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BACKGROUND: Becker muscular dystrophy is an X-linked, genetic disorder causing progressive degeneration of skeletal and cardiac muscle, with a widely variable phenotype. OBJECTIVE: A 3-year, longitudinal, prospective dataset contributed by patients with confirmed Becker muscular dystrophy was analyzed to characterize the natural history of this disorder. A better understanding of the natural history is crucial to rigorous therapeutic trials. METHODS: A cohort of 83 patients with Becker muscular dystrophy (5-75 years at baseline) were followed for up to 3 years with annual assessments. Muscle and pulmonary function outcomes were analyzed herein. Age-stratified statistical analysis and modeling were conducted to analyze cross-sectional data, time-to-event data, and longitudinal data to characterize these clinical outcomes. RESULTS: Deletion mutations of dystrophin exons 45-47 or 45-48 were most common. Subgroup analysis showed greater pairwise association between motor outcomes at baseline than association between these outcomes and age. Stronger correlations between outcomes for adults than for those under 18 years were also observed. Using cross-sectional binning analysis, a ceiling effect was seen for North Star Ambulatory Assessment but not for other functional outcomes. Longitudinal analysis showed a decline in percentage predicted forced vital capacity over the life span. There was relative stability or improved median function for motor functional outcomes through childhood and adolescence and decreasing function with age thereafter. CONCLUSIONS: There is variable progression of outcomes resulting in significant heterogeneity of the clinical phenotype of Becker muscular dystrophy. Disease progression is largely manifest in adulthood. There are implications for clinical trial design revealed by this longitudinal analysis of a Becker natural history dataset.

Background The BODY-Q is a widely used patient-reported outcome measure for comprehensive assessment of treatment outcomes specific to patients undergoing body contouring surgery (BCS). However, for the BODY-Q to be meaningfully interpreted and used in clinical practice, minimal important difference (MID) scores are needed. A MID is defined as the smallest change in outcome measure score that patients perceive as important. Objectives The aim of this study was to determine BODY-Q MID estimates for patients undergoing BCS to enhance the interpretability of the BODY-Q. Methods Data from an international, prospective cohort from Denmark, Finland, Germany, Italy, the Netherlands, and Poland were included. Two distribution-based methods were used to estimate MID: 0.2 standard deviations of mean baseline scores and the mean standardized response change of BODY-Q scores from baseline to 3 years postoperatively. Results A total of 12,554 assessments from 3237 participants (mean age 42.5 ± 9.3 years; BMI 28.9 ± 4.9 kg/m2) were included. Baseline MID scores ranged from 1 to 5 on the health-related quality of life (HRQL) scales and 3 to 6 on the appearance scales. The estimated MID scores from baseline to 3-year follow-up ranged from 4 to 5 for HRQL and from 4 to 8 on the appearance scales. Conclusions The BODY-Q MID estimates from before BCS to 3 years postoperatively ranged from 4 to 8 and are recommended for interpretation of patients' BODY-Q scores, evaluation of treatment effects of different BCS procedures, and calculation of sample size for future studies. Level of Evidence: 3 [ABSTRACT FROM AUTHOR]

The relationship between depression and severe non-alcoholic fatty liver disease (NAFLD) has not been clearly defined. We conducted a longitudinal cohort study and a two-sample Mendelian randomization (MR) analysis to assess the association of depression with severe NAFLD risk. We used individual data from the UK Biobank study with 481,181 participants, and summary data from published genome-wide association studies. The association between depression and severe NAFLD was assessed using Cox proportional hazards regression analysis. Two-sample MR for depression with NAFLD was conducted, the principal analysis employed the inverse variance weighted (IVW) approach. In the observational study, after a median follow-up of 13.46 years, 4,563 participants had severe NAFLD. In multivariable-adjusted model, participants with depression had an increased risk of severe NAFLD (hazards ratio:1.21, 95% confidence interval (CI):1.09–1.34), as compared to those without depression. In subgroup analyses, the association between depression and severe NAFLD risk was generally observed across different subgroups. For the MR, result also showed that genetically predicted depression was causally associated with a higher risk of NAFLD (odds ratio:1.55, 95%CI:1.10–2.19) in IVW. Our study revealed a prospective association of depression with severe NAFLD, thus potentially necessitating clinical monitoring of individuals with depression for severe NAFLD. [ABSTRACT FROM AUTHOR]

Pediatric peripheral intravenous (PIV) insertion is one of the most stressful experiences of hospitalization and is associated with patients' anxiety and health care avoidance. The use of specialist inserters for PIV insertions may result in improved experiences for patients, including increased use of comfort measures and increased first-attempt success rates. [ABSTRACT FROM AUTHOR]

Objectives The relationship between nut intake and disability-free survival (healthy lifespan) in later life is unclear. The objective was to evaluate the association between nut intake and disability-free survival in a cohort of adults aged ≥70 years, and whether this varied according to overall diet quality. Methods This prospective cohort study involved 9916 participants from the ASPREE Longitudinal Study of Older Persons. Participants completed a 49-item Food Frequency questionnaire from which frequency of nut intake was obtained and were asked to categories usual intake as no/infrequent [never/rarely, 1–2 times/month], weekly [1–2 times/week, often 3–6 times/week] or daily [every day or several times a day]. The outcome measured was a composite of first-event mortality, onset of dementia, or persistent physical disability. Cox proportional hazards regression models, adjusted for socio-demographic factors, health-related and clinical covariates and overall dietary quality were conducted to examine the association between varying levels of nut intake and disability-free survival. Results Over a mean of 3.9 years of follow-up, the risk of reaching the DFS endpoint were 23% lower (HR 0.77 [0.61–0.98]) for those who consumed nuts daily, when compared to those with no/infrequent nut consumption. Subgroup analysis demonstrated a significant association between daily nut consumption and healthy lifespan among individuals in the second dietary quality tertile (HR 0.71[0.51–0.98]). Conclusion For community-dwelling adults aged 70 years and over with sub-optimal diets, daily nut consumption is associated with the promotion of healthy lifespan (disability-free survival). [ABSTRACT FROM AUTHOR]

The aim of this prospective, multi-center, practice-based cohort study was to analyze factors associated with the success of implant supported all-ceramic single-unit crowns, made by computer-aided-design/computer-aided-manufacturing (CAD-CAM). All-ceramic crowns placed in a private practice-based research network (Ceramic Success Analysis, AG Keramik) were analyzed. Data from 567patients with CAD-CAM implant supported all-ceramic crowns placed between 2008–2023 by 54dentists were evaluated. Firstly, all crowns with at least one follow-up control were included (n = 907). Secondly, all crowns being followed up for ≥ 5years and all failures were included (n = 151). At the latest follow-up visit, crowns were considered as successful (not failed) if they were still in function without the need for additional therapy. Multi-level Cox proportional hazards models were used to evaluate the association between a range of predictors and time of success. Within a mean follow-up period (SD) of 2.5 (2)years (first scenario) and 6.2 (1.2)years (second scenario) [maximum:12years], 27crowns failed (annual failure rate [AFR]:0.74 %). The main failure types were decementation, (n = 11), fracture of the ceramic (n = 4) or Ti-Base (n = 4). In 5-year-scenario, crowns fabricated in the laboratory had 26times lower failure rate than those fabricated chairside (95 %CI:0.0–0.7;p = 0.038). Furthermore, the use of a silane (HR:0.051;95 %CI:0.0–0.5;p = 0.014) and etching of the ceramic (HR:0.053;95 %CI:0.0–0.8;p = 0.035) resulted in a significantly higher risk for failure than their non-use. For CAD-CAM manufactured implant supported all-ceramic crowns, high success rates were found in up to 12-year evaluation. Furthermore, after 5years, no patient-or implant-level factors, but operative-level factor (i.e.fabrication method, use of silane/etching) were significantly associated with failure. The study was registered in the German Clinical Trials Register (DRKS-ID: DRKS00020271). • Implant-supported ceramic crowns showed high success rates (97 %) after up to 12 yrs • After 5 years no patient-level factors were significantly associated with failure • After 5 years no implant-level factors were significantly associated with failure • Lab-side fabricated crowns showed a 26x lower failure rate than chairside ones [ABSTRACT FROM AUTHOR]

Aim: The extent to which recent potentially traumatic events (PTEs) hinder the recovery from pre‐existing mental health problems is largely unknown. The same applies to the extent to which non‐recovery from pre‐existing mental health problems increases the risk of posttraumatic stress disorder (PTSD). The aim of the present study is to gain insight in these effects. Methods: Data were extracted from six annual surveys of the Dutch population‐based Victims in Modern Society (VICTIMS) study. Of the adult respondents who participated in two subsequent surveys (labeled T1 and T2, n = 6942), those with severe anxiety and depression symptoms (ADS) at T1 (n = 487) were selected. We distinguished respondents exposed to PTEs (PTE‐group, n = 162) and not exposed to PTEs (comparison group, n = 325) between T1 and T2. We applied five indicators of recovery [based on the Reliable Change Index (RCI), degrees of symptom reduction, and the cut‐off score at T2]. Differences in the recovery from ADS and probable PTSD at T2 were examined using multivariate logistic regression. Results: The PTE group less often recovered from severe ADS between T1 and T2 than the comparison group according to all five indicators of recovery, while controlling for 11 different variables (0.40 ≤ adjusted OR's ≤ 0.66). Those in the PTE group who did not recover, considerably more often suffered from probable PTSD at T2 (63%–82%) than those who did recover (0%–29%; 8.96 ≤ adjusted OR ≤ 26.33). Conclusion: Recent potentially traumatic events hinder the recovery from pre‐existing anxiety and depression symptomatology and thereby increase the risk of probable PTSD. [ABSTRACT FROM AUTHOR]

