Impeding DNA Break Repair Enables Oocyte Quality Control.

Oocyte quality control culls eggs with defects in meiosis. In mouse, oocyte death can be triggered by defects in chromosome synapsis and recombination, which involve repair of DNA double-strand breaks (DSBs) between homologous chromosomes. We show that RNF212, a SUMO ligase required for crossing over, also mediates oocyte quality control. Both physiological apoptosis and wholesale oocyte elimination in meiotic mutants require RNF212. RNF212 sensitizes oocytes to DSB-induced apoptosis within a narrow window as chromosomes desynapse and cells transition into quiescence. Analysis of DNA damage during this transition implies that RNF212 impedes DSB repair. Consistently, RNF212 is required for HORMAD1, a negative regulator of inter-sister recombination, to associate with desynapsing chromosomes. We infer that oocytes impede repair of residual DSBs to retain a "memory" of meiotic defects that enables quality-control processes. These results define the logic of oocyte quality control and suggest RNF212 variants may influence transmission of defective genomes.

TAF4b transcription networks regulating early oocyte differentiation.

Establishment of a healthy ovarian reserve is contingent upon numerous regulatory pathways during embryogenesis. Previously, mice lacking TBP-associated factor 4b (Taf4b) were shown to exhibit a diminished ovarian reserve. However, potential oocyte-intrinsic functions of TAF4b have not been examined. Here, we use a combination of gene expression profiling and chromatin mapping to characterize TAF4b-dependent gene regulatory networks in mouse oocytes. We find that Taf4b-deficient oocytes display inappropriate expression of meiotic, chromatin modification/organization, and X-linked genes. Furthermore, dysregulated genes in Taf4b-deficient oocytes exhibit an unexpected amount of overlap with dysregulated genes in oocytes from XO female mice, a mouse model of Turner Syndrome. Using Cleavage Under Targets and Release Using Nuclease (CUT&RUN), we observed TAF4b enrichment at genes involved in chromatin remodeling and DNA repair, some of which are differentially expressed in Taf4b-deficient oocytes. Interestingly, TAF4b target genes were enriched for Sp/Klf family and NFY target motifs rather than TATA-box motifs, suggesting an alternative mode of promoter interaction. Together, our data connect several gene regulatory nodes that contribute to the precise development of the mammalian ovarian reserve.

Phylogenetic Biodiversity Metrics Should Account for Both Accumulation and Attrition of Evolutionary Heritage.

Phylogenetic metrics are essential tools used in the study of ecology, evolution and conservation. Phylogenetic diversity (PD) in particular is one of the most prominent measures of biodiversity and is based on the idea that biological features accumulate along the edges of phylogenetic trees that are summed. We argue that PD and many other phylogenetic biodiversity metrics fail to capture an essential process that we term attrition. Attrition is the gradual loss of features through causes other than extinction. Here we introduce "EvoHeritage", a generalization of PD that is founded on the joint processes of accumulation and attrition of features. We argue that while PD measures evolutionary history, EvoHeritage is required to capture a more pertinent subset of evolutionary history including only components that have survived attrition. We show that EvoHeritage is not the same as PD on a tree with scaled edges; instead, accumulation and attrition interact in a more complex non-monophyletic way that cannot be captured by edge lengths alone. This leads us to speculate that the one-dimensional edge lengths of classic trees may be insufficiently flexible to capture the nuances of evolutionary processes. We derive a measure of EvoHeritage and show that it elegantly reproduces species richness and PD at opposite ends of a continuum based on the intensity of attrition. We demonstrate the utility of EvoHeritage in ecology as a predictor of community productivity compared with species richness and PD. We also show how EvoHeritage can quantify living fossils and resolve their associated controversy. We suggest how the existing calculus of PD-based metrics and other phylogenetic biodiversity metrics can and should be recast in terms of EvoHeritage accumulation and attrition.

Graphene Failure under MPa: Nanowear of Step Edges Initiated by Interfacial Mechanochemical Reactions.

