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APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer’s disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4 -related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4 -related phenotypes and suggests APOE4 -related degenerative pathways contributing to AD pathogenesis. APOE4 is a strong genetic risk factor for late-onset Alzheimer’s disease. Here, the authors show that APOE4 is associated with AD features in hiPSCs-derived cerebral organoids. Isogenic conversion of APOE4 to APOE3 attenuates the AD-associated phenotype.

Michael Heseltine, the Deputy Prime Minister, yesterday suggested that the state education system would soon be good enough to educate Tory ministers' children. Only three members of the Cabinet sent their children to state schools, a survey by The Independent has revealed. The rest spent a combined total running into millions of pounds on an education in the independent sector. The Alma Mater of Cabinet ministers' children include most of the country's most famous public schools. Eton, Harrow, and Stowe are among them, along with a number of other leading boarding and day schools. Boarding school fees now come to more than pounds 12,000 per year in the most well-known schools.

Background. Chronic coinfection with herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus (HIV) has been associated with an increased HIV viral load and more rapid disease progression, perhaps related to HSV-2-associated alterations in host immunity. Methods. Studies were nested within (1) a cross-sectional study of men coinfected with HIV and HSV-2 and (2) women not infected with HIV, both before and after HSV-2 acquisition. HSV-2 infection status was determined by ELISA. HIV-specific CD8+ T cell epitopes were mapped, and proliferation of HIV-specific cells was also assessed. Systemic inflammatory and regulatory T cell populations were assayed by flow cytometry. Results. The breadth of both the HIV-specific CD8+ T cell interferon-γ and proliferative responses was reduced in participants coinfected with HIV and HSV-2, independent of the HIV plasma viral load and CD4+ T cell count, and the magnitude of the responses was also reduced. HSV-2 infection in this group was associated with increased T cell CD38 expression but not with differences in the proportion of CD4+ FoxP3+ regulatory T cells. However, in women not infected with HIV, acquisition of HSV-2 was associated with an increase in the proportion of regulatory T cells. Conclusions. HSV-2 coinfection was associated with reduced HIV-specific T cell responses and systemic inflammation. The immune effects of HSV-2 may underlie the negative impact that this coinfection has on the clinical course of HIV infection.

Traditional wheelchairs are pushed from behind the occupant, which hinders eye contact and communication. It was proposed that the wheelchair be pushed from the side using a push bar to place the caregiver beside the occupant. However, this method requires the caregiver to exert continuous effort to maintain a straight trajectory because the force at the lateral push location generates a moment. This study explores simple modifications to the front castor wheel of the wheelchair that allow pushing it from the side without additional effort. We used a three-dimensional dynamic model of the castor wheel to predict the effects of altering its dimensions and rake, cant, and bank angle and present a simplified steady-state solution. Experimental results support the model’s predictions, and a proof-of-concept experiment with a wheelchair showed that it is possible to push a wheelchair from the side without increasing forces or moments. The results also confirmed that the lateral ground reaction force generated on the castor wheel is proportional to the normal force and the cant angle, which can counter the moment caused by the lateral push location. The implications of this model extend beyond wheelchair design and can be applied to other applications that use castor wheels, such as robotics, trolleys, and walkers.

Background Low-resource settings are disproportionally burdened by chronic lung disease due to early childhood disadvantages and indoor/outdoor air pollution. However, data on the socioeconomic impact of respiratory diseases in these settings are largely lacking. Therefore, we aimed to estimate the chronic lung disease-related socioeconomic burden in diverse low-resource settings across the globe. To inform governmental and health policy, we focused on work productivity and activity impairment and its modifiable clinical and environmental risk factors. Methods We performed a cross-sectional, observational FRESH AIR study in Uganda, Vietnam, Kyrgyzstan, and Greece. We assessed the chronic lung disease-related socioeconomic burden using validated questionnaires among spirometry-diagnosed COPD and/or asthma patients (total N  = 1040). Predictors for a higher burden were studied using multivariable linear regression models including demographics (e.g. age, gender), health parameters (breathlessness, comorbidities), and risk factors for chronic lung disease (smoking, solid fuel use). We applied identical models per country, which we subsequently meta-analyzed. Results Employed patients reported a median [IQR] overall work impairment due to chronic lung disease of 30% [1.8–51.7] and decreased productivity (presenteeism) of 20.0% [0.0–40.0]. Remarkably, work time missed (absenteeism) was 0.0% [0.0–16.7]. The total population reported 40.0% [20.0–60.0] impairment in daily activities. Breathlessness severity (MRC-scale) (B = 8.92, 95%CI = 7.47–10.36), smoking (B = 5.97, 95%CI = 1.73–10.22), and solid fuel use (B = 3.94, 95%CI = 0.56–7.31) were potentially modifiable risk factors for impairment. Conclusions In low-resource settings, chronic lung disease-related absenteeism is relatively low compared to the substantial presenteeism and activity impairment. Possibly, given the lack of social security systems, relatively few people take days off work at the expense of decreased productivity. Breathlessness (MRC-score), smoking, and solid fuel use are potentially modifiable predictors for higher impairment. Results warrant increased awareness, preventive actions and clinical management of lung diseases in low-resource settings from health policymakers and healthcare workers.

