Epidemiological Study in Antiviral Innate Immunity.

This chapter summarizes the epidemiological study design of natural immune epidemiology studies based on recent COVID-19-related research. The epidemiological studies on antiviral innate immunity have mainly included randomized controlled trials (RCTs) and observational studies. Importantly, this chapter will discuss how to use these methodologies to answer an epidemiological question of natural immunity in the viral infection process based on previous studies. An observational case- or cohort-based study of antiviral innate immunity may support this theoretical hypothesis but is not appropriate for clinical practice or treatment. RCTs are the gold standard for epidemiological studies and occupy a greater role in the hierarchy of evidence.

Changes in Ocular Blood Flow After Intravitreal Injection for Diabetic Macular Edema Between Aflibercept and Faricimab.

Purpose: In this study, we aimed to evaluate and compare the effects of intravitreal aflibercept (IVA) and intravitreal faricimab (IVF) injections on the blood flow of retinal vessels in the peripapillary region and optic nerve head (ONH) in eyes with diabetic macular edema (DME) using laser speckle flowgraphy (LSFG). Patients and Methods: This study included 20 eyes of 18 patients treated with IVA and 15 eyes of 11 patients treated with IVF for DME. The mean blur rate (MBR) of the ONH and retinal artery and vein of the peripapillary region were measured using LSFG at baseline and 1 month after injection. Central retinal thickness (CRT) and best-corrected visual acuity (BCVA) were measured for all patients. Results: CRT decreased significantly in both IVA-treated (p = 0.0003) and IVF-treated groups (p = 0.0004). Some of the MBR-related parameters of the ONH, such as MBR of all areas (MA), MBR of vascular areas (MV), and MBR of tissue areas (MT), decreased significantly 1 month after IVA and IVF compared to baseline values (MA of IVA, p < 0.0001; MT of IVA, p = 0.0220; MA of IVF, p = 0.0002; MT of IVF, p = 0.0461). MBR of the retinal artery (MBR-A) and vein (MBR-V) also decreased significantly 1 month after IVA and IVF compared with baseline values (MBR-A of IVA, p = 0.0002; MBR-V of IVA, p = 0.0010; MBR-A of IVF, p = 0.0368). No significant difference in ocular perfusion was observed between the IVA-treated and IVF-treated groups. Conclusion: Intravitreal injection led to a reduction in ocular blood flow in both retinal peripapillary vessels and the ONH in both IVA-treated and IVF-treated groups. No significant difference was observed in MBR reduction between the IVA-treated and IVF-treated groups. Our findings warrant further long-term investigations to reveal differences between aflibercept and faricimab.

Utilization and cost of non-insulin glucose-lowering drugs in Australia from 2013 to 2023.

OBJECTIVES: To investigate the utilization and costs of non-insulin glucose-lowering drugs (GLDs) in Australia from 2013 to 2023. MATERIALS AND METHODS: We conducted a retrospective analysis of the Australian Pharmaceutical Benefits Scheme (PBS) administrative dataset of 118 727 494 GLD prescriptions. The main outcome measures were the annual number of GLD prescriptions dispensed, accounting for type 2 diabetes mellitus (T2DM) prevalence and healthcare system costs, adjusted for inflation. RESULTS: Utilization of GLDs doubled from 6.4 million prescriptions in 2013 to 15.6 million in 2023. The average annual percent increase in utilization was 8.1%, compared to the average annual increase in prevalence of T2DM of 1.8%. The biggest change was in sodium-glucose cotransporter-2 (SGLT2) inhibitors, for which there was an average annual increase in utilization of 59.4% (95% confidence interval [CI] 51.7%, 68.2%; p < 0.05) from 2014 (first full year of PBS listing), followed by glucagon-like peptide-1 receptor agonists (GLP-1RAs), which showed an increase of 31.4% (95% CI 28.5%, 33.8%; p < 0.05) annually (2013 to 2023). Dipeptidyl peptidase-4 inhibitor utilization tripled, with an average annual increase of 10.9% (95% CI 8.1%, 13.8%; p < 0.05), but this plateaued from 2020. Metformin utilization increased by 4.7% (95% CI 2.0%, 6.9%; p < 0.05) annually. In contrast, sulphonylurea, glitazone and acarbose utilization declined. Total GLD costs increased threefold over the same period. Despite only accounting for 11.7% of utilization, GLP-1RAs contributed to 35% of the costs. CONCLUSION: Utilization of GLDs doubled, and associated costs tripled over the past 11 years, with no sign of either utilization or costs plateauing, predominantly due to increased GLP-1RA and SGLT2 inhibitor prescribing.

