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Abstract Background Cameroon is amongst the worst affected countries by road traffic injuries with an estimated 1443 disability-adjusted life years per 100,000 population. There have been very limited reports on the crucial prehospital response to road traffic injuries in Cameroon. This study aimed to identify prehospital factors associated with RTI mortality in Cameroon. Methods We included patients enrolled between June 2022 and March 2023 in the Cameroon Trauma Registry. Information about prehospital factors and demographic data was obtained from patients or their proxies. We examined the association of prehospital care factors like care at the crash scene and type of transportation during crash with final patient outcome. We used Chi-squared test to investigate the association between selected independent variables and mortality. A multivariable logistic regression model was built to identify independent predictors of dying from an RTI. Results RTIs constituted 69.5% (n = 3203) of all injuries in the Cameroon Trauma Registry. Only 20.7% (n = 102) of 4 + wheel vehicle occupants had seatbelts on and just 2.7% (n = 53) of motorcycle riders were wearing helmets during the collision. Only 4.9% (n = 156) of patients received any form of scene care. In-hospital mortality was 4.3% (n = 139) and was associated with male sex (AOR = 1.7, 95%CI = 1.08–2.80), crashing on a motorcycle (AOR = 2.08, 95%CI = 1.1–3.67) and scene care (AOR = 0.25, 95%CI = 0.04–0.80). Conclusions Receiving any type of care at the scene such as bleeding control or being placed in the recovery position by bystanders is associated with improved survival. Improving on existing informal prehospital care responses should be a priority in Cameroon.

Abstract Background Breastfeeding is recognized as the gold standard of infant feeding and nutrition. The World Health Organization recommends exclusive breastfeeding (EBF) of infants for the first 6 months of life. A variety of factors may impact breastfeeding practices in-hospital which may continue after hospital discharge, such as the use of breastmilk substitutes (BMS). The Baby-Friendly Initiative (BFI), which aims to promote and support breastfeeding practices, established a target rate of 75% for EBF from birth to hospital discharge. Currently, this target is not being met at The Ottawa Hospital (TOH), indicating there is room for improvement in EBF rates. The purpose of this study is to explore health care professionals (HCP) decision-making around use of BMS and identify factors that drive the use of BMS with and without medical indications. Methods In this qualitative study, semi-structured interviews were conducted with HCPs within TOH from January to June 2022. All participants had experience in maternity or postpartum care and were probed on factors influencing use of BMS at this institution. Interview transcripts were coded using an inductive approach. Results A total of 18 HCPs were interviewed including physicians, midwives, lactation consultants, and registered nurses. Multilevel barriers influencing the use of BMS were categorized into patient, HCP, and institution-level factors. Subthemes that emerged ranged from parental preferences, training differences amongst HCPs, to budget and staffing issues. Over half of HCPs were prepared to answer questions on EBF and were familiar with the BFI. Although most were supportive of this institution receiving BFI designation, a few providers raised concerns of its impact on parents who would like to supplement. Conclusions Several modifiable factors influencing decision-making for use of BMS were identified. These findings will be used to inform unit leads, help identify effective strategies to address modifiable barriers, and develop tailored breastfeeding supports to improve EBF rates.

Objectives This study aimed to develop a machine learning (ML) model to predict disengagement from HIV care, high viral load or death among people living with HIV (PLHIV) with the goal of enabling proactive support interventions in Tanzania. The algorithm addressed common challenges when applying ML to electronic medical record (EMR) data: (1) imbalanced outcome distribution; (2) heterogeneity across multisite EMR data and (3) evolving virological suppression thresholds.Design Observational study using a national EMR database.Setting Conducted in two regions in Tanzania, using data from the National HIV Care database.Participants The study included over 6 million HIV care visit records from 295 961 PLHIV in two regions in Tanzania’s National HIV Care database from January 2015 to May 2023.Results Our ML model effectively identified PLHIV at increased risk of adverse outcomes. Key predictors included past disengagement from care, antiretroviral therapy (ART) status (which tracks a patient’s engagement with ART across visits), age and time on ART. The downsampling approach we implemented effectively managed imbalanced data to reduce prediction bias. Site-specific algorithms performed better compared with a universal approach, highlighting the importance of tailoring ML models to local contexts. A sensitivity analysis confirmed the model’s robustness to changes in viral load suppression thresholds.Conclusions ML models leveraging large-scale databases of patient data offer significant potential to identify PLHIV for interventions to enhance engagement in HIV care in resource-limited settings. Tailoring algorithms to local contexts and flexibility towards evolving clinical guidelines are essential for maximising their impact.

