Two zebrafish cacna1s loss-of-function variants provide models of mild and severe CACNA1S-related myopathy.

CACNA1S-related myopathy, due to pathogenic variants in the CACNA1S gene, is a recently described congenital muscle disease. Disease associated variants result in loss of gene expression and/or reduction of Cav1.1 protein stability. There is an incomplete understanding of the underlying disease pathomechanisms and no effective therapies are currently available. A barrier to the study of this myopathy is the lack of a suitable animal model that phenocopies key aspects of the disease. To address this barrier, we generated knockouts of the two zebrafish CACNA1S paralogs, cacna1sa and cacna1sb. Double knockout fish exhibit severe weakness and early death, and are characterized by the absence of Cav1.1 α1 subunit expression, abnormal triad structure, and impaired excitation-contraction coupling, thus mirroring the severe form of human CACNA1S-related myopathy. A double mutant (cacna1sa homozygous, cacna1sb heterozygote) exhibits normal development, but displays reduced body size, abnormal facial structure, and cores on muscle pathologic examination, thus phenocopying the mild form of human CACNA1S-related myopathy. In summary, we generated and characterized the first cacna1s zebrafish loss-of-function mutants, and show them to be faithful models of severe and mild forms of human CACNA1S-related myopathy suitable for future mechanistic studies and therapy development.

Induction therapy in heart transplantation: A systematic review and network meta-analysis for developing evidence-based recommendations.

INTRODUCTION: Induction therapy (IT) utility in heart transplantation (HT) remains contested. Commissioned by a clinical-practice guidelines panel to evaluate the effectiveness and safety of IT in adult HT patients, we conducted this systematic review and network meta-analysis (NMA). METHODS: We searched for studies from January 2000 to October 2022, reporting on the use of any IT agent in adult HT patients. Based on patient-important outcomes, we performed frequentist NMAs separately for RCTs and observational studies with adjusted analyses, and assessed the certainty of evidence using the GRADE framework. RESULTS: From 5156 publications identified, we included 7 RCTs and 12 observational studies, and report on two contemporarily-used IT agents-basiliximab and rATG. The RCTs provide only very low certainty evidence and was uninformative of the effect of the two agents versus no IT or one another. With low certainty in the evidence from observational studies, basiliximab may increase 30-day (OR 1.13; 95% CI 1.06-1.20) and 1-year (OR 1.11; 95% CI 1.02-1.22) mortality compared to no IT. With low certainty from observational studies, rATG may decrease 5-year cardiac allograft vasculopathy (OR .82; 95% CI .74-.90) compared to no IT, as well as 30-day (OR .85; 95% CI .80-.92), 1-year (OR .87; 95% CI .79-.96), and overall (HR .84; 95% CI .76-.93) mortality compared to basiliximab. CONCLUSION: With low and very low certainty in the synthetized evidence, these NMAs suggest possible superiority of rATG compared to basiliximab, but do not provide compelling evidence for the routine use of these agents in HT recipients.

Clinical utility of multiple secondary combined tests in prostate cancer screening.

INTRODUCTION: The clinical utility of concurrent Prostate Health Index (PHI) and ExosomeDx Prostate Intelliscore (EPI) testing is unclear. We sought to examine the performance of combined PHI and EPI testing on men undergoing elevated PSA work up. MATERIALS AND METHODS: Patients who received both EPI and PHI testing were identified from an institutional database of men referred to urology for an elevated total PSA. Cut points of EPI > 15.6 and PHI ≥ 36 were used to denote a positive test. Patients were placed into one of four groups determined by combination of EPI and PHI results. Demographic variables and biopsy recommendations were compared between groups. The concordance of test positivity between EPI and PHI was compared by Cohen's kappa. Demographic variables and secondary testing results were compared between patients' compliant and non-compliant with prostate biopsy recommendation. Biopsy pathology was compared between groups. RESULTS: A total of 162 patients had both EPI and PHI testing. Median age was 65 years, with a median PSA of 6.64 ng/mL. Age (p = 0.001), PSA (< 0.001) and biopsy recommendation (< 0.001) differed between combined secondary screening test result groups. Seventy-five percent of patients with both a positive EPI and PHI were found to have prostate cancer, with 54.2% being ≥ Gleason 7. Cohen's kappa was 0.19, indicating poor concordance. The AUC of EPI and PHI for clinically significant cancer was 0.563 (95% CI: 0.4331-0.6923) and 0.685 (95% CI: 0.569-0.8) (p = 0.147). CONCLUSIONS: Concurrently positive EPI and PHI indicate increased prostate cancer risk, with combined usage potentially influencing biopsy recommendation and compliance.