Strategies for Identifying and Recruiting Women at High Risk for Breast Cancer for Research Outside of Clinical Settings: Observational Study.

BACKGROUND: Research is needed to understand and address barriers to risk management for women at high (≥20% lifetime) risk for breast cancer, but recruiting this population for research studies is challenging. OBJECTIVE: This paper compares a variety of recruitment strategies used for a cross-sectional, observational study of high-risk women. METHODS: Eligible participants were assigned female at birth, aged 25-85 years, English-speaking, living in the United States, and at high risk for breast cancer as defined by the American College of Radiology. Individuals were excluded if they had a personal history of breast cancer, prior bilateral mastectomy, medical contraindications for magnetic resonance imaging, or were not up-to-date on screening mammography per American College of Radiology guidelines. Participants were recruited from August 2020 to January 2021 using the following mechanisms: targeted Facebook advertisements, Twitter posts, ResearchMatch (a web-based research recruitment database), community partner promotions, paper flyers, and community outreach events. Interested individuals were directed to a secure website with eligibility screening questions. Participants self-reported method of recruitment during the eligibility screening. For each recruitment strategy, we calculated the rate of eligible respondents and completed surveys, costs per eligible participant, and participant demographics. RESULTS: We received 1566 unique responses to the eligibility screener. Participants most often reported recruitment via Facebook advertisements (724/1566, 46%) and ResearchMatch (646/1566, 41%). Community partner promotions resulted in the highest proportion of eligible respondents (24/46, 52%), while ResearchMatch had the lowest proportion of eligible respondents (73/646, 11%). Word of mouth was the most cost-effective recruitment strategy (US $4.66 per completed survey response) and paper flyers were the least cost-effective (US $1448.13 per completed survey response). The demographic characteristics of eligible respondents varied by recruitment strategy: Twitter posts and community outreach events resulted in the highest proportion of Hispanic or Latina women (1/4, 25% and 2/6, 33%, respectively), and community partner promotions resulted in the highest proportion of non-Hispanic Black women (4/24, 17%). CONCLUSIONS: Although recruitment strategies varied in their yield of study participants, results overall support the feasibility of identifying and recruiting women at high risk for breast cancer outside of clinical settings. Researchers must balance the associated costs and participant yield of various recruitment strategies in planning future studies focused on high-risk women.

Assessment of Blood Prostaglandin E2 Metabolite Levels among Infants Born Preterm with Patent Ductus Arteriosus: A Prospective Study.

OBJECTIVE: To assess the role of prostaglandin E2 (PGE2) by measuring blood prostaglandin E2 metabolite (PGEM) concentrations in preterm infants with patent ductus arteriosus (PDA). STUDY DESIGN: A prospective observational study of preterm infants born before 32 weeks of gestational age (GA) was performed in a single tertiary hospital in Japan. Blood samples were collected to measure serum concentrations of PGEM, ibuprofen (IBU), and cytokines. Multiple regression analyses assessed associations between blood PGEM levels and perinatal factors, development of hemodynamically significant PDA (hsPDA), and IBU treatment response of hsPDA. RESULTS: Seventy-nine infants (median GA 28 weeks) were enrolled in this study. Forty-seven received IBU for hsPDA treatment 1 d after birth in median. PDA closure occurred in 25 infants after a single IBU treatment. Serum PGEM concentrations were associated with histological chorioamnionitis (p <0.01), but not with GA, respiratory distress syndrome, or serum IL-6 concentrations. Serum PGEM concentrations decreased after initial IBU treatment; however, they were not associated with hsPDA development (p = 0.39). IBU concentrations correlated with IBU treatment response (aOR 1.29, p <0.01). However, pre-IBU serum PGEM levels and PGEM reduction ratio did not (p = 0.13, 0.15, respectively). CONCLUSIONS: Serum PGEM concentrations in preterm infants were associated with maternal histological chorioamnionitis, but not hsPDA development. IBU treatment response was associated with higher blood IBU concentrations, but not PGEM concentrations.

Generating real-world evidence on diabetes technology using the CareLink Personal data management system.