The low wear resistance of macroscale graphene coatings does not match the ultrahigh mechanical strength and chemical inertness of the graphene layer itself; however, the wear mechanism responsible for this issue at low mechanical stress is still unclear. Here, we demonstrate that the susceptibility of the graphene monolayer to wear at its atomic step edges is governed by the mechanochemistry of frictional interfaces. The mechanochemical reactions activated by chemically active SiO2 microspheres result in atomic attrition rather than mechanical damage such as surface fracture and folding by chemically inert diamond tools. Correspondingly, the threshold contact stress for graphene edge wear decreases more than 30 times to the MPa level, and mechanochemical wear can be described well with the mechanically assisted Arrhenius-type kinetic model, i.e., exponential dependence of the removal rate on the contact stress. These findings provide a strategy for improving the antiwear of graphene-based materials by reducing the mechanochemical interactions at tribological interfaces.

Neocortical cholinergic pathology after neonatal brain injury is increased by Alzheimer's disease-related genes in mice.

Hypoxic-ischemic encephalopathy (HIE) in neonates causes mortality and neurologic morbidity, including poor cognition with a complex neuropathology. Injury to the cholinergic basal forebrain and its rich innervation of cerebral cortex may also drive cognitive pathology. It is uncertain whether genes associated with adult cognition-related neurodegeneration worsen outcomes after neonatal HIE. We hypothesized that neocortical damage caused by neonatal HI in mice is ushered by persistent cholinergic innervation and interneuron (IN) pathology that correlates with cognitive outcome and is exacerbated by genes linked to Alzheimer's disease. We subjected non-transgenic (nTg) C57Bl6 mice and mice transgenically (Tg) expressing human mutant amyloid precursor protein (APP-Swedish variant) and mutant presenilin (PS1-ΔE9) to the Rice-Vannucci HI model on postnatal day 10 (P10). nTg and Tg mice with sham procedure were controls. Visual discrimination (VD) was tested for cognition. Cortical and hippocampal cholinergic axonal and IN pathology and Aß plaques, identified by immunohistochemistry for choline acetyltransferase (ChAT) and 6E10 antibody respectively, were counted at P210. Simple ChAT+ axonal swellings were present in all sham and HI groups; Tg mice had more than their nTg counterparts, but HI did not affect the number of axonal swellings in APP/PS1 Tg mice. In contrast, complex ChAT+ neuritic clusters (NC) occurred only in Tg mice; HI increased that burden. The abundance of ChAT+ clusters in specific regions correlated with decreased VD. The frequency of attritional ChAT+ INs in the entorhinal cortex (EC) was increased in Tg shams relative to their nTg counterparts, but HI obviated this difference. Cholinergic IN pathology in EC correlated with NC number. The Aß deposition in APP/PS1 Tg mice was not exacerbated by HI, nor did it correlate with other metrics. Adult APP/PS1 Tg mice have significant cortical cholinergic axon and EC ChAT+ IN pathologies; some pathology was exacerbated by neonatal HI and correlated with VD. Mechanisms of neonatal HI induced cognitive deficits and cortical neuropathology may be modulated by genetic risk, perhaps accounting for some of the variability in outcomes.

Incidence and predictors of attrition from HIV treatment among adults living with HIV in high-caseload facilities following implementation of universal test and treat strategy in Ethiopia: A prospective cohort study.

