Age Strata Research Articles

Association of lncRNA MEG3 rs941576 polymorphism, expression profile, and its related targets with the risk of obesity-related colorectal cancer: potential clinical insights

The identification of novel screening tools is imperative to empower the early detection of colorectal cancer (CRC). The influence of the long non-coding RNA maternally expressed gene 3 (MEG3) rs941576 single nucleotide polymorphism on CRC susceptibility remains uninvestigated. This research appraised MEG3 rs941576 association with the risk and clinical features of CRC and obesity-related CRC and its impact on serum MEG3 expression and its targets miR-27a/insulin-like growth factor 1 (IGF1)/IGF binding protein 3 (IGFBP3) and miR-181a/sirtuin 1 (SIRT1), along with the potential of these markers in obesity-related CRC diagnosis. 130 CRC patients (60 non-obese and 70 obese) and 120 cancer-free controls (64 non-obese and 56 obese) were enrolled. MEG3 targets were selected using bioinformatics analysis. MEG3 rs941576 was associated with magnified CRC risk in overall (OR (95% CI) 4.69(1.51–14.57), P = 0.0018) and stratified age and gender groups, but not with obesity-related CRC risk or MEG3/downstream targets’ expression. Escalated miR-27a and IGFBP3 and reduced IGF1 serum levels were concomitant with MEG3 downregulation in overall CRC patients versus controls and obese versus non-obese CRC patients. Serum miR-181a and SIRT1 were upregulated in CRC patients versus controls but weren’t altered in the obese versus non-obese comparison. Serum miR-181a and miR-27a were superior in overall and obesity-related CRC diagnosis, respectively; meanwhile, IGF1 was superior in distinguishing obese from non-obese CRC patients. Only serum miR-27a was associated with obesity-related CRC risk in multivariate logistic analysis. Among overall CRC patients, MEG3 rs941576 was associated with lymph node (LN) metastasis and tumor stage, serum MEG3 was negatively correlated with tumor stage, while SIRT1 was correlated with the anatomical site. Significant correlations were recorded between MEG3 and anatomical site, SIRT1 and tumor stage, and miR-27a/IGFBP3 and LN metastasis among obese CRC patients, while IGF1 was correlated with tumor stage and LN metastasis among non-obese CRC patients. Conclusively, this study advocates MEG3 rs941576 as a novel genetic marker of CRC susceptibility and prognosis. Our findings accentuate circulating MEG3/miR-27a/IGF1/IGFBP3, especially miR-27a as valuable markers for the early detection of obesity-related CRC. This axis along with SIRT1 could benefit obesity-related CRC prognosis.

Abstract PO1-12-09: Doublet or triplet antiemetic prophylaxis for trastuzumab deruxtecan-induced nausea and vomiting: An open-label, randomized, multicenter, exploratory phase 2 study

Abstract Background: Trastuzumab deruxtecan (T-DXd) is classified as an anticancer agent that poses a moderate emetic risk according to international guidelines for antiemetic therapy, which recommend emesis prophylaxis using a two-drug combination therapy comprising 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA) and dexamethasone (DEX). The incidence rates of nausea and vomiting in patients in DESTINY BREAST01 and DESTINY BREAST03 were 77.7%, 45.7%, 72.8%, and 44%, respectively. However, no effective antiemetic therapy was observed. The high nausea and vomiting incidence associated with T-DXd is problematic. Hence, this exploratory phase 2 study aimed to assess the efficacy and safety of treatment with 5-HT3RA and DEX, with or without a neurokinin-1 receptor antagonist (NK1RA), in preventing T-DXd-induced nausea and vomiting. Methods: We conducted an open-label, randomized exploratory phase 2 study at 14 centers in Japan. Patients with breast cancer scheduled to receive T-DXd were enrolled in this study. Patients were randomly assigned to receive granisetron and dexamethasone (arm GD) or granisetron, dexamethasone, and aprepitant (fosaprepitant; arm GDA). Patients in both treatment arms were administered granisetron (1 mg i.v. 30 min before T-DXd on day 1). Those in the GD arm were administered DEX (6.6 mg i.v. 30 min before T-DXd on day 1 and 8 mg p.o. on days 2–3). The patients in the GDA arm were administered DEX (9.9 mg i.v. 30 min before T-DXd on day 1) and NK1-RA (125 mg of aprepitant p.o. 60 min before chemotherapy on day 1 and 80 mg p.o. on days 2 and 3, or 150 mg fosaprepitant i.v. 60 min before T-DXd on day 1). The primary endpoint was complete response (CR; no emesis or rescue therapy) during the overall phase (0–120 h after the start of T-DXd). The primary endpoint was estimated using the CR rate and 95% confidence intervals (CIs) following the Pearson–Clopper method. The Cochran–Mantel–Haenszel test was used to compare the exploratory results between the two treatment arms with age strata and previous experience with chemotherapy-induced nausea and vomiting. Logistic regression analyses were performed to determine the risk factors associated with the non-achievement of CR, non-achievement of complete control (CC), and non-achievement of total control (TC) in the overall and long-overall phases. Results: Between September 2020 and March 2023, 40 patients were enrolled and randomly assigned to either the GD (n = 19) or GDA (n = 21) arm. In the GDA group, one patient who did not complete the rescue medication listed in the diary was excluded from the efficacy analysis, including rescue medication use. The CR rates during the overall phase were 36.8% and 70.0% in the GD and GDA groups, respectively (odds ratio [OR], 0.1334; 95% confidence interval [CI], 0.0232–0.7672; P = 0.0190), with a difference of 33.2%. The CR rates during the long-overall phase were 31.6% in the GD arm and 70.0% in the GDA arm (OR, 0.1073; 95% CI, 0.0185–0.6239; P = 0.0087), a difference of 38.4%. NK1RA use was associated with a significant decrease in the non-achievement of CR, CC, and TC in the overall and long-overall phases. Only patients in the GDA arm (33.3%) reported being “very satisfied” with the treatment. No grade 3 or 4 toxicities related to antiemetic therapy were observed. Conclusions: Breast cancer patients receiving T-DXd require triple therapy, including mandatory NK1RA administration, for antiemetic prophylaxis. Further investigation is needed to explore the development of more appropriate combination therapies for T-DXd-induced nausea and vomiting. Citation Format: Manabu Futamura, Hirotoshi Iihara, Hiroko Bando, Yoshihiro Kawaguchi, Yutaka Mizuno, Akari Murakami, Masaaki Kawai, Tomokazu Iyoda, Kazshige Ishida, Kazuhiro Ishihara, Takumi Nakada, Makoto Takeuchi, Mika Kitahora, Yoshihisa Tokumaru, Mototsugu Shimokawa, Nobuhisa Matsuhashi. Doublet or triplet antiemetic prophylaxis for trastuzumab deruxtecan-induced nausea and vomiting: An open-label, randomized, multicenter, exploratory phase 2 study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-12-09.