AIM: To establish trust in real-world evidence (RWE) derived from CareLink Personal (CP), Medtronic's data management system for MiniMed system users, we show that this database and its analyses strictly adhere to the principles of RWE. METHODS: The methodology is applicable to all MiniMed iterations. We described every step from raw data to predefined outcomes. In addition, we showed CP's fitness-for-research by the below metrics (using last year's MiniMed 780G system data as a case study): representative population, relevant endpoints, appropriate granularity, high data completeness, high data representativity and consistency in results. RESULTS: The process from raw data to outcomes has been validated, and metrics/logics adhere to established definitions. Over 95% of users have a CP account; with 96% providing consent, this allows the use of >91% of the census population. There is no rationale for an over-representation of a specific phenotype among users not included. CP includes >50 endpoints, including 'International Consensus on Time in Range' based metrics. Data are recorded at 5-min intervals (maximum 288 per day), and on average there were 263 data points per person per day. Ninety-nine per cent of uploads were automated. For the last year, only 1 in 6 users had a data gap >1 day, and 1 in 50 had a gap >1 week. The time in range from in-silico studies was similar to that of real-world studies from different geographies and with ever growing populations. CONCLUSION: RWE from CP adheres to the principles of RWE and can serve as robust evidence on the performance and safety of MiniMed systems.

Sleep During the COVID-19 Pandemic: Longitudinal Observational Study Combining Multisensor Data With Questionnaires.

BACKGROUND: The COVID-19 pandemic prompted various containment strategies, such as work-from-home policies and reduced social contact, which significantly altered people's sleep routines. While previous studies have highlighted the negative impacts of these restrictions on sleep, they often lack a comprehensive perspective that considers other factors, such as seasonal variations and physical activity (PA), which can also influence sleep. OBJECTIVE: This study aims to longitudinally examine the detailed changes in sleep patterns among working adults during the COVID-19 pandemic using a combination of repeated questionnaires and high-resolution passive measurements from wearable sensors. We investigate the association between sleep and 5 sets of variables: (1) demographics; (2) sleep-related habits; (3) PA behaviors; and external factors, including (4) pandemic-specific constraints and (5) seasonal variations during the study period. METHODS: We recruited working adults in Finland for a 1-year study (June 2021-June 2022) conducted during the late stage of the COVID-19 pandemic. We collected multisensor data from fitness trackers worn by participants, as well as work and sleep-related measures through monthly questionnaires. Additionally, we used the Stringency Index for Finland at various points in time to estimate the degree of pandemic-related lockdown restrictions during the study period. We applied linear mixed models to examine changes in sleep patterns during this late stage of the pandemic and their association with the 5 sets of variables. RESULTS: The sleep patterns of 27,350 nights from 112 working adults were analyzed. Stricter pandemic measures were associated with an increase in total sleep time (TST) (ß=.003, 95% CI 0.001-0.005; P<.001) and a delay in midsleep (MS) (ß=.02, 95% CI 0.02-0.03; P<.001). Individuals who tend to snooze exhibited greater variability in both TST (ß=.15, 95% CI 0.05-0.27; P=.006) and MS (ß=.17, 95% CI 0.03-0.31; P=.01). Occupational differences in sleep pattern were observed, with service staff experiencing longer TST (ß=.37, 95% CI 0.14-0.61; P=.004) and lower variability in TST (ß=-.15, 95% CI -0.27 to -0.05; P<.001). Engaging in PA later in the day was associated with longer TST (ß=.03, 95% CI 0.02-0.04; P<.001) and less variability in TST (ß=-.01, 95% CI -0.02 to 0.00; P=.02). Higher intradaily variability in rest activity rhythm was associated with shorter TST (ß=-.26, 95% CI -0.29 to -0.23; P<.001), earlier MS (ß=-.29, 95% CI -0.33 to -0.26; P<.001), and reduced variability in TST (ß=-.16, 95% CI -0.23 to -0.09; P<.001). CONCLUSIONS: Our study provided a comprehensive view of the factors affecting sleep patterns during the late stage of the pandemic. As we navigate the future of work after the pandemic, understanding how work arrangements, lifestyle choices, and sleep quality interact will be crucial for optimizing well-being and performance in the workforce.

Comparison of performances between risk scores for predicting mortality at 30 days in patients with community acquired pneumonia.

