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Journal of Clinical Epidemiology Jun 2024Frailty is a dynamic health state that changes over time. Our hypothesis was that there are identifiable subgroups of the older population that have specific patterns of...
OBJECTIVE
Frailty is a dynamic health state that changes over time. Our hypothesis was that there are identifiable subgroups of the older population that have specific patterns of deterioration. The objective of this study was to evaluate the application of joint latent class model (JLCM) in identifying trajectories of frailty progression over time and their group-specific risk of death in older people.
STUDY DESIGN AND SETTING
The primary care records of UK patients, aged over 65 as of January 1 2010, included in the CPRD: GOLD and AURUM databases, were analysed and linked to mortality data. Electronic frailty index (eFI) scores were calculated at baseline and annually in subsequent years (2010-2013). JLCM was used to divide the population into clusters with different trajectories and associated mortality hazard ratios (HR). The model was built in GOLD and validated in AURUM.
RESULTS
Five trajectory clusters were identified and characterised based on baseline and speed of progression: low-slow, low-moderate, low-rapid, high-slow and high-rapid. The high-rapid cluster had the highest average starting eFI score; 7.9, while low-rapid cluster had the steepest rate of eFI progression; 1.7. Taking the low-slow cluster as reference, low-rapid and high-rapid had the highest HRs: 3.73 (95%CI 3.71 to 3.76) and 3.63 (3.57 to 3.69), respectively. Good validation was found in the AURUM population.
CONCLUSION
Our research found that there are vulnerable subgroups of the older population who are currently frail or have rapid frailty progression. Such groups may be targeted for greater healthcare monitoring.
PubMed: 38942178
DOI: 10.1016/j.jclinepi.2024.111442 -
Antiviral Research Jun 2024The SARS-CoV-2 Spike glycoprotein (S) utilizes a unique trimeric conformation to interact with the ACE2 receptor on host cells, making it a prime target for inhibitors...
The SARS-CoV-2 Spike glycoprotein (S) utilizes a unique trimeric conformation to interact with the ACE2 receptor on host cells, making it a prime target for inhibitors that block viral entry. We have previously identified a novel proteinaceous cavity within the Spike protein homotrimer that could serve as a binding site for small molecules. However, it is not known whether these molecules would inhibit, stimulate, or have no effect on viral replication. To address this, we employed structural-based screening to identify small molecules that dock into the trimer cavity and assessed their impact on viral replication. Our findings show that a cohort of identified small molecules binding to the Spike trimer cavity effectively reduces the replication of various SARS-CoV-2 variants. These molecules exhibited inhibitory effects on B.1 (European original, D614G, EDB2) and B.1.617.2 (δ) variants, while showing moderate activity against the B.1.1.7 (α) variant. We further categorized these molecules into distinct groups based on their structural similarities. Our experiments demonstrated a dose-dependent viral replication inhibitory activity of these compounds, with some, like BCC0040453 exhibiting no adverse effects on cell viability even at high concentrations. Further investigation revealed that pre-incubating virions with compounds like BCC0031216 at different temperatures significantly inhibited viral replication, suggesting their specificity towards the S protein. Overall, our study highlights the inhibitory impact of a diverse set of chemical molecules on the biological activity of the Spike protein. These findings provide valuable insights into the role of the trimer cavity in the viral replication cycle and aid drug discovery programs aimed at targeting the coronavirus family.
PubMed: 38942150
DOI: 10.1016/j.antiviral.2024.105949 -
Journal of Microbiological Methods Jun 2024Sepsis is a major health concern globally, and identification of the causative organism usually takes several days. Furthermore, molecular amplification using whole...