Aims/Introduction: PIONEER REAL Japan was a non‐interventional prospective study of oral semaglutide in adults with type 2 diabetes in Japanese clinical practice. Materials and Methods: Adults naïve to injectable glucose‐lowering therapies initiated oral semaglutide in routine clinical practice and were followed for 34–44 weeks. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to end of study; the co‐primary endpoint was number of adverse events (AEs). Secondary endpoints included change in bodyweight from baseline to end of study. Analyses were also carried out for subgroups aged <75 and ≥75 years. Results: A total of 624 participants initiated oral semaglutide; 578 completed the study. Mean baseline HbA1c and bodyweight were 7.7% and 72.4 kg, respectively. At end of study, estimated change (95% confidence interval [CI]) in HbA1c from baseline was −0.7 percentage points (−0.77, −0.61) overall, −0.8 percentage points (−0.86, −0.67) in the <75 years subgroup and −0.5 percentage points (−0.68, −0.41) in the ≥75 years subgroup (all P < 0.0001). Estimated change (95% CI) in bodyweight was −2.8 (−3.19, −2.50) kg overall, −2.9 (−3.38, −2.49) kg in the <75 years subgroup and − 2.7 (−3.18, −2.14) kg in the ≥75 years subgroup (all P < 0.0001). AEs occurred in 161 (25.8%) participants: 99 of 423 (23.4%) and 62 of 201 (30.8%) participants in the <75 and ≥75 years subgroups, respectively. Gastrointestinal AEs were the AEs most frequently leading to oral semaglutide discontinuation. Conclusions: In routine clinical practice, HbA1c and bodyweight were significantly reduced from baseline in adults initiating oral semaglutide, including those aged ≥75 years, with no new safety concerns. [ABSTRACT FROM AUTHOR]

The current study aimed to investigate the association between predicted vitamin D status and depression in a prospective Spanish cohort of university graduates. The SUN Project is a dynamic cohort study designed to investigate multiple aspects of health and lifestyle. Participants were asked to complete a comprehensive questionnaire consisting of 556 items, that included a validated food-frequency questionnaire. Participants initially free of depression were classified as incident cases if they reported a medical diagnosis of depression during follow-up. Serum vitamin D levels were predicted by a previously validated equation. Vitamin D deficiency was defined as vitamin D levels below 20 ng/mL. Cox models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI). We included 15,175 Spanish university graduates [mean (SD) age: 36.9 year (11.5)] followed-up for a median of 12.7 years. Among 192,976 person-years of follow-up, we identified 753 incident cases of depression. Participants with vitamin D deficiency had a 27% higher risk of depression as compared to those with vitamin D sufficiency (HR: 1.27, 95% CI: 1.09–1.48; p = 0.002) after adjusting for potential confounders. Furthermore, a significant effect modification by female sex was observed with higher depression risks associated with vitamin D deficiency in women than in men (p for interaction = 0.034). In educated middle-aged Spanish adults, we observed a direct association between vitamin D deficiency and the risk of depression, that was stronger among women. [Display omitted] • Vitamin D deficiency causes depression risk in educated middle-aged Spanish adults. • A validated equation was employed for predicting serum vitamin D levels. • Sex interacts in vitamin D-depression risk association. • Higher depression risk found in women with lower levels of vitamin D. • Addressing vitamin D deficiency is crucial for preventing depression. [ABSTRACT FROM AUTHOR]

Objective To explore the efficacy and safety of endovascular treatment (EVT) combined with eptifibatide in the treatment of acute ischemic stroke. Methods This study enrolled the 102 acute ischemic stroke patients at 15 centers in China received EVT combined with eptifibatide from April 2019 to March 2020. The primary efficacy outcome was the reperfusion rate of blood vessels within 24 h after treatment [modified Thrombolysis in Cerebral Infarction (mTICI) grade ≥ 2b], while the secondary efficacy outcomes were the complete reperfusion (mTICI grade 3) rate of blood vessels within 24 h after treatment and the 3-month neurological function prognosis [modified Rankin Scale (mRS) score ≤ 2]; the incidence of symptomatic intracranial hemorrhage (sICH) within 48 h after treatment was the primary safety outcome, while the incidence of intracranial hemorrhage (ICH), parenchymal hemorrhage (PH), hemorrhagic infarction (HI), remote parenchymal hemorrhage (rPH), intraventricular hemorrhage (IVH), and subarachnoid hemorrhage (SAH) within 48 h, and 3 - month mortality after treatment were secondary safety outcomes. Univariate and multivariate stepwise Logistic regression analyses were used to screen for the influencing factors of prognosis after EVT combined with eptifibatide for acute ischemic stroke. Results The successful reperfusion (mTICI grade ≥ 2b) rate and complete reperfusion (mTICI grade 3) rate of blood vessels within 24 h after treatment were 86.27% (88/102) and 68.63% (70/102), respectively. The good prognosis (mRS score ≤ 2) rate at 3-month after treatment was 54.90% (56/102). The incidence of sICH within 48 h after treatment was 4.90% (5/102). The incidence of ICH was 19.61% (20/102), PH was 11.76% (12/102), HI was 5.88% (6/102), rPH was 1.96% (2/102), IVH was 3.92% (4/102), and there was no SAH within 48 h after treatment. The mortality rate at 3-month after treatment was 16.67% (17/102). Logistic regression analysis showed that an admission National Institutes of Health Stroke Scale (NIHSS) score of > 15 was a risk factor for poor prognosis in patients with acute ischemic stroke after EVT combined with eptifibatide (OR = 0.118, 95%CI: 0.046-0.307; P = 0.000), while an Alberta Stroke Program Early CT Score (ASPECTS) of ≥ 6 was a protective factor for good prognosis (OR = 5.871, 95%CI: 1.812-19.020; P = 0.003). Conclusions The combined regimen of eptifibatide and EVT studied in this trial was effective and safe. Optimal administration method and randomized controlled trial are need to be further justified. [ABSTRACT FROM AUTHOR]

Study Design: Multicenter prospective study. Objective: Patients with central sensitization (CS) are reported to be at high risk of poor outcomes after spinal surgery. However, the influence of CS on surgical outcomes for lumbar disc herniation (LDH) remains unknown. This study aimed to examine the association between preoperative CS and surgical outcomes in LDH patients. Methods: A total of 100 consecutive patients with LDH (mean age 51.2) who underwent lumbar surgery were included in this study. The extent of CS was evaluated using the central sensitization inventory (CSI), a screening tool for CS-related symptoms. The patients completed the following CSI and clinical outcome assessments (COAs) preoperatively and 12 months postoperatively: the Japanese Orthopaedic Association (JOA) score for back pain, JOA back pain evaluation questionnaire (JOABPEQ), and Oswestry Disability Index (ODI). The association between preoperative CSI scores, and preoperative and postoperative COAs was analyzed, and the postoperative changes were statistically evaluated. Results: The preoperative CSI score significantly decreased 12 months postoperatively. Preoperative CSI scores showed a significant correlation with most COAs; however, a significant correlation was only identified in the social function and mental health domains of JOABPEC postoperatively. Higher preoperative CSI showed worse preoperative COAs; however, all COAs significantly improved regardless of CSI severity. There were no significant differences in any COAs among the CSI severity groups 12 months postoperatively. Conclusions: The results of this study showed that lumbar surgeries significantly improved the COAs regardless of preoperative severity of CS in patients with LDH. [ABSTRACT FROM AUTHOR]

This study examines myocardial T1, T2, and T2* values in a sizable cohort of healthy volunteers, analyzing variations by age, sex, and cardiac segments. It offers a novel approach to defining normal parametric mapping boundaries and represents the first comprehensive study of its kind in Turkey. Our prospective study was conducted between August 2021 and August 2022. Healthy volunteers aged 20–80 were grouped, with at least eight females and eight males per decade. Cardiac MRI examination measured T1 and T2 times in 16 left ventricle segments using parametric mapping techniques on a 1.5 Tesla MRI device. T2* mapping was also performed on the mid-section interventricular septum. The data analysis considered the impact of age, sex, and segments. One hundred eighteen cases were included in the study. Female volunteers observed significantly higher T1, T2, and T2* values than male volunteers. For the T2* and T1 times, significantly lower values were detected in women over 50 than those under 50. It was observed that the Midventricular approach (middle section) gave closer results than the Midventricular Septal approach (septal region of middle section) in predicting Global times. We present the normal reference ranges for cardiac T1, T2, and T2* times in a large cohort of healthy volunteers with homogeneous sex and age distribution. Sex was the most influential factor in our study. Therefore, we suggest using separate reference values for males, and females above and below 50 years old, instead of the standard reference intervals that do not account for specified sex in current guidelines. [ABSTRACT FROM AUTHOR]