BACKGROUND: Risk scores facilitate the assessment of mortality risk in patients with community-acquired pneumonia (CAP). Despite their utilities, there is a scarcity of evidence comparing the various RS simultaneously. This study aims to evaluate and compare multiple risk scores reported in the literature for predicting 30-day mortality in adult patients with CAP. METHODS: A retrospective cohort study on patients diagnosed with CAP was conducted across two hospitals in Colombia. The areas under receiver operating characteristic curves (ROC-curves) were calculated for the outcome of survival or death at 30 days using the scores obtained for each of the analyzed questionnaires. RESULTS: A total of 7454 potentially eligible patients were included, with 4350 in the final analysis, of whom 15.2% (662/4350) died within 30 days. The average age was 65.4 years (SD: 21.31), and 59.5% (2563/4350) were male. Chronic kidney disease was 3.7% (9.2% vs. 5.5%; p < 0.001) (OR: 1.85) higher in subjects who died compared to those who survived. Among the patients who died, 33.2% (220/662) presented septic shock compared to 7.3% (271/3688) of the patients who survived (p < 0.001). The best performances at 30 days were shown by the following scores: PSI, SMART-COP and CURB 65 scores with the areas under ROC-curves of 0.83 (95% CI: 0.8-0.85), 0.75 (95% CI: 0.66-0.83), and 0.73 (95% CI: 0.71-0.76), respectively. The RS with the lowest performance was SIRS with the area under ROC-curve of 0.53 (95% CI: 0.51-0.56). CONCLUSION: The PSI, SMART-COP and CURB 65, demonstrated the best diagnostic performances for predicting 30-day mortality in patients diagnosed with CAP. The burden of comorbidities and complications associated with CAP was higher in patients who died.

Association between liver fibrosis scores and short-term clinical outcomes in hospitalized chronic kidney disease patients: a prospective observational study.

Introduction: In resource-constrained countries, inadequate access to healthcare and prognostic tools can be the Achilles' heel in effectively managing chronic kidney disease (CKD). There is a significant similarity in the pathogenesis of CKD and liver fibrosis. The role of liver fibrosis (LF) scores in predicting short-term clinical outcomes in hospitalized patients with CKD is unknown. Our study aimed at calculating LF scores and studying the association of liver fibrosis with short-term mortality and morbidity in CKD patients. Methods: Patients aged above 15 years diagnosed with CKD as per the KDIGO criteria were enrolled. LF scores, namely, NFS, GPRI, and FIB-4 scores were calculated. Patients were followed up for a period of 28 days for good and poor composite outcomes, namely, the requirement of hemodialysis, non-invasive ventilation, prolonged hospital stay, and neurological and cardiovascular outcomes including death. Results: Among 163 patients, 70.5% were below 60 years of age, 82.2% were male and 35% were diabetic. At 28-day follow up, 52.1% had poor composite outcome. The AUROC for GPRI and FIB-4 in predicting poor outcomes was 0.783 (95% CI: 0.71-0.855) (p < 0.001) and 0.62 (95% CI: 0.534-0.706) (p = 0.008), respectively. The AUROC for GPRI and NFS in predicting all-cause mortality was 0.735 (95% CI: 0.627-0.843) (p = 0.001) and 0.876 (95% CI, 0.8-0.952) (p < 0.001), respectively. Conclusion: We found a positive association between LF scores and CKD outcomes in hospitalized patients. The LF scores significantly predicted poor outcomes in patients with CKD. Among the scores, GPRI was found to be a stronger predictor in predicting outcomes in both diabetic and non-diabetic patients with CKD. A high GPRI score was also associated with poor outcomes and increased mortality in both diabetics and non-diabetics.

An Emulated Target Trial Case Study of Real-World Overall Survival With Second-Line Maintenance Niraparib Versus Active Surveillance in Patients With Recurrent Ovarian Cancer.