Educational status and the risk of adverse outcomes in Asian patients with atrial fibrillation: a report from the prospective APHRS-AF Registry.

The aim of this study was to evaluate the impact of educational status (ES) on the clinical course of Asian patients with atrial fibrillation (AF). We used data from the prospective APHRS-AF Registry. ES was classified as follows: low (primary school), medium (secondary), and high (University). The primary outcome was a composite of all-cause death, thromboembolic events, acute coronary syndrome, and heart failure. Secondary outcomes were each component of the primary outcome, cardiovascular death, and major bleeding. The one-year risk of primary and secondary outcomes was assessed through Cox-regressions. Adherence to the Atrial fibrillation Better Care (ABC) pathway was assessed. Among 2697 AF patients (69±12 years, 34.8% females), 34.6% had low ES; 37.3% had medium ES; and 28.1% had high ES. Compared to patients with medium-high ES, patients with low ES were older, more often females, with a higher prevalence of cardiovascular risk factors, and a lower ABC pathway adherence (30.4% vs. 40.2%, P<0.001). On multivariable analysis, low ES was associated with a higher risk for the primary outcome (HR 1.52,95%CI 1.11-2.06) and all-cause death (HR 1.76,95%CI 1.10-2.83) than medium-high ES. A significant interaction was found for the risk of composite outcome among the different age strata, with the higher risk in the elderly (P for int=0.008), whereas the beneficial effect of the ABC pathway was irrespective of ES (P for int=0.691). In Asian AF patients, low ES is associated with high mortality. Efforts to improve education and include ES evaluation in the integrated care approach for AF are necessary to reduce the cardiovascular burden in these patients.

Food insecurity in high-risk rural communities before and during the COVID-19 pandemic

ObjectiveTo perform a geospatial analysis of food insecurity in a rural county known to have poor health outcomes and assess the effect of the COVID-19 pandemic. MethodsIn 2020, we mailed a comprehensive cross-sectional survey to all households in Sullivan County, a rural county with the second-worst health outcomes among all counties in New York State. Surveys of households included validated food insecurity screening questions. Questions were asked in reference to 2019, prior to the pandemic, and for 2020, in the first year of the pandemic. Respondents also responded to demographic questions. Raking adjustments were performed using age, sex, race/ethnicity, and health insurance strata to mitigate non-response bias. To identify significant hotspots of food insecurity within the county, we also performed geospatial analysis. FindingsFrom the 28,284 households surveyed, 20% of households responded. Of 4725 survey respondents, 26% of households reported experiencing food insecurity in 2019, and in 2020, this proportion increased to 35%. In 2020, 58% of Black and Hispanic households reported experiencing food insecurity. Food insecurity in 2020 was also present in 58% of unmarried households with children and in 64% of households insured by Medicaid. The geospatial analyses revealed that hotspots of food insecurity were primarily located in or near more urban areas of the rural county. ConclusionsOur countywide health survey in a high-risk rural county identified significant increases of food insecurity in the first year of the COVID-19 pandemic, despite national statistics reporting a stable rate. Responses to future crises should include targeted interventions to bolster food security among vulnerable rural populations.

