Secondary Analyses Research Articles

KRAS G12C mutation in NSCLC in a small genetic center: insights into sotorasib therapy response potential

Lung cancer remains a significant health challenge, characterized by aberrant tissue growth within the pulmonary system. Early carcinogenic events often involve genomic instability and the emergence of a mutator phenotype. In this study, we aimed to explore the mutator phenotype in 89 patients diagnosed with non-small-cell lung cancer (NSCLC). RNA isolation from formalin-fixed paraffin-embedded (FFPE) tissue samples was performed using the Promega ReliaPrep RNA Miniprep System, facilitating gene amplification relevant to cancer through the Archer® FusionPlexComprehensiveThyroid and Lung (CTL) kit. Next-generation sequencing (NGS) on the Illumina NextSeq platform enabled comprehensive analysis of target areas. Utilizing Archer Analysis software, secondary analyses involving data cleansing, alignment, and variant/fusion identification were executed against the human reference genome hg19 (GRCh37). Expression patterns were visualized using HeatMap graphics. Our findings revealed a notable presence of KRAS gene mutations in approximately 20% of NSCLC patients. Among these mutations, the G12C variant was predominant at 50%, followed by G12V and G12D variants at 11.2% each. Notably, patients harboring the G12C variant responded favorably to sotorasib medication. These results underscore the importance of mutational profiling and targeted therapeutic approaches in managing NSCLC, particularly highlighting the promising efficacy of sotorasib in G12C-mutated cases.

Effect of exercise referral schemes and self-management strategies on healthcare service utilisation among community-dwelling older adults: secondary analyses of two randomised controlled trials.

The objective of this study is to explore whether offering an integrated self-management strategy and exercise referral scheme intervention (ERS+SMS) or a stand-alone ERS intervention is more effective in reducing healthcare service utilisation among community-dwelling older adults over time compared with a stand-alone SMS/control intervention. Secondary analyses of two randomised controlled trials (RCTs) with linkage to Danish national health registries. Three Danish municipalities: Esbjerg, Slagelse and Odense. Danish community-dwelling older adults, aged 65 years or older, were included in the study. Participants originated from two completed RCTs: the Welfare Innovation in Primary Prevention (WIPP, n=115) and the SITLESS project (SITLESS, n=333). Participants in the two trials were randomly assigned to one of three intervention groups: ERS in combination with SMS (ERS+SMS), ERS alone or an SMS/control intervention. Annual number of days with contact to general practice (GP) and days hospitalised for all causes. No statistically significant between-group difference was observed in the annual number of days with contact with GP between participants randomised to ERS+SMS (p=0.759) or ERS only (p=0.156) compared with those randomised to the SMS/control group. In addition, no statistically significant between-group differences in days hospitalised were observed when comparing the ERS+SMS (p=0.222) or ERS only (p=0.060) group to the SMS/control group. Neither the integrated intervention (ERS+SMS) nor the ERS alone intervention was more effective in reducing healthcare service utilisation during a 2-year follow-up period compared with a stand-alone SMS/control intervention. A potential stabilising effect of ERS and/or SMS interventions on the general age-related increase in healthcare service utilisation cannot be ruled out but needs further exploration in future studies along with the exploration of the effects of long-term interventions. NCT04531852 : and : NCT02629666 : .

High correlation of quantitative susceptibility mapping and echo intensity measurements of nigral iron overload in Parkinson's disease.

Quantitative susceptibility mapping (QSM) and transcranial sonography (TCS) offer proximal evaluations of iron load in the substantia nigra. Our prospective study aimed to investigate the relationship between QSM and TCS measurements of nigral iron content in patients with Parkinson's disease (PD). In secondary analyses, we wanted to explore the correlation of substantia nigra imaging data with clinical and laboratory findings. Eighteen magnetic resonance imaging and TCS examinations were performed in 15 PD patients at various disease stages. Susceptibility measures of substantia nigra were calculated from referenced QSM maps. Echogenicity of substantia nigra on TCS was measured planimetrically (echogenic area) and by digitized analysis (echo-intensity). Iron-related blood serum parameters were measured. Clinical assessments included the Unified PD Rating Scale and non-motor symptom scales. Substantia nigra susceptibility correlated with echogenic area (Pearson correlation, r = 0.53, p = 0.001) and echo-intensity (r = 0.78, p < 0.001). Individual asymmetry indices correlated between susceptibility and echogenic area measurements (r = 0.50, p = 0.042) and, more clearly, between susceptibility and echo-intensity measurements (r = 0.85, p < 0.001). Substantia nigra susceptibility (individual mean of bilateral measurements) correlated with serum transferrin saturation (Spearman test, r = 0.78, p < 0.001) and, by trend, with serum iron (r = 0.69, p = 0.004). Nigral echogenicity was not clearly related to serum values associated with iron metabolism. Susceptibility and echogenicity measurements were unrelated to PD duration, motor subtype, and severity of motor and non-motor symptoms. The present results support the assumption that iron accumulation is involved in the increase of nigral echogenicity in PD. Nigral echo-intensity probably reflects ferritin-bound iron, e.g. stored in microglia.