PURPOSE: This retrospective real-world study compared overall survival (OS) between patients with BRCA wild-type (BRCAwt) recurrent epithelial ovarian cancer (OC) who received niraparib second-line maintenance (2LM) versus active surveillance (AS) using target trial emulation, cloning, inverse probability of censoring weighting (IPCW) methodology to minimize immortal time bias. METHODS: Eligible patients from a United States-based, deidentified, electronic health record-derived database were diagnosed with epithelial OC (January 1, 2011-May 31, 2021), were BRCAwt, and completed second-line (2L) therapy (January 1, 2017-March 2, 2022). Patient data were cloned at index (2L last treatment date), assigned to niraparib 2LM and AS cohorts, and censored when treatment deviated from clone assignment. Follow-up was measured from index to earliest of study end (May 31, 2022), last activity, or death. Median OS (mOS) and hazard ratios were estimated from stabilized IPCW Kaplan-Meier curves and Cox regression models. RESULTS: Overall, 199 patients received niraparib 2LM, and 707 had their care managed with AS. Key characteristics were balanced across cohorts after cloning and stabilized IPCW. Median follow-up was 15.6- and 9.3-months pre-cloning. IPCW mOS was 24.1 months (95% CI: 20.9-29.5) and 18.4 months (95% CI: 15.1-22.8) in niraparib 2LM and AS cohorts, respectively (hazard ratio, 0.77; 95% CI: 0.66-0.89). CONCLUSIONS: This real-world study provides supportive evidence of an OS benefit for patients with BRCAwt recurrent OC who received 2LM niraparib monotherapy compared with those whose care was managed with AS. The analytic strategies implemented were useful in minimizing immortal time bias and measured confounding.

Utility of the 52-Gene Risk Score to Identify Patients with Idiopathic Pulmonary Fibrosis at Greater Risk of Mortality in the Era of Antifibrotic Therapy.

PURPOSE: We investigated whether a 52-gene signature was associated with transplant-free survival and other clinically meaningful outcomes in patients with idiopathic pulmonary fibrosis (IPF) in the IPF-PRO Registry, which enrolled patients who were and were not taking antifibrotic therapy. METHODS: The 52-gene risk signature was implemented to classify patients as being at "high risk" or "low risk" of disease progression and mortality. Transplant-free survival and other outcomes were compared between patients with a low-risk versus high-risk signature. RESULTS: The 52-gene signature classified 159 patients as at low risk and 86 as at high risk; in these groups, respectively, 56.6% and 51.2% used antifibrotic therapy at enrollment. Among those taking antifibrotic therapy, patients with a low-risk versus high-risk signature were at decreased risk of death, a composite of lung transplant or death, and a composite of decline in DLco % predicted > 15%, lung transplant, or death. Similar results were observed in the overall cohort. CONCLUSIONS: These data suggest that the 52-gene signature can be used in patients with IPF treated with antifibrotic therapy to distinguish patients at higher risk of disease progression and mortality.

A Pictorial Essay of Coronary Artery Anomalies on Coronary CT Angiography: A Single-Centre Observational Study.

Background Congenital anomalies of the coronary artery anatomy (CAAs) encompass a spectrum of disorders, often asymptomatic but potentially carrying severe clinical implications such as arrhythmia, chest pain, myocardial infarction, or sudden death. The estimated prevalence of CAAs in the general population ranges from 0.3% to 1.3%, with underdiagnosis in asymptomatic individuals. Multidetector computed tomography angiography (CTA) has emerged as a vital non-invasive tool for diagnosing and characterising CAAs, offering improved visualisation and aiding in appropriate management decisions. This study aims to analyse the spectrum of CAAs in a tertiary care setting, focusing on imaging features, prevalence, and potential clinical significance, utilising data from patients who underwent multidetector CTA. Methodology A single-centre, retrospective analysis of consecutive coronary angiograms over a five-year period identified patients with CAAs, with imaging conducted using a 128-slice, single-source CT scanner. Detailed imaging evaluation was performed by experienced radiologists, with anomalies classified according to established criteria. Results Among 756 coronary CTA examinations analysed, 37 instances of anomalous coronary vessels were identified. The study revealed a diverse range of anomalies, including myocardial bridging, anomalous origin of coronary arteries, and extracardiac abnormalities. Conclusions This study contributes valuable insights into the prevalence and imaging features of CAAs, enhancing our understanding of these anomalies and guiding improved patient outcomes in cardiovascular care. Future research should focus on elucidating pathophysiological mechanisms and establishing multicenter registries to address the challenges associated with studying these infrequent but clinically significant anomalies.

Rhekiss-The German Register for Child Wish and Pregnancies in Inflammatory Rheumatic Diseases.