Compounding Effects of Aging and Sex on Cerebrovascular Endothelial Mitochondria

Despite the increasing burden of age-related neurological diseases such as vascular cognitive impairment and dementia or Alzheimer’s disease, the underlying mechanisms of these pathologies are not clear. Nonetheless, structural and functional changes in the microvasculature represent probable pathological aspects of these age-associated diseases. The silent and cumulative changes in endothelial mitochondria with subsequently compromised cerebral vascular function are thought to play a central role in neurological disease development. We tested the hypothesis that mitochondrial morphological changes in endothelial cells facilitate the distinct aging- and sex-related differences in the cerebral microvascular proteome and energetics. Mito-dendra2 (mt-D2) labeled endothelial mitochondria were imaged in vivo via a cranial window using two-photon microscopy at 875 nm in young and old, male and female, mito-Dendra2 mice (YM, YF, OM, and OF, respectively). Mt-D2 associated signal was analyzed in 3D stacks using the Huygens Pro CE 23.04.0p3 object analyzer (160 images, originated from 4-5 mt-D2 mice/groups). We also measured mRNA copy numbers of mitochondrial fission and fusion genes in isolated, cortical microvessels (&lt;70 μm) from YM, YF, OM, and OF C57Bl/6J mice (n=7-11/age/sex) using ddPCR. Kruskal-Wallis test with Dwass-Steel-Critchlow-Fligner post-hoc comparisons were used to compare mt-D2 signal among YM, YF, OM, and OF, whereas Mann-Whitney U test determined changes across age and sex strata. p&lt;0.05 was considered statistically significant. mRNA copy numbers were normalized to housekeeping genes (GAPDH, β-actin, and HPRT-1) and compared with one-way ANOVA based on data distribution. Analysis of four object parameters revealed that object surface was smaller in old vs. young that was significant in YM vs. OM. We found significantly greater corrected lateral width in OM vs. YM, OF vs. YF, and in YF vs. YM. The lateral aspect ratio was significantly greater in YM vs. OM, in YF vs. OF, as well as in YM vs. YF. Accordingly, the axial sphericity of the principal box was significantly greater in OM vs. YM, in OF vs. YF, and in YF vs. YM. Normalized mRNA copy numbers of mitochondrial fission and fusion genes were not statistically different in our samples for DRP-1, Fis-1 or Mfn-1/2, Opa-1, respectively. These results suggest that aging driven morphological differences, such as the shortening of endothelial mt-D2 signal are, at least in part, facilitated by altered fission/fusion protein abundances and/or activity rather than transcriptional changes in our samples. Although we are still analyzing other morphological parameters, by assessing the effect sizes and their physiological relevance, we postulate that these morphological differences contribute to the vulnerability of the aged cerebral microvasculature to injury. AG083567, 3P30GM145498-01, U54GM104940, HL148836. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

COST-EFFECTIVENESS OF SINGLE-PILL AND SEPARATE-PILL ADMINISTRATION OF ANTIHYPERTENSIVE TRIPLE-COMBINATION THERAPY: A POPULATION-BASED MICROSIMULATION STUDY

Objective: To evaluate the lifetime cost-effectiveness profile of the perindopril/amlodipine/indapamide single-pill combination (SPC) compared with the combination of an angiotensin-converting enzyme inhibitor, a calcium-channel blocker, and a diuretic as a SPC of two drugs plus the third drug separately from the Italian payer perspective. Design and method: A cost-effectiveness analysis was conducted employing multi-state semi-Markov modeling and microsimulation. Using the healthcare utilization database of the Lombardy Region (Italy), 30,172 and 65,817 patients aged &gt;=40 years who initiated SPC and two-pill combination, respectively, between 2015 and 2018 were identified. The observation period extended from the date of the first drug prescription until death, emigration, or December 31, 2019. Disease and cost models were parametrized using the study cohort, and a lifetime microsimulation was applied to project costs and life expectancy for the compared strategies Probabilistic sensitivity analysis with 1,000 samples was performed to address parameter uncertainty. Results: Compared with the two-pill combination, the SPC increased life expectancy by 0.86 years (95% confidence interval [CI] 0.61–1.14), with a reduction in total cost of –€12 (95% CI –9,719 to 8,131), making it the dominant strategy (ICER of –14, 95% CI –€15,871 to €7,113). The cost reduction associated with the SPC was primarily driven by savings in hospitalization costs, amounting to €1,850 (95% CI 17 to 7,813) and €2,027 (95% CI 19 to 8,603) for patients treated with the SPC and two-pill combination, respectively. Conversely, drug costs were higher for the SPC (€3,848, 95% CI 574 to 10,640 vs. €3,710, 95% CI 263 to 11,955). This was the case for all strata of age, sex, and clinical status. Conclusions: The SPC was projected to increase survival and reduce costs compared with the two-pill combination. This is likely explained by an improvement in drug compliance. As three-drug SPC is currently prescribed to only a few patients, the widespread use of this strategy could result in benefits for both patients and the healthcare system.