BACKGROUND: The introduction of universal test and treat (UTT) strategy has demonstrated a reduction in attrition in some low-resource settings. UTT was introduced in Ethiopia in 2016. However, there is a paucity of information regarding the magnitude and predictors of attrition from HIV treatment in Ethiopia. This study aims to assess the incidence and predictors of attrition from HIV treatment among adults living with HIV (PLHIV) in high-caseload facilities following the implementation of universal test and treat strategy in Ethiopia from March 2019 to June 2020. METHODS: A prospective cohort of individuals in HIV care from 39 high-caseload facilities in Oromia, Amhara, Tigray, Addis Ababa and Dire Dawa regions of Ethiopia was conducted for 12 months. Participants were adults aged 15 year and older who were first testers recruited for 3 months from March to June 2019. Subsequent follow-up was for 12 months, with data collected on sociodemographic and clinical conditions at baseline, 6 and 12 months and attrition at 6 and 12 months. We defined attrition as discontinuation from follow-up care due to loss to follow-up, dropout or death. Data were collected using Open Data Kit at field level and aggregated centrally. Kaplan-Meier survival analysis was employed to assess survival probability to the time of attrition from treatment. The Cox proportional hazards regression model was used to measure association of baseline predictor variables with the proportion of antiretroviral therapy (ART) patients retained in ART during the follow up period. RESULTS: The overall incidence rate for attrition from HIV treatment among the study participants during 12 months of follow-up was 5.02 cases per 1000 person-weeks [95% confidence interval (CI): 4.44-5.68 per 1000 person-weeks]. Study participants from health facilities in Oromia and Addis Ababa/Dire Dawa had 68% and 51% higher risk of attrition from HIV treatment compared with participants from the Amhara region, respectively [adjusted hazard ratio (AHR) = 1.68, 95% CI: 1.22-2.32 and AHR = 1.51, 95% CI: 1.05-2.17, respectively]. Participants who did not have a child had a 44% higher risk of attrition compared with those who had a child (AHR = 1.44, 95% CI: 1.12-1.85). Individuals who did not own mobile phone had a 37% higher risk of attrition than those who owned a mobile phone (AHR = 1.37, 95% CI: 1.02-1.83). Ambulatory/bedridden functional status at the time of diagnosis had a 44% higher risk of attrition compared with participants with a working functional status (AHR = 1.44, 95% CI: 1.08-1.92) at any time during the follow-up period. CONCLUSION: The overall incidence of attrition among people living with HIV enrolled into HIV treatment was not as high as what was reported by other studies. Independent predictors of attrition were administrative regions in Ethiopia where health facilities are located, not having a child, not owning a mobile phone and being ambulatory/bedridden functional status at the time of diagnosis. Concerted efforts should be taken to reduce the magnitude of attrition from HIV treatment and address its drivers.

Telomere length as biomarker of nutritional therapy for prevention of type 2 diabetes mellitus development in patients with coronary heart disease: CORDIOPREV randomised controlled trial.

BACKGROUND: Telomere Length (TL), a marker of cellular aging, holds promise as a biomarker to elucidate the molecular mechanism of diabetes. This study aimed to investigate whether shorter telomeres are associated with a higher risk of type 2 diabetes mellitus (T2DM) incidence in patients with coronary heart disease; and to determine whether the most suitable dietary patterns, particularly a Mediterranean diet or a low-fat diet, can mitigate the development of diabetes in these patients after a follow-up period of five years. METHODS: The CORonary Diet Intervention with Olive oil and cardiovascular PREVention study (CORDIOPREV study) was a single-centre, randomised clinical trial done at the Reina Sofia University Hospital in Córdoba, Spain. Patients with established coronary heart disease (aged 20-75 years) were randomly assigned in a 1:1 ratio by the Andalusian School of Public Health to receive two healthy diets. Clinical investigators were masked to treatment assignment; participants were not. Quantitative-PCR was used to assess TL measurements. FINDINGS: 1002 patients (59.5 ± 8.7 years and 82.5% men) were enrolled into Mediterranean diet (n = 502) or a low-fat diet (n = 500) groups. In this analysis, we included all 462 patients who did not have T2DM at baseline. Among them, 107 patients developed T2DM after a median of 60 months. Cox regression analyses showed that patients at risk of short telomeres (TL < percentile 20th) are more likely to experience T2DM than those at no risk of short telomeres (HR 1.65, p-value 0.023). In terms of diet, patients at high risk of short telomeres had a higher risk of T2DM incidence after consuming a low-fat diet compared to patients at no risk of short telomeres (HR 2.43, 95CI% 1.26 to 4.69, p-value 0.008), while no differences were observed in the Mediterranean diet group. CONCLUSION: Patients with shorter TL presented a higher risk of developing T2DM. This association could be mitigated with a specific dietary pattern, in our case a Mediterranean diet, to prevent T2DM in patients with coronary heart disease. TRIAL REGISTRATION: Clinicaltrials.gov number NCT00924937.

Perception of shared learning environment differs between vascular surgery and general surgery residents.

