Knowledge of aging, attitudes toward older people and willingness to engage in geriatric rehabilitation among rehabilitation students in southwestern China: a cross-sectional study.

BACKGROUND: As the global elderly population rises, providing quality care for older adults is increasingly challenging. Rehabilitation technicians are crucial in this effort. Their knowledge and attitudes significantly impact care quality and their willingness to work with the elderly. While many studies have examined healthcare professionals' attitudes toward older adults, few focus on rehabilitation students. This study assesses Chinese rehabilitation students' knowledge of aging, attitudes toward older individuals, willingness to care for them, and the factors influencing these aspects. METHODS: A sample of 890 rehabilitation students from three colleges and universities in southwestern China was investigated with a self-administered questionnaire, which included socio-demographic information, the Palmore Facts on Aging Quiz, the Kogan's Attitude towards Older People Scale and the Chinese Version of the Interpersonal Reactivity Index. Data analyses were conducted using SPSS version 25.0. Descriptive statistics were used to illustrate the demographic characteristics of the respondents. The frequency and percentage of responses was calculated. Means and standard deviations were computed for general knowledge of aging, attitudes toward older people, and empathy. Independent t-tests and one-way ANOVA assessed differences in FAQ, KAOP, and IRI-C scores between groups. Pearson's correlation examined correlations among general knowledge of aging, attitudes toward older people and empathy ability. Chi-square or Fisher's exact tests compared willingness to engage in geriatric rehabilitation across different respondent characteristics. Hierarchical multiple regression analysis explored the independent effect of different variables on attitudes toward older people. RESULTS: The Chinese rehabilitation students from three colleges and universities in southwestern China displayed a relatively low level of knowledge about aging, but a generally positive attitude towards older people. Females had significantly more positive attitudes toward older people than males(p<0.01). The students who had previous experience of being cared for by (maternal) grandparents, living with the elderly, and taking care of the elderly showed significantly more positive attitudes toward older people (p = 0.001, 0.007 and 0.007, respectively) and a significantly stronger willingness to engage in geriatric rehabilitation(p = 0.013, <0.01 and <0.01, respectively) than those who had not had these experiences. Students with good relationships with older people had more positive attitudes toward the elderly (p < 0.01) and greater willingness to engage in geriatric rehabilitation (p < 0.01). Those with frequent contact with the elderly also showed more positive attitudes (p < 0.01) and a stronger willingness to engage in geriatric rehabilitation (p = 0.002) compared to those with less contact. Knowledge of aging and empathy ability were both significantly positively related to attitudes toward older people and both independent predictors of attitudes toward older people(r = 0.143, p<0.01 and r = 0.337, p<0.01). CONCLUSIONS: It is crucial to prepare rehabilitation students with adequate knowledge and positive attitudes to ensure the quality of rehabilitation and care provided to older people. Educators should adopt effective strategies to promote rehabilitation students' geriatric rehabilitation knowledge and increase their positive attitudes toward older people.

Assessing nanotoxicity of food-relevant particles: A comparative analysis of cellular responses in cell monolayers versus 3D gut epithelial cultures.

Engineered nanoparticles (NPs) are extensively used in the food industry, yet safety concerns remain. The lack of validated methodologies is a bottleneck towards resolving this uncertainty. Hence, the current study aims to compare two cell models by examining the toxicological impacts of two food-relevant NPs (SiO2 and Ag) on intestinal epithelia using monolayer Caco-2 cells and full-thickness 3D tissue models of human small intestines (EpiIntestinal™). Comprehensive characterization and dosimetric analysis of the NPs were performed to determine effective doses and model realistic exposures. Neither genotoxicity nor cytotoxicity were detected in the 3D tissues after NP treatment, while the 2D cultures exhibited cytotoxic response from Ag NP treatment for 24 h at 1 µg/ml. Hyperspectral imaging and transmission electron microscopy confirmed uptake of both NPs by cells in both 2D and 3D culture models. Ag NPs caused an increase in autophagy, whereas SiO2 NPs induced increased cytoplasmic vacuolization. Based on realistic exposure levels studied, the 3D small intestinal tissue model was found to be more resilient to NP treatment compared to 2D cell monolayers. This comparative approach towards toxicological assessment of food relevant NPs could be used as a framework for future analysis of NP behavior and nanotoxicity in the gut.