Safety, Tolerability, and Immunogenicity of aH5N1 Vaccine in Adults with and without Underlying Medical Conditions.

Influenza pandemics pose a serious risk to the global population, with the potential for high morbidity and mortality. An adjuvanted H5N1 vaccine (aH5N1) has been approved for prophylaxis against the avian influenza virus H5N1, which is a likely cause of future pandemics. In this phase-III, stratified, randomized, controlled, observer-blind, multicenter study, we evaluated the safety and immunogenicity of aH5N1 in four separate groups of adults: adults 18-60 years of age who were healthy or had high-risk medical conditions and older adults ≥61 years of age who were healthy or had high-risk medical conditions. Subjects were randomly assigned to aH5N1 or the comparator, adjuvanted trivalent seasonal influenza vaccine (aTIV). Antibody responses to aH5N1 were increased in all four subgroups and, within each age stratum, largely consistent between healthy subjects and those with medical conditions. Injection-site pain was reported by 66-73% of younger and 36-42% of older-aH5N1 recipients, and fatigue and myalgia were reported by 22-41% of subjects across age and health subgroups. No serious adverse events or deaths were considered related to the study vaccine. In conclusion, aH5N1 increased antibody responses regardless of age or health status and demonstrated a clinically acceptable safety and tolerability profile.

Feeding characteristics and growth among children with prenatal exposure to Zika virus with and without microcephaly in the microcephaly epidemic research group pediatric cohort

ObjectiveTo describe the feeding characteristics and growth of children with prenatal exposure to Zika virus (ZIKV) from birth to 48 months.DesignUsing data from the prospective Microcephaly Epidemic Research Group Pediatric Cohort (MERG-PC), children without microcephaly born to mothers with evidence of ZIKV infection during pregnancy (ZIKV-exposed children without microcephaly) and children with Zika-related microcephaly were compared using repeated cross-sectional analyses within the following age strata: birth; 1 to 12; 13 to 24; 25 to 36; and 37 to 48 months. The groups were compared in relation to prematurity, birth weight, breastfeeding, alternative feeding routes, dysphagia and anthropometric profiles based on the World Health Organization Anthro z-scores (weight-length/height, weight-age, length/height-age and BMI-age).ResultsThe first assessment included 248 children, 77 (31.05%) with microcephaly and 171 (68.95%) without microcephaly. The final assessment was performed on 86 children. Prematurity was 2.35 times higher and low birth weight was 3.49 times higher in children with microcephaly. The frequency of breastfeeding was high (> 80%) in both groups. On discharge from the maternity hospital, the frequency of children requiring alternative feeding route in both groups was less than 5%. After 12 months of age, children with microcephaly required alternative feeding route more often than children without microcephaly. In children with microcephaly, the z-score of all growth indicators was lower than in children without microcephaly.ConclusionsChildren with Zika-related microcephaly were more frequently premature and low birth weight and remained with nutritional parameters, i.e., weight-for-age, weight-for-length/height and length/height-for-age below those of the children without microcephaly.

Dog Consumption at Tell Zirāʿa: Is It a “Cultural Marker” for the “Sea Peoples”?

It has been argued that the increase in the consumption of dogs in the southern Levant during the Iron Age was due to the advent of the Philistines/“Sea Peoples” into the region. In this study, we test this proposal through the presentation of new information on dog consumption and its depositional context in Bronze and Iron Age strata from the archaeological site of Tell Zirāʿa (Jordan), and we compare the results to other sites in the region. Our study does not support that such behaviour is a signal of ethnic identity.

Causal association of genetically determined caffeine intake from tea or coffee with bone health: a two-sample Mendelian randomization study.

Relationship of caffeine intake and consumption of caffeinated beverages, such as tea and coffee, with bone health remains controversial. This study aimed to evaluate whether genetically determined caffeine intake from tea or coffee has causal effects on overall total body bone mineral density (TB-BMD) and fracture. We also assessed the association with TB-BMD in five age strata. Using two-sample Mendelian randomization approach, summary statistics were retrieved from genome-wide association studies (GWAS)/GWAS meta-analyses of caffeine intake from tea (n = 395 866)/coffee (n = 373 522), TB-BMD (n = 66 628), and fracture (n = 426 795). Inverse variance weighted method was adopted as the main univariable analysis. Multivariable analysis was conducted to evaluate whether the causal effect is independent. In univariable analysis, genetically determined caffeine intake from tea had positive association with overall TB-BMD (per SD increase in genetically determined caffeine intake, beta of TB-BMD [in SD]: 0.166; 95% confidence interval (CI): 0.006-0.326) and inverse association with fracture (OR = 0.79; 95% CI: 0.654-0.954). Genetically determined caffeine intake from coffee was also positively associated with overall TB-BMD (beta = 0.231; 95% CI: 0.093-0.369). The association remained significant after adjustment for smoking in multivariable analysis. Genetically determined caffeine intake from tea or coffee was both positively associated with TB-BMD in the age strata of 45-60years, but we lacked evidence of association in other strata. Genetically, caffeine intake from tea or coffee may be beneficial to bone health. Due to the ascertainment method of caffeine intake from tea, our study also implied genetically higher tea consumption may improve TB-BMD and lower fracture risk.