BACKGROUND: An enriching learning environment is integral to resident wellness and education. Integrated vascular (VS) and general surgery (GS) residents share 18 months of core GS rotations during the postgraduate years 1-3 (PGY1-3); differences in their experiences may help identify practical levers for change. METHODS: We used a convergent mixed-methods design. Cross-sectional surveys were administered after the 2020 American Board of Surgery In-Training Examination and Vascular Surgery In-Training Examination, assessing eight domains of the learning environment and resident wellness. Multivariable logistic regression models identified factors associated with thoughts of attrition between categorical PGY1-3 residents at 57 institutions with both GS and VS programs. Resident focus groups were conducted during the 2022 Vascular Annual Meeting to elicit more granular details about the experience of the learning environment. Transcripts were analyzed using inductive and deductive logics until thematic saturation was achieved. RESULTS: Surveys were completed by 205 VS and 1198 GS PGY1-3 residents (response rates 76.8% for VS and 82.5% for GS). After adjusting for resident demographics, PGY level, and program type, GS residents were more likely than their VS peers to consider leaving their programs (odds ratio [OR]: 2.61, 95% confidence interval [CI]: 1.37-4.99). This finding did not persist after adjusting for differences in perceptions of the learning environment, specifically: GS residents had higher odds of mistreatment (OR: 1.99, 95% CI: 1.36-2.90), poorer work-life integration (OR: 2.88, 95% CI: 1.41-5.87), less resident camaraderie (OR: 3.51, 95% CI: 2.26-5.45), and decreased meaning in work (OR: 2.94, 95% CI: 1.80-4.83). Qualitative data provided insight into how the shared learning environment was perceived differently: (1) vascular trainees expressed that early specialization and a smaller, more invested faculty allow for an apprenticeship model with early operative exposure, hands-on guidance, frequent feedback, and thus early skill acquisition (meaning in work); (2) a smaller program is conducive to closer relationships with co-residents and faculty, increasing familiarity (camaraderie and work-life integration); and (3) due to increased familiarity with program leadership, vascular trainees feel more comfortable reporting mistreatment, allowing for prompt responses (mistreatment). CONCLUSIONS: Despite sharing a learning environment, VS and GS residents experience training differently, contributing to differential thoughts of attrition. These differences may be attributable to intrinsic features of the integrated training paradigm that are not easily replicated by GS programs, such as smaller program size and higher faculty investment due to early specialization. Alternative strategies to compensate for these inherent differences should be considered (eg, structured operative entrustment programs and faculty incentivization).

Factors affecting continuous participation in follow-up evaluations during a lifestyle intervention programme for type 2 diabetes prevention: The Feel4Diabetes-study.

AIMS: Community- and school-based lifestyle interventions are an efficient method of preventing type 2 diabetes in vulnerable populations. Many participants, however, fail to complete the necessary follow-ups. We investigated factors affecting the continuous participation in follow-up evaluations during the Feel4Diabetes-study, a multilevel intervention programme implemented across Europe. METHODS: Socioeconomic, sociodemographic and clinical factors were assessed for 2702 participants within six participating countries: Bulgaria and Hungary (low-to-middle-income countries, LMIC), Belgium and Finland (high-income countries, HIC) and Greece and Spain (high-income countries under austerity measures, HICAM). RESULTS: Statistically significant differences were detected with respect to sex, control group, education level, employment status, BMI and blood pressure measurements (systolic and diastolic blood pressure). Post hoc analysis revealed significant differences within socioeconomic regions. Higher levels of education were associated with significantly lower attrition in HIC (p < 0.05) and HICAM (p < 0.001), higher employment status was associated with lower attrition in HICAM (p < 0.001) and being female was associated with lower attrition in LMIC (p < 0.001). Surprisingly, the intervention group exhibited higher-than-expected attrition in HIC (p < 0.001) and HICAM (p = 0.003), and lower attrition in LMIC (p = 0.007). When tested together in the same multivariable predictive model, all sociodemographic and socioeconomic variables along with higher BMI retained their statistical significance, while systolic and diastolic blood pressure failed to remain significant. CONCLUSIONS: Key socioeconomic and sociodemographic factors along with BMI play a significant role in determining continuous participation in follow-up evaluations during school- and community-based intervention programmes.

Estimating generalized propensity scores with survey and attrition weighted data.