Introduction Adverse sexual and reproductive health (SRH) outcomes, such as unplanned pregnancies and HIV infection, disproportionately affect adolescent girls and young women (AGYW; aged 15–24 years) in east Africa. Increasing uptake of preventive SRH services via innovative, youth-centred interventions is imperative to addressing disparities in SRH outcomes.Methods and analysis From 2018 to 2019, we used human-centred design to co-develop a theoretically driven HIV and pregnancy prevention intervention for AGYW at private drug shops called Accredited Drug Dispensing Outlets (ADDOs) in Tanzania. The result, Malkia Klabu (Queen Club), was a customer loyalty programme designed to strengthen ADDOs’ role as SRH providers while encouraging uptake of critical SRH prevention products among AGYW. Malkia Klabu members had access to free contraceptives and oral HIV self-test (HIVST) kits and earned punches on a loyalty card for other shop purchases; punches were redeemable for small prizes. Our pilot among 40 shops showed that intervention ADDOs had higher AGYW patronage and distributed more HIVST kits and contraceptives to AGYW relative to business-as-usual (ie, client purchasing) comparison shops. We will conduct a cluster-randomised controlled trial (c-RCT) among 120–140 ADDOs in 40 health catchment areas in Shinyanga and Mwanza Regions (Lake Zone), Tanzania. ADDO shop recruitment includes a 1-month run-in with a tablet-based electronic inventory management system for tracking shop transactions, followed by enrolment, randomisation and a 24-month trial period. Our c-RCT evaluating the human-centred design-derived intervention will assess population impact on the primary outcomes of HIV diagnoses and antenatal care registrations, measured with routine health facility data. We will also assess secondary outcomes focusing on mechanisms of action, evaluate programme exposure and AGYW behaviour change in interviews with AGYW, and assess shop-level implementation strategies and fidelity.Ethics and dissemination Ethical approval was granted from both the University of California, San Francisco and the Tanzanian National Institute for Medical Research. Study progress and final outcomes will be posted annually to the National Clinical Trials website; study dissemination will occur at conferences, peer-reviewed manuscripts and local convenings of stakeholders.Trial registration number NCT05357144.

Background Acculturation affects hypertension prevalence among Hispanic people, but there have been no recent analyses specifically focused on Mexican American (MA) people. We sought to determine age‐adjusted hypertension prevalence, abdominal obesity, and acculturation trends among MA adults and non‐Hispanic White adults. Methods and Results Data from the NHANES (National Health and Nutrition Examination Survey) were analyzed in 2‐year increments to observe trends in hypertension and risk factors (age, sex, body mass index, smoking status, abdominal obesity, waist‐to‐height ratio (WHtR), education, and income). Acculturation was based on three commonly used measures. The sample included 30 920 adults. Age‐adjusted hypertension prevalence is higher in MA adults (52.7%) than White adults (48.3%). Hypertension risk factors—age, obesity prevalence, WHtR, acculturation—all significantly increased among MA adults, while smoking declined. Higher acculturation scores increased hypertension likelihood (odds ratio [OR], 1.44 [95% CI, 0.91–1.97]) for MA adults compared with those with lower acculturation scores. White adults with elevated WHtR >0.5 had a 40% higher risk of hypertension than those with WHtR

