Unveiling perspectives on the psychosocial impacts of childhood cancer survival on young adult survivors' reassimilation journey: A qualitative exploration.

Background: Approximately 82% of children with childhood cancer survive more than five years after diagnosis. Living as a cancer survivor elicits a new reality that can include psychosocial impacts. These psychosocial impacts interact collectively, especially regarding reassimilation, and are rarely explored. Objective: To explore the psychosocial impacts of surviving childhood cancer and reassimilation back into society in young adult survivors of childhood cancer. Methodology: Individual in-depth semi-structured interviews were conducted with childhood cancer survivors and explored psychosocial aspects associated with returning to work, school, and social environments after remission. Interpretive phenomenological analysis was conducted once interviews were manually transcribed. A group interview with survivors was held to discuss the study's findings and interpretation. Results: Individual interviews and the group interview revealed three major themes: outlook on reassimilating, outlook on coping, and outlook on cancer. Conclusions: This work is a first step to understanding how survivors' personal outlook on coping and healthcare system barriers play influential roles in reassimilation following cancer treatment. Survivors expressed the need for reliable survivorship information and improved communication with healthcare providers regarding what to expect, so they could feel prepared for life post-cancer. These aspects need to be explored more deeply through other qualitative studies.

RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells.

Breast cancer linked with BRCA1/2 mutations commonly recur and resist current therapies, including PARP inhibitors. Given the lack of effective targeted therapies for BRCA1-mutant cancers, we sought to identify novel targets to selectively kill these cancers. Here, we report that loss of RNF8 significantly protects Brca1-mutant mice against mammary tumorigenesis. RNF8 deficiency in human BRCA1-mutant breast cancer cells was found to promote R-loop accumulation and replication fork instability, leading to increased DNA damage, senescence, and synthetic lethality. Mechanistically, RNF8 interacts with XRN2, which is crucial for transcription termination and R-loop resolution. We report that RNF8 ubiquitylates XRN2 to facilitate its recruitment to R-loop-prone genomic loci and that RNF8 deficiency in BRCA1-mutant breast cancer cells decreases XRN2 occupancy at R-loop-prone sites, thereby promoting R-loop accumulation, transcription-replication collisions, excessive genomic instability, and cancer cell death. Collectively, our work identifies a synthetic lethal interaction between RNF8 and BRCA1, which is mediated by a pathological accumulation of R-loops.

Determinants of Health Care Needs in Relation to Vision Correction among Adolescents in the United Arab Emirates: A Cross-Sectional Study.

BACKGROUND: Uncorrected refractive error has been suggested to affect children's development, educational performance, and socialization. Sociodemographic and environmental differences among individuals may impact their accessibility to utilizing appropriate services, impacting their vision-dependent activities. METHODS: Guided by the population health framework, this retrospective study assessed the prevalence of self-reported vision correction needs and its determinants for a sample of adolescents (n = 6363) from the United Arab Emirates (UAE) aged 13 to 20 years between 2007 to 2009. RESULTS: The findings suggest a relatively high prevalence of self-reported vision correction needs (26.8%), with among 24.8% males and 31.7% among females. Factors that were significantly associated with vision correction needs included age, biological sex, location of residence (emirate), nationality, parental education and employment level, household financial status, screen time use, visiting an eye specialist in the past year, and daily functional capacity. CONCLUSION: Reporting the vision correction needs of the adolescent population and identifying its determinants may help identify and resolve modifiable barriers to accessing the appropriate vision care resources. Further research in assessing the type of refractive error, potential genetic and environmental factors, and vision care services in each emirate may help decision-makers set appropriate policies to improve the overall quality of eye health.

Lost in machine translation: The promises and pitfalls of machine translation for multilingual group work in global health education.

