion of RNA splicing factor.

Estimating the global impact of rotavirus vaccines on child mortality.

OBJECTIVES: We estimated the global impact of rotavirus vaccines on deaths among children under five years old by year. METHODS: We used a proportionate outcomes model with a finely disaggregated age structure to estimate rotavirus deaths prevented by vaccination over the period 2006-2019 in 186 countries. We ran deterministic and probabilistic uncertainty analyses and compared our estimates to surveillance-based estimates in 20 countries. RESULTS: We estimate that rotavirus vaccines prevented 139,000 under-five rotavirus deaths (95% uncertainty interval 98,000-201,000) in the period 2006-2019. In 2019 alone, rotavirus vaccines prevented 15% (95% uncertainty interval 11-21%) of under-five rotavirus deaths (0.5% of child mortality). Assuming global use of rotavirus vaccines and coverage equivalent to other co-administered vaccines could prevent 37% of under-five rotavirus deaths (1.2% of child mortality). Our estimates were sensitive to the choice of rotavirus mortality burden data and several vaccine impact modeling assumptions. The World Health Organization's recommendation to remove age restrictions in 2012 could have prevented up to 17,000 rotavirus deaths in the period 2013-2019. Our modeled estimates of rotavirus vaccine impact were broadly consistent with estimates from post-vaccination surveillance sites. CONCLUSION: Rotavirus vaccines have made a valuable contribution to global public health. Enhanced rotavirus mortality prevention strategies are needed in countries with high mortality in under-5-year-old children.

Effects of sex, age, and body mass index on serum bicarbonate.

Rationale: Obesity hypoventilation syndrome (OHS) is often underdiagnosed, with significant morbidity and mortality. Bicarbonate, as a surrogate of arterial carbon dioxide, has been proposed as a screening tool for OHS. Understanding the predictors of serum bicarbonate could provide insights into risk factors for OHS. We hypothesized that the bicarbonate levels would increase with an increase in body mass index (BMI), since the prevalence of OHS increases with obesity. Methods: We used the TriNetX Research Network, an electronic health record database with de-identified clinical data from participating healthcare organizations across the United States, to identify 93,320 adults without pulmonary or advanced renal diseases who had serum bicarbonate and BMI measurements within 6 months of each other between 2017 and 2022. We used linear regression analysis to examine the associations between bicarbonate and BMI, age, and their interactions for the entire cohort and stratified by sex. We also applied a non-linear machine learning algorithm (XGBoost) to examine the relative importance of age, BMI, sex, race/ethnicity, and obstructive sleep apnea (OSA) status on bicarbonate. Results: This cohort population was 56% women and 72% white and 80% non-Hispanic individuals, with an average (SD) age of 49.4 (17.9) years and a BMI of 29.1 (6.1) kg/m2. The mean bicarbonate was 24.8 (2.8) mmol/L, with higher levels in men (mean 25.2 mmol/L) than in women (mean 24.4 mmol/L). We found a small negative association between bicarbonate and BMI, with an expected change of -0.03 mmol/L in bicarbonate for each 1 kg/m2 increase in BMI (p < 0.001), in the entire cohort and both sexes. We found sex differences in the bicarbonate trajectory with age, with women exhibiting lower bicarbonate values than men until age 50, after which the bicarbonate levels were modestly higher. The non-linear machine learning algorithm similarly revealed that age and sex played larger roles in determining bicarbonate levels than the BMI or OSA status. Conclusion: Contrary to our hypothesis, BMI is not associated with elevated bicarbonate levels, and age modifies the impact of sex on bicarbonate.

Effects of methylphenidate on neuropsychiatric symptoms in Alzheimer's disease: Evidence from the ADMET 2 study.