Abstract Background Adolescent girls and young woman (AGYW) comprise a significant proportion of new HIV infections and unintended pregnancies in sub-Saharan Africa yet face many barriers to accessing family planning and reproductive health (FPRH) information and services. Developed via human-centered design, the Malkia Klabu (“Queen Club”) program aimed to facilitate access to HIV self-testing (HIVST) and FPRH information and products at privately-owned drug shops. We sought to understand barriers and facilitators to program implementation in a 4-month pilot in Tanzania. Methods Forty semi-structured interviews were conducted with participants in a cluster randomized trial of the Malkia Klabu program from November 2019 through March 2020, including 11 with AGYW, 26 with drug shopkeepers, and three with counselors at health facilities to whom AGYW were referred. Interviews were audio-recorded, transcribed, coded, and analyzed to identify key themes. The Consolidated Framework for Implementation Research (CFIR) was used to assess barriers and facilitators to program implementation at multiple levels. CFIR considers the outer setting (e.g., culture and systemic conditions), the inner setting where the intervention is implemented (e.g., incentives, relationships, and available resources), the individuals involved, the innovation as it relates to stakeholder needs, and the implementation process. Results The Malkia Klabu program reshaped and directed the role of drug shopkeepers as providers of information and resources rather than FPRH gatekeepers. Key implementation facilitators included the program’s adaptability to a wide range of needs and stages of readiness among AGYW, ability to capitalize on AGYW social networks for driving membership, responsiveness to AGYW’s need for privacy, and positive contributions to the income and community standing of drug shopkeepers. Components such as HIVST were highly acceptable to both AGYW and shopkeepers, and the introduction of the loyalty program and HIVST kits in shops opened doors to the provision of FPRH products and information, which was further facilitated by program tools such as videos, product displays, and symbol cards. Although some shopkeepers maintained beliefs that certain contraceptive methods were inappropriate for AGYW, most appeared to provide the products as part of the program. Conclusions The Malkia Klabu intervention's success was due in part to its ability to address key motivations of both AGYW and drug shopkeepers, such as maintaining privacy and increasing access to FPRH products for AGYW and increasing business for shops. Better understanding these implementation barriers and facilitators can inform the program’s future adaptation and scale-up. Trial registration: clinicaltrials.gov #NCT04045912.

Abstract Background Economic incentives can improve clinical outcomes among in-care people living with HIV (PLHIV), but evidence is limited for their effectiveness among out-of-care PLHIV or those at risk of disengagement. We propose a type 1 hybrid effectiveness-implementation study to advance global knowledge about the use of economic incentives to strengthen the continuity of HIV care and accelerate global goals for HIV epidemic control. Methods The Rudi Kundini, Pamoja Kundini study will evaluate two implementation models of an economic incentive strategy for supporting two groups of PLHIV in Tanzania. Phase 1 of the study consists of a two-arm, cluster randomized trial across 32 health facilities to assess the effectiveness of a home visit plus one-time economic incentive on the proportion of out-of-care PLHIV with viral load suppression (

Musculoskeletal disorders are among the main causes of disease‐associated disability. Moreover, the incidence and prevalence of osteoporosis and osteoarthritis, as well as the risk of bone fractures and the need for joint replacements, are expected to increase with longer life expectancy. New approaches based on electromagnetic stimulation have been developed, aiming to shorten bone healing time, attenuate osteoporosis and osteoarthritis, and increase implants' osseointegration. Inductive coupling (IC), a non‐invasive methodology to deliver magnetic stimuli, has reached clinical trials and some clinical practices but is not yet considered a standard procedure. Indeed, its feasibility in clinical use is still under discussion, and optimal stimulation parameters are fairly undefined. This comprehensive review describes the research trends and applicability of IC‐based therapeutics for musculoskeletal disorders, and starts identifying top‐performing magnetic stimulation parameters. Insights into the magnetic stimuli setups that promote osteogenesis are provided, based on pre‐clinical and clinical evidence from 117 in vivo studies in animal models and human patients. Potential cellular and molecular biomechanisms mediating IC‐induced effects on osteoblasts and osteoclasts are also explored. The transversal knowledge herein delivered will hopefully support innovative designs and medical devices that will implement IC stimulation as a clinical standard and effective therapeutic for musculoskeletal disorders.