A new-disease-causing dominant-negative variant in CARD11 gene in a Chinese case with recurrent fever.

Immunodeficiency 11B with atopic dermatitis (IMD11B, OMIM:617638) is rare primary immunodeficiency disease caused by germline dominant negative (DN) mutations in the CARD11 gene. Affected patients present with immune dysfunction, recurrent infections and atopic dermatitis. In this study, we sought to identify and characterize the genetic variant in one patient with periodic fever, recurrent infections, and eczema. Trio whole-exome sequencing (WES) was employed in this patient and her parents, and Sanger sequencing validated the potential pathogenic variant. In vitro functional study was performed to evaluate the pathogenicity of genetic variant identified. A very rare missense mutation (c.2324C > T, p.S775L) in CARD11 gene (NM_032415) was identified by WES in the patient but not her parents. Luciferase reporter assays and co-immunoprecipitation demonstrated mutation exerts a dominant-interfering effect on wild-type CARD11, inhibiting the activity of NF-κB. RNA sequencing analysis also confirmed that mutant CARD11 inhibited down-stream transcriptional activity of NF-κB. A review of literature doesn't found significant genotype-phenotype correlation. We identified a vary rare DN CARD11 mutation, expanding the genetic and phenotypic spectrum of CARD11.

Racial Differences in Adoption and Outcomes of Transcarotid Artery Revascularization among High-Risk Adults with Carotid Artery Stenosis.

BACKGROUND: Differential access to new technologies may contribute to racial disparities in surgical outcomes but has not been well-studied in the treatment of carotid artery stenosis. We examined race-based differences in adoption and outcomes of transcarotid artery revascularization (TCAR) among high-risk non-Hispanic (NH) Black and NH white adults undergoing carotid revascularization. METHODS: We conducted a retrospective analysis of TCAR, transfemoral carotid artery stenting (TF-CAS), and carotid endarterectomy (CEA) procedures performed for carotid artery stenosis from January 2015 to July 2023 in the Vascular Quality Initiative. NH Black and NH white adults were included if they met Centers for Medicare & Medicaid Services high-risk criteria. Hospitals and physicians were categorized as TCAR-capable if they had previously performed at least one TCAR prior to the time of a given procedure. We fit logistic and linear regressions, adjusted a priori for common demographic, clinical, and disease characteristics, to estimate associations of race with receipt of TCAR (versus CEA or TF-CAS), and to explore associations between race, hospital and physician characteristics, and perioperative composite stroke/death/myocardial infarction. RESULTS: Of 159,471 high-risk patients undergoing revascularization for carotid artery stenosis (mean age 72 years, 38.5% female, 5.3% NH Black), 28,722 (18.0%) received TCAR, including 16.9% of NH Black adults and 18.1% of NH white adults (P < 0.001). After controlling for patient and disease characteristics, NH Black patients were less likely than NH white patients to receive TCAR (aOR 0.92, 95% CI 0.87-0.99). The use of TCAR did not vary by race among patients treated at TCAR-capable hospitals (aOR 0.98, 95% CI 0.91-1.05) or by TCAR-capable physicians (aOR 1.01, 95% CI 0.93-1.10); however, NH Black race was associated with lower odds of receiving treatment in these settings (TCAR-capable hospital: aOR 0.93 [0.88-0.98]; TCAR-capable physician: aOR 0.92 [0.87-0.98]). NH Black race was associated with higher odds of stroke/death/MI in the full cohort (aOR 1.18, 95% CI 1.03-1.36), but not in the subgroup of patients who received TCAR (aOR 0.87, 95% CI 0.56-1.34). CONCLUSIONS: TCAR attenuated racial disparities in perioperative morbidity and mortality associated with carotid revascularization, but NH Black adults were less likely than NH white adults to receive TCAR. Relatively worse access for NH Black adults to technologically-advanced treatment settings may partially explain the broader persistence of race-based differences in carotid revascularization treatment patterns and outcomes.

Investigating the clinical appropriateness of Short Synacthen Testing (SST) and utility of a pre-test cortisol to predict SST outcome: A tertiary centre experience in Southeast Asia.