Mapping Patient Encounters in Breast Cancer Care: An Analysis of 8800 Clinical Encounters Among Patients Undergoing Mastectomy.

BACKGROUND: Transitions toward value-based systems require a comprehensive definition of the complexity and duration of provider effort required for a given diagnosis. This study modeled the numbers of clinical encounters involved in various treatment pathways among breast cancer patients undergoing mastectomy. METHODS: Clinical encounters with medical oncologists, radiation oncologists, breast surgeons, or plastic surgeons ≤4 years after diagnosis among all patients undergoing mastectomy from 2017 to 2018 were reviewed. Relative encounter volumes were modeled each 90-day period after diagnosis. RESULTS: A total of 8807 breast cancer-related encounters from 221 patients were analyzed, with mean (SD) encounter volume 39.9 (27.2) encounters per patient. Most encounters occurred in the first year after diagnosis (70.0%), with years 2, 3, and 4 representing 15.8%, 9.1%, and 3.5% of encounters, respectively. Overall stage was associated with encounter volume, with higher encounter volume with increasing stage (stages 0: 27.4 vs I: 28.5 vs II: 48.4 vs III: 61.1 vs IV: 80.8 mean encounters). Body mass index (odds ratio [OR], 0.22), adjuvant radiation (OR, 6.8), and receipt of breast reconstruction (OR, 3.5) were also associated with higher encounter volume (all P 's < 0.01). Duration of encounter volume varied by treatment phases, with medical oncology and plastic surgery sustaining high clinical encounter volume 3 years after diagnosis. CONCLUSIONS: Encounter utilization in breast cancer care persists 3 years after index diagnosis and is influenced by overall stage and treatment characteristics, including receipt of breast reconstruction. These results may inform the design of episode durations within value-based models and institutional resource allocation for breast cancer care.

Evaluating Disparities in Pathways to Breast Reconstruction.

BACKGROUND: Rates of postmastectomy breast reconstruction have been shown to vary by racial, ethnic, and socioeconomic factors. In this study, we evaluated disparities across pathways toward breast reconstruction. METHODS: All women who underwent mastectomy for breast cancer at a single institution from 2017 to 2018 were reviewed. Rates of discussions about reconstruction with breast surgeons, plastic surgery referrals, plastic surgery consultations, and ultimate decisions to pursue reconstruction were compared by race/ethnicity. RESULTS: A total of 218 patients were included, with the racial/ethnic demographic of 56% white, 28% Black, 1% American Indian/Native Alaskan, 4% Asian, and 4% Hispanic/Latina. The overall incidence of postmastectomy breast reconstruction was 48%, which varied by race (white: 58% vs. Black: 34%; p < 0.001). Plastic surgery was discussed by the breast surgeon with 68% of patients, and referrals were made in 62% of patients. While older age (p < 0.001) and nonprivate insurance (p < 0.05) were associated with lower rates of plastic surgery discussion and referral, it did not vary by race/ethnicity. The need for an interpreter was associated with lower rates of discussion (p < 0.05). After multivariate adjustment, a lower reconstruction rate was associated with the Black race (odds ratio [OR] = 0.33; p = 0.014) and body mass index (BMI) ≥ 35 (OR = 0.14; p < 0.001). Elevated BMI did not disproportionately lower breast reconstruction rates in Black versus white women (p = 0.27). CONCLUSION: Despite statistically equivalent rates of plastic surgery discussions and referrals, black women had lower breast reconstruction rates versus white women. Lower rates of breast reconstruction in Black women likely represent an amalgamation of barriers to care; further exploration within our community is warranted to better understand the racial disparity observed.

Diet and risk of Barrett's oesophagus: Melbourne collaborative cohort study.