Геологическое строение четвертичных отложений в долине нижней Печоры

The geological structure of Neopleistocene deposits was specified along a 19-kilometer section of the right bank of the lower Pechora between the villages of Garevo and Sergeevo-Shchelya. The presence of three glacial and two interglacial horizons was revealed in coastal outcrops, and the material composition of the composing sediments was studied. The formation of the most ancient moraine horizon was associated with Fennoscandinavia and occurred in the early Quaternary Pomusov (Oka) time. The Pomusov moraine was overlain by Chirva (Likhvin) interglacial alluvial and lacustrine sediments. In the Middle Neopleistocene glacial complex, two morainic strata of different ages were distinguished: Pechora (Dnieper) and Vychegda (Moscovian), separated by a pack of predominantly coastal-marine littoral sediments, and alluvial and lacustrine sediments, the age of which was determined as Rodionov (Shklov) by the palynological method. Differences in the lithological composition of moraines confirmed a double glaciation of the European North-East of Russia in the Middle Neopleistocene.

Association Between Life's Essential 8 Cardiovascular Health Metrics With Cardiovascular Events in the Cardiovascular Disease Lifetime Risk Pooling Project.

The American Heart Association recently launched updated cardiovascular health metrics, termed Life's Essential 8 (LE8). Compared with Life's Simple 7 (LS7), the new approach added sleep health as an eighth metric and updated the remaining 7 health factors and behaviors. The association of the updated LE8 score with long-term cardiovascular disease (CVD) outcomes and death is unknown. We pooled individual-level data from 6 contemporary US-based cohorts from the Cardiovascular Lifetime Risk Pooling Project. Total LE8 score (0-100 points), LE8 score without sleep (0-100 points), and prior LS7 scores (0-14 points) were calculated separately. We used multivariable-adjusted Cox models to evaluate the association of LE8 with CVD, CVD subtypes, and all-cause mortality among younger, middle, and older adult participants. Net reclassification improvement analysis was used to measure the improvement in CVD risk classification with the addition of LS7 and LE8 recategorization based on score quartile rankings. Our sample consisted of 32 896 US adults (7836 [23.8%] Black; 14 941 [45.4%] men) followed for 642 000 person-years, of whom 9391 developed CVD events. Each 10-point higher overall LE8 score was associated with lower risk by 22% to 40% for CVD, 24% to 43% for congenital heart disease, 17% to 34% for stroke, 23% to 38% for heart failure, and 17% to 21% for all causes of mortality events across age strata. LE8 score provided more granular differentiation of the related CVD risk than LS7. Overall, 19.5% and 15.5% of the study participants were recategorized upward and downward based on LE8 versus LS7 categories, respectively, and the recategorization was significantly associated with CVD risk in addition to LS7 score. The addition of recategorization between LE8 and LS7 categories improved CVD risk reclassification across age groups (clinical net reclassification improvement, 0.06-0.12; P<0.01). These findings support the improved utility of the LE8 algorithm for assessing overall cardiovascular health and future CVD risk.

Use of a novel bluetooth-connected device to measure handgrip strength: A practical tool to help healthcare professionals identify adults at nutritional risk

Background and AimsLow muscle strength is strongly tied to poor nutrition status, and nutritional interventions are likewise linked to maintenance and restoration of muscle strength and functional status. Nutrition plays a vital role in muscle mass, strength, and function, and losses in muscle (strength, function, and mass) are associated with poor health outcomes and added costs for healthcare services. For this study of outpatients, the main objective was to identify those at risk for low muscle strength, as evidenced by low handgrip strength (HGS) measures with risk stratified by age and sex. MethodsThis was a two-part study on HGS measures in adults attending outpatient clinics in India. In part one, we conducted HGS tests on dominant and non-dominant hands of patients who qualified for the study. For HGS measures, we used a validated tool, the SQUEGG device, a smart handgrip trainer, along with its companion Bluetooth-connected app, the Muscle Strength Assessment Tool (MSAT) app. In part two, we collected Healthcare Practitioners’ (HCP) feedback via a short digital survey on the use of the SQUEGG device + the MSAT app to do HGS risk screening as an indicator of needed nutritional intervention. ResultsNearly a third of community-living adults in India exhibited low HGS among the 3036 sampled. At each age stratum, dominant-hand HGS in women was lower by 25% to 35% compared to men. Among 353 HCPs, 293 (83%) provided insights via survey, and 85% of surveyed HCPs (n=249) strongly agreed or agreed that the SQUEGG device + MSAT app helped them identify HGS issues among their patients, and 85% (n=248) agreed or strongly agreed they would like to continue using the SQUEGG device + MSAT app to inform their practice. Nearly all surveyed HCPs (98%, n=288) recommended an oral nutritional supplement (ONS) to their patients with identified low HGS. ConclusionsOur findings demonstrate that HCPs would like to continue use of the SQUEGG device + MSAT app as it helped them identify adult patients who had decreased HGS (about 30% of the study population), in turn identifying opportunities to use nutritional interventions such as ONS to address nutrition shortfalls and to restore functional status.