Blood-Based Inflammatory Markers in Female Infertility: Evidence from Mendelian Randomisation Analysis.

Investigate causal associations between blood-based inflammatory markers and female infertility using Mendelian Randomisation (MR). MR using Genome-Wide-Association-Study data. Large female-only cohorts of European ancestry. Blood-based inflammatory markers (C-reactive protein, interleukins, monocyte chemoattractant protein-1, tumour necrosis factor-α, interferon-γ). Anovulatory infertility (1054 cases and 117,098 controls); female infertility of other/unspecified origin (5,667 cases and 117,098 controls); and medical treatment for female infertility (2,706 cases and 120,873 controls). Total causal effects were assessed using univariable two-sample methods including inverse variance weighted (IVW) as the primary analysis, as well as other secondary analyses (Mendelian Randomisation-Egger (MRE), weighted median (WMe), etc.), with relevant quality assessments. Interleukin-8 demonstrated a positive association with anovulatory infertility via IVW (odds ratio, 95% confidence interval: 1.51 [1.04, 2.21], p=0.032) and WMe (1.64 [1.05, 2.57], p=0.028) methods. Monocyte chemoattractant protein-1 was associated with anovulatory infertility via MRE (2.06 [1.13, 3.77], p=0.038). Inverse associations were found for interleukins-12 and -18 via IVW, with higher interleukin-12 being associated with lower medical treatment for female infertility (0.75 [0.59, 0.94], p=0.013), while higher interleukin-18 was associated with lower female infertility of other/unspecified origin (0.90 [0.83, 0.97], p=0.008). This is the first study to examine causal relationships between inflammation and female infertility using MR. Monocyte chemoattractant protein-1 and interleukin-8 are implicated in anovulatory infertility; however, only the relationship with interleukin-8 was evident in the primary analysis. Interleukins-12 and -18 demonstrated inverse associations with infertility outcomes. Further research is needed to uncover the mechanistic functions of these markers to confirm causality and examine their therapeutic potential for female infertility.

Mental Bandwidth is Associated with HIV and Viral Suppression Among Low-Income Women in Philadelphia.

Behavioral economics research suggests poverty may influence behavior by reducing mental bandwidth, increasing future discounting, and increasing risk aversion. It is plausible these decision-making processes are further impaired in the context of HIV or pregnancy. In this cross-sectional study of 86 low-income women in Philadelphia, HIV was associated with lower mental bandwidth (one of two measures) and lower risk aversion. Pregnancy was not associated with any decision-making factors. In secondary analyses, viral suppression was associated with greater mental bandwidth (one of two measures), and antenatal clinic attendance with lower future discounting. Anti-poverty interventions may be beneficial to improve HIV-related health behaviors.

Self-reported physical activity and gait in older adults without dementia: A longitudinal study.

Physical activity (PA) is associated with higher gait speed. We aimed to examine the associations between PA and change in spatial and temporal gait measures as well as fall risk in community-dwelling individuals free of dementia. Longitudinal study among 4173 individuals aged ≥50 years (mean age 71 years; 2078 males; median follow-up 4 years) enrolled in the Mayo Clinic Study of Aging. Self-reported late-life PA was used to calculate overall PA and moderate-vigorous PA (MVPA) scores. Gait was assessed using GAITRite® and Zeno™ systems. Incident falls information was based on diagnostic codes retrieved from medical records. We ran linear mixed effects models to examine associations between z-scored PA variables and longitudinal gait parameters, adjusted for age, sex, education, body mass index (BMI), medical comorbidities, and including interactions between PA and time since baseline. In secondary analyses, we calculated Cox Proportional hazard models with age as time scale predicting incident falls by PA, adjusting for sex, education, BMI, medical comorbidities, and falls history. At baseline, higher PA was associated with higher velocity (overall PA: estimate 2.9935; MVPA: 2.2961; p < 0.001), higher cadence (overall PA: 1.0665; MVPA: 0.9073; p < 0.001), greater stride length (overall PA: 2.0805; MVPA: 1.4726; p < 0.001), shorter double support time (overall PA: -0.0257; MVPA: -0.0205; p < 0.001), and lower stance time variability (overall PA: -0.0204, p < 0.001; MVPA: -0.0152; p = 0.006). Overall PA was longitudinally associated with less decline in cadence, and MVPA with less increase in intraindividual stance time variability. Overall PA (Hazard ratio 0.892, 95% confidence interval 0.828-0.961, p = 0.003) and MVPA (HR 0.901; 95% CI 0.835-0.973, p = 0.008) were associated with a decreased risk of incident falls. Late-life PA was associated with favorable gait outcomes and decreased risk of incident falls. Thus, late-life PA may help to maintain gait performance and decrease fall risk in old age.