Background: The current landscape of acne therapeutics is notably lacking in targeted treatments, highlighting a critical need for the discovery of new drug targets to improve treatment outcomes. Objectives: This study aims to investigate the connections between proteomics and genetics in relation to acne across extensive population cohorts, aspiring to identify innovative preventive and therapeutic approaches. Methods: Employing a longitudinal cohort of 54,306 participants from the UK Biobank Pharmacological Proteomics Project (UKB-PPP), we performed an exhaustive evaluation of the associations between 2,923 serum proteins and acne risk. Initial multivariate Cox regression analyses assessed the relationship between protein expression levels and acne onset, followed by two-sample Mendelian Randomization (TSMR), Summary-data-based Mendelian Randomization (SMR), and colocalization to identify genetic correlations with potential protein targets. Results: Within the UKB cohort, we identified 19 proteins significantly associated with the risk of acne. Subsequent analysis using Two-Sample Mendelian Randomization (TSMR) refined this to two specific proteins: FSTL1 and ANXA5. Each one-standard deviation increase in the expression levels of FSTL1 and ANXA5 was associated with a 24% and 32% increase in acne incidence, respectively. These results were further validated by additional Summary-databased Mendelian Randomization (SMR) and differential expression analyses. Conclusions: Our comprehensive analysis of proteomic and genetic data from a European adult cohort provides compelling causal evidence that several proteins are promising targets for novel acne treatments. [ABSTRACT FROM AUTHOR]

Background: Tau-PET is a diagnostic tool with high sensitivity and specificity for discriminating Alzheimer's disease (AD) dementia from other neurodegenerative disorders in well-controlled research environments. The role of tau-PET in real-world clinical practice, however, remains to be established. The aim of the TAP-TAU study is therefore to investigate the impact of tau-PET in clinical practice. Methods: TAP-TAU is a prospective, longitudinal multi-center study in 300 patients (≥ 50 years old) with mild cognitive impairment or mild dementia across five Dutch memory clinics. Patients are eligible if diagnostic certainty is < 85% after routine dementia screening and if the differential diagnosis includes AD. More specifically, we will include patients who (i) are suspected of having mixed pathology (e.g., AD and vascular pathology), (ii) have an atypical clinical presentation, and/or (iii) show conflicting or inconclusive outcomes on other tests (e.g., magnetic resonance imaging or cerebrospinal fluid). Participants will undergo a [18F]flortaucipir tau-PET scan, blood-based biomarker sampling, and fill out questionnaires on patient reported outcomes and experiences. The primary outcomes are change (pre- versus post- tau-PET) in diagnosis, diagnostic certainty, patient management and patient anxiety and uncertainty. Secondary outcome measures are head-to-head comparisons between tau-PET and less invasive and lower cost diagnostic tools such as novel blood-based biomarkers and artificial intelligence-based classifiers. Results: TAP-TAU has been approved by the Medical Ethics Committee of the Amsterdam UMC. The first participant is expected to be included in October 2024. Conclusions: In TAP-TAU, we will investigate the added clinical value of tau-PET in a real-world clinical setting, including memory clinic patients with diagnostic uncertainty after routine work-up. Findings of our study may contribute to recommendations regarding which patients would benefit most from assessment with tau-PET. This study is timely in the dawning era of disease modifying treatments as an accurate etiological diagnosis becomes increasingly important. Trial registration: This trial is registered and authorized on December 21st, 2023 in EU Clinical Trials with registration number 2023-505430-10-00. [ABSTRACT FROM AUTHOR]

Background: Physical activity (PA) and diet quality have each been shown to be inversely associated with mortality but their combined impact on longevity has been less explored, particularly when considering their changes over time. This study aimed to examine the separate and combined associations of PA, diet quality and their changes over time with mortality outcomes. Methods: A prospective cohort study was performed on 9349 adults aged 40 to 79 years from the population-based European Prospective Investigation into Cancer in Norfolk Study, with repeated measurements of PA and diet (from 1993 till 2004) and subsequent follow-up till 2022 (median follow-up 18.8 years). Validated questionnaires were used to derive physical activity energy expenditure (PAEE) as a proxy of total PA and adherence to the Mediterranean diet score (MDS, range 0–15 points) as an indicator of overall diet quality, and their changes over time (∆PAEE and ∆MDS). Cox regression models adjusted for potential confounders and mediators were used to estimate hazard ratios (HRs) and 95% CIs. Results: Over 149,681 person-years of follow-up, there were 3534 deaths. In adjusted models, for each 1-SD difference in baseline PAEE (4.64 kJ/kg/day), ∆PAEE (0.65 kJ/kg/day per year), baseline MDS (1.30 points) and ∆MDS (0.32 points per year), HRs (95% CI) for all-cause mortality were 0.90 (0.86 to 0.94), 0.89 (0.85 to 0.93), 0.95 (0.91 to 0.99) and 0.93 (0.90 to 0.97), respectively. Compared with participants with sustained low PAEE (< 5 kJ/kg/day) and low MDS (< 8.5 points), those with sustained high PAEE and high MDS had lower all-cause mortality (HR 0.78; 95% CI: 0.68–0.91), as did those who improved both PAEE and MDS (0.60; 0.44–0.82). There was no evidence of interaction between PA and diet quality exposures on mortality risk. Population impact estimates suggested that if all participants had maintained high levels of PA and diet quality consistently, cumulative adjusted mortality rate would have been 8.8% (95% CI: 2.4 to 15.3%) lower. Conclusions: These findings suggest that adopting and maintaining higher levels of PA and diet quality are associated with lower mortality. Significant public health benefits could be realised by enabling active living and healthy eating through adulthood. [ABSTRACT FROM AUTHOR]

Objective In the chronic phase after a stroke, limitations in basic activities of daily living (ADLs) and instrumental activities of daily living (IADLs) initially plateau before steadily increasing. The benefits of prestroke physical activity on these limitations remain unclear. To clarify this relationship, the effect of physical activity on the long-term evolution of functional limitations in a cohort of people with stroke compared to a cohort of matched adults without stroke was examined. Methods Longitudinal data from 2143 people with stroke and 10,717 adults without stroke aged 50 years and older were drawn from a prospective cohort study based on the Survey of Health, Ageing and Retirement in Europe (2004–2022; eight data collection waves). Physical activity was assessed in the prestroke wave. Functional limitations were assessed in the poststroke waves. Each person with stroke was matched with five adults without stroke who had similar propensity scores computed on the basis of key covariates, including baseline age, sex, body mass index, limitations in ADLs and IADLs, chronic conditions, and country of residence, before any of the participants from either cohort had experienced a stroke. Results Results showed an interaction between stroke status and physical activity on ADL limitations (b = −0.076; 95% CI = −0.142 to −0.011), with the beneficial effect of physical activity being stronger in people with stroke (b = −0.345; 95% CI = −0.438 to −0.252) than in adults without stroke (b = −0.269; 95% CI = −0.269 to −0.241). Conclusion The beneficial effect of prestroke physical activity on ADL limitations after stroke is stronger than its effect in matched adults without stroke followed for a similar number of years. Impact Physical activity, an intervention within the physical therapist's scope of practice, is effective in reducing the risk of functional dependence after stroke. Moreover, prestroke levels of physical activity can inform the prognosis of functional dependence in people with stroke. [ABSTRACT FROM AUTHOR]

Background Data on the presentation, management, and outcomes of Lassa fever (LF) in children are limited. Methods Description of the clinical and biological features, treatment, and outcomes of reverse transcriptase and polymerase chain reaction (RT-PCR)-confirmed LF in children aged under 15, enrolled in the LASsa fever clinical COurse and Prognostic factors in an Epidemic context (LASCOPE) prospective cohort study in Nigeria between April 2018 and February 2023. Results One hundred twenty-four children (aged under 12 months: 19; over 12 months: 105) were hospitalized with RT-PCR-confirmed LF. All received intravenous ribavirin. During follow-up, 99/124 (80%) had fever; 71/124 (57%) had digestive symptoms, vomiting (n  = 56/122, 46%) and abdominal pain (n  = 34/78 aged ≥5 years, 44%) more often than diarrhea (n  = 19/124, 15%); 17/124 (14%) had hemorrhagic signs; 44/112 (39%) had a hematocrit lower than 25%, of whom 32/44 (73%) received transfusions; 44/88 (50%) developed hypotension; 18/112 (16.1%) developed kidney disease improving global outcome (KDIGO) ≥2 acute kidney injury; 10/112 (8.9%) had KDIGO 3 acute kidney failure; 4/124 (3.2%) underwent renal replacement therapy. Seven children died, including 4 aged under 12 months (case fatality rate: under 12 months—22%, 95% confidence interval (CI): 7%–48%; over 12 months—2.9%, 95% CI: 0.7%–8.7%). In univariable analysis, age (P  = .003), impaired consciousness (P  = .026), and Lassa RT-PCR Ct value (P  = .006) were associated with Day 30 mortality. Conclusions The fatality rate for children over 12 months hospitalized with LF was lower than that previously reported for adults. Hypotension and acute kidney injury were the most frequent organ dysfunctions. Bleeding was relatively infrequent. Anemia and the need for transfusion were common, the relative contribution of ribavirin-induced hemolysis being unknown. [ABSTRACT FROM AUTHOR]