Safety and immunogenicity of the Euvichol-S oral cholera vaccine for prevention of Vibrio cholerae O1 infection in Nepal: an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial

In October, 2017, WHO launched a strategy to eliminate cholera by 2030. A primary challenge in meeting this goal is the limited global supply capacity of oral cholera vaccine and the worsening of cholera outbreaks since 2021. To help address the current shortage of oral cholera vaccine, a WHO prequalified oral cholera vaccine, Euvichol-Plus was reformulated by reducing the number of components and inactivation methods. We aimed to evaluate the immunogenicity and safety of Euvichol-S (EuBiologics, Seoul, South Korea) compared with an active control vaccine, Shanchol (Sanofi Healthcare India, Telangana, India) in participants of various ages in Nepal. We did an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial at four hospitals in Nepal. Eligible participants were healthy individuals aged 1-40 years without a history of cholera vaccination. Individuals with a history of hypersensitivity reactions to other preventive vaccines, severe chronic disease, previous cholera vaccination, receipt of blood or blood-derived products in the past 3 months or other vaccine within 4 weeks before enrolment, and pregnant or lactating women were excluded. Participants were randomly assigned (1:1:1:1) by block randomisation (block sizes of two, four, six, or eight) to one of four groups (groups A-D); groups C and D were stratified by age (1-5, 6-17, and 18-40 years). Participants in groups A-C were assigned to receive two 1·5 mL doses of Euvichol-S (three different lots) and participants in group D were assigned to receive the active control vaccine, Shanchol. All participants and site staff (with the exception of those who prepared and administered the study vaccines) were masked to group assignment. The primary immunogenicity endpoint was non-inferiority of immunogenicity of Euvichol-S (group C) versus Shanchol (group D) at 2 weeks after the second vaccine dose, measured by the seroconversion rate, defined as the proportion of participants who had achieved seroconversion (defined as ≥four-fold increase in V cholerae O1 Inaba and Ogawa titres compared with baseline). The primary immunogenicity endpoint was assessed in the per-protocol analysis set, which included all participants who received all their planned vaccine administrations, had no important protocol deviations, and who provided blood samples for all immunogenicity assessments. The primary safety endpoint was the number of solicited adverse events, unsolicited adverse events, and serious adverse events after each vaccine dose in all ages and each age stratum, assessed in all participants who received at least one dose of the Euvichol-S or Shanchol. Non-inferiority of Euvichol-S compared with Shanchol was shown if the lower limit of the 95% CI for the difference between the seroconversion rates in Euvichol-S group C versus Shanchol group D was above the predefined non-inferiority margin of -10%. The trial was registered at ClinicalTrials.gov, NCT04760236. Between Oct 6, 2021, and Jan 19, 2022, 2529 healthy participants (1261 [49·9%] males; 1268 [50·1%] females), were randomly assigned to group A (n=330; Euvichol-S lot number ES-2002), group B (n=331; Euvichol-S ES-2003), group C (n=934; Euvichol-S ES-2004]), or group D (n=934; Shanchol). Non-inferiority of Euvichol-S versus Shanchol in seroconversion rate for both serotypes at 2 weeks after the second dose was confirmed in all ages (difference in seroconversion rate for V cholerae O1 Inaba -0·00 [95% CI -1·86 to 1·86]; for V cholerae O1 Ogawa -1·62 [-4·80 to 1·56]). Treatment-emergent adverse events were reported in 244 (9·7%) of 2529 participants in the safety analysis set, with a total of 403 events; 247 events were reported among 151 (9·5%) of 1595 Euvichol-S recipients and 156 events among 93 (10·0%) of 934 Shanchol recipients. Pyrexia was the most common adverse event in both groups (57 events among 56 [3·5%] of 1595 Euvichol-S recipients and 37 events among 35 [3·7%] of 934 Shanchol recipients). No serious adverse events were deemed to be vaccine-related. A two-dose regimen of Euvichol-S vaccine was non-inferior to the active control vaccine, Shanchol, in terms of seroconversion rates 2 weeks after the second dose. The simplified formulation and production requirements of the Euvichol-S vaccine have the potential to increase the supply of oral cholera vaccine and reduce the gap between the current oral cholera vaccine supply and demand. The Bill & Melinda Gates Foundation. For the Nepali translation of the abstract see Supplementary Materials section.

Influence of age and sex on longitudinal metabolic profiles and body weight trajectories in the UK Biobank.