Investigating the association of mechanical restraint with somatic harmful outcomes: national register-based study.

Coercive measures to manage disruptive or violent behaviour are accepted as standard practice in mental healthcare, but systematic knowledge of potentially harmful outcomes is insufficient. To examine the association of mechanical restraint with several predefined somatic harmful outcomes. We conducted a population-based, observational cohort study linking data from the Danish national registers from 2007 to 2019. The primary analyses investigated the association of mechanical restraint with somatic adverse events, using panel regression analyses (within-individual analysis) to account for repeated exposures and outcomes. Secondary between-group analyses were performed with a control group exposed to types of coercion other than mechanical restraint. The study population comprised 13 022 individuals. We report a statistically significant association of mechanical restraint with thromboembolic events (relative risk 4.377, number needed to harm (NNH) 8231), pneumonia (relative risk 5.470, NNH 3945), injuries (relative risk 2.286, NNH 3240) and all-cause death (relative risk 5.540, NNH 4043) within 30 days after mechanical restraint. Estimates from the between-group analyses (comparing the exposed group with a control group of 22 643 individuals) were non-significant or indicated increased baseline risk in the control group. A positive dose-response analysis for cardiac arrest, injury and death supported a causative role of mechanical restraint in the reported associations. Although the observed absolute risk increases were small, the derived relative risks were non-negligible considering that less restrictive interventions are available. Clinicians and decision makers should be aware of the excess risk in future decisions on the use of mechanical restraint versus alternative interventions.

Prevalence and relevance of H558R in the efficacy and toxicity of flecainide in patients with atrial fibrillation: a cohort study.

The SCN5A gene polymorphism histidine-558-to-arginine (H558R) has been associated with atrial fibrillation (AF) and may affect the therapeutic effects of flecainide. This study aimed to assess the prevalence of the H558R polymorphism in a European cohort of patients with AF and examine its association with flecainide's effects on AF recurrence and toxicity. This cohort study included patients diagnosed with AF and prescribed flecainide between 2017 and 2021 in a regional health area. Patients without the polymorphism (H558R-/-) were compared with heterozygous patients (H558R+/-) for a primary outcome of combined 6-month AF recurrence or toxicity. Secondary analyses evaluated the long-term outcomes and compared the prevalence of H558R in the AF cohort to a general population sample (n=3401). A total of 104 patients were enrolled, with 57% H558R-/-, 37% H558R+/- and 6% H558R+/+. The prevalence of the H558R polymorphism was significantly higher in the AF cohort than in the general population (43.27% vs 24.37%, prevalence ratio 1.78, 95% CI 1.41 to 2.23, p<0.01). H558R+/- patients had a significantly lower risk of 6-month AF recurrence or toxicity (p=0.023, risk ratio 0.423, 95% CI 0.189 to 0.947), corresponding to an absolute risk difference of 21.5%. These findings were similar in the multivariable analysis. In long-term follow-up, H558R+/- patients continued to demonstrate a lower risk of AF recurrence or toxicity (p=0.039, HR 0.53, 95% CI 0.276 to 0.999). The H558R polymorphism is more prevalent in patients with AF compared with the general population and its presence is associated with a more favourable response to flecainide treatment.

Effect of sleep quality on wound healing among patients undergoing emergency laparotomy: an observational study.

To study the association between sleep-quality, total sleep duration and wound-healing among adult patients having good sleep-quality at the time of admission in hospital, undergoing laparotomy for various reasons. In this observational study , consecutive adult subjects undergoing emergency laparotomy were followed up until the eighth postoperative day. The primary outcome (wound healing) was assessed using the Southampton Wound Grading System. Sleep quality (assessed by the single item sleep quality scale) was the primary predictor. Pain was assessed using visual analogue pain scale. We studied the effect of postoperative sleep quality on wound healing on postoperative day 8. Secondary analyses assessed the effect of total sleep time, severity of pain and markers of systemic inflammation on wound healing. In this study 110 participants were included. The average age of participants was 41.7±16.2 years. On postoperative day 8, 34.5% rated their sleep quality as "poor to fair" and rest as "good". Postoperative poor sleep quality was associated with impaired wound healing, starting from third postoperative day (P<0.001 for each subsequent day). Multiple logistic regression was overall significant (χ2= 118.40; df=9; P<0.001), classified 92.7% cases correctly and explained 88% variance to the outcome. This model showed that shorter total-sleep-time (P=0.009), higher total leukocyte count (P=0.005), presence of comorbidities (P=0.01) and poor sleep quality during the postoperative week (OR=78.14; P=0.005) increased odds for impaired healing of wound. Poor sleep quality during the healing phase is associated with wound complications, a surrogate marker of impaired wound healing.