Background: Hypertension is a major contributor to the global burden of cardiovascular diseases, affecting over 1.28 billion adults worldwide. One of the primary contributors to the progression of cardiovascular diseases is hypertension, influenced by various psychosocial factors, including personality traits. The distinguishing attributes of Type D personality (TDP) are linked to adverse cardiovascular outcomes; however, its influence on the progression of hypertension is less understood. This investigation endeavored to analyze the affiliation between the onset of hypertension and TDP during five years in a sample of initially normotensive adults. Methods: A prospective cohort study included 500 initially normotensive participants in Baghdad, Iraq. The DS14 scale was used at baseline to assess TDP, and blood pressure was measured annually for five years. Cox proportional hazard regression models were employed to examine the association between TDP and incident hypertension, adjusting for traditional risk factors. Path analysis explored potential mediators, including physiological reactivity and health behaviors. Results: The incidence of hypertension was significantly higher among participants with TDP compared to non-type D participants (22.4% vs. 12.9%, P = 0.007). Individuals with TDP had a 1.63-fold increased risk of hypertension (95% Cl: 1.02-2.60; P = 0.040) after adjusting for age, sex, BMI, smoking, physical activity, and family history of hypertension. Path analysis revealed that physiological reactivity and health behaviors partially mediated the association between TDP and incident hypertension. Conclusion: TDP is independently associated with the development of hypertension in initially normotensive adults. Physiological reactivity and health behaviors partially explain the relationship between TDP and incident hypertension. Assessing the presence of TDP and implementing targeted interventions could help prevent the onset of hypertension and improve cardiovascular health. [ABSTRACT FROM AUTHOR]

Background Patient-reported penicillin allergy labels (PALs) are associated with adverse patient outcomes and inappropriate antibiotic prescribing. Removal of PALs via direct oral challenge (DOC) is associated with increased penicillin utilization post removal. Objectives To assess the impact of direct delabelling (allergy label removal via medical reconciliation alone) of type A adverse drug reaction (ADR) PALs on inpatient prescribing. Methods From January 2019 to December 2022 at two tertiary hospitals in Melbourne, patients aged ≥18 years with type A ADR PALs, as defined by the validated Antibiotic Allergy Assessment Tool, were offered direct delabelling or single-dose DOC. The primary endpoint was antibiotic use pre- and post-assessment (during index admission and 90 days post assessment). The secondary endpoint was the proportion of patients delabelled in the direct delabelling and DOC cohorts in the electronic medical record at 90 days post assessment. Results Allergy labels (n  = 4108) were assessed for 488 participants, with 490 individual type A ADR PAL assessments included. Three hundred and thirty-seven patients were directly delabelled, 69 underwent DOC and 84 were not delabelled. There was increased use of any penicillin following direct delabelling (OR 19.19, 95% CI 2.48–148.36) and DOC (OR 56.98, 95% CI 6.82–476.19) during the index admission, higher in the DOC group compared with direct delabelling (OR 2.97, 95% CI 1.39–6.37). Relabelling at 90 days was low with no statistically significant difference between direct delabelling (5/337; 1.5%) and DOC (0/69; 0%). Conclusions Both direct delabelling and DOC of type A ADR PALs increased penicillin usage; however, the impact was greatest with DOC. Most patients remain delabelled at 90 days. [ABSTRACT FROM AUTHOR]

Objective: This meta-analysis aims to investigate the long-term survival rates of dental implants over a 20-year period, providing a practical guide for clinicians while identifying potential areas for future research. Materials and methods: Data were sourced from recent publications, focusing exclusively on screw-shaped titanium implants with a rough surface. Both retrospective and prospective studies were included to ensure an adequate sample size. A systematic electronic literature search was conducted in the databases: MEDLINE (PubMed), Cochrane, and Web of Science. The risk of bias for all studies was analyzed using a tool by Hoy et al. Results: Three prospective studies (n = 237 implants) revealed a mean implant survival rate of 92% (95% CI: 82% to 97%), decreasing to 78% (95% CI: 74%-82%) after imputation (n = 422 implants). A total of five retrospective studies (n = 1440 implants) showed a survival rate of 88% (95% CI: 78%-94%). Implant failure causes were multifactorial. Conclusion: This review consolidates 20-year dental implant survival data, reflecting a remarkable 4 out of 5 implants success rate. It emphasizes the need for long-term follow-up care, addressing multifactorial implant failure. Prioritizing quality standards is crucial to prevent overestimating treatment effectiveness due to potential statistical errors. While dental implantology boasts reliable therapies, there is still room for improvement, and additional high-quality studies are needed, particularly to evaluate implant success. Clinical relevance: Never before have the implant survival over 20 years been systematically analyzed in a meta-analysis. Although a long-term survival can be expected, follow-up is essential and shouldn't end after insertion or even after 10 years. [ABSTRACT FROM AUTHOR]

Background Sigmoid colon cancer is a common type of colorectal cancer, frequently leading to liver metastasis. Predicting cause-specific survival and overall survival in patients with sigmoid colon cancer metastasis to liver is challenging because of the lack of suitable models. Methods Patients with sigmoid colon cancer metastasis to liver (2010-2017) in the Surveillance, Epidemiology, and End Results (SEER) Program were recruited. Patients were split into training and validation groups (7:3). Prognostic factors were identified using competing risk and Cox proportional hazards models, and nomograms for cause-specific survival and overall survival were developed. Model performance was evaluated with the concordance index and calibration curves, with a 2-sided P value less than  .05 considered statistically significant. Results A total of 4981 sigmoid colon cancer with liver metastasis patients were included, with a median follow-up of 20 months (interquartile range [IQR] = 9-33 months). During follow-up, 72.25% of patients died (68.44% from sigmoid colon cancer, 3.81% from other causes). Age, race, grade, T stage, N stage, surgery, chemotherapy, carcinoembryonic antigen, tumor deposits, lung metastasis, and tumor size were prognostic factors for cause-specific survival and overall survival. The models demonstrated good discrimination and calibration performance, with C index values of 0.79 (95% confidence interval [CI] = 0.78 to 0.80) for cause-specific survival and 0.74 (95% CI = 0.73 to 0.75) for overall survival. A web-based application for real-time cause-specific survival predictions was created, accessible at https://shuaishao.shinyapps.io/SCCLM/. Conclusion Prognostic factors for sigmoid colon cancer with liver metastasis patients were identified based on the SEER database, and nomograms for cause-specific survival and overall survival showed good performance. A web-based application was developed to predict sigmoid colon cancer with liver metastasis–specific survival, aiding in survival risk stratification. [ABSTRACT FROM AUTHOR]

The role of social determinants of health (SDOH) in controlling hypertension (HTN) in cancer patients is unknown. We hypothesize that high SDOH scores correlate with uncontrolled HTN in hypertensive cancer patients. In our prospective study, patients completed the Protocol for Responding to & Assessing Patients' Assets, Risks & Experiences questionnaire. After integrating home and clinic blood pressure readings, uncontrolled HTN was defined as systolic blood pressure greater than or equal to 140 mm Hg and/or diastolic blood pressure greater than or equal to 90 mm Hg. Using Cox regression, we analyzed the impact of SDOH on HTN control, adjusting for relevant factors. The study involved 318 participants (median age 66.4, median follow-up 166 days, SDOH score 6.5 ± 3.2), with stress, educational insecurity, and social isolation as prevalent adverse SDOH. High SDOH scores led to 77% increased risk of uncontrolled HTN (adjusted hazards ratio = 1.77; 95% confidence interval = 1.10 to 2.83, P  = .018). Urban residents with high SDOH scores were at an even greater risk. Identifying SDOH and mitigating underlying factors may help control HTN, the most typical disease process treated in all cardio-oncology clinics. [ABSTRACT FROM AUTHOR]

Rui Mao,1– 3 Tongtong Zhang,4 Ziye Yang,1– 3 Ji Li1– 3 1Department of Dermatology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 3National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 4Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University & The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu, 610031, People’s Republic of ChinaCorrespondence: Ziye Yang, Department of Dermatology, Xiangya Hospital, Central South University, People’s Republic of China, Email 2204170117@csu.edu.cnBackground: Current pharmacological treatments for psoriasis are generally non-specific and have significant limitations, particularly in the realm of targeted biologic therapies. There is an urgent need to identify and develop new therapeutic targets to improve treatment options.Objective: The aim of this study was to explore the proteome associated with psoriasis in large population cohorts to discover novel biomarkers that could guide therapy.Methods: We analyzed data from 54,306 participants enrolled in the UK Biobank Pharmacological Proteomics Project (UKB-PPP). We investigated the relationship between 2923 serum proteins and the risk of psoriasis using multivariate Cox regression models initially. This was complemented by two-sample Mendelian randomization (TSMR), Summary-data-based Mendelian Randomization (SMR), and coloc colocalization studies to identify genetic correlations with protein targets linked to psoriasis. A protein scoring system was created using the Cox proportional hazards model, and cumulative risk curves were generated to analyze psoriasis incidence variations.Results: Our study pinpointed 62 proteins significantly linked to the risk of developing psoriasis. Further analysis through TSMR narrowed these down to ten proteins with strong causal relationships to the disease. Additional deep-dive analyses such as SMR, colocalization, and differential expression studies highlighted four critical proteins (MMP12, PCSK9, PRSS8, and SCLY). We calculated a protein score based on the levels of these proteins, with higher scores correlating with increased risk of psoriasis.Conclusion: This study’s integration of proteomic and genetic data from a European adult cohort provides compelling evidence of several proteins as viable predictive biomarkers and potential therapeutic targets for psoriasis, facilitating the advancement of targeted treatment strategies.Keywords: psoriasis, plasma proteomics, prospective studies, Mendelian randomization

Abstract The relationship between depression and severe non-alcoholic fatty liver disease (NAFLD) has not been clearly defined. We conducted a longitudinal cohort study and a two-sample Mendelian randomization (MR) analysis to assess the association of depression with severe NAFLD risk. We used individual data from the UK Biobank study with 481,181 participants, and summary data from published genome-wide association studies. The association between depression and severe NAFLD was assessed using Cox proportional hazards regression analysis. Two-sample MR for depression with NAFLD was conducted, the principal analysis employed the inverse variance weighted (IVW) approach. In the observational study, after a median follow-up of 13.46 years, 4,563 participants had severe NAFLD. In multivariable-adjusted model, participants with depression had an increased risk of severe NAFLD (hazards ratio:1.21, 95% confidence interval (CI):1.09–1.34), as compared to those without depression. In subgroup analyses, the association between depression and severe NAFLD risk was generally observed across different subgroups. For the MR, result also showed that genetically predicted depression was causally associated with a higher risk of NAFLD (odds ratio:1.55, 95%CI:1.10–2.19) in IVW. Our study revealed a prospective association of depression with severe NAFLD, thus potentially necessitating clinical monitoring of individuals with depression for severe NAFLD.

