A single-cell and spatial RNA-seq database for Alzheimer's disease (ssREAD).

Alzheimer's Disease (AD) pathology has been increasingly explored through single-cell and single-nucleus RNA-sequencing (scRNA-seq & snRNA-seq) and spatial transcriptomics (ST). However, the surge in data demands a comprehensive, user-friendly repository. Addressing this, we introduce a single-cell and spatial RNA-seq database for Alzheimer's disease (ssREAD). It offers a broader spectrum of AD-related datasets, an optimized analytical pipeline, and improved usability. The database encompasses 1,053 samples (277 integrated datasets) from 67 AD-related scRNA-seq & snRNA-seq studies, totaling 7,332,202 cells. Additionally, it archives 381 ST datasets from 18 human and mouse brain studies. Each dataset is annotated with details such as species, gender, brain region, disease/control status, age, and AD Braak stages. ssREAD also provides an analysis suite for cell clustering, identification of differentially expressed and spatially variable genes, cell-type-specific marker genes and regulons, and spot deconvolution for integrative analysis. ssREAD is freely available at https://bmblx.bmi.osumc.edu/ssread/ .

Exploring the Role of the Private Sector in Tuberculosis Detection and Management in Lima, Peru: A Mixed-Methods Patient Pathway Analysis.

In Latin America, little is known about the involvement of private health-care providers in tuberculosis (TB) detection and management. We sought to gain a better understanding of current and potential roles of the private sector in delivering TB services in Peru. We conducted a mixed-methods study in North Lima, Peru. The quantitative component comprised a patient pathway analysis assessing the alignment of TB services with patient care-seeking behavior. The qualitative component comprised in-depth interviews with 18 private health-care providers and 5 key informants. We estimated that 77% of patients sought care initially at a facility with TB diagnostic capacity and 59% at a facility with TB treatment capacity. Among private facilities, 43% offered smear microscopy, 13% offered radiography, and none provided TB treatment. Among public-sector facilities, 100% offered smear microscopy, 26% offered radiography, and 99% provided TB treatment. Private providers believed they offered shorter wait times and a faster diagnosis, but they struggled with a lack of referral systems and communication with the public sector. Nonrecognition of private-sector tests by the public sector led to duplicate testing of referred patients. Although expressing willingness to collaborate with public-sector programs for diagnosis and referral, private providers had limited interest in treating TB. This study highlights the role of private providers in Peru as an entry point for TB care. Public-private collaboration is necessary to harness the potential of the private sector as an ally for early diagnosis.

Supporting Latine children's informal engineering learning through tinkering and oral storytelling.

Providing equitable informal science, technology, engineering, and mathematics (STEM) learning opportunities to young children from diverse backgrounds may be a way to increase access and interest in STEM and can help to address the broader goal of increasing representation. Importantly, these learning experiences must be meaningful and engage everyday cultural practices. Guided by a strengths-based approach, the current study examines how oral stories as a cultural resource can be harnessed to support Latine children's engagement in a tinkering activity. The project explores whether and how setting an at-home tinkering activity within a story context engenders rich parent-child conversations that provide engineering learning opportunities for young children. Fifty-two Latine parents and children (Mage = 7.69 years; 23 girls; 90.4% Mexican heritage) were randomly assigned to either hear a story as a frame for a hands-on tinkering activity or to engage in the same tinkering activity without the story. After families finished tinkering, a researcher elicited the children's reflections about their tinkering experience. Approximately 2 weeks after the activity, children were asked to share their tinkering reflections with a second researcher. Parents and children in the story condition talked more about engineering during tinkering, and these children also talked more about engineering during both reflections than did children in the no-story condition. These findings suggest that integrating oral storytelling into tinkering activities is a promising future direction for the creation of more equitable informal engineering learning opportunities for Latine children and families. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Exploring the role of the private sector in tuberculosis detection and management in Lima, Peru: a mixed-methods patient pathway analysis.