The rapid adoption of online technologies to deliver postsecondary education amid the COVID-19 pandemic has highlighted the potential for online learning, as well as important equity gaps to be addressed. For over ten years, McMaster University has delivered graduate global health education through a blended-learning approach. In partnership with universities in the Netherlands, India, Thailand, Norway, Colombia, and Sudan, experts from across the Consortium deliver lectures online to students around the world. In 2020, two courses were piloted with small groups of students from Canada and Colombia using machine translation supported by bilingual tutors. Students met weekly via video conferencing software, speaking in English and Spanish and relying on machine translation software to transcribe and translate for group members. Qualitative semi-structured interviews were conducted with students, tutors, and instructors to explore how artificial intelligence can be harnessed to integrate multilingual group work into course offerings, challenging the dominant use of English as the principal language of instruction in global health education. Findings highlight the potential for machine translation to bridge language divides, while also underscoring several key limitations of currently available technology. Further research is needed to investigate the potential for machine translation in facilitating multilingual online education as a pathway to more equitable and inclusive online learning environments.

RNF168 regulates R-loop resolution and genomic stability in BRCA1/2-deficient tumors.

Germline mutations in BRCA1 and BRCA2 (BRCA1/2) genes considerably increase breast and ovarian cancer risk. Given that tumors with these mutations have elevated genomic instability, they exhibit relative vulnerability to certain chemotherapies and targeted treatments based on poly (ADP-ribose) polymerase (PARP) inhibition. However, the molecular mechanisms that influence cancer risk and therapeutic benefit or resistance remain only partially understood. BRCA1 and BRCA2 have also been implicated in the suppression of R-loops, triple-stranded nucleic acid structures composed of a DNA:RNA hybrid and a displaced ssDNA strand. Here, we report that loss of RNF168, an E3 ubiquitin ligase and DNA double-strand break (DSB) responder, remarkably protected Brca1-mutant mice against mammary tumorigenesis. We demonstrate that RNF168 deficiency resulted in accumulation of R-loops in BRCA1/2-mutant breast and ovarian cancer cells, leading to DSBs, senescence, and subsequent cell death. Using interactome assays, we identified RNF168 interaction with DHX9, a helicase involved in the resolution and removal of R-loops. Mechanistically, RNF168 directly ubiquitylated DHX9 to facilitate its recruitment to R-loop-prone genomic loci. Consequently, loss of RNF168 impaired DHX9 recruitment to R-loops, thereby abrogating its ability to resolve R-loops. The data presented in this study highlight a dependence of BRCA1/2-defective tumors on factors that suppress R-loops and reveal a fundamental RNF168-mediated molecular mechanism that governs cancer development and vulnerability.

Coronary artery calcium progresses rapidly and discriminates incident cardiovascular events in chronic kidney disease regardless of diabetes: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND AND AIMS: Chronic kidney disease (CKD) is associated with high prevalence of cardiovascular disease (CVD) events. We sought to assess the prognostic utility of coronary artery calcium (CAC) scores in discriminating incident CVD events among subpopulations of CKD, particularly those without diabetes mellitus (DM). METHODS: Using the Multi-Ethnic Study of Atherosclerosis, we identified 4 groups based on present/absent CKD/diabetes (CKD-/DM-, n = 5308; CKD-/DM+, n = 586, CKD+/DM-, n = 620; CKD+/DM+, n = 266). Baseline and follow-up CAC (Agatston units) measurements, and association between CAC and incident CVD events in median follow-up of 13 years were evaluated using proportional hazards regression adjusting for demographics, clinical, biomarker variables. RESULTS: Prevalence of CKD and DM in the cohort was 13% and 12.5% respectively. Annual progression in adjusted median CAC score was 24.8%, 27.9%, 26.7%, 36.8% and unadjusted cumulative incident CVD rates were 12.6%, 22.3%, 23.1%, 39.8% for CKD-/DM-, CKD-/DM+, CKD+/DM-, CKD+/DM+, respectively. After full adjustment (CKD-/DM-referent), hazard ratios (HR, 95% CI) for incident CVD events were 1.25 (1.01-1.53) CKD-/DM+, 1.10 (0.90-1.33) CKD+/DM- and 2.18 (1.73-2.76) CKD+/DM+. Using CKD-/DM-/baseline CAC = 0 referent, adjusted HRs (95% CI) for incident CVD in CKD+/DM- were 1.30 (0.81-2.07), 2.05 (1.4-2.99), and 4.15 (2.94-5.86) for baseline CAC = 0, 1-100, and >300 Agatston units respectively while for CKD+/DM+, adjusted HRs were 3.15 (2.04-4.86), 3.56 (2.26-5.62), 7.90 (5.35-11.67), respectively. CONCLUSIONS: CAC provides incremental prognostic information to predict incident CVD events in CKD regardless of DM. Moreover, baseline CAC categories discriminate incident CVD among CKD without DM, which may have implications in individualizing approach to primary prevention in this high-risk population.