Objectives: When exposed to iodine contrast medium (ICM), thyroid dysfunction may develop, due to excess amounts of iodide. The incidence of contrast-induced thyroid dysfunction has been difficult to interpret, because of the observational and retrospective designs of most previous studies. With the Swedish CArdioPulmonary bioImage Study (SCAPIS), where randomly selected individuals aged 50–65 years, underwent contrast-enhanced coronary CT angiography (CCTA), we were able to prospectively assess the incidence, magnitude and clinical impact of contrast-induced thyroid dysfunction. Methods: In 422 individuals, thyroid hormone levels were analysed before and 4–12 weeks after CCTA. Thyroid-related patient-reported outcome questionnaires (ThyPRO) at the time of pre and post-CCTA blood samplings were provided by 368 of those individuals. Thyroid peroxidase antibodies (TPOab) were analysed and an ultrasound of the thyroid gland was performed to detect any thyroid nodules. Results: There was a small statistically significant effect on thyroid hormone levels but no cases of overt hypo- or hyperthyroidism after ICM. Subclinical hypo- or hyperthyroidism or isolated low/high levels of free thyroxine (fT4) developed in 3.5% of the population with normal hormone levels pre-CCTA but without any increased thyroid-related symptoms compared to the remaining cohort. Elevated TPOab and being born outside Sweden were risk factors for developing subclinical hypothyroidism. The presence of thyroid nodules was not associated with ICM-induced thyroid dysfunction. Conclusion: The results of this prospective study support the notion that in iodine-sufficient countries, ICM-associated thyroid dysfunction is rare, usually mild, self-limiting and oligo/asymptomatic in subjects aged 50–65 years.

ABSTRACT Aims/Introduction PIONEER REAL Japan was a non‐interventional prospective study of oral semaglutide in adults with type 2 diabetes in Japanese clinical practice. Materials and Methods Adults naïve to injectable glucose‐lowering therapies initiated oral semaglutide in routine clinical practice and were followed for 34–44 weeks. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to end of study; the co‐primary endpoint was number of adverse events (AEs). Secondary endpoints included change in bodyweight from baseline to end of study. Analyses were also carried out for subgroups aged

Abstract Background Tau-PET is a diagnostic tool with high sensitivity and specificity for discriminating Alzheimer’s disease (AD) dementia from other neurodegenerative disorders in well-controlled research environments. The role of tau-PET in real-world clinical practice, however, remains to be established. The aim of the TAP-TAU study is therefore to investigate the impact of tau-PET in clinical practice. Methods TAP-TAU is a prospective, longitudinal multi-center study in 300 patients (≥ 50 years old) with mild cognitive impairment or mild dementia across five Dutch memory clinics. Patients are eligible if diagnostic certainty is

Disorders of consciousness are neurological conditions characterized by impaired arousal and awareness of self and environment. Behavioural responses are absent or are present but fluctuate. Disorders of consciousness are commonly encountered as a consequence of both acute and chronic brain injuries, yet reliable epidemiological estimates would require inclusive, operational definitions of the concept, as well as wider knowledge dissemination among involved professionals. Whereas several manifestations have been described, including coma, vegetative state/unresponsive wakefulness syndrome and minimally conscious state, a comprehensive neurobiological definition for disorders of consciousness is still lacking. The scientific literature is primarily observational, and studies-specific aetiologies lead to disorders of consciousness. Despite advances in these disease-related forms, there remains uncertainty about whether disorders of consciousness are a disease-agnostic unitary entity with a common mechanism, prognosis or treatment response paradigm. Our knowledge of disorders of consciousness has also been hampered by heterogeneity of study designs, variables, and outcomes, leading to results that are not comparable for evidence synthesis. The different backgrounds of professionals caring for patients with disorders of consciousness and the different goals at different stages of care could partly explain this variability. The Prospective Studies working group of the Neurocritical Care Society Curing Coma Campaign was established to create a platform for observational studies and future clinical trials on disorders of consciousness and coma across the continuum of care. In this narrative review, the author panel presents limitations of prior observational clinical research and outlines practical considerations for future investigations. A narrative review format was selected to ensure that the full breadth of study design considerations could be addressed and to facilitate a future consensus-based statement (e.g. via a modified Delphi) and series of recommendations. The panel convened weekly online meetings from October 2021 to December 2022. Research considerations addressed the nosographic status of disorders of consciousness, case ascertainment and verification, selection of dependent variables, choice of covariates and measurement and analysis of outcomes and covariates, aiming to promote more homogeneous designs and practices in future observational studies. The goal of this review is to inform a broad community of professionals with different backgrounds and clinical interests to address the methodological challenges imposed by the transition of care from acute to chronic stages and to streamline data gathering for patients with disorders of consciousness. A coordinated effort will be a key to allow reliable observational data synthesis and epidemiological estimates and ultimately inform condition-modifying clinical trials.

Interest in incorporating historical data in the clinical trial has increased with the rising cost of conducting clinical trials. The intervention arm for the current trial often requires prospective data to assess a novel treatment, and thus borrowing historical control data commensurate in distribution to current control data is motivated in order to increase the allocation ratio to the current intervention arm. Existing historical control borrowing adaptive designs adjust allocation ratios based on the commensurability assessed through study-level summary statistics of the response agnostic of the distributions of the trial subject characteristics in the current and historical trials. This can lead to distributional imbalance of the current trial subject characteristics across the treatment arms as well as between current control data and borrowed historical control data. Such covariate imbalance may threaten the internal validity of the current trial by introducing confounding factors that affect study endpoints. In this article, we propose a Bayesian design which borrows and updates the treatment allocation ratios both covariate-adaptively and commensurate to covariate dependently assessed similarity between the current and historical control data. We employ covariate-dependent discrepancy parameters which are allowed to grow with the sample size and propose a regularized local regression procedure for the estimation of the parameters. The proposed design also permits the current and the historical controls to be similar to varying degree, depending on the subject level characteristics. We evaluate the proposed design extensively under the settings derived from two placebo-controlled randomized trials on vertebral fracture risk in post-menopausal women.

BACKGROUND: Sepsis is a highly heterogeneous syndrome, which has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine approach aimed at identifying biologically homogenous subgroups of patients with septic shock and critical illnesses. Transcriptomic analysis can identify subclasses derived from differences in underlying pathophysiological processes that may provide the basis for new targeted therapies. The goal of this study was to elucidate pathophysiological pathways and identify pediatric septic shock subclasses based on whole blood RNA expression profiles. METHODS: The subjects were critically ill children with cardiopulmonary failure who were a part of a prospective randomized insulin titration trial to treat hyperglycemia. Genome-wide expression profiling was conducted using RNA sequencing from whole blood samples obtained from 46 children with septic shock and 52 mechanically ventilated noninfected controls without shock. Patients with septic shock were allocated to subclasses based on hierarchical clustering of gene expression profiles, and we then compared clinical characteristics, plasma inflammatory markers, cell compositions using GEDIT, and immune repertoires using Imrep between the two subclasses. RESULTS: Patients with septic shock depicted alterations in innate and adaptive immune pathways. Among patients with septic shock, we identified two subtypes based on gene expression patterns. Compared with Subclass 2, Subclass 1 was characterized by upregulation of innate immunity pathways and downregulation of adaptive immunity pathways. Subclass 1 had significantly worse clinical outcomes despite the two classes having similar illness severity on initial clinical presentation. Subclass 1 had elevated levels of plasma inflammatory cytokines and endothelial injury biomarkers and demonstrated decreased percentages of CD4 T cells and B cells and less diverse T cell receptor repertoires. CONCLUSIONS: Two subclasses of pediatric septic shock patients were discovered through genome-wide expression profiling based on whole blood RNA sequencing with major biological and clinical differences. Trial Registration This is a secondary analysis of data generated as part of the observational CAF-PINT ancillary of the HALF-PINT study (NCT01565941). Registered March 29, 2012.

The BCL2 inhibitor venetoclax promotes apoptosis in blood cancer cells and is approved for treatment of chronic lymphocytic leukemia and acute myeloid leukemia. However, multiple myeloma cells are frequently more dependent on MCL-1 for survival, conferring resistance to venetoclax. Here we report that mevalonate pathway inhibition with statins can overcome resistance to venetoclax in multiple myeloma cell lines and primary cells. In addition, statins sensitize to apoptosis induced by MCL-1 inhibitor, S63845. In retrospective analysis of venetoclax clinical studies in multiple myeloma, background statin use was associated with a significantly enhanced rate of stringent complete response and absence of progressive disease. Statins sensitize multiple myeloma cells to venetoclax by upregulating two proapoptotic proteins: PUMA via a p53-independent mechanism and NOXA via the integrated stress response. These findings provide rationale for prospective testing of statins with venetoclax regimens in multiple myeloma.SignificanceBH3 mimetics including venetoclax hold promise for treatment of multiple myeloma but rational combinations are needed to broaden efficacy. This study presents mechanistic and clinical data to support addition of pitavastatin to venetoclax regimens in myeloma. The results open a new avenue for repurposing statins in blood cancer.