Barrett's oesophagus (BE) is the precursor of oesophageal adenocarcinoma, which has become the most common type of oesophageal cancer in many Western populations. Existing evidence on diet and risk of BE predominantly comes from case-control studies, which are subject to recall bias in measurement of diet. We aimed to investigate the potential effect of diet, including macronutrients, carotenoids, food groups, specific food items, beverages and dietary scores, on risk of BE in over 20 000 participants of the Melbourne Collaborative Cohort Study. Diet at baseline (1990-1994) was measured using a food frequency questionnaire. The outcome was BE diagnosed between baseline and follow-up (2007-2010). Logistic regression models were used to estimate OR and 95 % CI for diet in relation to risk of BE. Intakes of leafy vegetables and fruit were inversely associated with risk of BE (highest v. lowest quartile: OR = 0·59; CI: 0·38, 0·94; P-trend = 0·02 and OR = 0·58; CI: 0·37, 0·93; P-trend = 0·02 respectively), as were dietary fibre and carotenoids. Stronger associations were observed for food than the nutrients found in them. Positive associations were observed for discretionary food (OR = 1·54; CI: 0·97, 2·44; P-trend = 0·04) and total fat intake (OR per 10 g/d = 1·11; CI: 1·00, 1·23), the association for fat was less robust in sensitivity analyses. No association was observed for meat, protein, dairy products or diet scores. Diet is a potential modifiable risk factor for BE. Public health and clinical guidelines that incorporate dietary recommendations could contribute to reduction in risk of BE and, thereby, oesophageal adenocarcinoma.

Demographic and lifestyle risk factors for gastroesophageal reflux disease and Barrett's esophagus in Australia.

We examined demographic and lifestyle risk factors for incidence of gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE) in an Australian cohort of 20,975 participants aged 40-63 at recruitment (1990-1994). Information on GERD and BE was collected between 2007 and 2010. GERD symptoms were defined as self-reported heartburn or acid regurgitation. BE was defined as endoscopically confirmed columnar-lined esophagus. Risk factors for developing GERD symptoms, BE diagnosis, age at symptom onset, and age at BE diagnosis were quantified using regression. During a mean follow-up of 15.8 years, risk of GERD symptoms was 7.5% (n = 1,318) for daily, 7.5% (n = 1,333) for 2-6 days/week, and 4.3% (n = 751) for 1 day/week. There were 210 (1.0%) endoscopically diagnosed BE cases, of whom 141 had histologically confirmed esophageal intestinal metaplasia. Female sex, younger age, lower socioeconomic position (SEP) and educational attainment, and former smoking were associated with higher GERD risk. Male sex and smoking were associated with earlier GERD symptom onset. Men, older participants, those with higher SEP, and former smokers were at higher BE risk. There was some evidence higher SEP was associated with earlier BE diagnosis. GERD and BE had different demographic risk factors but shared similar lifestyle factors. Earlier GERD symptom onset for men and smokers might have contributed to higher BE risk. The SEP patterns observed for GERD and BE suggest potential inequity in access to care. These findings would be important in the development of clinical risk prediction models for early detection of BE.

Diet and risk of gastro-oesophageal reflux disease in the Melbourne Collaborative Cohort Study.

OBJECTIVE: To examine associations between diet and risk of developing gastro-oesophageal reflux disease (GERD). DESIGN: Prospective cohort with a median follow-up of 15·8 years. Baseline diet was measured using a FFQ. GERD was defined as self-reported current or history of daily heartburn or acid regurgitation beginning at least 2 years after baseline. Sex-specific logistic regressions were performed to estimate OR for GERD associated with diet quality scores and intakes of nutrients, food groups and individual foods and beverages. The effect of substituting saturated fat for monounsaturated or polyunsaturated fat on GERD risk was examined. SETTING: Melbourne, Australia. PARTICIPANTS: A cohort of 20 926 participants (62 % women) aged 40-59 years at recruitment between 1990 and 1994. RESULTS: For men, total fat intake was associated with increased risk of GERD (OR 1·05 per 5 g/d; 95 % CI 1·01, 1·09; P = 0·016), whereas total carbohydrate (OR 0·89 per 30 g/d; 95 % CI 0·82, 0·98; P = 0·010) and starch intakes (OR 0·84 per 30 g/d; 95 % CI 0·75, 0·94; P = 0·005) were associated with reduced risk. Nutrients were not associated with risk for women. For both sexes, substituting saturated fat for polyunsaturated or monounsaturated fat did not change risk. For both sexes, fish, chicken, cruciferous vegetables and carbonated beverages were associated with increased risk, whereas total fruit and citrus were associated with reduced risk. No association was observed with diet quality scores. CONCLUSIONS: Diet is a possible risk factor for GERD, but food considered as triggers of GERD symptoms might not necessarily contribute to disease development. Potential differential associations for men and women warrant further investigation.