Accurate characterization of how age influences body weight and metabolism at different stages of life is important for understanding ageing processes. Here, we explore observational longitudinal associations between metabolic health and weight from the fifth to the seventh decade of life, using carefully adjusted statistical designs. Body measures and biochemical data from blood and urine (220 measures) across two visits were available from 10 104 UK Biobank participants. Participants were divided into stable (within ±4% per decade), weight loss and weight gain categories. Final subgroups were metabolically matched at baseline (48% women, follow-up 4.3 years, ages 41-70; n = 3368 per subgroup) and further stratified by the median age of 59.3 years and sex. Pulse pressure, haemoglobin A1c and cystatin-C tracked ageing consistently (P < 0.0001). In women under 59, age-associated increases in citrate, pyruvate, alkaline phosphatase and calcium were observed along with adverse changes across lipoprotein measures, fatty acid species and liver enzymes (P < 0.0001). Principal component analysis revealed a qualitative sex difference in the temporal relationship between body weight and metabolism: weight loss was not associated with systemic metabolic improvement in women, whereas both age strata converged consistently towards beneficial (weight loss) or adverse (weight gain) phenotypes in men. We report longitudinal ageing trends for 220 metabolic measures in absolute concentrations, many of which have not been described for older individuals before. Our results also revealed a fundamental dynamic sex divergence that we speculate is caused by menopause-driven metabolic deterioration in women.

Incidence of Influenza-related Medical Encounters and the Associated Healthcare Resource Use and Complications Across Adult Age Groups in the United States During the 2015-2020 Influenza Seasons.

Research on influenza burden in adults has focused on crude subgroups with cut-points at 65 years, limiting insight into how burden varies with increasing age. This study describes the incidence of influenza-related outpatient visits, emergency room visits, and hospitalizations, along with healthcare resource use and complications in the aging adult population. Individuals aged ≥18 years in the United States were evaluated retrospectively in 5 seasonal cohorts (2015-2020 seasons) in strata of age with 5-year increments. Person-level electronic medical records linked to pharmacy and medical claims were used to ascertain patient characteristics and outcomes. Influenza-related medical encounters were identified based on diagnostic codes (International Classification of Diseases, 10th Edition, codes J09*-J11*). Incidence of influenza-related outpatient visits was highest among people aged 18-34 years and declined with increasing age. For emergency room visits, incidence tended to be elevated for people aged 18-34 years, relatively stable from 35 through 60, and increased rapidly after age 60 years. Hospitalization incidence remained relatively stable until about 50 years of age and then increased with age. One in 3 patients was diagnosed with pneumonia after hospitalization, regardless of age. Across seasons, age groups, and clinical settings, on average, 40.8% of individuals were prescribed antivirals and 17.2% antibiotics. Incidence of influenza-related hospitalizations begins to increase around age 50 years rather than the more common cut-point of 65, whereas incidence of outpatient visits was highest among younger adults. Influenza infections frequently led to antiviral and antibiotic prescriptions, underscoring the role influenza vaccination can play in combating antimicrobial resistance.

Evaluation of Myo-Intimal Media Thickness and Atheromatous Plaques in People Living with HIV from the Archiprevaleat Cohort vs. HIV-Negative Subjects.

Antiretroviral therapy has allowed a clear improvement in prognosis for HIV patients, but metabolic problems, such as dyslipidemia, remain. This can lead to the development of atheromatous plaques. Our study aims to evaluate whether HIV-positive (HIV+) patients show higher myo-intimal media thickness (IMT) and atheromatous plaques compared to HIV-negative (HIV-) patients. To evaluate the association between HIV infection in experienced patients and vascular pathology, we performed a cross-sectional study, observing 1006 patients, 380 HIV+ enrolled in the Archiprevaleat cohort, and 626 HIV- as a control group. All patients underwent a Doppler scan of the supra-aortic vessels. We compared the prevalence of IMT > 1.0 mm and plaques in the two groups. Patients in the HIV+ group were younger than those in the HIV- group, with a lower prevalence of hypertension and diabetes and higher dyslipidemia. The prevalence of plaques in strata of age was higher in the HIV+ group than in the HIV- group and was associated with the length of ART exposure. Our cross-sectional, retrospective study shows that HIV+ experienced patients are at greater risk of IMT and atheromatous plaques compared to HIV-. The risk is associated with being HIV+ and with the length of ART exposure. This finding may be useful in preventing cardiovascular risk.

Switching to Dolutegravir/Lamivudine Two-Drug Regimen: Durability and Virologic Outcomes by Age, Sex, and Race in Routine US Clinical Care.