ObjectiveCannabis demand (i.e., relative value), assessed cross-sectionally via a hypothetical marijuana purchase task (MPT), has been associated with use, problems, and dependence symptoms, among others. However, limited work exists on the prospective stability of the MPT. Furthermore, cannabis demand among veterans endorsing cannabis use, and the prospective cyclical relationship between demand and use over time, have yet to be investigated.MethodTwo waves of data from a veteran sample (N = 133) reporting current (past 6-month) cannabis use were analyzed to assess stability in cannabis demand over 6 months. Autoregressive cross-lagged panel models (CLPMs) assessed the longitudinal associations between demand indices (i.e., intensity, Omax, Pmax, breakpoint) and cannabis use.ResultsBaseline cannabis use predicted greater intensity (β = .32, p < .001), Omax (β = .37, p < .001), breakpoint (β = .28, p < .001), and Pmax (β = .21, p = .017) at 6 months. Conversely, baseline intensity (β = .14, p = .028), breakpoint (β = .12, p = .038), and Pmax (β = .12, p = .043), but not Omax, predicted greater use at 6 months. Only intensity demonstrated acceptable prospective reliability.ConclusionsCannabis demand demonstrated stability over 6 months in CLPM models, varying along with natural changes in cannabis use. Importantly, intensity, Pmax, and breakpoint displayed bidirectional predictive associations with cannabis use, and the prospective pathway from use to demand was consistently stronger. Test-retest reliability ranged from good to poor across indices. Findings highlight the value of assessing cannabis demand longitudinally, particularly among clinical samples, to determine how demand fluctuates in response to experimental manipulation, intervention, and treatment. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

PurposeIn a phase III randomized trial, adding a radiation boost to tumor(s) visible on MRI improved prostate cancer (PCa) disease-free and metastasis-free survival without additional toxicity. Radiation oncologists' ability to identify prostate tumors is critical to widely adopting intraprostatic tumor radiotherapy boost for patients. A diffusion MRI biomarker, called the Restriction Spectrum Imaging restriction score (RSIrs), has been shown to improve radiologists' identification of clinically significant PCa. We hypothesized that (1) radiation oncologists would find accurately delineating PCa tumors on conventional MRI challenging and (2) using RSIrs maps would improve radiation oncologists' accuracy for PCa tumor delineation.Methods and materialsIn this multi-institutional, international, prospective study, 44 radiation oncologists (participants) and 2 expert radiologists (experts) contoured prostate tumors on 39 total patient cases using conventional MRI with or without RSIrs maps. Participant volumes were compared to the consensus expert volumes. Contouring accuracy metrics included percent overlap with expert volume, Dice coefficient, conformal number, and maximum distance beyond expert volume.Results1604 participant volumes were produced. 40 of 44 participants (91%) completely missed ≥1 expert-defined target lesion without RSIrs, compared to 13 of 44 (30%) with RSIrs maps. On conventional MRI alone, 134 of 762 contour attempts (18%) completely missed the target, compared to 18 of 842 (2%) with RSIrs maps. Use of RSIrs maps improved all contour accuracy metrics by approximately 50% or more. Mixed effects modeling confirmed that RSIrs maps were the main variable driving improvement in all metrics. System Usability Scores indicated RSIrs maps significantly improved the contouring experience (72 vs. 58, p

BACKGROUND: Benign prostatic hyperplasia, lower urinary tract symptoms, and prostate cancer often co-occur. Their effect on urinary function is an important consideration regarding prostate cancer treatment choices. While prostate volume (PV) and urinary symptoms are commonly used in treatment choice decision making, their association with post-treatment urinary function is unknown. We evaluated the associations between PV and baseline urinary function with treatment choice and post-treatment urinary function among men with localized prostate cancer. METHODS: We identified 1647 patients from CEASAR, a multicenter population-based, prospective cohort study of men with localized prostate cancer, for analysis. Primary outcomes were treatment choice and health-related quality of life (HRQOL) assessed by the 26-item Expanded Prostate Index Composite (EPIC-26) at pre-specified intervals up to 5 years. Multivariable analysis was performed, controlling for demographic and clinicopathologic features. RESULTS: Median baseline PV was 36 mL (IQR 27-48), and baseline urinary irritative/obstructive domain score was 87 (IQR 75-100). There was no observed clinically meaningful association between PV and treatment choice or post-treatment urinary function. Among patients with poor baseline urinary function, treatment with radiation or surgery was associated with statistically and clinically significant improvement in urinary function at 6 months which was durable through 5 years (improvement from baseline at 5 years: radiation 20.4 points, surgery 24.5 points). CONCLUSIONS: PV was not found to be associated with treatment modality or post-treatment urinary irritative/obstructive function among men treated for localized prostate cancer. Men with poor baseline urinary irritative/obstructive function improve after treatment with surgery or radiation therapy.

The consequences of pain in early onset Parkinson's disease (EOPD) remain under appreciated even though pain may exert an increasingly negative impact on patient quality of life as motor and non-motor symptoms worsen. In this prospective study, we investigate the prevalence and severity of pain in 135 Vietnamese patients with EOPD from three medical centers using the King's PD Pain Scale (KPPS), the Mini Mental Status Exam (MMSE), the Unified Parkinson's Disease Rating Scale (UPDRS) and the Non-Motor Symptoms Scale (NMSS). Pain was reported by 79.3%. The most common subtype of pain was musculoskeletal (70.1%), followed by nocturnal (43.9%), radicular (43.0%), chronic (42.1%), fluctuation-related (34.6%) and orofacial pain (16.8%). Most patients (74.8%) experienced more than one pain subtype. Fluctuation-related pain and orofacial pain were significantly more prevalent among patients with higher Hoehn & Yahr (H&Y) stages (3-5) versus lower H&Y stages (1-2). Pain subtype and severity were not significantly related to gender or age of PD onset. Patients with H&Y stages 3-5 had statistically significantly higher KPPS scores for fluctuation-related pain (p = 0.018) and radicular pain (p = 0.026). Independent associations were found between pain severity and age (p = 0.028), depression severity (p = 0.018), perceptual problems/hallucinations (p = 0.033) and sexual function (p = 0.024). Patients with depression and higher H&Y stages (3-5) had statistically significantly higher mean KPPS scores versus patients without depression and at lower H&Y stages (1-2). Pain may be more common and severe in EOPD patients than previously appreciated. Older age, depression, perceptual problems/hallucinations and sexual dysfunction were independently associated with higher pain severity.

Background & aimsAlpha-fetoprotein (AFP) predicts hepatocellular carcinoma (HCC) recurrence after liver transplant (LT) but remains an imperfect biomarker. The role of DCP (des-gamma-carboxyprothrombin) and AFP-L3 (AFP bound to Lens culinaris agglutinin) in predicting HCC recurrence remains incompletely characterized. AFP-L3 and DCP could identify patients at high risk of post-transplant HCC recurrence and serve as liver transplant exclusion criteria to defer transplant until patients receive additional risk-reducing pre-transplant locoregional therapy.MethodsThis prospective cohort study included consecutive patients with HCC who underwent LT (within or down-staged to Milan criteria) between 2017 and 2022. Pre-transplant AFP, AFP-L3, and DCP measurements were obtained. The primary endpoint was the ability of biomarkers to predict HCC recurrence-free survival.ResultsThis cohort included 285 patients with a median age of 67 (IQR 63-71). At LT, median biomarker values were AFP 5.0 ng/ml (IQR 3.0-12.1), AFP-L3 6.7% (0.5-13.2), and DCP 1.0 ng/ml (0.3-2.8). Most (94.7%) patients received pre-LT locoregional therapy. After a median post-LT follow-up of 3.1 years, HCC recurrence was observed in 18 (6.3%) patients. AFP-L3 and DCP outperformed AFP with C-statistics of 0.81 and 0.86 respectively, compared with 0.74 for AFP. A dual-biomarker combination of AFP-L3 ≥15% and DCP ≥7.5 predicted 61.1% of HCC recurrences, whereas HCC only recurred in 7 of 265 (2.6%) patients not meeting this threshold. The Kaplan-Meier recurrence-free survival rate at 3 years post-LT was 43.7% for patients with dual-positive biomarkers compared to 97.0% for all others (p