Lactobacillus plantarum PS128 alleviates neurodegenerative progression in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse models of Parkinson's disease.

Evidence suggests that the Parkinson's disease (PD) pathogenesis is strongly associated with bidirectional pathways in the microbiota-gut-brain axis (MGBA), and psychobiotics may inhibit PD progression. We previously reported that the novel psychobiotic strain, Lactobacillus plantarum PS128 (PS128), ameliorated abnormal behaviors and modulated neurotransmissions in dopaminergic pathways in rodent models. Here, we report that orally administering PS128 for 4 weeks significantly alleviated the motor deficits, elevation in corticosterone, nigrostriatal dopaminergic neuronal death, and striatal dopamine reduction in 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced PD mouse models. PS128 ingestion suppressed glial cell hyperactivation and increased norepinephrine and neurotrophic factors in the striatum of the PD-model mice. PS128 administration also attenuated MPTP-induced oxidative stress and neuroinflammation in the nigrostriatal pathway. Fecal analysis showed that PS128 modulated the gut microbiota. L. plantarum abundance was significantly increased along with methionine biosynthesis-related microbial modules. PS128 also suppressed the increased family Enterobacteriaceae and lipopolysaccharide and peptidoglycan biosynthesis-related microbial modules caused by MPTP. In conclude, PS128 ingestion alleviated MPTP-induced motor deficits and neurotoxicity.PS128 supplementation inhibited neurodegenerative processes in PD-model mice and may help prevent PD.

Ubiquitin phosphorylated at Ser57 hyper-activates parkin.

Malfunction of the ubiquitin (Ub) E3 ligase, parkin, leads to defects in mitophagy and protein quality control linked to Parkinson's disease. Parkin activity is stimulated by phosphorylation of Ub at Ser65 (pUbS65). Since the upstream kinase is only known for Ser65 (PINK1), the biochemical function of other phosphorylation sites on Ub remain largely unknown. We used fluorescently labelled and site-specifically phosphorylated Ub substrates to quantitatively relate the position and stoichiometry of Ub phosphorylation to parkin activation. Fluorescence measurements show that pUbS65-stimulated parkin is 5-fold more active than auto-inhibited and un-stimulated parkin, which catalyzes a basal level of auto-ubiquitination. We consistently observed a low but detectable level of parkin activity with pUbS12. Strikingly, pUbS57 hyper-activates parkin, and our data demonstrate that parkin is able to selectively synthesize poly-pUbS57 chains, even when 90% of the Ub in the reaction is un-phosphorylated. We further found that parkin ubiquitinates its physiological substrate Miro-1 with chains solely composed of pUbS65 and more efficiently with pUbS57 chains. Parkin hyper-activation by pUbS57 demonstrates the first PINK1-independent route to active parkin, revealing the roles of multiple ubiquitin phosphorylation sites in governing parkin stimulation and catalytic activity. This article is part of a Special Issue entitled "Biochemistry of Synthetic Biology - Recent Developments" Guest Editor: Dr. Ilka Heinemann and Dr. Patrick O'Donoghue.

Tailoring Enzyme-Like Activities of Gold Nanoclusters by Polymeric Tertiary Amines for Protecting Neurons Against Oxidative Stress.