Effect of a home-based exercise program on subsequent falls among community-dwelling older adults with cognitive frailty: A sub-group analysis of a randomized controlled trial

ObjectivesCognitive frailty is characterized by concurrent physical frailty and mild cognitive impairment and is associated with increased risk of falls. Exercise is an evidence-based strategy to prevent falls, but whether exercise reduces falls in people with cognitive frailty is unknown. We examined the effects of home-based exercise on subsequent falls among community-dwelling older adults with cognitive frailty who have previously fallen. Study designA sub-group analysis of a 12-month, single-blind, randomized controlled trial among 344 adults aged 70 years or more who had fallen within the past 12 months. Participants were randomized to either 12 months of home-based exercise (n = 172) or usual care (n = 172). In this sub-analysis, we included 192 participants with cognitive frailty (home-based exercise = 93; usual care = 99) with Short Physical Performance Battery scores ≤9/12 and Montreal Cognitive Assessment scores <26/30. Main outcome measuresOur primary analysis examined the effect of exercise on self-reported falls rate over 12 months. Secondary analyses investigated the intervention's effects on scores on the Short Physical Performance Battery and the Montreal Cognitive Assessment. We also explored whether greater than or equal to mean average monthly adherence (i.e., ≥45.5 %) moderated treatment effects. ResultsAt 12 months, falls rates were 35 % lower in the home-based exercise group compared with the usual care group (IRR = 0.65; p = 0.042). Score on the Short Physical Performance Battery significantly improved among home-based exercise participants with greater than or equal to mean adherence vs. those with less than mean adherence (estimated mean difference: 0.94; p = 0.022). ConclusionsExercise is a promising strategy for reducing subsequent falls in people with cognitive frailty. Greater exercise adherence improved physical function in this population.ClinicalTrials.gov identifier: NCT01029171

Association of testosterone replacement therapy with atrial fibrillation and acute kidney injury.

Secondary analyses of the Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial revealed significantly higher rates of new-onset atrial fibrillation (AF) and acute kidney injury (AKI) in the testosterone replacement therapy (TRT) cohort. To validate the secondary findings of the TRAVERSE trial. We utilized the TriNetX Research Network to identify a cohort of men ages 45-80years old who met similar inclusion criteria to the TRAVERSE trial. We compared hypogonadal men (testosterone 100-300ng/dL) who had a prescription for topical testosterone therapy and men who did not. Propensity score matching was used to match patient populations. Kaplan Meier survival analysis was used to determine the relative risk of new-onset AF and AKI within 3years. New-onset AF and AKI within 3years. There were 2134 men included in each cohort after propensity score matching. Men on TRT had significantly lower testosterone (T) at the time of diagnosis compared to men not prescribed TRT (207 ± 66ng/dL vs 246 ± 140ng/dL, P< 0.001). Kaplan-Meier survival analysis showed a significantly increased risk of AKI among men on TRT (RR 1.53, 95% CI 1.07-2.18). However, TRT was not associated with a significantly increased risk of new-onset AF (RR 1.48, 95% CI 0.93-2.37). Hypogonadal men with underlying cardiovascular risk factors or pre-existing cardiovascular disease who receive TRT may be at increased risk of AKI after starting therapy. We evaluated a large global research database and utilized similar inclusion and exclusion to the TRAVERSE trial. However, our results are limited by the retrospective study design and reliance on documented claims data. Similar to the TRAVERSE trial, our study demonstrated an increased risk of AKI among men on TRT, but did not find increased risk of AF. However, further studies are required to validate these results.