BackgroundFindings on the associations between prenatal PFAS exposures and offspring adiposity are inconsistent. Whether such associations may extend to adolescence is especially understudied.ObjectivesWe investigated associations of prenatal PFAS exposures with offspring adiposity and body composition at 16-20 years of age.MethodsWe studied 545 mother-child pairs in the prospective prebirth cohort Project Viva (Boston, Massachusetts). We measured six PFAS (PFOA, PFOS, PFNA, PFHxS, EtFOSAA, and MeFOSAA) in maternal early pregnancy (median age=9.6wk, range: 5.7-19.6 wk) plasma samples. At the late adolescence visit (median age=17.4 y, range: 15.9-20.0 y), we obtained anthropometric measures and assessed body composition using bioelectrical impedance analysis and dual-energy X-ray absorptiometry. We examined associations of individual PFAS with obesity [i.e., age- and sex-specific body mass index (BMI) ≥95th percentile] and adiposity and body composition using multivariable Poisson and linear regression models, respectively. We assessed PFAS mixture effects using Bayesian kernel machine regression (BKMR) and quantile g-computation. We used fractional-polynomial models to assess BMI trajectories (at 3-20 years of age) by prenatal PFAS levels.ResultsThirteen percent (n=73) of the children had obesity in late adolescence. After multivariable adjustment, higher prenatal PFAS concentrations were associated with higher obesity risk [e.g., 1.59 (95% CI: 1.19, 2.12), 1.24 (95% CI: 0.98, 1.57), and 1.49 (95% CI: 1.11, 1.99) times the obesity risk per doubling of PFOS, PFOA, and PFNA, respectively]. BKMR showed an interaction between PFOA and PFOS, where the positive association between PFOS and obesity was stronger when PFOA levels were lower. Each quartile increment of the PFAS mixture was associated with 1.52 (95% CI: 1.03, 2.25) times the obesity risk and 0.52 (95% CI: -0.02, 1.06) kg/m2 higher BMI. Children with higher prenatal PFOS, EtFOSAA, and MeFOSAA concentrations had higher rates of BMI increase starting from 9-11 years of age.DiscussionPrenatal PFAS exposures may have obesogenic effects into late adolescence. https://doi.org/10.1289/EHP12597.

BACKGROUND: The number of breast cancer survivors is increasing, yet evidence to inform dietary and lifestyle guidelines is limited. METHODS: This analysis included 3,658 participants from the Pathways Study, a prospective cohort of women diagnosed with invasive breast cancer. A healthy plant-based dietary index score (hPDI), an American Cancer Society (ACS) nutrition guidelines score, a 2015 Healthy Eating Index score (HEI), hours per week of moderate to vigorous physical activity (PA), and lifetime cumulative pack-years of cigarette smoking (SM) were each measured at diagnosis, 6, 24, and 72 months. Using g-computation, 5- and 10-year risk ratios (RR), risk differences, and 95% confidence intervals (CI) for all-cause mortality under hypothetical interventions on diet quality, PA, and SM, compared with the natural course (no intervention) were calculated. RESULTS: Hypothetical moderate to extreme interventions on hPDI, ACS, and HEI, each in combination with PA and SM, showed 11% to 56%, 9% to 38%, and 9% to 49% decreases in 5-year risks of all-cause mortality compared with no intervention, respectively [(hPDI: RRmoderate = 0.89, 95% CI: 0.82-0.94; RRextreme = 0.44, 95% CI: 0.26-0.67), (ACS: RRmoderate = 0.91, 95% CI: 0.85-0.96; RRextreme = 0.62, 95% CI: 0.43-0.82), (HEI: RRmoderate = 0.91, 95% CI: 0.84-0.95; RRextreme = 0.51, 95% CI: 0.33-0.72)]. While 10-year relative risks were slightly attenuated, absolute risk reductions were more pronounced. CONCLUSIONS: Interventions to improve diet quality, increase PA, or reduce SM at the time of diagnosis may improve survival among breast cancer survivors. IMPACT: We estimate that over 10% of deaths could be delayed by even moderate adoption of these behaviors.

Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P

Opinion statementThe treatment landscape of renal cell carcinoma (RCC) has evolved significantly over the past three decades. Active surveillance and tumor ablation are alternatives to extirpative therapy in appropriately selected patients. Stereotactic body radiation therapy (SBRT) is an emerging noninvasive alternative to treat primary RCC tumors. The advent of immune checkpoint inhibitors (ICIs) has greatly improved the overall survival of advanced RCC, and now the ICI-based doublet (dual ICI-ICI doublet; or ICI in combination with a vascular endothelial growth factor tyrosine kinase inhibitor, ICI-TKI doublet) has become the standard frontline therapy. Based on unprecedented outcomes in the metastatic with ICIs, they are also being explored in the neoadjuvant and adjuvant setting for patients with high-risk disease. Adjuvant pembrolizumab has proven efficacy to reduce the risk of RCC recurrence after nephrectomy. Historically considered a radioresistant tumor, SBRT occupies an expanding role to treat RCC with oligometastasis or oligoprogression in combination with systemic therapy. Furthermore, SBRT is being investigated in combination with ICI-doublet in the advanced disease setting. Lastly, given the treatment paradigm is shifting to adopt ICIs at earlier disease course, the prospective studies guiding treatment sequencing in the post-ICI setting is maturing. The effort is ongoing in search of predictive biomarkers to guide optimal treatment option in RCC.

BACKGROUND: Few hospitals have built surveillance for diagnostic errors into usual care or used comparative quantitative and qualitative data to understand their diagnostic processes and implement interventions designed to reduce these errors. OBJECTIVES: To build surveillance for diagnostic errors into usual care, benchmark diagnostic performance across sites, pilot test interventions, and evaluate the programs impact on diagnostic error rates. METHODS AND ANALYSIS: Achieving diagnostic excellence through prevention and teamwork (ADEPT) is a multicenter, real-world quality and safety program utilizing interrupted time-series techniques to evaluate outcomes. Study subjects will be a randomly sampled population of medical patients hospitalized at 16 US hospitals who died, were transferred to intensive care, or had a rapid response during the hospitalization. Surveillance for diagnostic errors will occur on 10 events per month per site using a previously established two-person adjudication process. Concurrent reviews of patients who had a qualifying event in the previous week will allow for surveys of clinicians to better understand contributors to diagnostic error, or conversely, examples of diagnostic excellence, which cannot be gleaned from medical record review alone. With guidance from national experts in quality and safety, sites will report and benchmark diagnostic error rates, share lessons regarding underlying causes, and design, implement, and pilot test interventions using both Safety I and Safety II approaches aimed at patients, providers, and health systems. Safety II approaches will focus on cases where diagnostic error did not occur, applying theories of how people and systems are able to succeed under varying conditions. The primary outcome will be the number of diagnostic errors per patient, using segmented multivariable regression to evaluate change in y-intercept and change in slope after initiation of the program. ETHICS AND DISSEMINATION: The study has been approved by the University of California, San Francisco Institutional Review Board (IRB), which is serving as the single IRB. Intervention toolkits and study findings will be disseminated through partners including Vizient, The Joint Commission, and Press-Ganey, and through national meetings, scientific journals, and publications aimed at the general public.

BackgroundWe aimed to understand the association between maternal stress in the first year of life and childhood body mass index (BMI) from 2 to 4 years of age in a large, prospective United States-based consortium of cohorts.MethodsWe used data from the Environmental influences on Child Health Outcomes program. The main exposure was maternal stress in the first year of life measured with the Perceived Stress Scale (PSS). The main outcome was the first childhood BMI percentile after age 2 until age 4 years. We used an adjusted linear mixed effects model to examine associations between BMI and PSS quartile.ResultsThe mean BMI percentile in children was 59.8 (SD 30) measured at 3.0 years (SD 1) on average. In both crude models and models adjusted for maternal BMI, age, race, ethnicity, infant birthweight, and health insurance status, no linear associations were observed between maternal stress and child BMI.ConclusionsAmong 1694 maternal-infant dyads, we found no statistically significant relationships between maternal perceived stress in the first year of life and child BMI after 2 through 4 years.ImpactAlthough existing literature suggests relationships between parental stress and childhood BMI, we found no linear associations between maternal stress in the first year of life and childhood BMI at 2-4 years of age among participants in ECHO cohorts. Higher maternal stress was significantly associated with Hispanic ethnicity, Black race, and public health insurance. Our analysis of a large, nationally representative sample challenges assumptions that maternal stress in the first year of life, as measured by a widely used scale, is associated with offspring BMI.

Adolescents involved in juvenile legal system are at increased risk for self-cutting behavior, however, correlates associated with elevated risk remain underresearched, particularly among youth with first involvement with the court. This study utilized an epidemiological two-year longitudinal study involving 401 adolescents at first contact with the court (Mage = 14.47; SDage = 1.94 years; 43% female; 42% Latinx/Hispanic) and an involved caregiver. Study aims examined key prospective psychosocial correlates of self-cutting behavior. Baseline assessments captured individual and family level risk and protective factors; self-cutting behavior was assessed longitudinally every four months post-baseline for 24 months. Psychosocial correlates of self-cutting behavior included adolescent affect dysregulation, post-traumatic stress disorder symptoms, impulsive decision making, anxiety and depression symptoms. Significant protective factors included positive communication with caregiver and family, higher self-esteem, and having a caring and supportive family. These findings suggest that internalizing symptoms as well as difficulties with emotion regulation and impulsive decision making are correlated with heightened risk for self-cutting behavior among adolescents involved in the juvenile legal system. The findings also suggest that individual and family level protective factors, like positive communication and a supportive family, are associated with decreased risk for self-cutting behavior among adolescents at first contact with the court.