The cytotoxicity of nanozymes has drawn much attention recently because their peroxidase-like activity can decompose hydrogen peroxide (H2 O2 ) to produce highly toxic hydroxyl radicals (•OH) under acidic conditions. Although catalytic activities of nanozymes are highly associated with their surface properties, little is known about the mechanism underlying the surface coating-mediated enzyme-like activities. Herein, it is reported for the first time that amine-terminated PAMAM dendrimer-entrapped gold nanoclusters (AuNCs-NH2 ) unexpectedly lose their peroxidase-like activity while still retaining their catalase-like activity in physiological conditions. Surprisingly, the methylated form of AuNCs-NH2 (i.e., MAuNCs-N(+) R3 , where R = H or CH3 ) results in a dramatic recovery of the intrinsic peroxidase-like activity while blocking most primary and tertiary amines (1°- and 3°-amines) of dendrimers to form quaternary ammonium ions (4°-amines). However, the hidden peroxidase-like activity is also found in hydroxyl-terminated dendrimer-encapsulated AuNCs (AuNCs-OH, inside backbone with 3°-amines), indicating that 3°-amines are dominant in mediating the peroxidase-like activity. The possible mechanism is further confirmed that the enrichment of polymeric 3°-amines on the surface of dendrimer-encapsulated AuNCs provides sufficient suppression of the critical mediator •OH for the peroxidase-like activity. Finally, it is demonstrated that AuNCs-NH2 with diminished cytotoxicity have great potential for use in primary neuronal protection against oxidative damage.

Comorbidity of Atopic Disorders with Autism Spectrum Disorder and Attention Deficit/Hyperactivity Disorder.

OBJECTIVE: To assess the relationship between allergic manifestations in early life and the occurrence of newly diagnosed autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) throughout childhood. STUDY DESIGN: We collected a population-based longitudinal cohort comprising children enrolled in Taiwan's National Health Insurance Program during 2000-2010. We first identified 387,262 children who had a diagnosis of atopic dermatitis (AD) before age 2 years, with 1:1 individualized matching to children without AD. Cox regression analyses were performed to estimate the early-onset and cumulative effects of allergic manifestations on ASD and ADHD. RESULTS: An estimated 0.5% of AD-exposed children received a diagnosis of ASD, and 3.7% were diagnosed with ADHD, significantly higher than the respective rates of 0.4% and 2.9% found in their nonexposed peers. Having AD before age 2 years was associated with an increased hazard ratio (HR) for ASD by 10% and that for ADHD by 16%; such increases were particularly prominent among those with earlier-onset or more severe AD. HRs were especially higher for children with persistent AD and emerging atopic respiratory diseases in childhood (eg, for ASD, adjusted HR, 1.75 and 2.13, respectively; P < .001). CONCLUSION: The observed increased risks of ASD and ADHD associated with AD in infancy suggest that a disordered immunologic response may exert effects on neurodevelopment and have implications for research into etiology and treatment strategies.

Reciprocal relationship between unhealthy eating behaviours and depressive symptoms from childhood to adolescence: 10-year follow-up of the Child and Adolescent Behaviors in Long-Term Evolution study.

OBJECTIVE: To investigate the reciprocal relationship between unhealthy eating behaviours and depressive symptoms from childhood to adolescence. DESIGN: Unhealthy eating behaviours were measured by the frequencies of eating foods with excess salt, sugar or fat in the past week. Depressive symptoms in the past two weeks were measured using a seven-item scale. Hierarchical linear growth models were used to analyse longitudinal associations between unhealthy eating behaviours and depressive symptoms. Time-fixed variables (sex, parents' education level and household monthly income) and time-varying variables (parents' marital status, family activities, body weight, vegetable or fruit consumption, exercising and smoking) were controlled for. SETTING: The Child and Adolescent Behaviors in Long-Term Evolution study, which commenced in 2001 and has annual follow-up. SUBJECTS: Students (n 2630) followed from 2nd grade (8 years old in 2002) to 11th grade. RESULTS: The frequency of unhealthy eating behaviours in the previous year and the difference between the frequency in the previous and successive year were positively associated with the initiation and growth rate of depressive symptoms. Depressive symptoms in the previous year and the difference in depressive symptoms between the previous and successive year were positively associated with the initial state and growth rate of unhealthy eating behaviours. CONCLUSIONS: Our results suggest a reciprocal relationship between depressive symptoms and unhealthy eating behaviours. This relationship should be considered when developing programmes targeting depressive symptoms and unhealthy diet in children and adolescents.

Noggin inhibits hypoxia-induced proliferation by targeting store-operated calcium entry and transient receptor potential cation channels.