Brotes, epidemias, eventos y otros términos epidemiológicos de uso cotidiano / Brotes [outbreaks], epidemias [epidemics], eventos [events], and other Epidemiological Terms of Daily Usage

En la práctica habitual de la salud pública cubana son muchos los factores que se relacionan con el funcionamiento de la vigilancia y control de las enfermedades potencialmente epidémicas. Aunque esta práctica es parte del trabajo cotidiano de los médicos y enfermeras de la familia, no son los únicos profesionales que intervienen en ella. Es un trabajo multidisciplinario en el que participan epidemiólogos, higienistas, directivos, decisores políticos y administrativos y de manera general median todos los profesionales de la salud. Por lo que el presente artículo tiene la intención de describir algunos términos epidemiológicos de uso cotidiano en la salud pública. Esto responde a la necesidad especial de actualizar conceptos, relacionados con la vigilancia y el control epidemiológico, que están siendo utilizados por técnicos e instituciones oficiales y organismos internacionales de forma inexacta por su sinonimia(AU)

The common practice of Cuban public health includes many factors related to the operation of surveillance and control of potentially epidemic diseases. Although this practice is part of the daily work of family physicians and nurses, they are not the only professionals involved in it. This is a multidisciplinary work carried out with the involvement of epidemiologists, hygienists, managers, political and administrative decision-makers, and, in general, with the participation of all health professionals. Therefore, this article is aimed at describing some epidemiological terms of daily usage in public health. This focus responds to the special need to update concepts related to epidemiological surveillance and control, which, due to their synonymy, are being used, inaccurately, by official institutions and technical practitioners, as well as by international organizations(AU)

Change in NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) Level and Risk of Dementia in Multi-Ethnic Study of Atherosclerosis (MESA).

Cross-sectionally measured NT-proBNP (N-terminal pro-B-type natriuretic peptide) is related to incident dementia. However, data linking changes in NT-proBNP to risk of future dementia are lacking. We aimed to examine the association of change in NT-proBNP over 3.2 years with incident dementia. We included 4563 participants in MESA (Multi-Ethnic Study of Atherosclerosis) prospective cohort who were free of cardiovascular disease at enrollment, had NT-proBNP level measured at MESA exams 1 (baseline, 2000-2002) and 3 (2004-2005), and had no diagnosis of dementia before exam 3. The association of change in NT-proBNP level between MESA exams 1 through 3 and all-cause hospitalized dementia (by International Classification of Diseases, Ninth Revision, codes) after MESA exam 3 (2004-2005) through 2015 was assessed using competing-risks Cox proportional hazard regression analysis. During 45 522 person-years of follow-up, 223 dementia cases were documented. Increase in log-NT-proBNP from MESA exams 1 through 3 was positively associated with incidence of dementia (multivariable hazard ratio, 1.28 [95% CI, 1.001-1.64]; P=0.049). An increase of at least 25% in NT-proBNP level from MESA exam 1 through 3 was associated with a 55% (P=0.02) increase in the risk of dementia in multivariable analysis. Addition of temporal NT-proBNP change to a model including risk factors and baseline NT-proBNP improved the prediction of dementia (Harrell C statistic from 0.85 to 0.87, P=0.049). Increase in NT-proBNP is independently associated with future all-cause hospitalized dementia and offers a moderately better predictive performance for risk of dementia compared with risk factors and baseline NT-proBNP. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00005487.

Impact on 30-d readmissions for cirrhotic patients with ascites after an educational intervention: A pilot study.