OBJECTIVE: This study examined the relationship between age at diagnosis and disease characteristics and damage in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Analysis of a prospective longitudinal cohort of patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA) in the Vasculitis Clinical Research Consortium (2013-2021). Disease cohorts were divided by age at diagnosis (years): children (65). Data included demographics, ANCA type, clinical characteristics, Vasculitis Damage Index (VDI) scores, ANCA Vasculitis Index of Damage (AVID) scores, and novel disease-specific and non-disease-specific damage scores built from VDI and AVID items. RESULTS: Analysis included data from 1020 patients with GPA/MPA and 357 with EGPA. Female predominance in GPA/MPA decreased with age at diagnosis. AAV in childhood was more often GPA and proteinase 3-ANCA positive. Children with GPA/MPA experienced more subglottic stenosis and alveolar hemorrhage; children and young adults with EGPA experienced more alveolar hemorrhage, need for intubation, and gastrointestinal involvement. Older adults (GPA/MPA) had more neurologic manifestations. After adjusting for disease duration, medications, tobacco, and ANCA, all damage scores increased with age at diagnosis for GPA/MPA (P

BACKGROUND: Long-term noise exposure is associated with cardiovascular disease (CVD), including acute cardiovascular events such as myocardial infarction and stroke. However, longitudinal cohort studies in the U.S. of long-term noise and CVD are almost exclusively from Europe and few modeled nighttime noise, when an individual is likely at home or asleep, separately from daytime noise. We aimed to examine the prospective association of outdoor long-term nighttime and daytime noise from anthropogenic sources with incident CVD using a U.S.-based, nationwide cohort of women. METHODS: We linked L50 nighttime and L50 daytime anthropogenic modeled noise estimates from a U.S. National Parks Service model (L50: sound pressure levels exceeded 50 percent of the time) to geocoded residential addresses of 114,116 participants in the Nurses Health Study. We used time-varying Cox proportional hazards models to estimate risk of incident CVD, coronary heart disease (CHD), and stroke associated with long-term average (14-y measurement period) noise exposure, adjusted for potential individual- and area-level confounders and CVD risk factors (1988-2018; biennial residential address updates; monthly CVD updates). We assessed effect modification by population density, region, air pollution, vegetation cover, and neighborhood socioeconomic status, and explored mediation by self-reported average nightly sleep duration. RESULTS: Over 2,548,927 person-years, there were 10,331 incident CVD events. In fully adjusted models, the hazard ratios for each interquartile range increase in L50 nighttime noise (3.67 dBA) and L50 daytime noise (4.35 dBA), respectively, were 1.04 (95% CI: 1.02, 1.06) and 1.04 (95% CI: 1.02, 1.07). Associations for total energy-equivalent noise level (Leq) measures were stronger than for the anthropogenic statistical L50 noise measures. Similar associations were observed for CHD and stroke. Interaction analyses suggested that associations of L50 nighttime and L50 daytime noise with CVD did not differ by prespecified effect modifiers. We found no evidence that inadequate sleep (

BACKGROUND AND AIMS: Data on how to teach endosonographers needle-based confocal laser endomicroscopy (nCLE)-guided histologic diagnosis of pancreatic cystic lesions (PCLs) are limited. Hence, we developed and tested a structured educational program to train early-career endosonographers in nCLE-guided diagnosis of PCLs. METHODS: Twenty-one early-career nCLE-naïve endosonographers watched a teaching module outlining nCLE criteria for diagnosing PCLs. Participants then reviewed 80 high-yield nCLE videos, recorded diagnoses, and received expert feedback (phase 1). Observers were then randomized to a refresher feedback session or self-learning at 4 weeks. Eight weeks after training, participants independently assessed the same 80 nCLE videos without feedback and provided histologic predictions (phase 2). Diagnostic performance of nCLE to differentiate mucinous versus nonmucinous PCLs and to diagnose specific subtypes were analyzed using histopathology as the criterion standard. Learning curves were determined using cumulative sum analysis. RESULTS: Accuracy and diagnostic confidence for differentiating mucinous versus nonmucinous PCLs improved as endosonographers progressed through nCLE videos in phase 1 (P < .001). Similar trends were observed with the diagnosis of PCL subtypes. Most participants achieved competency interpreting nCLE, requiring a median of 38 assessments (range, 9-67). During phase 2, participants independently differentiated PCLs with high accuracy (89%), high confidence (83%), and substantial interobserver agreement (κ = .63). Accuracy for nCLE-guided PCL subtype diagnoses ranged from 82% to 96%. The learned nCLE skills did not deteriorate at 8 weeks and were not impacted by a refresher session. CONCLUSIONS: We developed a practical, effective, and durable educational intervention to train early-career endosonographers in nCLE-guided diagnosis of PCLs.

PURPOSE: To evaluate the accuracy of a point-of-view cataract surgery simulation video in representing different subjective experiences of patients undergoing the procedure. METHODS: One hundred consecutive post-cataract-surgery patients were shown a short simulation video of the surgery obtained through a porcine eye model during the first postoperative week. Patients then answered a multiple-choice questionnaire regarding their visual and tactile intraoperative experiences and how those experiences matched the simulation. RESULTS: Of the patients surveyed (n = 100), 78% (n = 78) recalled visual experiences during surgery, 11% recalled pain (n = 11), and 6.4% (n = 5) recalled frightening experiences. Thirty-six percent of patients (n = 36) were interviewed after their second cataract surgery; there was no statistically significant difference between anxiety scores reported before the first eye surgery and second eye surgery (p = 0.147). Among all patients who recalled visual experiences (n = 78), nearly half (47.4%) reported that the video was the same/similar to their experience. Forty-eight percent of the patients recommended future patients to watch the video before their procedures, and more than a third (36%) agreed that watching the video before surgery would have helped them to relax. CONCLUSIONS: Our model reflects the wide range of subjective patient experiences during and after surgery. The high percentage of patients who found the video accurate in different ways suggests that, with more development, point-of-view cataract simulation videos could prove useful for educational or clinical use. Further research may be done to confirm the simulations utility, by screening the video for subjects before operations.

A growing body of literature has documented high rates of adverse childhood experiences (ACEs) and their effects on behavioral health among adolescents impacted by the juvenile legal system. Most research with justice-impacted youth assesses the ten standard ACEs, encompassing abuse, neglect, and household dysfunction. This body of work has largely ignored the five expanded ACEs which assess social and community level adversity. Justice-impacted youth commonly experience expanded ACEs (racial discrimination, placement in foster care, living in a disadvantaged neighborhood, witnessing violence, bullying), and inclusion of these adversities may enhance predictive utility of the commonly used ACEs score. The current study examined the prospective impact of total ACEs (standard and expanded) on alcohol and cannabis use, substance-related consequences, and psychiatric symptoms during the year following first ever contact with the juvenile court. Results indicate justice-impacted youth experience multiple expanded ACEs prior to first court contact. The expanded ACEs did not predict any of the behavioral health outcomes assessed, over and above the standard ACEs. Inclusion of expanded ACEs in the standard ACEs score may not increase utility in identifying prospective behavioral health outcomes among youth in first time contact with the juvenile legal system.

Background and aimsNonalcoholic fatty liver disease (NAFLD) has reached pandemic proportions. Early detection can identify at-risk patients who can be linked to hepatology care. The vibration-controlled transient elastography (VCTE) controlled attenuation parameter (CAP) is biopsy validated to diagnose hepatic steatosis (HS). We aimed to develop a novel clinical predictive algorithm for HS using the CAP score at a Veterans' Affairs hospital.MethodsWe identified 403 patients in the Greater Los Angeles VA Healthcare System with valid VCTEs during 1/2018-6/2020. Patients with alcohol-associated liver disease, genotype 3 hepatitis C, any malignancies, or liver transplantation were excluded. Linear regression was used to identify predictors of NAFLD. To identify a CAP threshold for HS detection, receiver operating characteristic analysis was applied using liver biopsy, MRI, and ultrasound as the gold standards.ResultsThe cohort was racially/ethnically diverse (26% Black/African American; 20% Hispanic). Significant positive predictors of elevated CAP score included diabetes, cholesterol, triglycerides, BMI, and self-identifying as Hispanic. Our predictions of CAP scores using this model strongly correlated (r = 0.61, p

The extent to which receptive anal intercourse (RAI) increases the HIV acquisition risk of women compared to receptive vaginal intercourse (RVI) is poorly understood. We evaluated RAI practice over time and its association with HIV incidence during three prospective HIV cohorts of women: RV217, MTN-003 (VOICE), and HVTN 907. At baseline, 16% (RV 217), 18% (VOICE) of women reported RAI in the past 3 months and 27% (HVTN 907) in the past 6 months, with RAI declining during follow-up by around 3-fold. HIV incidence in the three cohorts was positively associated with reporting RAI at baseline, albeit not always significantly. The adjusted hazard rate ratios for potential confounders (aHR) were 1.1 (95% Confidence interval: 0.8-1.5) for VOICE and 3.3 (1.6-6.8) for RV 217, whereas the ratio of cumulative HIV incidence by RAI practice was 1.9 (0.6-6.0) for HVTN 907. For VOICE, the estimated magnitude of association increased slightly when using a time-varying RAI exposure definition (aHR = 1.2; 0.9-1.6), and for women reporting RAI at every follow-up survey (aHR = 2.0 (1.3-3.1)), though not for women reporting higher RAI frequency (> 30% acts being RAI vs. no RAI in the past 3 months; aHR = 0.7 (0.4-1.1)). Findings indicated precise estimation of the RAI/HIV association, following multiple RVI/RAI exposures, is sensitive to RAI exposure definition, which remain imperfectly measured. Information on RAI practices, RAI/RVI frequency, and condom use should be more systematically and precisely recorded and reported in studies looking at sexual behaviors and HIV seroconversions; standardized measures would aid comparability across geographies and over time.