INTRODUCTION: Methylphenidate has been shown to improve apathy in patients with Alzheimer's disease (AD). The authors evaluated the impact of methylphenidate on neuropsychiatric symptoms (NPS) of AD, excluding apathy, using data from the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) study. METHODS: A secondary analysis was conducted on data from the ADMET 2 study to determine the effect of methylphenidate on Neuropsychiatric Inventory (NPI) scores outside of apathy. Caregiver scores were compared from baseline to month 6 in 199 participants receiving methylphenidate (20 mg/day) or placebo regarding the presence or absence of individual neuropsychiatric symptoms, emergence of new symptoms, and individual domain scores. RESULTS: No clinically meaningful improvement was observed in any NPI domain, excluding apathy, in participants treated with methylphenidate compared to placebo after 6 months. A statistical difference between groups was appreciated in the domains of elation/euphoria (P = 0.044) and appetite/eating disorders (P = 0.014); however, these findings were not considered significant. DISCUSSION: Methylphenidate is a selective agent for symptoms of apathy in patients with AD with no meaningful impact on other NPS. Findings from this secondary analysis are considered exploratory and multiple limitations should be considered when interpreting these results, including small sample size and use of a single questionnaire.HIGHLIGHTS: Methylphenidate was not associated with significant improvement on the Neuropsychiatric Inventory in domains outside of apathy.Methylphenidate did not show a statistically significant emergence of new neuropsychiatric symptoms (NPS) throughout the 6-month treatment period compared to placebo.Methylphenidate appears to be a highly selective agent for apathy in Alzheimer's disease, potentially supporting catecholaminergic dysfunction as the driving force behind this presentation of symptoms.

An effectiveness-implementation trial protocol to evaluate PrEP initiation among U.S. cisgender women using eHealth tools vs. standard care.

Background: The United States' (U.S.) initiative to End the HIV Epidemic aims to reduce new HIV infections in areas of high HIV prevalence. Despite national efforts to reduce HIV incidence, cisgender women continue to represent approximately one out of every five new HIV diagnoses in the U.S. Taking pre-exposure prophylaxis (PrEP) is an effective HIV prevention strategy; however, PrEP initiation among cisgender women is suboptimal, with only 10% of eligible women receiving PrEP prescriptions in 2019. Methods: We designed a trial to test the effectiveness of interventions to increase PrEP initiation, while evaluating the implementation strategy (hybrid type II trial) in seven obstetrics and gynecology (OB/GYN) clinics (two federally qualified health centers, three community-based, and two academic) in Baltimore, Maryland. A total of 42 OB/GYN providers will be enrolled and randomized (1:1:1) into one of three clinical trial arms (standard of care, patient-level intervention, or multi-level intervention). Eligible patients of enrolled providers will receive a sexual health questionnaire before their appointment through the electronic health record's (EHR) patient portal. The questionnaire will be scored in three tiers (low, moderate, and high) to assess HIV risk. Patients at low risk will be offered an HIV test only, while those who score medium or high risk will be included in the clinical trial and assigned to the clinical trial arm associated with their provider. Differences in PrEP initiation, our primary outcome, across the three arms will be analyzed using generalized linear mixed-effect models with logistic regression. We will adjust results for demographic differences observed between arms and examine PrEP initiation stratified by patient's and provider's race and ethnicity.Additionally, a comprehensive economic analysis for each intervention will be conducted. Discussion: We hypothesize that gathering information on sensitive sexual behaviors electronically, communicating HIV risk in an understandable and relatable format to patients and OB/GYN providers, and deploying EHR alerts will increase PrEP initiation and HIV testing. Trial Registration: The trial is registered with ClinicalTrials.gov (NCT05412433) on 09 June 2022. https://clinicaltrials.gov/ct2/show/NCT05412433?term=NCT05412433&draw=2&rank=1.

Heterogeneity of Response to Methylphenidate in Apathetic Patients in the ADMET 2 Trial.