Two-drug regimens (2DR) may address drug-drug interactions and toxicity concerns. Dolutegravir/lamivudine (DTG/3TC) 2DR was approved in the US for both treatment-naïve and treatment-experienced individuals with a viral load <50 copies/mL. This study describes real-world DTG/3TC 2DR treatment outcomes among treatment-experienced individuals, stratified by age, sex, and race. From the OPERA® cohort, people with HIV with a viral load <50 copies/mL who switched from a commonly used three-drug regimen to DTG/3TC 2DR as per the label between April 8, 2019 and April 30, 2021 were included. Incidence rates (Poisson regression) for loss of virologic control (first viral load ≥50 copies/mL), confirmed virologic failure (2 viral loads ≥200 copies/mL or discontinuation after 1 viral load ≥200 copies/mL), and DTG/3TC 2DR discontinuation were estimated overall and stratified by age, sex, and race. The 787 individuals included were followed for a median of 13.6 months (IQR: 8.2, 22.3). Confirmed virologic failure occurred in ≤5 individuals. Loss of virologic control occurred at a rate of 14.0 per 100 person-years (95% CI: 11.7, 16.8). DTG/3TC 2DR discontinuation occurred at a rate of 17.5 per 100 person-years (95% CI: 15.0, 20.3); 4% discontinued for treatment-related reasons (viremia, adverse diagnosis, side effect, lab abnormality). For all outcomes, incidence rates were comparable across strata of age, sex, and race. This descriptive study demonstrates that DTG/3TC 2DR is an effective and well-tolerated treatment option for people with HIV with a viral load <50 copies/mL at switch, regardless of their age, sex, or race.

Efficacy and safety of a new low-volume PEG with citrate and simethicone bowel preparation for pediatric elective colonoscopy: Phase 3 RCT.

Background and study aims Currently available polyethylene glycol (PEG)-based preparations continue to represent a challenge in children. The aim of this study was to compare the efficacy and safety of a new low-volume PEG preparation with a conventional PEG-electrolyte solution (PEG-ES) in children and adolescents. Patients and methods This was a multicenter, randomized, observer-blind, parallel-group, phase 3 clinical trial, where patients were randomized between PMF104 (Clensia) and a conventional PEG-ES (Klean-Prep), and stratified by age stratum (2 to <6; 6 to < 12;12 to <18 years). The primary endpoint was to test the non-inferiority of PMF104 versus PEG-ES, in terms of colon cleansing. Safety, tolerability, acceptability, palatability, and compliance were also assessed. Efficacy endpoints were analyzed in the per protocol set (PPS) and full analysis set (FAS) and safety and tolerability endpoints in the safety set (SAF). Results Of the 356 patients enrolled, 258 were included in the PPS, 346 in the FAS, and 351 in the SAF. Non-inferiority of PMF104 was confirmed for children aged > 6 years and for all age groups in PPS and FAS, respectively. Optimal compliance was reported more frequently in the PMF104 than in the PEG-ES group, in both PPS (86.1% vs. 68.4%) and FAS (82.9% vs. 65.3%). Both preparations were equally safe and tolerable. Palatability and acceptability were considered better in the PMF104 group than in the PEG-ES group (27.1% vs. 15.3% and 15.3% vs. 3.5%, respectively). Conclusions In children aged 6 to 17 years, the new low-volume product PMF104 is non-inferior to the reference PEG-ES in terms of bowel cleansing, safety, and tolerability, with slightly better results in compliance, palatability, and acceptability.

Cross-sectional analysis of plasma n-3 fatty acid levels and self-reported hearing difficulty in the UK Biobank Cohort

BackgroundDisabling hearing loss affects ∼430 million people globally. Fish consumption and long-chain n-3 polyunsaturated fatty acid (PUFA) intake were inversely associated with risk of hearing loss, but the association of plasma n-3 PUFAs and hearing loss is unclear. ObjectiveTo examine the associations between plasma n-3 PUFA fractions (as % of total fatty acids), i.e., DHA% and Other n-3 PUFA% (defined as total n-3 PUFA minus DHA), with self-reported hearing difficulty in a population-based cohort in the UK. MethodsOur study includes 175,177 UK Biobank participants (40-69y, 54% women) with data on plasma n-3 PUFA and hearing status. Baseline plasma PUFA levels were analyzed by nuclear magnetic resonance, and self-reported hearing difficulty was obtained by questionnaire between 2007 and 2010. Logistic regression was used to estimate age-adjusted odds ratios (ORs), multivariable-adjusted odds ratios (MVORs) by adjusting for 14 demographic, behavioral, biomarker and health-related potential confounders, and 95% confidence intervals (CIs). ResultsHearing difficulty was reported by 26.7% of participants. Higher plasma n-3 PUFA levels were independently associated with lower odds of self-reported hearing difficulty. The prevalence of hearing difficulty rose across age strata (40-49y, 15.8%; 50-59y, 24.9% and 60+y, 34.4%; p<0.0001) and overall was higher in males (33.2%) than females (21.3%). Compared with those in the lowest quintile of plasma DHA% or Other n-3 PUFA%, the MVOR (95% CI) for hearing difficulty was 0.88 (0.85, 0.92) in highest quintile of plasma DHA%, and 0.91 (0.87, 0.94) in the highest quintile of Other n-3 PUFA%. The associations with DHA% did not differ by age or sex (p-for-interaction 0.83and 0.58, respectively). MVORs for DHA% and Other n-3 PUFA% were similar among the 44,486 individuals with data on noise exposure at work. ConclusionsHigher plasma n-3 PUFA levels were independently associated with lower odds of hearing difficulty.