Prior work in causal inference has shown that using survey sampling weights in the propensity score estimation stage and the outcome model stage for binary treatments can result in a more robust estimator of the effect of the binary treatment being analyzed. However, to date, extending this work to continuous treatments and exposures has not been explored nor has consideration been given for how to handle attrition weights in the propensity score model. Nonetheless, generalized propensity score (GPS) analyses are being used for estimating continuous treatment effects on outcomes when researchers have observational data, and those data sets often have survey or attrition weights that need to be accounted for in the analysis. Here, we extend prior work and show with analytic results that using survey sampling or attrition weights in the GPS estimation stage and the outcome model stage for continuous treatments can result in a more robust estimator than one that does not. Simulation study results show that, although using weights in both estimation stages is sufficient for robust estimation, it is not necessary and unbiased estimation is possible in some cases under various approaches to using weights in estimation. Analysts do not know if the conditions of our simulation studies hold, so use of weights in both estimation stages might provide insurance for reducing potential bias. We discuss the implications of our results in the context of an empirical example.

Understanding General Surgery Recruitment and Attrition During the COVID-Era: A 1-Year Follow-Up Study.

INTRODUCTION: The COVID-19 pandemic resulted in modifications to resident selection. The success of these new recruitment strategies as well as the impact on trainee attrition and competency is unknown. We previously evaluated how selection of general surgery applicants changed early in the pandemic. Here we supplement that work by reporting further modifications to the recruitment process and the perceived impact on resident attrition and competency. METHODS: An anonymous cross-sectional survey sent via the Association of Program Directors in Surgery listserv in June 2022 to programs directors (PDs) at Accreditation Council for Graduate Medical Education accredited general surgery programs. Surveys contained demographic questions, 5-point Likert scale questions evaluating factors related to recruitment and match process, and postgraduate year 1 performance. RESULTS: 60 PDs responded to the survey. PDs continue to value the same post-COVID factors related to determining a resident's commitment to surgery but began to shift back to nonvirtual based strategies to recruit applicants in this new interview cycle. PD commentary frequently noted desire to return to in-person interviewing. 5.4% of postgraduate year 1s comprising this first class of residents who underwent virtual-only interviews and rotations did not reach Accreditation Council for Graduate Medical Education level 1 milestones, similar to prior years. The attrition rate amongst this class increased from 1.3% to 2.7%. CONCLUSIONS: The attrition rate for postgraduate year 1 categorical general surgery residents has increased since the onset of the pandemic. The recruitment strategies adopted early in the pandemic have not maintained their initial perceived impact.

Leadership Development and Its Association With Retention of Surgical Versus Nonsurgical Faculty at a Large Academic Health Center.

INTRODUCTION: Leadership development programs are the key for engaging physicians as partners in health-care administration. These programs have become common; however, one potential consequence of leadership training is attrition. METHODS: Using a prospectively collected database, Kaplan-Meier curves were used to analyze attrition of physician faculty following an intramural leadership program at an academic health center. RESULTS: Six cohorts totaling 165 faculty successfully completed our leadership program. Sixty-one faculty (37%) were from surgical departments (Group A) and 104 (63%) from nonsurgical departments (Group B). Thirty-six program graduates (21.8%) departed the institution at a mean follow-up of 68 mo for an annualized attrition rate of 3.6%. Attrition rates for Group B were significantly greater than for Group A (P = 0.05). Most faculty left for career advancement opportunities elsewhere. CONCLUSIONS: Our annualized attrition rate for leadership trained faculty was 3.6%, well below the attrition rate of our academic health center (5.3%) over a similar time period, and the 2018 national physician attrition rate of 7.8%. Strategies to improve retention are discussed.

Gender Parity Among Vascular Surgeons: Progress and Attrition.

INTRODUCTION: Improving representation of women in medicine and surgery has been tempered by higher rates of attrition from residencies and from academic medicine among women compared to men. The attrition of women from the practicing vascular surgery workforce has not been studied. METHODS: We utilized the Center for Medicare and Medicaid Services' Doctors and Clinicians database to study vascular surgery employment patterns from 2015 to 2022. We examined gender balance within the workforce and attrition rates among male and female vascular surgeons. We utilized a logistic regression to calculate the odds of attrition by gender. RESULTS: The percentage of female vascular surgeons grew from 11% to 16% between 2015 and 2022, with each graduating class since 2005 having between 20% and 38% women. Yet, female surgeons were 2.05 (95% confidence interval: 1.36-3.08) times more likely to leave practice than their male counterparts when controlling for graduation year and practice in academic medicine. CONCLUSIONS: The proportion of women in vascular surgery is increasing as more women graduate into the specialty. Despite increasing representation, women are more likely than men to leave the workforce.