Global, regional, and national stillbirths at 20 weeks' gestation or longer in 204 countries and territories, 1990–2021: findings from the Global Burden of Disease Study 2021

Stillbirth is a devastating and often avoidable adverse pregnancy outcome. Monitoring stillbirth levels and trends-in a comprehensive manner that leaves no one uncounted-is imperative for continuing progress in pregnancy loss reduction. This analysis, completed as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021, methodically accounted for different stillbirth definitions with the aim of comprehensively estimating all stillbirths at 20 weeks or longer for 204 countries and territories from 1990 to 2021. We extracted data on stillbirths from 11 412 sources across 185 of 204 countries and territories, including 234 surveys, 231 published studies, 1633 vital statistics reports, and 10 585 unique location-year combinations from vital registration systems. Our final dataset comprised 11 different definitions, which were adjusted to match two gestational age thresholds: 20 weeks or longer (reference) and 28 weeks or longer (for comparisons). We modelled the ratio of stillbirth rate to neonatal mortality rate with spatiotemporal Gaussian process regression for each location and year, and then used final GBD 2021 assessments of fertility and all-cause neonatal mortality to calculate total stillbirths. Secondary analyses evaluated the number of stillbirths missed with the more restrictive gestational age definition, trends in stillbirths as a function of Socio-demographic Index, and progress in reducing stillbirths relative to neonatal deaths. In 2021, the global stillbirth rate was 23·0 (95% uncertainty interval [UI] 19·7-27·2) per 1000 births (stillbirths plus livebirths) at 20 weeks' gestation or longer, compared to 16·1 (13·9-19·0) per 1000 births at 28 weeks' gestation or longer. The global neonatal mortality rate in 2021 was 17·1 (14·8-19·9) per 1000 livebirths, corresponding to 2·19 million (1·90-2·55) neonatal deaths. The estimated number of stillbirths occurring at 20 weeks' gestation or longer decreased from 5·08 million (95% UI 4·07-6·35) in 1990 to 3·04 million (2·61-3·62) in 2021, corresponding to a 39·8% (31·8-48·0) reduction, which lagged behind a global improvement in neonatal deaths of 45·6% (36·3-53·1) for the same period (down from 4·03 million [3·86-4·22] neonatal deaths in 1990). Stillbirths in south Asia and sub-Saharan Africa comprised 77·4% (2·35 million of 3·04 million) of the global total, an increase from 60·3% (3·07 million of 5·08 million) in 1990. In 2021, 0·926 million (0·792-1·10) stillbirths, corresponding to 30·5% of the global total (3·04 million), occurred between 20 weeks' gestation and 28 weeks' gestation, with substantial variation at the country level. Despite the gradual global decline in stillbirths between 1990 and 2021, the overall number of stillbirths remains substantially high. Counting all stillbirths is paramount to progress, as nearly a third-close to 1 million in total-are left uncounted at the 28 weeks or longer threshold. Our findings draw attention to the differential progress in reducing stillbirths, with a high burden concentrated in countries with low development status. Scarce data availability and poor data quality constrain our capacity to precisely account for stillbirths in many locations. Addressing inequities in universal maternal health coverage, strengthening the quality of maternal health care, and improving the robustness of data systems are urgently needed to reduce the global burden of stillbirths. Bill & Melinda Gates Foundation.

Normal Accident Theory and Learning from Major Accidents at the National Aeronautics and Space Administration (NASA).

A review of NASA’s accident history through the lens of Normal Accident Theory (NAT) offers insights into the prospects for safety during the Artemis Program. NAT is applied to NASA’s four major human spaceflight accidents: the Apollo launch pad fire, Apollo 13, Challenger and Columbia. NAT predicts that in the complex and tightly coupled systems used for human spaceflight, an accident type known as the “normal accident”, is inevitable. These accidents are attributable to hidden system interactions that overwhelm the cognitive abilities of human operators and, thereby, escape detection. A review of the four official accident reports and supporting secondary analyses suggests NASA has had one such accident: Apollo 13. It was also the only major accident without injury and a successful recovery effort. NAT would categorize the other three as component failure accidents. Unlike normal accidents, component failure accidents are not inevitable. They stem from an organization’s failure to appropriately monitor, assess and mitigate the risk associated with a faulty component. In such cases, NAT would ask if production pressures, often rooted in scheduling and resource constraints, were a factor.Production pressures are ultimately imposed on organizations through the exercise of power. These pressures impede an organization’s ability to adequately assess risk and increase the likelihood of component failure accidents. The substantial organizational literature on NASA’s human spaceflight accidents has yielded potential remedies to help mitigate the risks associated with production pressure. This paper discusses these remedies and their potential safety benefits. It also proposes a modification to a safety governance mechanism recommended by the Columbia Accident Investigation Board (CAIB). The resulting changes could help NASA, and other organizations administering high risk technologies, further improve safety.

Low-Dose Morphine Does Not Cause Sleepiness in Chronic Obstructive Pulmonary Disease: A Secondary Analysis of a Randomized Clinical Trial.