Sepsis is a major health concern globally, and identification of the causative organism usually takes several days. Furthermore, molecular amplification using whole blood from patients with sepsis remains challenging because of primer cross-reactivity with human DNA, which can delay appropriate clinical intervention. To address these concerns, we designed primers that could reduce cross-reactivity. By evaluating these primers against human DNA, we confirmed that the cross-reactivity observed with conventional primers was notably absent. In silico PCR further demonstrated the specificity and efficiency of the designed primers across 23 bacterial species that are often associated with sepsis. When tested using blood samples from sepsis patients, the designed primers showed moderate sensitivity and high specificity. Surprisingly, our method identified bacteria even in samples that were detected at other sites but tested negative using conventional blood culture methods. Although we identified some challenges, such as contamination with Acetobacter aceti due to the saponin pretreatment of samples, the developed method demonstrates remarkable potential for rapid identification of the causative organisms of sepsis and provides a new avenue for diagnosis in clinical practice.
PubMed: 38942122
DOI: 10.1016/j.mimet.2024.106982 -
Journal of Lipid Research Jun 2024Increasing evidence hints that DNA hypermethylation may mediate the pathogenic response to cardiovascular risk factors. Here, we tested a corollary of that hypothesis,...
Increasing evidence hints that DNA hypermethylation may mediate the pathogenic response to cardiovascular risk factors. Here, we tested a corollary of that hypothesis, i.e., that the DNA methyltransferase inhibitor decitabine (Dec) ameliorates the metabolic profile of mice fed a moderately high-animal fat and protein diet (HAFPD), a proxy of cardiovascular risk-associated Western-type diet. HAFPD-fed mice were exposed to Dec or vehicle for eight weeks (8W set, 4-32/group). To assess any memory of past exposure to Dec, we surveyed a second mice set treated as 8W but HAFPD-fed for further eight weeks without any Dec (16W set, 4-20/group). In 8W, Dec markedly reduced HAFPD-induced body weight gain in females, but marginally in males. Characterization of females revealed that Dec augmented skeletal muscle lipid content, while decreasing liver fat content and increasing plasma non-esterified fatty acids, adipose insulin resistance, and -although marginally- whole blood acylcarnitines, compared to HAFPD alone. Skeletal muscle mitochondrial DNA copy number was higher in 8W mice exposed to HAFPD and Dec, or in 16W mice fed HAFPD only, relative to 8W mice fed HAFPD only, but Dec induced a transcriptional profile indicative of ameliorated mitochondrial function. Memory of past Dec exposure was tissue-specific and sensitive to both duration of exposure to HAFPD and age. In conclusion, Dec redirected HAFPD-induced lipid accumulation towards the skeletal muscle, likely due to augmented mitochondrial functionality and increased lipid demand. As caveat, Dec induced adipose insulin resistance. Our findings may help identifying strategies for prevention and treatment of lipid dysmetabolism.
PubMed: 38942113
DOI: 10.1016/j.jlr.2024.100586 -
The Lancet. Rheumatology Jun 2024Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a proinflammatory cytokine overproduced in several inflammatory and autoimmune diseases, including axial...
Granulocyte-macrophage colony-stimulating factor neutralisation in patients with axial spondyloarthritis in the UK (NAMASTE): a randomised, double-blind, placebo-controlled, phase 2 trial.
BACKGROUND
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a proinflammatory cytokine overproduced in several inflammatory and autoimmune diseases, including axial spondyloarthritis. Namilumab is a human IgG1 monoclonal anti-GM-CSF antibody that potently neutralises human GM-CSF. We aimed to assess the efficacy of namilumab in participants with moderate-to-severe active axial spondyloarthritis.
METHODS
This proof-of-concept, randomised, double-blind, placebo-controlled, phase 2, Bayesian (NAMASTE) trial was done at nine hospitals in the UK. Participants aged 18-75 years with axial spondyloarthritis, meeting the Assessment in SpondyloArthritis international Society (ASAS) criteria and the ASAS-defined MRI criteria, with active disease as defined by a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), were eligible. Those who had inadequately responded or had intolerance to previous treatment with an anti-TNF agent were included. Participants were randomly assigned (6:1) to receive subcutaneous namilumab 150 mg or placebo at weeks 0, 2, 6, and 10. Participants, site staff (except pharmacy staff), and central study staff were masked to treatment assignment. The primary endpoint was the proportion of participants who had an ASAS ≥20% improvement (ASAS20) clinical response at week 12 in the full analysis set (all randomly assigned participants). This trial is registered with ClinicalTrials.gov (NCT03622658).