Reasons for Surgical Attrition Among Nonmetastatic Upper Gastrointestinal Cancer Patients: A Single Institutional Experience.

INTRODUCTION: Upper gastrointestinal (UGI) cancers require multidisciplinary treatment, but surgery provides the only potentially curative option. We sought to understand reasons for attrition before surgery within our regional hospital network. METHODS: We performed chart reviews of patients (age 18-80) with stage I-III UGI cancers (gastroesophageal junction, gastric, and hepatopancreatobiliary adenocarcinomas) in our multihospital cancer registry from 2015 to 2021. Our primary outcome was reasons for surgical attrition. Univariable analysis identified factors related to surgical attrition and the Kaplan-Meier method estimated overall survival based on surgery receipt. RESULTS: Seven hundred and ninety-two patients were included in our analysis, of whom 107 (13.5%) did not undergo curative surgery. Reasons for not undergoing surgery included medical comorbidities (30.8%), patient preference/nonmedical barriers (24.3%, which included: not interested without further explanation, worried about complications, nonadherence to appointments, insurance issues, did not wish for blood transfusion, lack of social support, preferring home care, and worried about recurrence), psychosocial (5.6%), progression while on neoadjuvant therapy or waiting for transplant (15.0% and 7.5%), poor performance status (3.7%), side effects of neoadjuvant therapy (3.7%), and death unrelated to treatment or unknown cause (9.4%). Nonsurgical management was not associated with race, socioeconomic status, or distance traveled for care. Survival was greatly improved for patients who underwent surgery (158 vs. 63 weeks, p < 0.05). CONCLUSION: Nearly one in seven patients (18-80 years old) with UGI cancers evaluated at our academic cancer center did not undergo surgical resection. Reasons for surgical attrition included potentially modifiable issues, and addressing these barriers could help overcome inequities in cancer treatment and survival.

School-based physical activity interventions: which intervention characteristics are associated with participation and retention? A meta-analysis.

OBJECTIVE: Many school-based intervention studies are conducted to increase students' physical activity (PA). Recruitment and retention problems potentially impact the robustness of RCT findings. We conducted a meta-analysis to summarize recruitment and retention rates in long-term secondary school-based PA intervention studies and examined associated participant and intervention characteristics. METHODS: Web of Science, Pubmed, Medline, and PsychInfo were searched until March 20th 2023. We included studies on secondary school-based PA interventions ≥12 weeks, aimed at typically developing adolescents. We abstracted number of schools and students invited, randomized, and participating at follow-up to calculate pooled recruitment and retention rates; participant and intervention characteristics were abstracted to execute subgroup or meta-regression analyses. RESULTS: Recruitment rates were 51% for invited schools and 80% for invited students, the retention for schools was almost 100% and for students 91%. Interventions with fixed and flexible components, executed in Asia and South America, and from later publication years had higher student recruitment rates. Students' retention rates were lower for interventions which had flexible components, were theory/model-based, used an accelerometer, had a longer intervention duration, and included more females. CONCLUSION: Recruitment and retention rates in school-based PA interventions are high. Some participant and intervention characteristics influence these rates: flexibility of the intervention, theory/model-based intervention, accelerometer use, intervention duration, continent, and number of females. Researchers should consider these characteristics in intervention development to achieve optimal balance between intervention effectiveness, recruitment, and retention.

Developing survey weights to ensure representativeness in a national, matched cohort study: results from the children and young people with Long Covid (CLoCk) study.