BACKGROUND: A low proportion of patients admitted to hospital with cirrhosis receive quality care with timely paracentesis an important target for improvement. We hypothesized that a medical educational intervention, delivered to medical residents caring for patients with cirrhosis, would improve quality of care. AIM: To determine if an educational intervention can improve quality of care in cirrhotic patients admitted to hospital with ascites. METHODS: We performed a pilot prospective cohort study with time-based randomization over six months at a large teaching hospital. Residents rotating on hospital medicine teams received an educational intervention while residents rotating on hospital medicine teams on alternate months comprised the control group. The primary outcome was provision of quality care- defined as adherence to all quality-based indicators derived from evidence-based practice guidelines- in admissions for patients with cirrhosis and ascites. Patient clinical outcomes- including length of hospital stay (LOS); 30-d readmission; in-hospital mortality and overall mortality- and resident educational outcomes were also evaluated. RESULTS: Eighty-five admissions (60 unique patients) met inclusion criteria over the study period-46 admissions in the intervention group and 39 admissions in the control group. Thirty-seven admissions were female patients, and 44 admissions were for alcoholic liver disease. Mean model for end-stage liver disease (MELD)-Na score at admission was 25.8. Forty-seven (55.3%) admissions received quality care. There was no difference in the provision of quality care (56.41% vs 54.35%, P = 0.9) between the two groups. 30-d readmission was lower in the intervention group (35% vs 52.78%, P = 0.1) and after correction for age, gender and MELD-Na score [RR = 0.62 (0.39, 1.00), P = 0.05]. No significant differences were seen for LOS, complications, in-hospital mortality or overall mortality between the two groups. Resident medical knowledge and self-efficacy with paracentesis improved after the educational intervention. CONCLUSION: Medical education has the potential to improve clinical outcomes in patients admitted to hospital with cirrhosis and ascites.

Hospitalist-Operated Compression Ultrasonography: a Point-of-Care Ultrasound Study (HOCUS-POCUS).

BACKGROUND: Venous thromboembolism includes deep vein thrombosis (DVT) and pulmonary embolism. Compression ultrasonography is the most common way to evaluate DVT and is typically performed by sonographers and interpreted by radiologists. Yet there is evidence that ultrasound examinations can be safely and accurately performed by clinicians at the bedside. OBJECTIVE: To measure the operating characteristics of hospital medicine providers performing point-of-care ultrasound (POCUS) for evaluation of DVT. DESIGN: This is a prospective cohort study enrolling a convenience sample of patients. Hospital medicine providers performed POCUS for DVT and the results were compared with the corresponding formal vascular study (FVS) interpreted by radiologists. PARTICIPANTS: Hospitalized non-ICU patients at four tertiary care hospitals for whom a DVT ultrasound was ordered. MAIN MEASURES: The primary outcomes were the sensitivity, specificity, and predictive values of the POCUS compression ultrasound compared with a FVS. The secondary outcome was the elapsed time between order and the POCUS study compared with the time the FVS was ordered to when the formal radiology report was finalized. KEY RESULTS: One hundred twenty-five limbs from 73 patients were scanned. The prevalence of DVT was 6.4% (8/125). The sensitivity of POCUS for DVT was 100% (95% CI 74-100%) and specificity was 95.8% (95% CI 91-98%) with a positive predictive value of 61.5% (95% CI 35-84%) and a negative predictive value of 100% (95% CI 98-100%). The median time from order to POCUS completion was 5.8 h versus 11.5 h median time from order until the radiology report was finalized (p = 0.001). CONCLUSION: Hospital medicine providers can perform compression-only POCUS for DVT on inpatients with accuracy similar to other specialties and settings, with results available sooner than radiology. The observed prevalence of DVT was lower than expected. POCUS may be reliable in excluding DVT but further study is required to determine how to incorporate a positive POCUS DVT result into clinical practice.

Metalloprotease inhibitor TIMP proteins control FGF-2 bioavailability and regulate skeletal growth.