BACKGROUND: No studies have investigated the predictors of an adequate cortisol response to short synacthen test (SST) and appropriateness of patient selection for SST in Southeast Asian population. AIM: To investigate the predictors and indications of SSTs and concordance with SST outcomes. DESIGN: A retrospective study investigating all SSTs performed over a year in a tertiary center. METHODS: We extracted clinical data of patients who had SST between February 2022 and February 2023. We determined the appropriateness of SST testing. Binary logistic regression was used to assess the parameters that predict adequate cortisol response on SST. Proportion of individuals with biochemical "pass" or "fail" on SST were compared with chi-square test. Baseline cortisol level that predicted SST pass were determined using AuROC curves. RESULTS: Of the 781 SSTs, 83.9% of SSTs showed an adequate cortisol response. Postural hypotension (26.9%) and exogenous GC administration (14.2%) were common indications for SST. In our cohort, 50.2% of the SSTs were inappropriately indicated. Pre-test serum cortisol and albumin predict biochemical pass on SST. A pre-test cortisol level of 300nmol/L predicted SST response with 93% sensitivity, and a cortisol level of < 100nmol/L confirmed adrenal insufficiency (AI) with 97.3% specificity. Using these cortisol thresholds could avoid 302 (38.5%) of SSTs. CONCLUSION: Our analysis showed that clinical features of AI do not reliably predict SST outcomes. We advocate careful assessment of the pre-test probability of AI in patients referred for SST. A pre-test cortisol level can reduce the number of SSTs, with cost savings implications.

Improving completion rate of advance care planning at a tertiary rheumatological centre in Singapore: a quality improvement project.

Advanced care planning (ACP) is a series of ongoing voluntary discussions between patients, families and healthcare professionals to plan for their future healthcare needs. Despite patients with rheumatic diseases having high symptom burden and disease complications, the ACP completion rates in patients with rheumatic diseases remain low. In this quality improvement project, we aimed to increase the number of completed ACP in a tertiary referral rheumatology centre in Singapore from 0 to 1 per month. We showed a statistically significant increase in ACP completion across 1 year with two Plan-Do-Study-Act cycles. Further studies are needed to explore further interventions for ACP completion in patients with rheumatic diseases.

Revisiting the conceptualisation and implications of medicine's 'hidden curriculum'.

In medical training and practice, our professional attributes, attitudes, perceptions, character traits and identities are fundamentally shaped by our lived experiences and observations in clinical and para-clinical settings instead of being inculcated through formal curriculum or classroom teaching. For instance, clinical acumen, communication skills and bedside manners are learnt through role modelling and experiential learning in the course of clinical rotations. Likewise, one's attitudes, professional behaviours and inclinations are often also influenced by direct/indirect observations of the actions of others in the medical fraternity in various clinical and non-clinical settings. This is also what is often termed as the 'hidden curriculum' of medicine. In this article, we sought to provide a practical conceptualisation of the hidden curriculum in medical training, which we describe as lived experiences and personal observations of medical trainees and residents in clinical and para-clinical spaces, which shape their perceptions of the medical profession (vocational identity and purpose), patients (patient-physician relationship) and colleagues (intra- and inter-professional relationships), with downstream implications on physician well-being and clinical decision-making. Although this idea of a 'hidden curriculum' has conventionally carried predominantly negative connotations in medical literature, we suggest that it is an inevitable part of medical education and practice, which, through deliberate regulation, can potentially be shaped to create more positive and meaningful effects in the professional development of medical trainees.

Understanding the role of ten-eleven translocation family proteins in kidney diseases.

Epigenetic mechanisms play a critical role in the pathogenesis of human diseases including kidney disorders. As the erasers of DNA methylation, Ten-eleven translocation (TET) family proteins can oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), thus leading to passive or active DNA demethylation. Similarly, TET family proteins can also catalyze the same reaction on RNA. In addition, TET family proteins can also regulate chromatin structure and gene expression in a catalytic activity-independent manner through recruiting the SIN3A/HDAC co-repressor complex. In 2012, we reported for the first time that the genomic 5-hydroxymethylcytosine level and the mRNA levels of Tet1 and Tet2 were significantly downregulated in murine kidneys upon ischemia and reperfusion injury. Since then, accumulating evidences have eventually established an indispensable role of TET family proteins in not only acute kidney injury but also chronic kidney disease. In this review, we summarize the upstream regulatory mechanisms and the pathophysiological role of TET family proteins in major types of kidney diseases and discuss their potential values in clinical diagnosis and treatment.