OBJECTIVE: The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) found that methylphenidate was effective in treating apathy with a small-to-medium effect size but showed heterogeneity in response. We assessed clinical predictors of response to help determine individual likelihood of treatment benefit from methylphenidate. DESIGN: Univariate and multivariate analyses of 22 clinical predictors of response chosen a priori. SETTING: Data from the ADMET 2 randomized, placebo controlled multi-center clinical trial. PARTICIPANTS: Alzheimer's disease patients with clinically significant apathy. MEASUREMENTS: Apathy assessed with the Neuropsychiatric Inventory apathy domain (NPI-A). RESULTS: In total, 177 participants (67% male, mean [SD] age 76.4 [7.9], mini-mental state examination 19.3 [4.8]) had 6-months follow up data. Six potential predictors met criteria for inclusion in multivariate modeling. Methylphenidate was more efficacious in participants without NPI anxiety (change in NPI-A -2.21, standard error [SE]:0.60) or agitation (-2.63, SE:0.68), prescribed cholinesterase inhibitors (ChEI) (-2.44, SE:0.62), between 52 and 72 years of age (-2.93, SE:1.05), had 73-80 mm Hg diastolic blood pressure (-2.43, SE: 1.03), and more functional impairment (-2.56, SE:1.16) as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living scale. CONCLUSION: Individuals who were not anxious or agitated, younger, prescribed a ChEI, with optimal (73-80 mm Hg) diastolic blood pressure, or having more impaired function were more likely to benefit from methylphenidate compared to placebo. Clinicians may preferentially consider methylphenidate for apathetic AD participants already prescribed a ChEI and without baseline anxiety or agitation.

Treatment Guideline Nonadherence Pretransport Associated With Need for Higher Level of Care in Children Transferred to a Pediatric Tertiary Care Center for Status Epilepticus.

OBJECTIVES: We sought to investigate the association between adherence to the American Epilepsy Society (AES) 2016 guidelines for management of convulsive status epilepticus (SE) and clinical outcomes among children requiring interhospital transport for SE. We hypothesized that pretransport guideline nonadherence would be associated with needing higher level of care posttransfer. METHODS: This was a retrospective cohort study of children aged 30 days to 18 years transferred to our pediatric tertiary center from 2017 to 2019 for management of SE. Their care episodes were classified as 2016 American Epilepsy Society guideline adherent or nonadherent. There were 40 referring hospitals represented in this cohort. RESULTS: Of 260 care episodes, 55 (21%) were guideline adherent, 184 (71%) were guideline nonadherent, and 21 (8%) had insufficient data to determine guideline adherence. Compared with the adherent group, patients in the nonadherent care group had longer hospitalizations (32 hours [17-68] vs 21 hours [7-48], P = 0.006), were more likely to require intensive care unit admission (47% vs 31%), and less likely to be discharged home from the emergency department (16% vs 35%; χ 2 test, P = 0.01). Intubation rates did not differ significantly between groups (25% vs 18%, P = 0.37). When we fit a multivariable model to adjust for confounding variables, guideline nonadherence was associated with need for higher level of care (odds ratio, 2.04; 95% confidence interval, 1.04-3.99). Treatment guideline adherence did not improve over the 3-year study period (2017: 22%, 2018: 19%, 2019: 29% [χ 2 test for differences between any 2 years, P = 0.295]). CONCLUSIONS: Guideline nonadherence pretransport was associated with longer hospitalizations and need for higher level of care among children transferred for SE at our institution. These findings suggest a need to improve SE guideline adherence through multifaceted quality improvement efforts targeting both the prehospital and community hospital settings.

Behavioral determinants of arsenic-safe water use among Great Plains Indian Nation private well users: results from the Community-Led Strong Heart Water Study Arsenic Mitigation Program.