BACKGROUND: Findings from studies assessing Long Covid in children and young people (CYP) need to be assessed in light of their methodological limitations. For example, if non-response and/or attrition over time systematically differ by sub-groups of CYP, findings could be biased and any generalisation limited. The present study aimed to (i) construct survey weights for the Children and young people with Long Covid (CLoCk) study, and (ii) apply them to published CLoCk findings showing the prevalence of shortness of breath and tiredness increased over time from baseline to 12-months post-baseline in both SARS-CoV-2 Positive and Negative CYP. METHODS: Logistic regression models were fitted to compute the probability of (i) Responding given envisioned to take part, (ii) Responding timely given responded, and (iii) (Re)infection given timely response. Response, timely response and (re)infection weights were generated as the reciprocal of the corresponding probability, with an overall 'envisioned population' survey weight derived as the product of these weights. Survey weights were trimmed, and an interactive tool developed to re-calibrate target population survey weights to the general population using data from the 2021 UK Census. RESULTS: Flexible survey weights for the CLoCk study were successfully developed. In the illustrative example, re-weighted results (when accounting for selection in response, attrition, and (re)infection) were consistent with published findings. CONCLUSIONS: Flexible survey weights to address potential bias and selection issues were created for and used in the CLoCk study. Previously reported prospective findings from CLoCk are generalisable to the wider population of CYP in England. This study highlights the importance of considering selection into a sample and attrition over time when considering generalisability of findings.

Correlates of ART attrition among adults under antiretroviral therapy in Southern Ethiopia, retrospective cohort study.

High attrition rates from ART are the primary contributors to morbidity, death, hospitalisation, rising transmission rates, treatment failure, rising burden of opportunistic infections (OIs), and the evolution of HIV-virus resistance (HIVDR). In Sub-Saharan Africa, more than two-thirds of ART patients will not receive continuous care. There is little information about the correlates that contribute to attrition from ART services among ART patients in Southern Ethiopia. Hence, this study aims to identify correlates of attrition from antiretroviral therapy services for adults under antiretroviral therapy at Otona Teaching and Referral Hospital, Wolaita Zone, Southern Ethiopia. From 1 January 2013 to 31 December 2017, a retrospective cohort analysis was performed. The pre-determined 328 medical records were chosen using a simple random sampling technique using computer-generated random numbers. Epi Info version 3.5.3 was used to enter and clean the data, which were then exported to STATA version 11 for analysis. The Cox proportional hazards model, both bivariate and multivariable, was used. Variables with p-values less than 0.25 in bivariate analysis were considered candidates for multivariable analysis, and variables with p-values less than 0.05 were deemed statistically important in multivariable analysis. The intensity of the correlation and statistical significance were determined using the CHR, AHR, and 95 per cent confidence intervals. The magnitude of attrition from ART service was 21.60% (95% CI: 17.10, 26.10). The distance between home and hospital is more than five kilometres (AHR:3.84;95% CI: 1.99,7.38), no registered phone number (AHR:2.47;95%CI:1.32,4.09), have not taken isoniazid prophylaxis (AHR:2.23;95%CI:1.30,4.09), alcohol consumption (AHR: 1.77; 95% CI:1.01, 3.12), and had no caregiver (AHR: 2.11; 95% CI:1.23, 3.60) were statistically significant in the Cox proportional hazard model. Distance between home and hospital, phone number registration on follow-up chart, having a history of alcohol consumption, isoniazid prophylaxis provision, and having family support were independent correlates of attrition from antiretroviral treatment services.

Folic acid alleviated oxidative stress-induced telomere attrition and inhibited apoptosis of neurocytes in old rats.

PURPOSE: Oxidative stress has been reported to cause telomere attrition, which triggers cell apoptosis. Apoptosis of neurocytes may play an essential role in the pathogenesis of neurodegenerative diseases. This study hypothesized that folic acid (FA) supplementation decreased neurocyte apoptosis by alleviating oxidative stress-induced telomere attrition in 25-month-old Sprague Dawley (SD) rats. METHODS: Three-month-old male SD rats were randomly divided into four diet groups by different concentrations of folic acid in equal numbers, with intervention for 22 months. Folate, homocysteine (Hcy), reactive oxygen species (ROS) levels, antioxidant activities, and telomere length in the brain tissues were tested at 11, 18, and 22 months of intervention, and 8-hydroxy-deoxyguanosine (8-OHdG) levels, neurocyte apoptosis and telomere length in the cerebral cortex and hippocampal regions were tested during the 22-month intervention. An automated chemiluminescence system, auto-chemistry analyzer, Q-FISH, qPCR, and TUNEL assay were used in this study. RESULTS: The rats had lower folate concentrations and higher Hcy, ROS, and 8-OHdG concentrations in brain tissue with aging. However, FA supplementation increased folate concentrations and antioxidant activities while decreasing Hcy, ROS, and 8-OHdG levels in rat brain tissue after 11, 18, and 22 months of intervention. Furthermore, FA supplementation alleviated telomere length shortening and inhibited neurocyte apoptosis during the 22-month intervention. CONCLUSION: FA supplementation alleviated oxidative stress-induced telomere attrition and inhibited apoptosis of neurocytes in 25-month-old rats.