Exploring Factors Influencing Cervical Cancer Screening Participation among Singaporean Women: A Social Ecological Approach.

Background/Objectives: Cervical cancer screening uptake in Singapore remains suboptimal. This study employed the Social Ecological Model (SEM) to investigate factors influencing cervical cancer screening participation among Singaporean women. Methods: The study included 665 women, aged 25-69 years, who reported awareness of cancer screening and no personal cancer history. Data were collected through a previously described online survey. Hierarchical logistic regression analysis was conducted to identify significant factors influencing screening participation. Results: Only 30% of participants reported cervical cancer screening participation. Women aged 25-29 years (OR = 0.33; 95% CI = 0.12-0.77), Malay women (OR = 0.42; 95% CI = 0.20-0.83), and unmarried women (OR = 0.30; 95% CI = 0.18-0.48) were less likely to be screened. Positive associations with screening participation were observed with good cervical cancer screening knowledge (OR = 2.90; 95% CI = 1.96-4.32), awareness of primary care providers' role in delivering screening services (OR = 1.94; 95% CI = 1.24-3.10), cancer information seeking behavior (OR = 1.59; 95% CI = 1.07-2.39), and acceptance of self-sampling options (OR = 1.81; 95% CI = 1.22-2.70). Conclusions: Our study highlights the cumulative impact of factors at various SEM levels on screening participation and underscores the necessity for more targeted and multi-pronged strategies to improve cervical cancer screening uptake in Singapore.

Posterior Basolateral Amygdala is a Critical Amygdaloid Area for Temporal Lobe Epilepsy.

The amygdaloid complex consists of multiple nuclei and is a key node in controlling temporal lobe epilepsy (TLE) in both human and animal model studies. However, the specific nucleus in the amygdaloid complex and the neural circuitry governing seizures remain unknown. Here, it is discovered that activation of glutamatergic neurons in the posterior basolateral amygdala (pBLA) induces severe seizures and even mortality. The pBLA glutamatergic neurons project collateral connections to multiple brain regions, including the insular cortex (IC), bed nucleus of the stria terminalis (BNST), and central amygdala (CeA). Stimulation of pBLA-targeted IC neurons triggers seizures, whereas ablation of IC neurons suppresses seizures induced by activating pBLA glutamatergic neurons. GABAergic neurons in the BNST and CeA establish feedback inhibition on pBLA glutamatergic neurons. Deleting GABAergic neurons in the BNST or CeA leads to sporadic seizures, highlighting their role in balancing pBLA activity. Furthermore, pBLA neurons receive glutamatergic inputs from the ventral hippocampal CA1 (vCA1). Ablation of pBLA glutamatergic neurons mitigates both acute and chronic seizures in the intrahippocampal kainic acid-induced mouse model of TLE. Together, these findings identify the pBLA as a pivotal nucleus in the amygdaloid complex for regulating epileptic seizures in TLE.

WOX1 controls leaf serration development via temporally restricting BZR1 and CUC3 expression in Arabidopsis.

Leaves evolve shape diversity ranging from simple leaves with smooth margin to complicated shape with toothed/serrated, lobed and dissected leaves with leaflets. In the model plant Arabidopsis thaliana with simple leaves producing serrated margin, boundary regulatory factors CUP SHAPED COTYLEDON 2 (CUC2) and CUC3 play important roles in promoting leaf serration initiation and maintenance. Stem cell related WUSCHEL-RELATED HOMEOBOX1 (WOX1) and PRESSED FLOWER/WOX3 are also essential for leaf margin morphogenesis, but the role of WOX1 and PRS as well as the relationships between CUCs and WOXs on tooth development was unclear. In this study, we found that WOX1, but not PRS, prevents overproduction of tooth number and excessive tooth size by limiting CUC3 expression to a moderate level in a temporally regulated manner. We also revealed that BRASSINAZOLE RESISTANT 1 (BZR1), a known regulator for plant development including boundary regions, is involved in WOX1 negative regulation of tooth development by repressing CUC3 expression during the initiation/early stage of tooth development. WOX1 parallelly limits BZR1 and CUC3 expression from the late stage of the first 2 teeth, while restricts CUC3 activity in a BZR1 dependent manner from the initiation/early stage of subsequently developed teeth. This study uncovers a new mechanism for WOX1 in fine-tuning the leaf margin geometry.