Rationale: Regular, low-dose, sustained-release morphine is frequently prescribed for persistent breathlessness in chronic obstructive pulmonary disease (COPD). However, effects on daytime sleepiness, perceived sleep quality, and daytime function have not been rigorously investigated. Objectives: We sought to determine the effects of regular, low-dose, sustained-release morphine on sleep parameters in COPD. Methods: We conducted prespecified secondary analyses of validated sleep questionnaire data from a randomized trial of daily, low-dose, sustained-release morphine versus placebo over 4 weeks commencing at 8 or 16 mg/d with blinded up-titration over 2 weeks to a maximum of 32 mg/d. Primary outcomes for these analyses were Week-1 Epworth Sleepiness Scale (ESS) and Karolinska Sleepiness Scale (KSS) scores on morphine versus placebo. Secondary outcomes included Leeds Sleep Evaluation Questionnaire scores (end of Weeks 1 and 4), KSS and ESS scores beyond Week 1, and associations between breathlessness, morphine, and questionnaire scores. Measurements and Main Results: One hundred fifty-six people were randomized. Week-1 sleepiness scores were not different on morphine versus placebo (ΔESS [95% confidence interval] versus placebo: 8-mg group, -0.59 [-1.99, 0.81], P = 0.41; 16-mg group, -0.72 [-2.33, 0.9], P = 0.38; ΔKSS vs. placebo, 8-mg group: 0.11 [-0.7, 0.9], P = 0.78; 16-mg group, -0.41 [-1.31, 0.49], P = 0.37). This neutral effect persisted at later time points. In addition, participants who reported reduced breathlessness with morphine at 4 weeks also showed improvement in LSEQ domain scores including perceived sleep quality and daytime function. Conclusions: Regular, low-dose morphine does not worsen sleepiness when used for breathlessness in COPD. Individual improvements in breathlessness with morphine may be related to improvements in sleep. Clinical trial registered with www.clinicaltrials.gov (NCT02720822).

Self-Reported Difficulty with and Assistance Needed by People with Spinal Cord Injury to Prepare Meals at Home

Individuals with spinal cord injury (SCI) experience an increased risk for obesity and cardiometabolic disease. Recommendations to prevent and treat obesity for those with SCI follow those of the US Department of Agriculture to adopt a healthy eating pattern that includes eating a variety of fruits, vegetables, grains, dairy, and protein, plus limiting added sugars, saturated fats, and sodium. Yet, people with SCI eat too many calories, fat, and carbohydrates and too few fruits, vegetables, and whole grains. The study is based on secondary analyses of SCI participants (n = 122) who enrolled in a weight loss study to determine how SCI may impact their ability to prepare food at home. We hypothesize those with higher-level spinal injuries (specifically, those with cervical versus those with thoracic or lumbar/sacral injuries) experience significantly greater difficulty and are more likely to rely on others’ assistance to perform meal preparation tasks. Physiologic (weight, BMI, blood pressure, hemoglobin A1c) and self-reported data (demographic plus responses to the Life Habits Short Survey and meal prep items) were collected at baseline and qualitative data were obtained from a subsample after the intervention during phone interviews. Participants’ average age was 50 ± 14.7 years old, they lived with SCI for an average of 13.0 ± 13.1 years, and their average BMI was 32.0 ± 6.5. Participants were predominantly white (76.1%) men (54.1%) who had some college education (76.3%), though only 28.8% worked. A substantial proportion of respondents (30% to 68%) reported difficulty across the 13 tasks related to purchasing and preparing meals, with a proxy reported as the most common assistance type used across all tasks (17% to 42%). Forty-nine percent reported difficulty preparing simple meals, with 29% reporting a proxy does the task. More than half reported difficulty using the oven and stove, though between 60% to 70% reported no difficulty using other kitchen appliances (e.g., coffee machine, food processor, can opener), the refrigerator, or microwave. There was a significant difference in kitchen function by injury level. Those living with cervical-level injuries had significantly greater limitations than those with thoracic-level injuries. Spouses, other family members, and caregivers were most likely to serve as proxies and these individuals exerted both positive and negative influences on respondents’ dietary intake, based on qualitative data obtained during interviews. The results suggest that many people living with SCI experience functional and environmental barriers that impact their ability to prepare food and use kitchen appliances. Future research should examine how SCI-related functional limitations, transportation access, accessibility of the kitchen, ability to use appliances, availability of financial resources, and assistance by others to prepare foods impact people’s ability to follow a healthy eating pattern.

Causal association between insulin sensitivity index and Alzheimer's disease.