Abnormally elevated bone morphogenetic protein 4 (BMP4) expression and mediated signaling play a critical role in the pathogenesis of chronic hypoxia-induced pulmonary hypertension (CHPH). In this study, we investigated the expression level and functional significance of four reported naturally occurring BMP4 antagonists, noggin, follistatin, gremlin1, and matrix gla protein (MGP), in the lung and distal pulmonary arterial smooth muscle cell (PASMC). A 21-day chronic hypoxic (10% O2) exposure rat model was utilized, which has been previously shown to successfully establish experimental CHPH. Among the four antagonists, noggin, but not the other three, was selectively downregulated by hypoxic exposure in both the lung tissue and PASMC, in correlation with markedly elevated BMP4 expression, suggesting that the loss of noggin might account for the hypoxia-triggered BMP4 signaling transduction. Then, by using treatment of extrogenous recombinant noggin protein, we further found that noggin significantly normalized 1) BMP4-induced phosphorylation of cellular p38 and ERK1/2; 2) BMP4-induced phosphorylation of cellular JAK2 and STAT3; 3) hypoxia-induced PASMC proliferation; 4) hypoxia-induced store-operated calcium entry (SOCE), and 5) hypoxia-increased expression of transient receptor potential cation channels (TRPC1 and TRPC6) in PASMC. In combination, these data strongly indicated that the hypoxia-suppressed noggin accounts, at least partially, for hypoxia-induced excessive PASMC proliferation, while restoration of noggin may be an effective way to inhibit cell proliferation by suppressing SOCE and TRPC expression.

Prenatal Infection and Autism Spectrum Disorders in Childhood: A Population-Based Case-Control Study in Taiwan.

BACKGROUND: Infection in pregnancy has long been linked with negative postnatal development and health. This study aims to assess the association between prenatal infections and autism spectrum disorders (ASDs) across three trimesters and to probe possible sex heterogeneity in such link. METHOD: A total of 4184 children with incident ASDs and 16,734 matched children were identified from the 2000-2007 National Health Insurance Research Database. For each child, information pertaining to the mother's infection during pregnancy, sociodemographics, and medical history was retrieved from healthcare records. Conditional logistic analyses were carried out to estimate the strength of associations with adjustment for multiple comparisons. RESULT: Pooled analyses demonstrated that having two or more outpatient visits for genital infection [adjusted odds ratio (aOR): 1.34; 95% confidence interval (95% CI) 1.12, 1.60; false discovery rate (FDR) < 0.01] and bacterial infection (aOR: 1.24; 95% CI 1.06, 1.43; FDR < 0.05) in the third trimester were slightly associated with increased risk of ASDs. No statistically significant sex differences were found. CONCLUSION: The present study contributes updated population-based evidence about the connection between prenatal infection and ASDs. Potential effect of bacterial and genital tract infections during the third trimester on risk of ASDs warrants further exploration.

Routinely collected burn clinical data in Canada: Determining the knowledge gap.

Unlike other developed countries that hold national burn registries to monitor burn injury and care, Canada relies on single-centre secondary datasets and administrative databases as surveillance mechanisms. The objective of this study was to determine the knowledge gap faced in Canada for not having a dedicated burn registry. A comprehensive scoping review was conducted to identify the burn literature that has arisen from secondary datasets in Canada. Literature of all study designs was included with the exception of case reports and cases series. Once data extraction was concluded, a thematic framework was constructed based on the information that arose from nations that hold national burn registries. Eighty-eight studies were included. Twelve studies arose from national datasets, and 18 from provincial databases, most of which were from Ontario and British Columbia. Only seven studies were conducted using a combination of Canadian units' single-centre datasets. The majority of included studies (58%) resulted from non-collaborative use of single-centre secondary datasets. Research efforts were predominantly conducted by burn units in Ontario, British Columbia, Manitoba and Alberta. A significant number of the included studies were outdated and several provinces/territories had no published burn data whatsoever. Efforts should be made towards the development of systems to surveil burn injury and care in Canada. This study supports the development of a nation-wide burn registry to bridge this knowledge gap.

Müllerian-type carcinosarcoma arising in gastric endometriosis: Case report and review of the literature.

Although endometriosis is a common condition, both extrapelvic endometriosis and endometriosis associated malignancy (EAM) are rare. We describe the first reported case of a patient with Müllerian-type carcinosarcoma arising in gastric endometriosis.

Biased effects of pre-diagnostic physical activity on breast cancer survival: Systematic review and meta-analysis.