In pharmacoepidemiology, robust data are needed to judge the impact of drug treatment on pregnancy, pregnancy outcomes and breast-fed infants. As pregnant and breastfeeding women are usually excluded from randomised clinical trials, observational studies are required. One of those data sources are pregnancy registers specifically developed to focus on certain diseases or disease groups. The German Rhekiss register investigates pregnancies in women with chronic inflammatory rheumatic diseases (IRD). Rhekiss is a nationwide, multicentre, longitudinal study, in which women aged 18 years or older with an underlying IRD can be enrolled by a rheumatologist either when planning a pregnancy or in the first half of pregnancy. Data are collected prospectively at regular follow-up visits. Rheumatologists and patients provide information in a web-based system before conception (if enrolment was at the time of pregnancy planning), during and after pregnancy. A smartphone app is available for patients. Maternal and clinical information, general laboratory markers, treatment with antirheumatic and other drugs, adverse events, items related to course and outcome of pregnancy and the health of the child are uniformly assessed for all diseases. Individual information on the IRD includes classification criteria, diagnosis-specific laboratory parameters, clinical parameters and validated instruments to measure disease activity or damage. Furthermore, patient-reported outcome measures are captured. A total of 2013 individual patients have been enrolled in the register, and data on 1801 completed pregnancies are available. In summary, Rhekiss is a comprehensive and complex register that can answer various research questions about pregnancy in women with chronic IRDs.

Performance of a silicone foam dressing in management of wounds in a community setting: a sub-analysis of the VIPES study.

OBJECTIVE: Managing the gap between the dressing and the wound bed can facilitate the healing of exuding wounds. A silicone foam dressing (Biatain Silicone; Coloplast A/S, Denmark) was developed for application to exuding wounds. A sub-analysis of the real-world, prospective, observational VIPES (Observatoire en Ville des Plaies ExSudatives) study was conducted to investigate the use and performance of the silicone foam dressing in a community nursing setting in France. METHOD: The sub-analysis included patients from the VIPES study who received the silicone foam dressing as a primary dressing for an acute or hard-to-heal (chronic) wound. Epidemiological and wound healing outcomes were reported via a smartphone application. RESULTS: Overall, 64 patients were included in the sub-analysis. At baseline, most wounds (n=33/40; 82.5%) were in treatment failure (i.e., were stagnant, non-healing or had poor exudate management). At the last follow-up visit, a median of 22.5 (range: 3-151) days post baseline, 48.4% of wounds had healed and 25.0% were progressing towards healing. From baseline to the last follow-up visit, significant reductions in exudate level (p<0.0001) and exudate pooling (p<0.0001), and significant improvements in wound edges (p≤0.0001) and periwound skin (p<0.01) were observed. A total of 62.3% of patients had re-epithelialising wounds at the last follow-up visit. The majority of nurses (88.3%) and patients (85.0%) reported that the wound had improved and, at most dressing removals (93.5%), nurses reported that the dressing conformed closely to the wound bed. CONCLUSION: Overall, the data suggest that use of the silicone foam dressing in community practice supported the healing of wounds, illustrating the importance of exudate and gap management.

Vitamin B12 status and the risk of developing sepsis in patients with bacterial infection: a prospective observational cohort study.

BACKGROUND: Data have shown that vitamin B12 has immunomodulatory effects via different pathways, which could influence the pathophysiology of sepsis. The objective of this study was to investigate whether vitamin B12 levels, assessed by the measurement of holotranscobalamin (HTC), total vitamin B12 (B12), and methylmalonic acid (MMA, which accumulates in case of B12 deficiency), are associated with the development of sepsis in patients with onset of bacterial infection. METHODS: This was a single-center, prospective observational pilot study. Adult patients who presented to the emergency department with bacterial infection confirmed by a positive microbiological culture result were included in the study and followed up for 6 days to assess whether they developed sepsis or not. The primary objective was to compare HTC concentration in patients who developed sepsis to those who did not develop sepsis. Secondary objectives were the evaluation of B12 and MMA concentrations in those two groups. Multiple logistic regression models were used, with presence of sepsis as the outcome variable, and HTC, B12, and MMA concentrations as predictor variables, separately, and adjusted for potential confounders. RESULTS: From 2019 to 2022, 2131 patients were assessed for eligibility, of whom 100 met the inclusion criteria. One patient was excluded from the analysis due to missing data. Of the 99 patients, 29 developed sepsis. There was no evidence for an association between HTC or B12 concentration and the development of sepsis (OR 0.65, 95% CI 0.31-1.29, p = 0.232, OR 0.84, 95% CI 0.44-1.54, p = 0.584, respectively). There was an association between MMA concentration and the development of sepsis, with a positive effect, i.e. with increasing MMA, the odds for sepsis increased (OR 2.36, 95% CI 1.21-4.87, p = 0.014). This association remained significant when adjusted for confounders (OR 2.72, 95% CI 1.23-6.60, p = 0.018). CONCLUSIONS: Our study found an association between elevated MMA concentration and the development of sepsis. We did not find an association between HTC and B12 concentrations and the development of sepsis. Further, larger studies are warranted, as it could lead to interventional trials investigating whether B12 supplementation provides a clinical benefit to patients with infection or sepsis. TRIAL REGISTRATION: The study was registered on ClinicalTrials.gov under the identifier NCT04008446 on June 17, 2019.