In Latin America, little is known about the involvement of private healthcare providers in TB detection and management. We sought to gain a better understanding of current and potential roles of the private sector in delivering TB services in Peru. We conducted a mixed-methods study in Lima, Peru. The quantitative component comprised a patient pathway analysis assessing the alignment of TB services with patient care-seeking behavior. The qualitative component comprised in-depth interviews with 18 private healthcare providers and 5 key informants. We estimated that 77% of patients initially sought care at a facility with TB diagnostic capacity and 59% at a facility with TB treatment capacity. The lack of TB services at initial care-seeking location was driven by the 41% of patients estimated to seek care first at a private facility. Among private facilities, 43% offered smear microscopy, 13% offered radiography, and none provided TB treatment. Among public sector facilities, 100% offered smear microscopy, 26% offered radiography, and 99% provided TB treatment. Interviews revealed that private providers believed that they offered shorter wait times and a quicker diagnosis, but they struggled with a lack of follow-up systems and communication barriers with the public sector. While expressing willingness to collaborate with public sector programs for diagnosis and referral, private providers had limited interest in treating TB. This study highlights the role of private providers in Peru as an entry point for TB care. Public-private collaboration is necessary to harness the potential of the private sector as an ally for early diagnosis.

Real-World Evidence of Tofacinitib in Ulcerative Colitis: Short-Term and Long-Term Effectiveness and Safety.

INTRODUCTION: The objective of this study was to assess the durability, short-term and long-term effectiveness, and safety of tofacitinib in ulcerative colitis (UC) in clinical practice. METHODS: This is a retrospective multicenter study including patients with UC who had received the first tofacitinib dose at least 8 weeks before the inclusion. Clinical effectiveness was based on partial Mayo score. RESULTS: A total of 408 patients were included. Of them, 184 (45%) withdrew tofacitinib during follow-up (mean = 18 months). The probability of maintaining tofacitinib was 67% at 6 m, 58% at 12 m, and 49% at 24 m. The main reason for tofacitinib withdrawal was primary nonresponse (44%). Older age at the start of tofacitinib and a higher severity of clinical activity were associated with tofacitinib withdrawal. The proportion of patients in remission was 38% at week 4, 45% at week 8, and 47% at week 16. Having moderate-to-severe vs mild disease activity at baseline and older age at tofacitinib start were associated with a lower and higher likelihood of remission at week 8, respectively. Of 171 patients in remission at week 8, 83 (49%) relapsed. The probability of maintaining response was 66% at 6 m and 54% at 12 m. There were 93 adverse events related to tofacitinib treatment (including 2 pulmonary thromboembolisms [in patients with risk factors] and 2 peripheral vascular thrombosis), and 29 led to tofacitinib discontinuation. DISCUSSION: Tofacitinib is effective in both short-term and long-term in patients with UC. The safety profile is similar to that previously reported.

Spatially resolved transcriptomics reveals genes associated with the vulnerability of middle temporal gyrus in Alzheimer's disease.

Human middle temporal gyrus (MTG) is a vulnerable brain region in early Alzheimer's disease (AD), but little is known about the molecular mechanisms underlying this regional vulnerability. Here we utilize the 10 × Visium platform to define the spatial transcriptomic profile in both AD and control (CT) MTG. We identify unique marker genes for cortical layers and the white matter, and layer-specific differentially expressed genes (DEGs) in human AD compared to CT. Deconvolution of the Visium spots showcases the significant difference in particular cell types among cortical layers and the white matter. Gene co-expression analyses reveal eight gene modules, four of which have significantly altered co-expression patterns in the presence of AD pathology. The co-expression patterns of hub genes and enriched pathways in the presence of AD pathology indicate an important role of cell-cell-communications among microglia, oligodendrocytes, astrocytes, and neurons, which may contribute to the cellular and regional vulnerability in early AD. Using single-molecule fluorescent in situ hybridization, we validated the cell-type-specific expression of three novel DEGs (e.g., KIF5A, PAQR6, and SLC1A3) and eleven previously reported DEGs associated with AD pathology (i.e., amyloid beta plaques and intraneuronal neurofibrillary tangles or neuropil threads) at the single cell level. Our results may contribute to the understanding of the complex architecture and neuronal and glial response to AD pathology of this vulnerable brain region.

The impact of the COVID-19 pandemic on patients' experiences obtaining a tuberculosis diagnosis in Peru: a mixed-methods study.