BACKGROUND: Pre-diagnostic physical activity is reported to improve survival for women with breast cancer. However, studies of pre-diagnostic exposures and cancer survival are susceptible to bias, made clear when applying a target trial framework. We investigated the impact of selection bias, immortal time bias, confounding and bias due to inappropriate adjustment for post-exposure variables in a systematic review and meta-analysis of pre-diagnostic physical activity and survival after breast cancer. METHODS: Medline, Embase and Emcare were searched from inception to November 2021 for studies examining pre-diagnostic physical activity and overall or breast cancer-specific survival for women with breast cancer. Random-effects meta-analysis was used to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs) comparing highest versus lowest pre-diagnostic physical activity. Subgroup meta-analyses were used to compare HRs of studies with and without different biases. ROBINS-E was used to assess risk of bias. RESULTS: We included 22 studies. Women with highest versus lowest pre-diagnostic physical activity had higher overall and breast cancer-specific survival across most analyses. The overall risk of bias was high. We observed marked differences in estimated HRs between studies that did and did not adjust for post-exposure variables or have immortal time bias. All studies were at risk of selection bias due to participants becoming eligible for study when they have survived to post-exposure events (e.g., breast cancer diagnosis). Insufficient studies were available to investigate confounding. CONCLUSION: Biases can substantially change effect estimates. Due to misalignment of treatment assignment (before diagnosis), eligibility (survival to post-exposure events) and start of follow-up, bias is difficult to avoid. It is difficult to lend a causal interpretation to effect estimates from studies of pre-diagnostic physical activity and survival after cancer. Biased effect estimates that are difficult to interpret may be less useful for clinical or public health policy applications.

Which Social Variables Predict Diabetes Onset? Robust Findings in Two National Surveys.

BACKGROUND AND OBJECTIVES: The role of social factors in diabetes onset has been obscured by wide variation in their conceptualization and operationalization. We apply three theoretical frameworks to categorize social relationship variables along several dimensions and identify which dimension(s) are robustly associated with incident diabetes in the older adult population. RESEARCH DESIGN AND METHODS: The National Social Life, Health, and Aging Project (n=2,365) and the Health and Retirement Study (n=11,824) provided longitudinal data from 57-90 year-old respondents over a 4- to 5-year period. Logistic regression models were used to test associations of 15 social variables measured identically in both datasets with diabetes onset measured as respondents' first report of a physician's diagnosis. RESULTS: In both studies, not being married, experiencing strain in a spousal relationship, and feeling lonely were associated with increased risk for diabetes onset at follow-up. Inconsistent or null findings were observed for social support, social activity, network size, number of friends and relatives, living alone, and closeness to network members. DISCUSSION AND IMPLICATIONS: Robust findings in two large-scale surveys support the importance of the valence dimension (i.e., positive and negative); specifically, alleviating negative aspects of social life might more effectively reduce risk for diabetes than augmenting positive ones. Findings were not aligned with social variables differing on the subjectivity dimension (i.e., structural, functional, and qualitative aspects of social connections). Future work needs consistent conceptualization and measurement of social factors to correctly identify and categorize risk factors for diabetes onset and other health conditions in older adults.

Anti-aging effects of Lacticaseibacillus paracasei PS117 on cognitive and intestinal health in naturally-aged mice: A focus on senescence-related proteins and microbiota composition.

The rising global aging population underscores the urgency of maintaining the health and well-being of the elderly while reducing the healthcare burden. Anti-aging probiotics have emerged as a promising strategy. This study identified a novel anti-senescence probiotic, Lacticaseibacillus paracasei PS117 (PS117). The effects of PS117 and heat-treated PS117 (HT-PS117) supplementation on cognitive function of naturally-aged male mice were investigated. It was found that PS117 supplementation improved the cognitive performance of aged mice in the Y-maze test. Furthermore, the level of senescence-related protein p16INK4a (p16) were reduced, while anti-senescence protein sirtuin 1 (Sirt1) were increased in the hippocampus. In addition, there was an overall improvement in the intestinal function. Distinct changes in the gut microbiota were also identified, suggesting a potential contribution to the beneficial effects of PS117 supplementation. In conclusion, these results suggest that PS117 supplements could improve cognitive and intestinal functions in naturally-aged mice, while HT-117 improves only intestinal function, possibly by improving the gut microbiota composition.