FINDINGS
From Sept 6, 2018, to July 25, 2019, 60 patients with moderate-to-severe active axial spondyloarthritis were assessed for eligibility and 42 were randomly assigned to receive namilumab (n=36) or placebo (n=six). The mean age of participants was 39·5 years (SD 13·3), 17 were women, 25 were men, 39 were White, and seven had previously received anti-TNF therapy. The primary endpoint was not met. At week 12, the proportion of patients who had an ASAS20 clinical response was lower in the namilumab group (14 of 36) than in the placebo group (three of six; estimated between-group difference 6·8%). The Bayesian posterior probability η was 0·72 (>0·927 suggests high clinical significance). The rates of any treatment-emergent adverse events in the namilumab group were similar to those in the placebo group (31 vs five).
INTERPRETATION
Namilumab did not show efficacy compared with placebo in patients with active axial spondyloarthritis, but the treatment was generally well tolerated.
FUNDING
Izana Bioscience, NIHR Oxford Biomedical Research Centre (BRC), NIHR Birmingham BRC, and Clinical Research Facility.
PubMed: 38942047
DOI: 10.1016/S2665-9913(24)00099-7 -
The Lancet. Global Health Jun 2024Insufficient physical activity increases the risk of non-communicable diseases, poor physical and cognitive function, weight gain, and mental ill-health. Global...
National, regional, and global trends in insufficient physical activity among adults from 2000 to 2022: a pooled analysis of 507 population-based surveys with 5·7 million participants.
BACKGROUND
Insufficient physical activity increases the risk of non-communicable diseases, poor physical and cognitive function, weight gain, and mental ill-health. Global prevalence of adult insufficient physical activity was last published for 2016, with limited trend data. We aimed to estimate the prevalence of insufficient physical activity for 197 countries and territories, from 2000 to 2022.
METHODS
We collated physical activity reported by adults (aged ≥18 years) in population-based surveys. Insufficient physical activity was defined as not doing 150 minutes of moderate-intensity activity, 75 minutes of vigorous-intensity activity, or an equivalent combination per week. We used a Bayesian hierarchical model to compute estimates of insufficient physical activity by country or territory, year, age, and sex. We assessed whether countries or territories, regions, and the world would meet the global target of a 15% relative reduction of the prevalence of insufficient physical activity by 2030 if 2010-22 trends continue.
FINDINGS
We included 507 surveys across 163 countries and territories. The global age-standardised prevalence of insufficient physical activity was 31·3% (95% uncertainty interval 28·6-34·0) in 2022, an increase from 23·4% (21·1-26·0) in 2000 and 26·4% (24·8-27·9) in 2010. Prevalence was increasing in 103 (52%) of 197 countries and territories and six (67%) of nine regions, and was declining in the remainder. Prevalence was 5 percentage points higher among female (33·8% [29·9-37·7]) than male (28·7% [25·0-32·6]) individuals. Insufficient physical activity increased in people aged 60 years and older in all regions and both sexes, but age patterns differed for those younger than 60 years. If 2010-22 trends continue, the global target of a 15% relative reduction between 2010 and 2030 will not be met (posterior probability <0·01); however, two regions, Oceania and sub-Saharan Africa, were on track with considerable uncertainty (posterior probabilities 0·70-0·74).
INTERPRETATION
Concerted multi-sectoral efforts to reduce insufficient physical activity levels are needed to meet the 2030 target. Physical activity promotion should not exacerbate sex, age, or geographical inequalities.
FUNDING
Ministry of Public Health, Qatar, and World Health Organization.
TRANSLATIONS
For the Spanish and Portuguese translations of the abstract see Supplementary Materials section.
PubMed: 38942042
DOI: 10.1016/S2214-109X(24)00150-5 -
Archives of Gerontology and Geriatrics Jun 2024A meta-analysis was conducted to evaluate the impact of resistance training on pro-inflammatory cytokines c-reactive protein (CRP), interleukin 6 (IL 6), and tumor...