BACKGROUND: The COVID-19 pandemic disrupted TB services worldwide, leading to diagnostic delays. There have been few published reports describing how the pandemic affected people's pathway to diagnosis from their own perspectives. We sought to evaluate the impact on the pandemic on people's experiences obtaining a TB diagnosis. METHODS: We performed a mixed-methods study, enrolling newly diagnosed TB patients from 12 health centers in Lima, Peru. We used structured surveys to quantify diagnostic delay, defined as the time between symptom onset and diagnosis, and in-depth interviews to understand the ways in which the pandemic affected the pathway to care. We compared diagnostic delay between patients enrolled during the first year of the pandemic to those diagnosed after using a Wilcoxon rank-sum test. We used an inductive content analysis approach to analyze interview content related to the pandemic. RESULTS: We enrolled 51 patients during November 2020-April 2021 (during the first year of the pandemic) and 49 patients during October 2021-February 2022. Median diagnostic delay was longer for patients diagnosed during the first year of the pandemic (median 15 [IQR 5-26] weeks compared to 6 [IQR 3-18] weeks, p = 0.027). Qualitative analysis of 26 interviews revealed that the pandemic affected participants' care-seeking behavior and their ability to access to TB diagnostic services, particularly for those diagnosed in the first year of the pandemic. Many participants initially had their symptoms attributed to COVID-19, resulting in delayed TB evaluation and additional costs for COVID-19 treatment. CONCLUSIONS: The COVID-19 pandemic impacted multiple steps in the pathway to care for TB patients in Lima, causing delays in TB diagnosis. These findings demonstrate how the shifting of health care resources to prioritize COVID-19 can lead to collateral damage for people with TB and other conditions.

Biomimetic Synthesis of PANI/Graphitic Oxidized Carbon Nitride for Supercapacitor Applications.

Polyaniline (PANI) composites have gained momentum as supercapacitive materials due to their high energy density and power density. However, some drawbacks in their performance remain, such as the low stability after hundreds of charge-discharge cycles and limitations in the synthesis scalability. Herein, we report for the first time PANI-Graphitic oxidized carbon nitride composites as potential supercapacitor material. The biomimetic polymerization of aniline assisted by hematin, supported by phosphorous and oxygen-modified carbon nitrides (g-POCN and g-OCN, respectively), achieved up to 89% yield. The obtained PAI/g-POCN and PANI/g-OCN show enhanced electrochemical properties, such as conductivity of up to 0.0375 S/cm, specific capacitances (Cs) of up to 294 F/g (at high current densities, 5 A/g) and a stable operation after 500 charge-discharge cycles (at 3 A/g). In contrast, the biomimetic synthesis of Free PANI, assisted by stabilized hematin in cosolvents, exhibited lower performance properties (65%). Due to their structural differences, the electrochemical properties of Free PANI (conductivity of 0.0045 S/cm and Cs of up to 82 F/g at 5 A/g) were lower than those of nanostructured PANI/g-POCN and g-OCN supports, which provide stability and improve the properties of biomimetically synthesized PANI. This work reveals the biomimetic synthesis of PANI, assisted by hematin supported by modified carbon nitrides, as a promising strategy to produce nanostructured supercapacitors with high performance.

Geospatial analysis of reported activity locations to identify sites for tuberculosis screening.

Mobile screening units can help close tuberculosis case detection gaps. Placing screening units where people at high risk for undiagnosed tuberculosis preferentially spend time could make screening more resource-effective. We conducted a case-control study in Lima, Peru to identify locations where people with tuberculosis were more likely to spend time than community controls. We surveyed participants about activity locations over the past 6 months. We used density-based clustering to assess how patient and control activity locations differed, and logistic regression to compare location-based exposures. We included 109 tuberculosis patients and 79 controls. In density-based clustering analysis, the two groups had similar patterns of living locations, but their work locations clustered in distinct areas. Both groups were similarly likely to use public transit, but patients predominantly used buses and were less likely to use rapid transit (adjusted odds ratio [aOR] 0.31, 95% confidence interval [CI] 0.10-0.96) or taxis (aOR 0.42, 95% CI 0.21-0.85). Patients were more likely to have spent time in prison (aOR 11.55, 95% CI 1.48-90.13). Placing mobile screening units at bus terminals serving locations where tuberculosis patients have worked and within and around prisons could help reach people with undiagnosed tuberculosis.