Abstract Background Applying the knowledge gained through implementation science can support the uptake of research evidence into practice; however, those doing and supporting implementation (implementation practitioners) may face barriers to applying implementation science in their work. One strategy to enhance individuals’ and teams’ ability to apply implementation science in practice is through training and professional development opportunities (capacity-building initiatives). Although there is an increasing demand for and offerings of implementation practice capacity-building initiatives, there is no universal agreement on what content should be included. In this study we aimed to explore what capacity-building developers and deliverers identify as essential training content for teaching implementation practice. Methods We conducted a convergent mixed-methods study with participants who had developed and/or delivered a capacity-building initiative focused on teaching implementation practice. Participants completed an online questionnaire to provide details on their capacity-building initiatives; took part in an interview or focus group to explore their questionnaire responses in depth; and offered course materials for review. We analyzed a subset of data that focused on the capacity-building initiatives’ content and curriculum. We used descriptive statistics for quantitative data and conventional content analysis for qualitative data, with the data sets merged during the analytic phase. We presented frequency counts for each category to highlight commonalities and differences across capacity-building initiatives. Results Thirty-three individuals representing 20 capacity-building initiatives participated. Study participants identified several core content areas included in their capacity-building initiatives: (1) taking a process approach to implementation; (2) identifying and applying implementation theories, models, frameworks, and approaches; (3) learning implementation steps and skills; (4) developing relational skills. In addition, study participants described offering applied and pragmatic content (e.g., tools and resources), and tailoring and evolving the capacity-building initiative content to address emerging trends in implementation science. Study participants highlighted some challenges learners face when acquiring and applying implementation practice knowledge and skills. Conclusions This study synthesized what experienced capacity-building initiative developers and deliverers identify as essential content for teaching implementation practice. These findings can inform the development, refinement, and delivery of capacity-building initiatives, as well as future research directions, to enhance the translation of implementation science into practice.

Abstract Background Moving evidence into practice is complex, and pregnant and birthing people and their infants do not always receive care that aligns with the best available evidence. Implementation science can inform how to effectively move evidence into practice. While there are a growing number of examples of implementation science being studied in maternal-newborn care settings, it remains unknown how real-world teams of healthcare providers and leaders approach the overall implementation process when making practice changes. The purpose of this study was to describe maternal-newborn hospital teams’ approaches to implementing practice changes. We aimed to identify what implementation steps teams take (or not) and identify strengths and potential areas for improvement based on best practices in implementation science. Methods We conducted a supplementary qualitative secondary analysis of 22 interviews completed in 2014–2015 with maternal-newborn nursing leaders in Ontario, Canada. We used directed content analysis to code the data to seven steps in an implementation framework (Implementation Roadmap): identify the problem and potential best practice; assemble local evidence; select and customize best practice; discover barriers and drivers; tailor implementation strategies; field-test, plan evaluation, prepare to launch; launch, evaluate, and sustain. Frequency counts are presented for each step. Results Participants reported completing a median of 4.5 of 7 Implementation Roadmap steps (range = 3–7), with the most common being identifying a practice problem. Other steps were described less frequently (e.g., selecting and adapting evidence, field-testing, outcome evaluation) or discussed frequently but not optimally (e.g., barriers assessment). Participants provided examples of how they engaged point-of-care staff throughout the implementation process, but provided fewer examples of engaging pregnant and birthing people and their families. Some participants stated they used a formal framework or process to guide their implementation process, with the most common being quality improvement approaches and tools. Conclusions We identified variability across the 22 hospitals in the implementation steps taken. While we observed many strengths, we also identified areas where further support may be needed. Future work is needed to create opportunities and resources to support maternal-newborn healthcare providers and leaders to apply principles and tools from implementation science to their practice change initiatives.

Abstract Striatal dysfunction has been implicated in the pathophysiology of schizophrenia, a disorder characterized by positive symptoms such as hallucinations and delusions. Haloperidol is a typical antipsychotic medication used in the treatment of schizophrenia that is known to antagonize dopamine D2 receptors, which are abundantly expressed in the striatum. However, haloperidol’s delayed therapeutic effect also suggests a mechanism of action that may go beyond the acute blocking of D2 receptors. Here, we performed proteomic analysis of striatum brain tissue and found more than 400 proteins significantly altered after 30 days of chronic haloperidol treatment in mice, namely proteins involved in glutamatergic and GABAergic synaptic transmission. Cell-type specific electrophysiological recordings further revealed that haloperidol not only reduces the excitability of striatal medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) but also affects D1-MSNs by increasing the ratio of inhibitory/excitatory synaptic transmission (I/E ratio) specifically onto D1-MSNs but not D2-MSNs. Therefore, we propose the slow remodeling of D1-MSNs as a mechanism mediating the delayed therapeutic effect of haloperidol over striatum circuits. Understanding how haloperidol exactly contributes to treating schizophrenia symptoms may help to improve therapeutic outcomes and elucidate the molecular underpinnings of this disorder.