BACKGROUND AND OBJECTIVE
A meta-analysis was conducted to evaluate the impact of resistance training on pro-inflammatory cytokines c-reactive protein (CRP), interleukin 6 (IL 6), and tumor necrosis factor- α (TNF- α) in middle-aged and elderly individuals.
METHODS
The retrieval period for the Web of Science and other large electronic databases is set by default to March 2022. Both included and excluded researchers are independent examination literature on the impact of resistance exercise on markers of inflammation in the elderly. The physical medical care Evidence Database scale (Physical Therapy Evidence Database, PEDro) was used to evaluate the research quality, and Revmen 5.3 was used to end the index analysis.
RESULTS
After a total of four rounds of elimination, 12 items were eventually included. The total sample size for the research was 388 persons. Resistance training substantially reduced CRP levels in middle-aged and older individuals, with SMD = -0.56 and 95 % confidence interval ([-0.78, -0.34], P < 0.00001, correspondingly. Resistance training can successfully lower IL6 concentrations in middle-aged and older adults, although the combined impact is not substantial. SMD = -0.25, 95 % CI [-0.54, 0.04]; P = 0.09. TNF- concentrations did not alter significantly following resistance exercise in middle-aged and older adults. The overall effect was SMD = -0.07, with a 95 % confidence interval [-0.37, 0.23], while P = 0.64.
CONCLUSION
Resistance training reduces CRP, IL6, and TNF-α levels among middle-aged and elderly people. However, it has no significant anti-inflammatory effects on TNF-α. Resistance exercise at a moderate level for 3 times / week with a duration of 6-12 weeks or 16-32 weeks, significantly reduced CRP levels. This work contributing to exploring the resistance training program for the elderly to reduce inflammatory markers, and further, providing suggestions for the elderly to participate in resistance training and reduce the concentration of inflammatory markers.
PubMed: 38941946
DOI: 10.1016/j.archger.2024.105536 -
Gaceta Sanitaria Jun 2024To evaluate the modifying effect of social capital on the relationship between living in violent communities and the presence of psychological distress in adolescents...
OBJECTIVE
To evaluate the modifying effect of social capital on the relationship between living in violent communities and the presence of psychological distress in adolescents and youth in Mexico.
METHOD
The analysis of the Social Cohesion Survey for the Prevention of Violence and Crime (ECOPRED, by its acronym in Spanish) was conducted. The analytic sample consisted of 39,639 participants aged 12 to 29 years. Community violence and social capital were measured at the census tract level using the average answers of a household's head sample. These environmental variables were independent of the experiences of the participants. Social capital variables included structural (social ties, recreational participation, collaborative participation, and social cohesion), and cognitive (trust in neighbors) dimensions. Multilevel structural equation models were used.
RESULTS
Recreational participation, collaborative participation, and social cohesion modified the relationship between community environments and psychological distress. In females who lived in places with less recreational participation or less social cohesion, the higher the social disorder, the higher the psychological distress. A similar relationship between vandalism and psychological distress was identified, but only in males who lived in places with less collaborative participation, and in females with less social cohesion.
CONCLUSIONS
Our results suggest that dimensions of the structural social capital (organization and interest in the community and its members) were the ones that had the buffering effect of the exposure to disordered community environments on psychological distress.
PubMed: 38941885
DOI: 10.1016/j.gaceta.2024.102408 -
Journal of Psychosomatic Research Jun 2024Identifying whether experienced symptom burden in individuals with medical predisposition indicates somatic symptom disorder (SSD) is challenging, given the high overlap...
OBJECTIVE
Identifying whether experienced symptom burden in individuals with medical predisposition indicates somatic symptom disorder (SSD) is challenging, given the high overlap in the phenomenology of symptoms within this group. This study aimed to enhance understanding SSD in individuals at risk for heart failure.