Diagnostic performance of metagenomic sequencing in patients with suspected infection: a large-scale retrospective study.

Background: Metagenomic next-generation sequencing (mNGS) has been widely reported to identify pathogens in infectious diseases (IDs). In this work, we intended to investigate the diagnostic value and clinical acceptance of paired-samples mNGS as compared to the culture method. Methods: A total of 361 patients with suspected infection were retrospectively included. With reference to the clinical diagnosis, we compared the diagnostic performance and clinical acceptance in pathogen detection between mNGS and culture tests. Moreover, the pathogen concordance of paired blood and respiratory tract (RT) samples in mNGS assay was investigated. Results: Among 511 samples, 62.04% were shown to be pathogen positive by mNGS, and that for clinical diagnosis was 51.86% (265/511). When compared to culture assay (n = 428), mNGS had a significantly higher positivity rate (51.87% vs. 33.18%). With reference to the clinical diagnosis, the sensitivity of mNGS outperformed that of culture (89.08% vs. 56.72%). Importantly, mNGS exhibited a clinically accepted rate significantly superior to that of culture. In addition, the mNGS result from 53 paired blood and RT samples showed that most pairs were pathogen positive by both blood and RT, with pathogens largely being partially matched. Conclusion: Through this large-scale study, we further illustrated that mNGS had a clinically accepted rate and sensitivity superior to those of the traditional culture method in diagnosing infections. Moreover, blood and paired RT samples mostly shared partial-matched positive pathogens, especially for pathogens with abundant read numbers in RT, indicating that both blood and RT mNGS can aid the identification of pathogens for respiratory system infection.

Inhibitor Development for α-Synuclein Fibril's Disordered Region to Alleviate Parkinson's Disease Pathology.

The amyloid fibrils of α-synuclein (α-syn) are crucial in the pathology of Parkinson's disease (PD), with the intrinsically disordered region (IDR) of its C-terminal playing a key role in interacting with receptors like LAG3 and RAGE, facilitating pathological neuronal spread and inflammation. In this study, we identified Givinostat (GS) as an effective inhibitor that disrupts the interaction of α-syn fibrils with receptors such as LAG3 and RAGE through high-throughput screening. By exploring the structure-activity relationship and optimizing GS, we developed several lead compounds, including GSD-16-24. Utilizing solution-state and solid-state NMR, along with cryo-EM techniques, we demonstrated that GSD-16-24 binds directly to the C-terminal IDR of α-syn monomer and fibril, preventing the fibril from binding to the receptors. Furthermore, GSD-16-24 significantly inhibits the association of α-syn fibrils with membrane receptors, thereby reducing neuronal propagation and pro-inflammatory effects of α-syn fibrils. Our findings introduce a novel approach to mitigate the pathological effects of α-syn fibrils by targeting their IDR with small molecules, offering potential leads for the development of clinical drugs to treat PD.

Optical Coherence Tomography Angiography Analysis of Peripapillary Choroidal Microvascular Density in normal-tension Glaucoma and Primary open-angle Glaucoma.