Abstract Background The field of violence prevention research is unequivocal that interventions must target contextual factors, like social norms, to reduce gender-based violence. Limited research, however, on the social norms contributing to intimate partner violence or reproductive coercion exists. One of the driving factors is lack of measurement tools to accurately assess social norms. Methods Using an item response modelling approach, this study psychometrically assesses the reliability and validity of a social norms measure of the acceptability of intimate partner violence to exert control over wife agency, sexuality, and reproductive autonomy with data from a population-based sample of married adolescent girls (ages 13–18) and their husbands in rural Niger (n = 559 husband-wife dyads) collected in 2019. Results A two-dimensional Partial Credit Model for polytomous items was fit, showing evidence of reliability and validity. Higher scores on the “challenging husband authority” dimension were statistically associated with husband perpetration of intimate partner violence. Conclusions This brief scale is a short (5 items), practical measure with strong reliability and validity evidence. This scale can help identify populations with high-need for social norms-focused IPV prevention and to help measure the impact of such efforts.

Abstract Background Concerns about the interconnected relationship between HIV and mental health were heightened during the COVID-19 pandemic. This study assessed whether there were temporal changes in the mental health status of people living with HIV presenting for care in Shinyanga region, Tanzania. Specifically, we compared the prevalence of depression and anxiety before and during COVID-19, with the goal of describing the changing needs, if any, to person-centered HIV services. Methods We analyzed baseline data from two randomized controlled trials of adults initiating ART in Shinyanga region, Tanzania between April-December 2018 (pre-COVID-19 period, n = 530) and May 2021-March 2022 (COVID-19 period, n = 542), respectively. We compared three mental health indicators that were similarly measured in both surveys: loss of interest in things, hopelessness about the future, and uncontrolled worrying. We also examined depression and anxiety which were measured using the Hopkins Symptom Checklist-25 in the pre-COVID-19 period and the Patient Health Questionnaire-4 in the COVID-19 period, respectively, and classified as binary indicators per each scale’s threshold. We estimated prevalence differences (PD) in adverse mental health status before and during the COVID-19 pandemic, using stabilized inverse probability of treatment weighting to adjust for underlying differences in the two study populations. Results We found significant temporal increases in the prevalence of feeling ‘a lot’ and ‘extreme’ loss of interest in things [‘a lot’ PD: 38, CI 34,41; ‘extreme’ PD: 9, CI 8,12)], hopelessness about the future [‘ a lot’ PD: 46, CI 43,49; ‘extreme’ PD: 4, CI 3,6], and uncontrolled worrying [‘ a lot’ PD: 34, CI 31,37; ‘extreme’ PD: 2, CI 0,4] during the COVID-19 pandemic. We also found substantially higher prevalence of depression [PD: 38, CI 34,42] and anxiety [PD: 41, CI 37,45]. Conclusions After applying a quasi-experimental weighting approach, the prevalence of depression and anxiety symptoms among those starting ART during COVID-19 was much higher than before the pandemic. Although depression and anxiety were measured using different, validated scales, the concurrent increases in similarly measured mental health indicators lends confidence to these findings and warrants further research to assess the possible influence of COVID-19 on mental health among adults living with HIV. Trial Registration NCT03351556, registered November 24, 2017; NCT04201353, registered December 17, 2019.

IntroductionLittle is known regarding health care seeking behaviors of women in sub-Saharan Africa, specifically Cameroon, who experience violence. The proportion of women who experienced violence enrolled in the Cameroon Trauma Registry (CTR) is lower than expected.MethodsWe concatenated the databases from the October 2017-December 2020 CTR and 2018 Cameroon Demographic and Health Survey (DHS) into a singular database for cross-sectional study. Continuous and categorical variables were compared with Wilcoxon rank-sum and Fisher's exact test. Multivariable logistic regression examined associations between demographic factors and women belonging to the DHS or CTR cohort. We performed additional classification tree and random forest variable importance analyses.Results276 women (13%) in the CTR and 197 (13.1%) of women in the DHS endorsed violence from any perpetrator. A larger percentage of women in the DHS reported violence from an intimate partner (71.6% vs. 42.7%, pConclusionWomen who experienced violence presenting for hospital care have characteristics associated with higher SES and are less likely to demonstrate factors associated with residence in a rural setting compared to the general population of women experiencing violence.