SUBJECTS AND METHODS
Cross-sectional data from the Hamburg City Health Study was analyzed including randomly selected individuals from the general population of Hamburg, Germany recruited from February 2016 to November 2018. SSD symptoms assessed with the Somatic Symptom Scale-8 and the Somatic Symptom Disorder-12 scale were categorized by applying cluster analysis including 412 individuals having at least 5% risk for heart failure-related hospitalization within the next ten years. Clusters were compared for biomedical and psychological factors using ANOVA and chi-square tests. Linear regressions, adjusting for sociodemographic, biomedical, and psychological factors, explored associations between clusters with general practitioner visits and quality of life.
RESULTS
Three clusters emerged: none (n = 215; 43% female), moderate (n = 151; 48% female), and severe (n = 46; 54% female) SSD symptom burden. The SSS-8 mean sum scores were 3.4 (SD = 2.7) for no, 6.4 (SD = 3.4) for moderate, and 12.4 (SD = 3.7) for severe SSD symptom burden. The SSD-12 mean sum scores were 3.1 (SD = 2.6) for no, 12.2 (SD = 4.2) for moderate, and 23.5 (SD = 6.7) for severe SSD symptom burden. Higher SSD symptom burden correlated with biomedical factors (having diabetes: p = .005 and dyspnea: p ≤ .001) and increased psychological burden (depression severity: p ≤ .001; anxiety severity: p ≤ .001), irrespective of heart failure risk (p = .202). Increased SSD symptoms were associated with more general practitioner visits (β = 0.172; p = .002) and decreased physical quality of life (β = -0.417; p ≤ .001).
CONCLUSION
Biomedical factors appear relevant in characterizing individuals at risk for heart failure, while psychological factors affect SSD symptom experience. Understanding SSD symptom diversity and addressing subgroup needs could prove beneficial.
PubMed: 38941711
DOI: 10.1016/j.jpsychores.2024.111848 -
Public Health Jun 2024COVID-19 revealed major shortfalls in healthcare workers (HCWs) trained in acute and critical care worldwide, especially in low-resource settings. We aimed to assess...
OBJECTIVES
COVID-19 revealed major shortfalls in healthcare workers (HCWs) trained in acute and critical care worldwide, especially in low-resource settings. We aimed to assess mass online courses' efficacy in preparing HCWs to manage COVID-19 patients and to determine whether rapidly deployed e-learning can enhance their knowledge and confidence during a pandemic.
STUDY DESIGN
Retrospective cohort study.
METHODS
This international retrospective cohort study, led by a large Academic Medical Centre (AMC), was conducted via YouTube and the AMC's online learning platform. From 2020 to 2021, multidisciplinary experts developed and deployed six online training courses based on the latest evidence-based management guidelines. Participants were selected through a voluntary sample following an electronic campaign. Training outcomes were assessed using pre-and post-test questionnaires, evaluation forms, and post-training assessment surveys. Kirkpatrick's Model guided training evaluation to measure self-reported knowledge, clinical skills, and confidence improvement. We also captured the number and type of COVID-19 patients managed by HCWs after the trainings.
RESULTS
Every 22.8 reach/impression and every 1.2 engagements led to a course registration. The 10,425 registrants (56.8% female, 43.1% male) represented 584 medical facilities across 154 cities. The largest segments of participants were students/interns (20.6%) and medical officers (13.4%). Of the 2169 registered participants in courses with tests, 66.9% completed post-tests. Test scores from all courses increased from the initial baseline to subsequent improvement post-course. Participants completing post-training assessment surveys reported that the online courses improved their knowledge and clinical skills (83.5%) and confidence (89.4%). Respondents managed over 19,720 COVID-19 patients after attending the courses, with 47.7% patients being moderately/severely ill.
CONCLUSIONS
Participants' confidence in handling COVID-19 patients is increased by rapidly deploying mass training to a substantial target population through digital tools. The findings present a virtual education and assessment model that can be leveraged for future global public health issues, and estimates for future electronic campaigns to target.
PubMed: 38941682
DOI: 10.1016/j.puhe.2024.05.006