Evidence from observational and Mendelian randomization (MR) studies suggested that insulin resistance (IR) was associated with Alzheimer's disease (AD). However, the causal effects of different indicators of IR on AD remain inconsistent. Here, we aim to assess the causal association between the insulin sensitivity index (ISI), a measure of post-prandial IR, and the risk of AD. We first conducted primary and secondary univariable MR analyses. We selected 8 independent genome-wide significant (p < 5E-08, primary analyses) and 61 suggestive (p < 1E-05, secondary analyses) ISI genetic variants from large-scale genome-wide association studies (GWAS; N = 53 657), respectively, and extracted their corresponding GWAS summary statistics from AD GWAS, including IGAP2019 (N = 63 926) and FinnGen_G6_AD_WIDE (N = 412 181). We selected five univariable MR methods and used heterogeneity, horizontal pleiotropy test, and leave-one-out sensitivity analysis to confirm the stability of MR estimates. Finally, we conducted a meta-analysis to combine MR estimates from two non-overlapping AD GWAS datasets. We further performed multivariable MR (MVMR) to assess the potential mediating role of type 2 diabetes (T2D) on the association between ISI and AD using two MVMR methods. In univariable MR, utilizing 8 genetic variants in primary analyses, we found a significant causal association of genetically increased ISI with decreased risk of AD (OR = 0.79, 95% CI: 0.68-0.92, p = 0.003). Utilizing 61 genetic variants in secondary analyses, we found consistent findings of a causal effect of genetically increased ISI on the decreased risk of AD (OR = 0.89, 95% CI: 0.82-0.96, p = 0.003). Heterogeneity, horizontal pleiotropy test, and leave-one-out sensitivity analysis ensured the reliability of the MR estimates. In MVMR, we found no causal relationship between ISI and AD after adjusting for T2D (p > 0.05). We provide genetic evidence that increased ISI is significantly and causally associated with reduced risk of AD, which is mediated by T2D. These findings may inform prevention strategies directed toward IR-associated T2D and AD.

Long-term hair cortisone and perceived stress are associated with long-term hedonic eating tendencies in patients with obesity

IntroductionLong-term biological stress, reflected in hair cortisol and cortisone levels, predicts future weight gain and metabolic deterioration. This is likely at least partially mediated by glucocorticoid-induced increases in hedonic overeating. Yet, the relationship between long-term biological stress and long-term hedonic eating tendencies remains to be elucidated. MethodsWe included N=108 adults with lifestyle-induced obesity (91 women, median body-mass-index=38.4 kg/m2) for our primary analysis investigating cross-sectional associations between long-term biological stress (hair cortisol and cortisone measured in the first 3 cm of scalp hair using liquid chromatography tandem mass spectrometry) and self-reported long-term hedonic eating tendencies (emotional and external eating, ‘Dutch Eating Behavior Questionnaire’, and trait food craving, ‘Food Craving Questionnaire-Trait’). In secondary analyses, we investigated the moderating role of long-term psychological stress (Perceived Stress Scale-14 score) on the relation between hair glucocorticoid levels and hedonic eating tendencies. ResultsHigher hair cortisone levels, but not higher hair cortisol levels, were associated with more food cravings after adjustment for sex and age (p<0.05). The association remained significant after additional adjustment for psychological stress (p<0.05). Psychological stress correlated positively with food craving and hedonic eating (p<0.05), and, in trend, with external eating (p<0.1). Stratification of stress groups (high vs. low psychological stress in addition to high vs. low biological stress) showed food cravings and emotional eating to be highest in the group with both high psychological-stress and high hair-cortisone (p<0.05), suggesting potential additive effects of different stress measures. ConclusionLong-term psychological and biological stress correlate with hedonic eating tendencies with potentially adverse additive effects on weight management and clinical features of obesity.

Pressurized Intraperitoneal Aerosol Chemotherapy for Peritoneal Carcinomatosis in Colorectal Cancer Patients: A Systematic Review of the Evidence.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) consists of the administration of aerosolized chemotherapy into the abdominal cavity of patients suffering from peritoneal carcinomatosis. Our aim was to review the evidence supporting PIPAC in patients with peritoneal carcinomatosis from colorectal cancer. A systematic review was performed in accordance with the 2020 PRISMA guideline. MEDLINE and CENTRAL were searched using combinations of terms including "Peritoneal carcinomatosis", "Peritoneal metastasis", "PIPAC", "Pressurized intraperitoneal aerosol chemotherapy" and "Colorectal cancer". Original studies, in English, including patients treated with PIPAC for colorectal peritoneal carcinomatosis, were considered eligible. Case reports, non-English or French language articles and secondary analyses were excluded. A total of 385 articles were screened and 374 articles were excluded, leaving 11 publications for inclusion in the qualitative analysis. The included studies totalized 949 patients who received PIPAC for peritoneal carcinomatosis due to colorectal cancer. The median peritoneal carcinomatosis index (PCI) ranged from 10 to 31. In all studies, the complete PIPAC protocol was achieved with an average of two to three 3 PIPAC sessions per patient. Oxaliplatin (OX) was used as a chemotherapeutic agent in all studies and could be associated with intravenous 5-FU and leucovorin. Most post-operative adverse events were recorded as mild to moderate with no intraoperative complications. Only four studies reported a decrease in the average PCI score for 50% of the patients. Median overall survival ranged from 8 to 37.8 months. Quality of life indicators were stable between PIPAC-OX cycles with a small but not statistically significant trend of improvement of most functional scales. PIPAC for peritoneal carcinomatosis from colorectal origin is feasible, safe and tolerable. Its impact on survival outcomes or quality of life remains to be demonstrated by randomized trials.