BACKGROUND: The objective of this study was to evaluate the behavioral determinants associated with exclusive use of arsenic-safe water in the community-led Strong Heart Water Study (SHWS) arsenic mitigation program. METHODS: The SHWS is a randomized controlled trial of a community-led arsenic mitigation program designed to reduce arsenic exposure among private well users in American Indian Great Plains communities. All households received point-of-use (POU) arsenic filters installed at baseline and were followed for 2 years. Behavioral determinants selected were those targeted during the development of the SHWS program, and were assessed at baseline and follow-up. RESULTS: Among participants, exclusive use of arsenic-safe water for drinking and cooking at follow-up was associated with higher self-efficacy for accessing local resources to learn about arsenic (OR: 5.19, 95% CI: 1.48-18.21) and higher self-efficacy to resolve challenges related to arsenic in water using local resources (OR: 3.11, 95% CI: 1.11-8.71). Higher commitment to use the POU arsenic filter faucet at baseline was also a significant predictor of exclusive arsenic-safe water use for drinking (OR: 32.57, 95% CI: 1.42-746.70) and cooking (OR: 15.90, 95% CI: 1.33-189.52) at follow-up. From baseline to follow-up, the SHWS program significantly increased perceived vulnerability to arsenic exposure, self-efficacy, descriptive norms, and injunctive norms. Changing one's arsenic filter cartridge after installation was associated with higher self-efficacy to obtain arsenic-safe water for drinking (OR: 6.22, 95% CI: 1.33-29.07) and cooking (OR: 10.65, 95% CI: 2.48-45.68) and higher perceived vulnerability of personal health effects (OR: 7.79, 95% CI: 1.17-51.98) from drinking arsenic-unsafe water. CONCLUSIONS: The community-led SHWS program conducted a theory-driven approach for intervention development and evaluation that allowed for behavioral determinants to be identified that were associated with the use of arsenic safe water and changing one's arsenic filter cartridge. These results demonstrate that theory-driven, context-specific formative research can influence behavior change interventions to reduce water arsenic exposure. The SHWS can serve as a model for the design of theory-driven intervention approaches that engage communities to reduce arsenic exposure. TRIAL REGISTRATION: The SHWS is registered with ClinicalTrials.gov (Identifier: NCT03725592).

The Future of Sexually Transmitted Infection Research: Understanding Adolescent Perspectives for Implementation of a Chlamydia Vaccine.

PURPOSE: Despite advancements in developing a vaccine for Chlamydia trachomatis (CT), vaccine hesitancy has historically limited the adoption of sexually transmitted infection immunization. This report investigates adolescent perspectives toward a potential CT vaccine and vaccine research. METHODS: As part of the Technology Enhanced Community Health Nursing (TECH-N) study, conducted from 2012-2017, we surveyed 112 adolescents and young adults aged 13-25 years who presented with pelvic inflammatory disease regarding their perspectives on a CT vaccine and willingness to participate in vaccine research. Descriptive statistical analyses were conducted. RESULTS: Most participants were African American (95%), on Medicaid (89%), and sexually experienced (100%). Most respondents would accept a vaccine (95%) and preferred a provider's recommendation (86%) over parents, partners, or friends. A majority (70%) would not be embarrassed to participate in research. DISCUSSION: Respondents showed favorable attitudes toward CT vaccination and research in this high-risk study population.

Clinical Features Associated With Rate of Fractures in Patients With Systemic Sclerosis: A US Cohort Study.

OBJECTIVE: Systemic sclerosis (SSc) is associated with several specific risk factors for fracture due to the complications of the disease and related medications. The present study was undertaken to examine the relationship between SSc-associated clinical features and fracture rate in a large US cohort. METHODS: Participants with SSc in FORWARD, The National Databank for Rheumatic Diseases, were included (1998-2019). Age- and sex-matched individuals with osteoarthritis (OA) from the same database were included as comparators. The primary end point was self-reported major osteoporotic fracture. Cox proportional hazards models were used to study the associations between risk factors and fractures. RESULTS: The study included 922 individuals (SSc patients, n = 154; OA patients, n = 768). Eighty-seven percent were female, with a mean age of 57.8 years. Fifty-one patients developed at least 1 fracture during a median of 4.2 years (0.5-22.0 years) of follow-up. Patients with SSc had more frequent fractures compared to OA comparators (hazard ratio [HR] 2.38 [95% confidence interval (95% CI) 1.47-3.83]). Among patients with SSc, a higher Rheumatic Disease Comorbidity Index score (HR 1.45 [95% CI 1.20-1.75]) and a higher Health Assessment Questionnaire disability index score (HR 3.83 [95% CI 2.12-6.93]) were associated with more fractures. Diabetes mellitus (HR 5.89 [95% CI 2.51-13.82]) and renal disease (HR 2.43 [95% CI 1.10-5.37]) were independently associated with fracture among SSc patients relative to SSc patients without these comorbidities. CONCLUSION: Our findings highlight factors associated with fracture among patients with SSc. Disability as measured by the HAQ DI is a particularly strong indicator of fracture rate in SSc. Improving SSc patients' functional status, where possible, may lead to better long-term outcomes.