Regulated growth plate activity is essential for postnatal bone development and body stature, yet the systems regulating epiphyseal fusion are poorly understood. Here, we show that the tissue inhibitors of metalloprotease (TIMP) gene family is essential for normal bone growth after birth. Whole-body quadruple-knockout mice lacking all four TIMPs have growth plate closure in long bones, precipitating limb shortening, epiphyseal distortion, and widespread chondrodysplasia. We identify TIMP/FGF-2/IHH as a novel nexus underlying bone lengthening where TIMPs negatively regulate the release of FGF-2 from chondrocytes to allow IHH expression. Using a knock-in approach that combines MMP-resistant or ADAMTS-resistant aggrecans with TIMP deficiency, we uncouple growth plate activity in axial and appendicular bones. Thus, natural metalloprotease inhibitors are crucial regulators of chondrocyte maturation program, growth plate integrity, and skeletal proportionality. Furthermore, individual and combinatorial TIMP-deficient mice demonstrate the redundancy of metalloprotease inhibitor function in embryonic and postnatal development.

Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis.

The E3 ubiquitin ligase RNF8 plays critical roles in maintaining genomic stability by promoting the repair of DNA double-strand breaks (DSBs) through ubiquitin signaling. Abnormal activation of Notch signaling and defective repair of DSBs promote breast cancer risk. Here, we found that low expression of the full-length RNF8 correlated with poor prognosis for breast cancer patients. Our data revealed that in addition to its role in the repair of DSBs, RNF8 regulated Notch1 signaling and cell-fate determination of mammary luminal progenitors. Mechanistically, RNF8 acted as a negative regulator of Notch signaling by ubiquitylating the active NOTCH1 protein (N1ICD), leading to its degradation. Consistent with abnormal activation of Notch signaling and impaired repair of DSBs in Rnf8-mutant mammary epithelial cells, we observed increased risk of mammary tumorigenesis in mouse models for RNF8 deficiency. Notably, deficiency of RNF8 sensitized breast cancer cells to combination of pharmacological inhibitors of Notch signaling and poly(ADP-ribose) polymerase (PARP), suggesting implications for treatment of breast cancer associated with impaired RNF8 expression or function.

Weight gain after kidney donation: Association with increased risks of type 2 diabetes and hypertension.

In the general population, obesity is associated with an increased risk of developing hypertension (HTN), type 2 diabetes mellitus (DM), and end-stage renal disease (ESRD). Therefore, most transplant centers have a body mass index (BMI) threshold for accepting living kidney donors. But there have been no studies of postdonation weight gain trends and any associated risks. We tracked serial BMIs in 940 donors for a median (IQ range) follow-up of 22.3 (15.4-35.8) years. We studied the impact of postdonation weight gain in a model adjusted for family history of HTN or DM. Donor characteristics included age, sex, smoking, fasting blood glucose, eGFR, systolic and diastolic BP, and BMI at time of donation and time postdonation. Postdonation weight gain was associated with a significant increase in the relative risk of developing HTN RR 1.93 (95% CI 1.51-2.46) (P < 0.001) and/or DM RR 4.18 (95% CI 2.05-8.5) (P < 0.0001), but not (to date) cardiovascular disease (CVD), reduced eGFR or death. Like the general population, donors gained weight as they aged; a higher BMI was associated with higher incidence of DM and HTN. Postdonation care should include ongoing counseling on the risks of substantial weight gain.

N-Terminal pro-Brain Natriuretic Peptide and Associations With Brain Magnetic Resonance Imaging (MRI) Features in Middle Age: The CARDIA Brain MRI Study.