Aproximación a los factores predisponentes a la deprivación sociocultural en los ámbitos familia, escuela, comunidad / Approach to Predisposing Factors to Sociocultural Deprivation in the Family, School, and Community Settings

Resumen El presente artículo presenta los factores predisponentes a la deprivación sociocultural en escuelas públicas en los ámbitos familia, escuela y comunidad. Los resultados evidencian que la dimensión apoyo social comunitario presenta los niveles más altos y la dinámica familiar los más bajos. Asimismo, se presenta un marco expositivo que relaciona la escuela, familia y comunidad como factores predisponentes a la deprivación sociocultural. El abordaje metodológico fue de un estudio mixto de prevalencia cualitativa. En la primera fase se empleó el método cuantitativo, de tipo descriptivo y transversal y en la fase cualitativa se utiliza un enfoque biográfico narrativo.

Abstract This article introduces the predisposing factors to sociocultural deprivation in public schools in the family, school and community environments. The results show that the dimension community social support presents the highest levels and family dynamics presents the lowest. Likewise, an expository framework is presented, which relates school, family, and community as predisposing factors to sociocultural deprivation. The methodological approach was a mixed qualitative prevalence study. In the first phase, a quantitative, descriptive and cross-sectional method was used, and in the qualitative phase, a biographical narrative approach was used.

Wolframin is a novel regulator of tau pathology and neurodegeneration.

Selective neuronal vulnerability to protein aggregation is found in many neurodegenerative diseases including Alzheimer's disease (AD). Understanding the molecular origins of this selective vulnerability is, therefore, of fundamental importance. Tau protein aggregates have been found in Wolframin (WFS1)-expressing excitatory neurons in the entorhinal cortex, one of the earliest affected regions in AD. The role of WFS1 in Tauopathies and its levels in tau pathology-associated neurodegeneration, however, is largely unknown. Here we report that WFS1 deficiency is associated with increased tau pathology and neurodegeneration, whereas overexpression of WFS1 reduces those changes. We also find that WFS1 interacts with tau protein and controls the susceptibility to tau pathology. Furthermore, chronic ER stress and autophagy-lysosome pathway (ALP)-associated genes are enriched in WFS1-high excitatory neurons in human AD at early Braak stages. The protein levels of ER stress and autophagy-lysosome pathway (ALP)-associated proteins are changed in tau transgenic mice with WFS1 deficiency, while overexpression of WFS1 reverses those changes. This work demonstrates a possible role for WFS1 in the regulation of tau pathology and neurodegeneration via chronic ER stress and the downstream ALP. Our findings provide insights into mechanisms that underpin selective neuronal vulnerability, and for developing new therapeutics to protect vulnerable neurons in AD.

Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer's disease.

Abnormalities in brain glucose metabolism and accumulation of abnormal protein deposits called plaques and tangles are neuropathological hallmarks of Alzheimer's disease (AD), but their relationship to disease pathogenesis and to each other remains unclear. Here we show that succinylation, a metabolism-associated post-translational protein modification (PTM), provides a potential link between abnormal metabolism and AD pathology. We quantified the lysine succinylomes and proteomes from brains of individuals with AD, and healthy controls. In AD, succinylation of multiple mitochondrial proteins declined, and succinylation of small number of cytosolic proteins increased. The largest increases occurred at critical sites of amyloid precursor protein (APP) and microtubule-associated tau. We show that in vitro, succinylation of APP disrupted its normal proteolytic processing thereby promoting Aß accumulation and plaque formation and that succinylation of tau promoted its aggregation to tangles and impaired microtubule assembly. In transgenic mouse models of AD, elevated succinylation associated with soluble and insoluble APP derivatives and tau. These findings indicate that a metabolism-linked PTM may be associated with AD.

Post-translational modifications within tau paired helical filament nucleating motifs perturb microtubule interactions and oligomer formation.