This paper examines the ordeals actors of SMEs face in the adoption process of Emerging Digital Marketing Technology (EDMT). A conceptual framework was proposed to capture actors that participate in EMDT and the difficulties they (themselves) pose that hinder successful adoption. However, a purposive sample of 26 participants drawn from Crunch online database, Luton were interviewed on unstructured and semi-structured bases and analyzed using a thematic approach. The interviews on the problems were coded and classified based on the actors involved in the adoption process to extend the T-O-E framework. The findings revealed that while extant problems relate to the contexts of technology, organization, and environment, the extended T-O-E framework unraveled more critical problems that are linked to the in-grained human context. Implicit is that vendors should work on decision-makers, given that some of the adoption decisions are critically and continuously influenced by the actors.

Therapeutic nucleic acids (TNAs) are gaining increasing interest in the treatment of severe diseases including viral infections, inherited disorders, and cancers. However, the efficacy of intracellularly functioning TNAs is also reliant upon their delivery into the cellular environment, as unmodified nucleic acids are unable to cross the cell membrane mainly due to charge repulsion. Here we show that TNAs can be effectively delivered into the cellular environment using engineered nanoscale metal-organic frameworks (nanoMOFs), with the additional ability to tailor which cells receive the therapeutic cargo determined by the functional moieties grafted onto the nanoMOF's surface. This study paves the way to integrate the highly ordered programmable nucleic acids into larger-scale functionalized nanoassemblies.

Oxidation–reduction post-translational modifications (redox-PTMs) are chemical alterations to amino acids of proteins. Redox-PTMs participate in the regulation of protein conformation, localization and function, acting as signalling effectors that impact many essential biochemical processes in the cells. Crucially, the dysregulation of redox-PTMs of proteins has been implicated in the pathophysiology of numerous human diseases, including neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. This review aims to highlight the current gaps in knowledge in the field of redox-PTMs biology and to explore new methodological advances in proteomics and computational modelling that will pave the way for a better understanding of the role and therapeutic potential of redox-PTMs of proteins in neurodegenerative diseases. Here, we summarize the main types of redox-PTMs of proteins while providing examples of their occurrence in neurodegenerative diseases and an overview of the state-of-the-art methods used for their detection. We explore the potential of novel computational modelling approaches as essential tools to obtain insights into the precise role of redox-PTMs in regulating protein structure and function. We also discuss the complex crosstalk between various PTMs that occur in living cells. Finally, we argue that redox-PTMs of proteins could be used in the future as diagnosis and prognosis biomarkers for neurodegenerative diseases.

Methicillin-resistant Staphylococcus aureus (M RSA) infections, in particular biofilm-organized bacteria, remain a clinical challenge and a serious health problem. Rifabutin (RFB), an antibiotic of the rifamycins class, has shown in previous work excellent anti-staphylococcal activity. Here, we proposed to load RFB in liposomes aiming to promote the accumulation of RFB at infected sites and consequently enhance the therapeutic potency. Two clinical isolates of MRSA, MRSA-C1 and MRSA-C2, were used to test the developed formulations, as well as the positive control, vancomycin (VCM). RFB in free and liposomal forms displayed high antibacterial activity, with similar potency between tested formulations. In MRSA-C1, minimal inhibitory concentrations (MIC) for Free RFB and liposomal RFB were 0.009 and 0.013 μg/mL, respectively. Minimum biofilm inhibitory concentrations able to inhibit 50% biofilm growth (MBIC50) for Free RFB and liposomal RFB against MRSA-C1 were 0.012 and 0.008 μg/mL, respectively. Confocal microscopy studies demonstrated the rapid internalization of unloaded and RFB-loaded liposomes in the bacterial biofilm matrix. In murine models of systemic MRSA-C1 infection, Balb/c mice were treated with RFB formulations and VCM at 20 and 40 mg/kg of body weight, respectively. The in vivo results demonstrated a significant reduction in bacterial burden and growth index in major organs of mice treated with RFB formulations, as compared to Control and VCM (positive control) groups. Furthermore, the VCM therapeutic dose was two fold higher than the one used for RFB formulations, reinforcing the therapeutic potency of the proposed strategy. In addition, RFB formulations were the only formulations associated with 100% survival. Globally, this study emphasizes the potential of RFB nanoformulations as an effective and safe approach against MRSA infections.