OBJECTIVE: As part of research on the heart-brain axis, we investigated the association of N-terminal pro-brain natriuretic peptide (NT-proBNP) with brain structure and function in a community-based cohort of middle-aged adults from the Brain Magnetic Resonance Imaging sub-study of the Coronary Artery Risk Development in Young Adults (CARDIA) Study. APPROACH AND RESULTS: In a cohort of 634 community-dwelling adults with a mean (range) age of 50.4 (46-52) years, we examined the cross-sectional association of NT-proBNP to total, gray (GM) and white matter (WM) volumes, abnormal WM load and WM integrity, and to cognitive function tests [the Digit Symbol Substitution Test (DSST), the Stroop test, and the Rey Auditory-Verbal Learning Test]. These associations were examined using linear regression models adjusted for demographic and cardiovascular risk factors and cardiac output. Higher NT-proBNP concentration was significantly associated with smaller GM volume (ß = -3.44; 95% CI = -5.32, -0.53; p = 0.003), even after additionally adjusting for cardiac output (ß = -2.93; 95% CI = -5.32, -0.53; p = 0.017). Higher NT-proBNP levels were also associated with lower DSST scores. NT-proBNP was not related to WM volume, WM integrity, or abnormal WM load. CONCLUSION: In this middle-aged cohort, subclinical levels of NT-proBNP were related to brain function and specifically to GM and not WM measures, extending similar findings in older cohorts. Further research is warranted into biomarkers of cardiac dysfunction as a target for early markers of a brain at risk.

Hypertension after kidney donation: Incidence, predictors, and correlates.

Incidence of postdonation hypertension, risk factors associated with its development, and impact of type of treatment received on renal outcomes were determined in 3700 kidney donors. Using Cox proportional hazard model, adjusted hazard ratios (HRs) for cardiovascular disease (CVD); estimated glomerular filtration rate (eGFR) <60, <45, <30 mL/min/1.73m2 ; end stage renal disease (ESRD); and death in hypertensive donors were determined. After a mean (standard deviation [SD]) of 16.6 (11.9) years of follow-up, 1126 (26.8%) donors developed hypertension and 894 with known antihypertensive medications. Hypertension developed in 4%, 10%, and 51% at 5, 10, and 40 years, respectively, and was associated with proteinuria, eGFR < 30, 45, and 60 mL/min/1.73m2 , CVD, and death. Blood pressure was <140/90 mm Hg at last follow-up in 75% of hypertensive donors. Use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (compared to other antihypertensive agents) was associated with a lower risk for eGFR <45 mL/min/1.73m², HR 0.64 (95% confidence interval [CI] 0.45-0.9), P = .01, and also less ESRD; HR 0.03 (95% CI 0.001-0.20), P = .004. In this predominantly Caucasian cohort, hypertension is common after donation, well controlled in most donors, and factors associated with its development are similar to those in the general population.

Intermuscular Adipose Tissue and Subclinical Coronary Artery Calcification in Midlife: The CARDIA Study (Coronary Artery Risk Development in Young Adults).

OBJECTIVE: Excess deposition of fat within and around vital organs and nonadipose tissues is hypothesized to contribute to cardiovascular disease (CVD) risk. We evaluated the association of abdominal intermuscular adipose tissue (IMAT) volume with coronary artery calcification in the CARDIA study (Coronary Artery Risk Development in Young Adults) participants. APPROACH AND RESULTS: We measured IMAT in the abdominal muscles, visceral adipose tissue and pericardial adipose tissue, and coronary artery calcification using computed tomography in 3051 CARDIA participants (56% women) at the CARDIA year 25 examination (2010-2011). Mean IMAT volume and mean IMAT/total muscle volume (IMAT normalized for muscle size) were calculated in a 10-mm block of slices centered at L3-L4. Multivariable analyses included potential confounders and traditional cardiovascular disease risk factors. Compared with the lowest quartile, the upper quartile of abdominal IMAT volume was associated with higher coronary artery calcification prevalence (odds ratio [95% confidence interval], 1.6 [1.2-2.1]) after adjusting for cardiovascular disease risk factors. Results were similar for highest versus lowest quartile of IMAT normalized to total muscle volume (odds ratio [95% confidence interval], 1.5 [1.1-2.0]). Significant associations of higher IMAT and normalized IMAT with coronary artery calcification prevalence persisted when body mass index, visceral adipose tissue, or pericardial adipose tissue were added to the models. CONCLUSIONS: In a large, community-based, cross-sectional study, we found that higher abdominal skeletal muscle adipose tissue volume was associated with subclinical atherosclerosis independent of traditional cardiovascular disease risk factors and other adipose depots.