PRCIS: Glaucoma patients had a reduction in the inner annulus peripapillary choroidal microvascular density (PCMD) that became worse as the glaucoma severity progressed, which might provide new evidence supporting the vascular theory. PURPOSE: To compare PCMD among normal-tension glaucoma (NTG), primary open-angle glaucoma (POAG), and healthy controls using optical coherence tomography (OCT) angiography (OCTA). METHODS: The study included 40 POAG, 25 NTG, and 33 healthy controls. All subjects underwent OCT and OCTA testing. Inner annulus and outer annulus PCMD, as well as peripapillary vessel density (VD), was calculated. One-way analysis of variance was used to compare the vascular parameters of the three groups. Pearson correlation analysis or Spearman correlation test was used to evaluate the correlation between PCMD and glaucomatous severity factors. The spatial positional relationship between PCMD and corresponding peripapillary retinal nerve fiber layer (RNFL) thickness and visual field (VF) mean deviation (MD) was also assessed. RESULTS: The average and four quadrants of the inner annulus PCMD and peripapillary VD in the two glaucomatous groups were significantly lower than in normal eyes (P<0.05). Strong correlations were found between inner annulus PCMD and VF MD, peripapillary VD, and RNFL in POAG patients. Similarly, the inner annulus PCMD in NTG patients was strongly correlated with peripapillary VD and RNFL (all r>0.5). Strong positional correlations were found between inner superior quadrantal PCMD and RNFL thickness in both POAG and NTG patients (r=0.566, r=0.731, respectively). Likewise, inner inferior quadrantal PCMD exhibited a strong correlation with RNFL thickness in POAG patients (r=0.608). Strong positional correlations were also found between inner superior PCMD and VF MD in both POAG and NTG patients (r=0.589, r=0.622, respectively). Inner inferior PCMD exhibited a moderate correlation with VF MD in both POAG and NTG patients (r=0.487, r=0.440, respectively). CONCLUSION: The study found that the inner annulus PCMD decreased to varying degrees in NTG and POAG patients. The inner annulus PCMD was closely related to the structural and visual function parameters of glaucoma in both NTG and POAG. Furthermore, inner PCMD demonstrated a spatial correlation with corresponding RNFL thickness and VF MD.

Sequence Types and Antimicrobial Resistance Profiles of Salmonella Typhimurium in the Food Chain in Singapore.

Salmonella remains a significant foodborne pathogen globally with S. Typhimurium presenting as a frequently occurring serovar. This study aimed to characterize 67 S. Typhimurium isolates from humans, food, farms, and slaughterhouses collected in Singapore from 2016 to 2017. Using whole-genome sequencing analysis, the isolates were found to belong to either ST19 (n = 33) or ST36 (n = 34). ST36 predominated in human intestinal and chicken isolates, while human extra-intestinal and non-chicken food isolates belonged to ST19. Plasmids were predicted in 88.1% (n = 59) of the isolates with the most common incompatibility group profiles being IncFIB(S), IncFII(S) and IncQ1. IncFIB(S) (adjusted p-value < 0.05) and IncFII(S) (adjusted p-value < 0.05) were significantly more prevalent in ST19 isolates, while Col156 (adjusted p-value < 0.05) was more significantly found in ST36 isolates. ST36 isolates exhibited higher resistance to multiple antibiotic classes such as penicillins, phenicols, folate pathway inhibitors, aminoglycosides, ß-lactam/ß-lactamase inhibitor combinations, tetracyclines, and fluoroquinolones. Phylogenetics analysis suggested potential shared routes of transmission among human, chicken, farm and slaughterhouse environments. Taken together, this study offers a cross-sectional epidemiological insight into the genomic epidemiology and antimicrobial landscape of S. Typhimurium isolates in Singapore, informing strategies for future public health and food safety surveillance.

Effectiveness of Wolbachia-mediated sterility coupled with sterile insect technique to suppress adult Aedes aegypti populations in Singapore: a synthetic control study.