Stem cells have potential applications in the field of neurological diseases, as they allow for the development of new biological models. These models can improve our understanding of the underlying pathologies and facilitate the screening of new therapeutics in the context of precision medicine. Stem cells have also been applied in clinical tests to repair tissues and improve functional recovery. Nevertheless, although promising, commonly used stem cells display some limitations that curb the scope of their applications, such as the difficulty of obtention. In that regard, urine-derived cells can be reprogrammed into induced pluripotent stem cells (iPSCs). However, their obtaining can be challenging due to the low yield and complexity of the multi-phased and typically expensive differentiation protocols. As an alternative, urine-derived stem cells (UDSCs), included within the population of urine-derived cells, present a mesenchymal-like phenotype and have shown promising properties for similar purposes. Importantly, UDSCs have been differentiated into neuronal-like cells, auspicious for disease modeling, while overcoming some of the shortcomings presented by other stem cells for these purposes. Thus, this review assesses the current state and future perspectives regarding the potential of UDSCs in the ambit of neurological diseases, both for disease modeling and therapeutic applications.

Abstract Background Insects are known to be important sources of food and bioproducts, and companies around the world are currently offering goods and services based on their production and use. Colombia is one of the richest countries in the world in terms of biodiversity, with a great variety of insects that are not exploited for these uses at this time. Most studies relating to insects in Colombia are focused on agricultural pests or disease transmitters, and in most cases the advantages and potential applications of insects in the areas of agro-industry, medicine, biotechnology, and food are poorly known. To recognize the native species previously considered as a source of bioproducts, it is necessary to better evaluate their potential uses, as well as the possibilities of innovating with products derived from them. It is also important to consider advantages and disadvantages of using insects for specific purposes, minimum quality requirements and national and international regulations for production and marketing. Main body The growing world population has led to an increase in the demand for food and animal products, increasing the need for animal production. This has resulted in high pressure on the environment, water resources and biodiversity, which also contribute to climate change. New strategies are required, and emerging solutions include the use of alternative sources for bioproducts or meat, changing diets, and migrating to sustainable production systems. In the present study, available information pertaining to 107 species of insects reported in Colombia that have been indicated to be sources to produce bioproducts, or that are currently being used for that purpose is revised and analyzed. The insects documented are from 67 genera and mainly include the orders Hymenoptera (59%), Coleoptera (10%), and Blattaria (11%). Seventy-one percent (71%) of the insect species included are important as foods or food supplements, with 9% related to established or commercial products currently in development; and 36% currently recognized for their importance in obtaining valuable non-edible bioproducts within the pharmaceutical industry, medicine, biotechnology, and agro-inputs sectors. A list of species is presented and uses and applications are discussed. Conclusions Despite Colombia's enormous potential for sustainable development of insect-derived products, there is a lack of studies in this area. Most of the insects reported in this work are related to local and traditional knowledge and folk medicine of some populations in the country. In addition to apiculture, there are not industrialized insect farms in Colombia; however, there have been some initiatives to produce crickets of the species Acheta domestica and mealworms Tenebrio mollitor for human and animal consumption. Recently the traditional consumption of ants and certain termite species in some areas of the country has been refreshed by some chefs experimenting with insects in gourmet restaurants. There are few studies on the nutritional value or pharmaceutical uses of the local species and there is no clear regulation for breeding or use. This highlights the need for in-depth study and discussion of the advantages and disadvantages for potential use in the country.