Dark tea consumption is associated with a reduced risk of dysglycaemia and increased urinary glucose and sodium excretion in Chinese adults.

AIM: To examine the associations of tea consumption (both frequency and type) with (1) prediabetes and diabetes and (2) urinary glucose and sodium excretion in Chinese community-dwelling adults. MATERIALS AND METHODS: In 1923 participants (457 with diabetes, 720 with prediabetes, and 746 with normoglycaemia), the frequency (occasional, frequent, daily, or nil) and type (green, black, dark, or other) of tea consumption were assessed using a standardized questionnaire. Morning spot urinary glucose and urine glucose-to-creatinine ratios (UGCRs) were assessed as markers of urinary glucose excretion. Tanaka's equation was used to estimate 24-h urinary sodium excretion. Logistic and multivariate linear regression analyses were performed. RESULTS: Compared with non-tea drinkers, the corresponding multivariable-adjusted odds ratios (ORs) for prediabetes and diabetes were 0.63 (95% confidence interval [CI] 0.48, 0.83) and 0.58 (95% CI 0.41, 0.82) in participants drinking tea daily. However, only drinking dark tea was associated with reduced ORs for prediabetes (0.49, 95% CI 0.36, 0.66) and diabetes (0.41, 95% CI 0.28, 0.62). Dark tea consumption was associated with increased morning spot urinary glucose (0.22 mmol/L, 95% CI 0.11, 0.34 mmol/L), UGCR (0.15 mmol/mmol, 95% CI 0.05, 0.25 mmol/L) and estimated 24-h urinary sodium (7.78 mEq/day, 95% CI 2.27, 13.28 mEq/day). CONCLUSIONS: Regular tea consumption, especially dark tea, is associated with a reduced risk of dysglycaemia and increased urinary glucose and sodium excretion in Chinese community-dwelling adults.

Correlates of Frailty in Hospitalized Older Adults with Hypertension and Its Influence on Clinical Prognosis.

Objective: This study aims to explore the correlates of frailty in hospitalized elderly hypertensive patients and its impact on clinical prognosis, and to construct a predictive model for the occurrence of frailty in this population. Methods: A cross-sectional and prospective observational cohort study was conducted, involving 312 elderly hypertensive patients diagnosed at the institution from January to June 2022. Frailty was diagnosed using the Fried Frailty Phenotype (FP), while the Charlson Comorbidities Index (CCI) assessed the presence of chronic conditions. Data analysis was performed using SPSS 22.0. Binary logistic regression analysis was conducted with frailty as the dependent variable to identify risk factors. Patients were followed for one year to monitor readmission rates and all-cause mortality. Results: Multivariate logistic regression identified CCI grade (P=0.030), gender (OR=21.618, 95% CI: 4.062-115.061, P < 0.001), age (OR=1.147, 95% CI: 1.086-1.211, P < 0.001), bedridden state (OR=11.620, 95% CI: 3.282-41.140, P < 0.001), arrhythmia (OR=14.414, 95% CI: 4.558-45.585, P < 0.001), heart failure (OR=5.439, 95% CI: 1.029-28.740, P < 0.05), along with several biochemical markers, as independent predictors of frailty. A predictive model was developed, demonstrating a robust discriminative ability with an area under the receiver operating characteristic curve (AUC) of 0.915. Statistically significant differences in readmission rates and all-cause mortality were observed among the frail, pre-frail, and non-frail groups (P<0.001), with the frail group exhibiting the highest incidence of these adverse outcomes. Notably, frailty emerged as a significant predictor of readmission (P<0.05) but not of all-cause mortality in this cohort. Conclusion: This study establishes a robust frailty prediction model for elderly hypertensive patients, highlighting the influence of CCI grade, gender, age, and other clinical and biochemical factors on frailty. The model offers a valuable tool for healthcare providers to identify at-risk elderly individuals, facilitating targeted intervention strategies for cardiovascular disease management.