Oral swab analysis (OSA) has been shown to detect Mycobacterium tuberculosis (MTB) DNA in patients with pulmonary tuberculosis (TB). In previous analyses, qPCR testing of swab samples collected from tongue dorsa was up to 93% sensitive relative to sputum GeneXpert, when 2 swabs per patient were tested. The present study modified sample collection methods to increase sample biomass and characterized the viability of bacilli present in tongue swabs. A qPCR targeting conserved bacterial ribosomal rRNA gene (rDNA) sequences was used to quantify bacterial biomass in samples. There was no detectable reduction in total bacterial rDNA signal over the course of 10 rapidly repeated tongue samplings, indicating that swabs collect only a small portion of the biomass available for testing. Copan FLOQSwabs collected ~2-fold more biomass than Puritan PurFlock swabs, the best brand used previously (p = 0.006). FLOQSwabs were therefore evaluated in patients with possible TB in Uganda. A FLOQSwab was collected from each patient upon enrollment (Day 1) and, in a subset of sputum GeneXpert Ultra-positive patients, a second swab was collected on the following day (Day 2). Swabs were tested for MTB DNA by manual IS6110-targeted qPCR. Relative to sputum GeneXpert Ultra, single-swab sensitivity was 88% (44/50) on Day 1 and 94.4% (17/18) on Day 2. Specificity was 79.2% (42/53). Among an expanded sample of Ugandan patients, 62% (87/141) had colony-forming bacilli in their tongue dorsum swab samples. These findings will help guide further development of this promising TB screening method.

The collective investment schemes in Kenya have witnessed increased volatility in their earnings, resulting in irregular growth in the industry. This necessitates the need to understand the factors contributing to poor financial returns from collective investment schemes. Hence this study sought to investigate the effect of equity investments and bond investments on Kenyan CIS’s performance. The specific objectives were: To assess the effect of equity investments, bond investments on financial performance of collective investment schemes in Kenya. The study was anchored on: modern portfolio theory and the efficient market hypothesis. The positivism philosophy was applied, with the firms adopting an explanatory research design. The target population was 17 Collective Investment Schemes registered by the Capital Markets Authority and were operational in the period 2010 to 2018.  Secondary data was sought from the Capital Markets Authority Annual reports and from the respective websites of the CIS’. Data was analyzed using descriptive statistics, correlational analysis and panel regression analysis. Hypotheses were tested at a significance level of 0.05. Findings indicate that equity investment, bond investments have an insignificant effect on CIS’ return on assets. Further, equity investments had a positive and significant effect on liquidity whereas bond investments had an insignificant effect on liquidity. The study recommends that CISs actively revise their equity investments and bond investments to stimulate financial returns.

Background Bacterial infections in the Intensive Care Units are a threat to the lives of critically ill patients. Their vulnerable immunity predisposes them to developing bacteria-associated sepsis, deteriorating their already fragile health. In the face of increasing antibiotics resistance, the problem of bacterial infection in ICU is worsening. Surveillance of bacterial infections in ICUs and drug resistance will help to understand the magnitude of the problem it poses and inform response strategies. We assessed bacterial infections in ICU setting by identifying prevalent Gram-negative bacterial species and characterized their antibiotic susceptibility patterns. Methods Cross-sectional samples collected from Kenyatta National Hospital ICU between January and June 2021 were cultured and phenotypic identification of culture-positive samples performed using VITEK 2. Antibiotic susceptibility patterns were determined based on Antimicrobial Susceptibility Testing (AST) results. Cephalosporin-resistant Gram-negative bacteria were assessed by PCR to detect the presence of ESBL genes including ( bla CTX-M, bla SHV, bla TEM, bla OXA) Results and discussion Out of the 168 Gram-negative isolates, Acinetobacter baumanii was the most abundant (35%). Other isolates that were present at frequencies more than 15% are Klebsiella pneumoniae and Escherichia. coli. A. baumaniii is known to be a notorious bacterium in ICU due to its multidrug resistance nature. Indeed, A. baumanii isolates from Kenyatta National Hospital showed significantly high level of phenotypic resistance. Concordant with the high level of phenotypic resistance, we found high carriage of the ESBL genes among the isolates analysed in this study. Moreover, majority of isolates harboured all the four ESBL genes. Conclusion A high rate of phenotypic and genetic resistance was detected among the tested isolates. Resistance to cephalosporins was primarily driven by acquisition of the ESBL genes. The high prevalence rate of ESBL genes in ICU bacterial isolates shown in this study has a important implication for ICU patient management and general antibiotics use.