Post-translationally modified tau is the primary component of tau neurofibrillary tangles, a pathological hallmark of Alzheimer's disease and other tauopathies. Post-translational modifications (PTMs) within the tau microtubule (MT)-binding domain (MBD), which encompasses two hexapeptide motifs that act as critical nucleating regions for tau aggregation, can potentially modulate tau aggregation as well as interactions with MTs and membranes. Here, we characterize the effects of a recently discovered tau PTM, lysine succinylation, on tau-tubulin interactions and compare these to the effects of two previously reported MBD modifications, lysine acetylation and tyrosine phosphorylation. As generation of site-specific PTMs in proteins is challenging, we used short synthetic peptides to quantify the effects on tubulin binding of three site-specific PTMs located within the PHF6∗ (paired helical filament [PHF] residues 275-280) and PHF6 (residues 306-311) hexapeptide motifs: K280 acetylation, Y310 phosphorylation, and K311 succinylation. We compared these effects to those observed for MBD PTM-mimetic point mutations K280Q, Y310E, and K311E. Finally, we evaluated the effects of these PTM-mimetic mutations on MBD membrane binding and membrane-induced fibril and oligomer formation. We found that all three PTMs perturb tau MT binding, with Y310 phosphorylation exerting the strongest effect. PTM-mimetic mutations partially recapitulated the effects of the PTMs on MT binding and also disrupted tau membrane binding and membrane-induced oligomer and fibril formation. These results imply that these PTMs, including the novel and Alzheimer's disease-specific succinylation of tau K311, may influence both the physiological and pathological interactions of tau and thus represent targets for therapeutic intervention.

Tinkering With Testing: Understanding How Museum Program Design Advances Engineering Learning Opportunities for Children.

Using a design-based research approach, we studied ways to advance opportunities for children and families to engage in engineering design practices in an informal educational setting. 213 families with 5-11-year-old children were observed as they visited a tinkering exhibit at a children's museum during one of three iterations of a program posing an engineering design challenge. Children's narrative reflections about their experience were recorded immediately after tinkering. Across iterations of the program, changes to the exhibit design and facilitation provided by museum staff corresponded to increased families' engagement in key engineering practices. In the latter two cycles of the program, families engaged in the most testing, and in turn, redesigning. Further, in the latter cycles, the more children engaged in testing and retesting during tinkering, the more their narratives contained engineering-related content. The results advance understanding and the evidence base for educational practices that can promote engineering learning opportunities for children.

The safety of drugs for inflammatory bowel disease during pregnancy and breastfeeding: the DUMBO registry study protocol of GETECCU.

BACKGROUND: Active disease during conception and pregnancy in women with inflammatory bowel disease (IBD) increases the risk of pregnancy complications and adverse neonatal outcomes. The use of IBD treatments during pregnancy should be weighed against their adverse effects on the neonate, but longer-term safety data and data on serious infection rates and malignancies postnatally are lacking, particularly for newer drugs, such as tofacitinib, vedolizumab and ustekinumab. METHODS: This ongoing, prospective registry study being conducted at 70 centres in Spain is enrolling pregnant women who are ⩾18 years, are at any point in pregnancy up to the end of the second trimester and have a diagnosis of Crohn's disease, ulcerative colitis or unclassified IBD. Patients will receive treatment decided independently by their IBD specialist. Each incident gestation will be followed up through pregnancy and the first 4 years postnatally. Three cohorts will be compared: biologicals exposed, immunomodulatory exposed and non-exposed. The primary endpoint is the risk of severe infection in newborns postnatally up to 4 years of age; other endpoints include serious adverse events (SAEs) such as pregnancy and delivery complications, neonatal SAEs, development [Ages and Stages Questionnaire-3 (ASQ3)], and malignancy incidence, up to 4 years of age. IBD specialists will collect maternal data (baseline/end of each trimester/1 month post-delivery), neonatal birth data, and the SAE and ASQ3 data in children exposed during pregnancy, reported every 3 months by the mother. Statistical analysis will include summary statistics for quantitative variables, comparisons of qualitative variables with significance set at p < 0.025 and a binary logistic regression model to determine the risk factors for severe infections. RESULTS: Enrolment began in September 2019 and study completion is expected in September 2028. CONCLUSIONS: This prospective, controlled study will provide evidence on the long-term safety profile in children after intrauterine and lactation exposure to biological and immunomodulatory IBD treatments, including data on postnatal severe infections, development and malignancies. CLINICALTRIALSGOV IDENTIFIER: NCT03894228.

Wild pigs (Sus scrofa) population as reservoirs for deleterious mutations in the RYR1 gene associated with Porcine Stress Syndrome.