BACKGROUND: Incompatible insect technique (IIT) coupled with sterile insect technique (SIT) via the release of sterile male Wolbachia-infected mosquitoes is a promising tool for Aedes-borne disease control. Yet, real-world evidence on the suppressive effectiveness of IIT-SIT on mosquito abundance remains mostly limited to small semi-rural village and suburban localities over short trial durations. However, a large proportion of Aedes-borne diseases occur in dense, urban, and high-rise locations, limiting the applicability of previous studies for these settings with high disease burden. The sustainability and use of this technology over multiple years is also unknown. METHODS: In this synthetic control study, we conducted a large-scale, field trial of IIT-SIT targeting Aedes aegypti among high-rise public housing estates in Singapore, an equatorial city state. Routinely collected data from a large, nationwide surveillance system of 57 990 unique mosquito traps, combined with a high-dimensional set of anthropogenic and environmental confounders were collected to ascertain mosquito abundance and its key drivers. Four townships were selected as the intervention groups (approximate population size of 607 872 residents as of 2022), wherein interventions that combined ITT with SIT over the course of the study period were conducted. Townships were subject to releases of wAlbB-SG male A aegypti mosquitoes twice a week. Data were assessed over the course of epidemiological weeks (EWs), which provide the finest temporal resolution of recorded Wolbachia release schedule and mosquito abundance data. A novel synthetic control framework was then developed to account for the non-randomised and staggered adoption setting of the intervention across trial sectors to identify the direct suppressive effectiveness of IIT-SIT on female A aegypti populations, the spillover effects in non-release areas, and the effect of the intervention on other mosquito populations such as Aedes albopictus. Furthermore, we recalculated effectiveness in terms of calendar time, time since intervention, and over multiple sites to examine heterogeneities in IIT-SIT effectiveness. FINDINGS: Between EW27 2018 and EW26 2022, Wolbachia releases were conducted across 117 sectors, of which 97 had sufficient trap data, which were collected between EW8 2019 and EW26 2022. We found that Wolbachia-based IIT-SIT reduced wild-type female A aegypti populations by a mean of 62·01% (95% CI 60·68 to 63·26) by 3 months, 78·40% (77·56 to 79·18) by 6 months, and 91·32% (90·95 to 91·66) by at least 18 months of releases. We also found a smaller but non-negligible spillover suppression effect that gradually increased over time (mean spillover intervention effectiveness 61·02% [95% CI 57·89 to 63·72] in adjacent, non-intervention sectors). Although no consistent change in A albopictus populations was seen across the four intervention townships after Wolbachia releases, the average intervention effectiveness on the A albopictus population across all release sectors was -25·80% (95% CI -30·93 to -21·05), which was driven by increases in two towns. INTERPRETATION: Our results demonstrate the potential of IIT-SIT for strengthening long-term, large-scale vector control in tropical cities, where dengue burden is the greatest. The effect of these interventions in different geographical settings should be assessed in future work. FUNDING: Singapore's Ministry of Finance, Ministry of Sustainability and the Environment, National Environment Agency, and National Robotics Program.

Orthostatic intolerance during early mobilization following thoracoscopic lung resection: a prospective observational study.

BACKGROUND: Early postoperative mobilization is important for enhanced recovery but can be hindered by orthostatic intolerance. However, study on postoperative orthostatic intolerance in thoracoscopic lung resection is limited. Thus, this investigation aims to examine the prevalence and variables contributing to orthostatic intolerance on the first day following thoracoscopic lung cancer resection. METHODS: A prospective observational study was conducted from February 01 to May 05, 2023, at the First Affiliated Hospital of Chongqing Medical University. Typically, 215 subjects subjected to thoracoscopic lung resection were enrolled in this study. Their general information, disease, and treatment information were collected, and the occurrence of orthostatic intolerance was recorded. RESULTS: Typically, 64 patients (29.77%) demonstrated orthostatic intolerance during early mobilization, and 43.75% failed to walk. The prevalence of nausea, dizziness, and impaired vision was 60.94%, 92.19%, and 25.00%, respectively, and no patient experienced syncope. The factors shown to be independently linked with orthostatic intolerance were being female (OR = 2.98, 1.53 to 5.82) and high pain level during sitting (OR = 2.69, 1.79 to 4.04). Individuals with orthostatic intolerance had a longer postoperative hospital stay with a mean of 5.42 days against 4.25 days (p = 0.003). CONCLUSIONS: Orthostatic intolerance was prevalent following thoracoscopic lung cancer resection and affected patients' capability to mobilize and prolonged postoperative hospitalization. Being female and having high pain levels during sitting were identified as independent factors for orthostatic intolerance. This suggests that more emphasis should be given to risky patients, and for these groups, we may optimize pain management to adjust the risk of emerging orthostatic intolerance, facilitating early mobilization and early postoperative rehabilitation.

HLA A*24:02-restricted T cell receptors cross-recognize bacterial and preproinsulin peptides in type 1 diabetes.