Cladribine effects on patient-reported outcomes and their clinical and biometric correlates in highly active relapsing multiple sclerosis at first switch: the observational, multicenter, prospective, phase IV CLADFIT-MS study.

Patient-reported outcomes (PROs) are essential for understanding the effects of MS and its treatments on patients' lives; they play an important role in multiple sclerosis (MS) research and practice. We present the protocol for an observational study to prospectively assess the effect of cladribine tablets on PROs and their correlation to disability and physical activity in adults with highly active relapsing MS switching from a first disease modifying drug (DMD) to cladribine tablets in routine clinical practice at study sites in Italy. The primary objective will be to evaluate changes from baseline in the impact of highly active MS on self-assessed physical functioning 52 weeks after the switch to cladribine tablets using the Multiple Sclerosis Impact Scale-29 (MSIS-29). Secondary objectives will include self-assessed psychological impact of highly active MS in daily life and general health after the switch to cladribine tablets as well as changes in cognitive function, anxiety, and depression symptoms. Additional PRO measures will include the Hospital Anxiety and Depression Scale (HADS), the EuroQoL 5-Dimension 5-Level (EQ-5D-5L), the Work Productivity and Activity Impairment Questionnaire: Multiple Sclerosis (WPAI:MS), and the Patient-Reported Outcomes Measurement Information System (PROMIS). Wearable devices will acquire activity data (step counts, walking speed, time asleep, and energy expenditure). Additional clinical, radiological, and laboratory data will be collected when available during routine management. The findings will complement data from controlled trials by providing insight from daily clinical practice into the effect of cladribine tablets on the patient's experience and self-assessed impact of treatment on daily life.

Cystic fibrosis-related diabetes develops from a combination of insulin secretion defects and insulin resistance.

AIM: The relative contributions of insulin secretory defects and possible additional contribution of insulin resistance for the development of cystic fibrosis (CF)-related diabetes (CFRD) are poorly understood. We aimed to (a) determine which indices of insulin resistance predict progression to CFRD, and (b) to model the relative contributions of insulin secretory function and insulin resistance to predict the risk of CFRD. MATERIALS AND METHODS: Three hundred and three individuals living with CF underwent a 2-h oral glucose tolerance test with blood sampling every 30 min at 12-24-month intervals until they developed CFRD or until the end of follow-up (up to 15 years). Indices of insulin resistance (e.g. Stumvoll) and insulin secretion were calculated from oral glucose tolerance test glucose and insulin measurements. CFRD-free survival was assessed by survival analysis. RESULTS: Estimated insulin resistance showed associations with glucose homeostasis and risk of progression to CFRD. The CFRD-free survival was significantly different between quartiles of insulin resistance (p < 0.0001). When patients were subdivided according to both insulin resistance and insulin secretion (insulinogenic index), CFRD-free survival was significantly lower in those with combined lowest insulin secretion and highest insulin resistance (Stumvoll) indices (hazard ratio: 11.2; p < 0.0001). There was no significant difference when the same analysis was performed for the nine other indices. CONCLUSIONS: Insulin resistance is correlated with glucose homeostasis and the risk of progression to CFRD. Patients combining low insulin secretion and high insulin resistance had the greatest odds of developing CFRD over a 15-year period.

Power Analysis of Exposure Mixture Studies via Monte Carlo Simulations.

Estimating sample size and statistical power is an essential part of a good epidemiological study design. Closed-form formulas exist for simple hypothesis tests but not for advanced statistical methods designed for exposure mixture studies. Estimating power with Monte Carlo simulations is flexible and applicable to these methods. However, it is not straightforward to code a simulation for non-experienced programmers and is often hard for a researcher to manually specify multivariate associations among exposure mixtures to set up a simulation. To simplify this process, we present the R package mpower for power analysis of observational studies of environmental exposure mixtures involving recently-developed mixtures analysis methods. The components within mpower are also versatile enough to accommodate any mixtures methods that will developed in the future. The package allows users to simulate realistic exposure data and mixed-typed covariates based on public data set such as the National Health and Nutrition Examination Survey or other existing data set from prior studies. Users can generate power curves to assess the trade-offs between sample size, effect size, and power of a design. This paper presents tutorials and examples of power analysis using mpower.