Recruitment and retention of adolescents for an ecological momentary assessment measurement burst mental health study: The MHIM engagement strategy.

INTRODUCTION: Recruitment and long-term retention of adolescent participants in longitudinal research are challenging and may be especially so in studies involving remote measurement and biosampling components. The ability to effectively recruit and retain participants can be supported by the use of specific evidence-based engagement strategies that are built in from the earliest stages. METHODS: Informed by a review of the evidence on effective engagement strategies and consultations with adolescents (via two Young Person Advisory Groups [YPAGs]; ages 11-13 and 14-17), the current protocol describes the planned participant engagement strategy for the Mental Health in the Moment Study: a multimodal measurement burst study of adolescent mental health across ages 11-19. RESULTS: The protocol incorporates engagement strategies in four key domains: consultations/co-design with the target population, incentives, relationship-building and burden/barrier reduction. In addition to describing general engagement strategies in longitudinal studies, we also discuss specific concerns regarding engagement in data collection methods such as biosampling and ecological momentary assessment where a paucity of evidence exists. CONCLUSION: Engagement strategies for adolescent mental health studies should be based on existing evidence and consultations with adolescents. We present our approach in developing the planned engagement strategies and also discuss limitations and future directions in engaging adolescents in longitudinal research. PATIENT OR PUBLIC CONTRIBUTION: The study design for this project places a strong emphasis on the active engagement of adolescents throughout its development. Specifically, the feedback and suggestions provided by the YPAGs have been instrumental in refining our strategies for maximising the recruitment and retention of participants.

Obesity-Senescence-Breast Cancer: Clinical Presentation of a Common Unfortunate Cycle.

There are few convincing studies establishing the relationship between endogenous factors that cause obesity, cellular aging, and telomere shortening. Without a functional telomerase, a cell undergoing cell division has progressive telomere shortening. While obesity influences health and longevity as well as telomere dynamics, cellular senescence is one of the major drivers of the aging process and of age-related disorders. Oxidative stress induces telomere shortening, while decreasing telomerase activity. When progressive shortening of telomere length reaches a critical point, it triggers cell cycle arrest leading to senescence or apoptotic cell death. Telomerase activity cannot be detected in normal breast tissue. By contrast, maintenance of telomere length as a function of human telomerase is crucial for the survival of breast cancer cells and invasion. Approximately three-quarters of breast cancers in the general population are hormone-dependent and overexpression of estrogen receptors is crucial for their continued growth. In obesity, increasing leptin levels enhance aromatase messenger ribonucleic acid (mRNA) expression, aromatase content, and its enzymatic activity on breast cancer cells, simultaneously activating telomerase in a dose-dependent manner. Meanwhile, applied anti-estrogen therapy increases serum leptin levels and thus enhances leptin resistance in obese postmenopausal breast cancer patients. Many studies revealed that shorter telomeres of postmenopausal breast cancer have higher local recurrence rates and higher tumor grade. In this review, interlinked molecular mechanisms are looked over between the telomere length, lipotoxicity/glycolipotoxicity, and cellular senescence in the context of estrogen receptor alpha-positive (ERα+) postmenopausal breast cancers in obese women. Furthermore, the effect of the potential drugs, which are used for direct inhibition of telomerase and the inhibition of human telomerase reverse transcriptase (hTERT) or human telomerase RNA promoters as well as approved adjuvant endocrine therapies, the selective estrogen receptor modulator and selective estrogen receptor down-regulators are discussed.