CD8+ T cells destroy insulin-producing pancreatic ß cells in type 1 diabetes through HLA class I-restricted presentation of self-antigens. Combinatorial peptide library screening was used to produce a preferred peptide recognition landscape for a patient-derived T cell receptor (TCR) that recognized the preproinsulin-derived (PPI-derived) peptide sequence LWMRLLPLL in the context of disease risk allele HLA A*24:02. Data were used to generate a strong superagonist peptide, enabling production of an autoimmune HLA A*24:02-peptide-TCR structure by crystal seeding. TCR binding to the PPI epitope was strongly focused on peptide residues Arg4 and Leu5, with more flexibility at other positions, allowing the TCR to strongly engage many peptides derived from pathogenic bacteria. We confirmed an epitope from Klebsiella that was recognized by PPI-reactive T cells from 3 of 3 HLA A*24:02+ patients. Remarkably, the same epitope selected T cells from 7 of 8 HLA A*24+ healthy donors that cross-reacted with PPI, leading to recognition and killing of HLA A*24:02+ cells expressing PPI. These data provide a mechanism by which molecular mimicry between pathogen and self-antigens could have resulted in the breaking of self-tolerance to initiate disease.

Dexamethasone Inhibits the Growth of B-Lymphoma Cells by Downregulating DOT1L.

BACKGROUND: Dexamethasone (Dex), a synthetic glucocorticoid that acts by binding to the glucocorticoid receptor (GR), has been widely applied to treat leukemia and lymphoma; however, the precise mechanism underlying Dex action is still not well elucidated. DOT1L, a histone H3-lysine79 (H3K79) methyltransferase, has been linked to multiple cancer types, particularly mixed lineage leukemia (MLL) gene rearranged leukemia, but its contribution to lymphoma is yet to be delineated. Analysis from the TCGA database displayed that DOT1L was highly expressed in lymphoma and leukemia. RESULTS: We initially demonstrated that DOT1L served as a new target gene controlled by GR, and the downregulation of DOT1L was critical for the killing of B-lymphoma cells by Dex. Further study revealed that Dex had no impact on the transcriptional activity of the DOT1L promoter, rather it reduced the mRNA level of DOT1L at the posttranscriptional level. In addition, knockdown of DOT1L remarkably inhibited the B-lymphoma cell growth. CONCLUSIONS: Overall, our findings indicated that DOT1L may serve as a potential drug target and a promising biomarker of Dex sensitivity when it comes to treating B lymphoma.

[Mechanism of Huangqi Simiao Decoction in treatment of type 2 diabetes mellitus based on network pharmacology and metabonomics].

This article analyzed the mechanism of Huangqi Simiao Decoction(HSD) for the treatment of type 2 diabetes mellitus(T2DM). The component targets of HSD and the related disease targets of T2DM were screened through network pharmacology. The protein-protein interaction(PPI) network of intersecting targets and the drug-component-intersecting target network were constructed to screen the potential active ingredients and targets. Molecular docking was performed using AutoDock Vina software to verify the interaction between potential components and core targets. The serum was tested by ultra performance liquid chromatography-tandem mass spectrometry, and multivariate statistical analyses, such as principal component analysis(PCA) and partial least squares discriminant analysis(PLS-DA), were used to search for the differential metabolites and related metabolic pathways of each group by combining with the MetaboAnalyst database. The same metabolic pathways were analyzed by combining the screened differential metabolites with the intersecting targets screened by network pharmacology. Network pharmacology showed that the nine core components of HSD for the treatment of T2DM were quercetin, kaempferol, stigmasterol, baicalein, ß-sitosterol, flavodoxin, canthaxanthin, canthaxanthin, berberine, and berberine, and the five core targets included AKT1, TP53, TNF, IL6, and VEGFA. Molecular docking showed that the core components bound well to the target genes. Metabolomics showed that a total of 112 common differential metabolites were identified, of which 88 metabolites exhibited increased concentration and 24 metabolites decreased concentration after treatment with HSD. Enrichment analysis showed that HSD regulated the body metabolism of patients with T2DM, mainly related to seven metabolic pathways, such as amino acid metabolism and tricarboxylic acid cycle. The joint analysis of metabolomics and network pharmacology showed that both involved histidine metabolism, arginine and proline metabolic pathways. This study suggests that HSD has a good efficacy for T2DM. Based on the combined analysis of metabolomics and network pharmacology, it was found that the mechanism may be that the pharmacodynamic bases of quercetin, kaempferol, and stigmasterol in HSD enhance the effects on histidine metabolism, arginine and proline metabolic pathways by modulating a variety of metabolites, which provides the basis for further prevention and treatment of T2DM.