Estimands and Cumulative Incidence Function Regression in Clinical Trials: Some New Results on Interpretability and Robustness.

Regression analyses based on transformations of cumulative incidence functions are often adopted when modeling and testing for treatment effects in clinical trial settings involving competing and semi-competing risks. Common frameworks include the Fine-Gray model and models based on direct binomial regression. Using large sample theory we derive the limiting values of treatment effect estimators based on such models when the data are generated according to multiplicative intensity-based models, and show that the estimand is sensitive to several process features. The rejection rates of hypothesis tests based on cumulative incidence function regression models are also examined for null hypotheses of different types, based on which a robustness property is established. In such settings supportive secondary analyses of treatment effects are essential to ensure a full understanding of the nature of treatment effects. An application to a palliative study of individuals with breast cancer metastatic to bone is provided for illustration.

Long-term all-cause and cardiovascular-related mortality in patients with ATTR-CM treated with continuous tafamidis vs placebo to tafamidis by NAC stage at baseline

Abstract Background The National Amyloidosis Centre (NAC) staging system is used to stratify patients with transthyretin amyloid cardiomyopathy (ATTR-CM) into prognostic categories.[1] Purpose This post hoc analysis evaluated all-cause and cardiovascular (CV)-related mortality in patients receiving tafamidis 80 mg or placebo by NAC stage at baseline in the phase 3 Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and its long-term extension (LTE) study.[2,3] Methods Patients in ATTR-ACT were randomised to tafamidis meglumine 80 mg, 20 mg, or placebo for 30 months, stratified by transthyretin (TTR) genotype (wild-type or variant) and NYHA class (I or II/III). Patients with an NT-proBNP &amp;lt;600 ng/l or eGFR &amp;lt;25 ml/min/1.73m² were excluded. After completing ATTR-ACT, patients could receive tafamidis 61 mg up to 60 months in the open-label LTE study. Heart transplant and cardiac mechanical assist device implantation were treated as death in the mortality assessments. Secondary analyses were change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical and overall summary (CS, OS) scores and frequency of all-cause and CV-related hospitalisations. Results Of 350 patients, 42%, 38% and 20% had NAC stage I, II and III at baseline, respectively. Patients at stage III tended to be older, more likely female, and with a variant TTR genotype vs those at a lower stage (Table). At the end of follow-up, all-cause mortality was consistently lower in patients continuously treated with tafamidis vs those who initially received placebo across NAC stages (I: 36% vs 61%; : 55% vs 74%; III: 69% vs 88%). The hazard ratio (HR [95% CI]) for all-cause mortality with continuous tafamidis treatment vs placebo to tafamidis was 0.43 (0.26-0.70; P&amp;lt;0.001), 0.51 (0.33-0.80; P=0.003) and 0.75 (0.44-1.29; P=0.298), for patients at stage I, II and III, respectively. Similar trends were observed in CV-related mortality at the end of follow-up, where HR (95% CI) for continuous tafamidis-treated patients at stage I, II and III was 0.39 (0.22-0.70; P=0.001), 0.51 (0.31-0.85; P=0.009) and 0.75 (0.42-1.33; P=0.320). The separation of survival curves was seen in the first few months of tafamidis treatment in patients at NAC stage I (Figure A). Such early separation was not seen in those at stage II or III. Starting from Month 18, statistically smaller declines in KCCQ-OS and CS scores were frequently observed in the continuous tafamidis vs placebo to tafamidis groups at stages I and II. Across NAC stages, all-cause and CV-related hospitalisations were lower in the continuous tafamidis vs placebo to tafamidis group (Figure B). Conclusions Continuous tafamidis treatment reduced mortality and hospitalisations (both all-cause and CV-related) across all NAC stages. These reductions were larger and occurred earlier in patients with NAC stage I, emphasising the importance of early disease-modifying treatment in patients with ATTR-CM.[3] NCT01994889, NCT02791230.