Porcine Stress Syndrome (PSS) is a disorder codified by the ryanodine receptor 1 gene (RYR1) and affects both animal welfare and the quality of the meat product. As a consequence, individuals with this syndrome generate great worldwide economic losses in the porcine industry. In Argentina, the Buenos Aires Province is the most involved on this activity, and productions are to be in open field with a higher frequency of pigs with diverse pathologies. On the other hand, the biggest and oldest wild pigs population is located on the Atlantic coast of Buenos Aires Province, which presents a continuous bidirectional flow of individuals with the productive areas nearby. The aim of this study is to detect the presence of the RYR1 deleterious allele in the wild population from the Atlantic coast of Buenos Aires, in order to evaluate its possible role as a genetic reservoir for said allele. For this purpose, 106 wild pigs from 28 sites were studied, finding a 6.6% of carrier individuals, indicating that the wild population is not free of this allele. This constitutes the first analysis to detect the presence of the RYR1 deleterious allele, associated to the PSS in wild pigs from Argentina, being one of the few studies to report it worldwide and suggesting wild pigs populations to be a possible genetic reservoir for this disease.

Revisión de cirugía laparoscópica durante la pandemia por COVID-19 / Laparoscopic surgery during the COVID-19 pandemic a review

The SARS-CoV-2 pandemic has changed the management protocols of the different surgical areas and practices of health institutions around the world. The countries most affected by the disease have reported an alarming impact on the number of infected and deceased by COVID-19 among health workers. Personnel specialized in airway management have a greater risk of contagion when directly exposed to the aerosolization of the virus. This leads us to consider the probability of postponing or restricting procedures due to limited resources and/or due to patient conditions that increase the risk of death, given that the usual surgical techniques generate more aerosols. This narrative review article aims to analyze the risk of contamination of professionals in laparoscopic surgery of patients infected by COVID-19, proposing strategies to minimize the risk of exposure, identifying the necessary protection measures for health professionals, providing recommendations and adaptations of both the surgical technique and the organization of the operating room according to clinical and scientific evidence.

La pandemia por el SARS-CoV-2 ha cambiado los protocolos de manejo de las distintas áreas y prácticas quirúrgicas de las instituciones de salud en el mundo. Los países con mayor afectación de la enfermedad han reportado un impacto alarmante sobre el número de infectados y fallecidos por COVID-19 entre trabajadores de la salud. El personal especializado en el manejo de la vía aérea, posee un mayor riesgo de contagio al exponerse directamente a la aerosolización del virus. Esto conlleva a considerar la probabilidad de posponer o restringir procedimientos por limitación de los recursos y/o por condiciones del paciente que aumenten el riesgo de muerte, dado que las técnicas quirúrgicas habituales generan más aerosoles. Este artículo, de revisión narrativa, pretende analizar el riesgo de contaminación de los profesionales en cirugía laparoscópica de pacientes infectados por COVID-19, proponiendo estrategias para minimizar el riesgo de exposición, identificando las medidas necesarias de protección para los profesionales de la salud, aportando recomendaciones y adaptaciones tanto de la técnica quirúrgica como de la organización del quirófano según la evidencia clínica y científica

Tau induces PSD95-neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration.

Cerebrovascular abnormalities have emerged as a preclinical manifestation of Alzheimer's disease and frontotemporal dementia, diseases characterized by the accumulation of hyperphosphorylated forms of the microtubule-associated protein tau. However, it is unclear whether tau contributes to these neurovascular alterations independent of neurodegeneration. We report that mice expressing mutated tau exhibit a selective suppression of neural activity-induced cerebral blood flow increases that precedes tau pathology and cognitive impairment. This dysfunction is attributable to a reduced vasodilatation of intracerebral arterioles and is reversible by reducing tau production. Mechanistically, the failure of neurovascular coupling involves a tau-induced dissociation of neuronal nitric oxide synthase (nNOS) from postsynaptic density 95 (PSD95) and a reduced production of the potent vasodilator nitric oxide during glutamatergic synaptic activity. These data identify glutamatergic signaling dysfunction and nitric oxide deficiency as yet-undescribed early manifestations of tau pathobiology, independent of neurodegeneration, and provide a mechanism for the neurovascular alterations observed in the preclinical stages of tauopathies.