Abstract Background COVID-19 vaccines are recommended for pregnant and lactating individuals, and there is substantial evidence for their safety and effectiveness. As the pandemic continues, information on worries and beliefs surrounding perinatal COVID-19 vaccination remains important to inform efforts aimed at improving vaccine uptake. Our objectives were to assess factors associated with COVID-19 vaccination among perinatal individuals; and to explore motivational factors associated with willingness to be vaccinated among unvaccinated perinatal individuals. Methods This was a cross-sectional web-based survey of preconception, pregnant, and lactating individuals in Canada. The outcomes of interest were vaccination with at least one dose of any COVID-19 vaccine and willingness to be vaccinated among unvaccinated individuals. Sample characteristics were summarized using frequencies and percentages. The association between eight prespecified risk factors and two outcomes (vaccination status and willingness to be vaccinated) was assessed by logistic regression. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for the total sample, and across perinatal sub-groups. Results Among 3446 survey respondents, there were 447 (13.0%) preconception, 1832 (53.2%) pregnant, and 1167 (42.4%) lactating. There were 1460 (42.4%) and 1982 (57.5%) who were vaccinated and unvaccinated, respectively. Factors positively associated with COVID-19 vaccine status were speaking to a healthcare provider about vaccination during the perinatal period (aOR:2.35, 95% CI:1.97–2.80) and believing that the COVID-19 vaccine is effective (aOR:1.91, 95% CI:1.46–2.48). Factors negatively associated with vaccine status included worries about fetal growth and development (aOR:0.55, 95% CI:0.43–0.70) and future child behavioral/neurodevelopmental problems (aOR:0.59, 95% CI:0.46–0.75). Among unvaccinated individuals specifically, characteristics positively associated with willingness to vaccinate were speaking to a healthcare provider (aOR:1.67, 95% CI:1.32–2.12) and believing the COVID-19 vaccine is effective (aOR:3.56, 95% CI:2.70–4.69). Factors negatively associated with willingness were concerns over infertility (aOR:0.66, 95% CI:0.49–0.88), fetal growth and development (aOR:0.33, 95% CI:0.24–0.46), and future child behavioral/neurodevelopmental problems (aOR:0.64, 95% CI:0.48–0.84). Conclusions In this Canadian perinatal population, approximately 42% reported COVID-19 vaccination. Among unvaccinated individuals, willingness to receive vaccination was high (73%). Factors enhancing vaccine willingness included discussions with healthcare providers and believing the vaccine was effective. Concerns regarding vaccine safety, particularly with respect to fetal/child development, were the greatest barriers to vaccine uptake.

During the rapid deployment of COVID-19 vaccines in 2021, safety concerns may have led some pregnant individuals to postpone vaccination until after giving birth. This study aimed to describe temporal patterns and factors associated with COVID-19 vaccine series initiation after recent pregnancy in Ontario, Canada. Using the provincial birth registry linked with the COVID-19 vaccine database, we identified all individuals who gave birth between January 1 and December 31, 2021, and had not yet been vaccinated by the end of pregnancy, and followed them to June 30, 2022 (follow-up ranged from 6 to 18 months). We used cumulative incidence curves to describe COVID-19 vaccine initiation after pregnancy and assessed associations with sociodemographic, pregnancy-related, and health behavioral factors using Cox proportional hazards regression to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). Among 137,198 individuals who gave birth in 2021, 87,376 (63.7%) remained unvaccinated at the end of pregnancy; of these, 65.0% initiated COVID-19 vaccination by June 30, 2022. Lower maternal age (

IntroductionCancer is a major public health problem with over 19 million cases reported in 2020. Similarly to humans, dogs are also largely affected by cancer, with non-Hodgkin's lymphoma (NHL) among the most common cancers in both species. Comparative medicine has the potential to accelerate the development of new therapeutic options in oncology by leveraging commonalities between diseases affecting both humans and animals. Within this context, in the present study, we investigated the potential of panobinostat (Pan)-loaded folate-targeted PEGylated liposomes (FA-PEG-Pan-Lip) for the treatment of canine B-cell lymphoma, while contributing to new perspectives in comparative oncology.Methods and resultsTwo formulations were developed, namely: PEG-Pan-Lip and FA-PEG-Pan-Lip. Firstly, folate receptor expression in the CLBL-1 canine B-cell lymphoma cell line was assessed. After confirming receptor expression, both Pan-loaded formulations (PEG-Pan-Lip, FA-PEG-Pan-Lip) demonstrated dose-dependent inhibitory effects on CLBL-1 cell proliferation. The FA-PEG-Pan-Lip formulation (IC50 = 10.9 ± 0.03 nM) showed higher cytotoxicity than the non-targeted PEG-Pan-Lip formulation (IC50 = 12.9 ± 0.03 nM) and the free panobinostat (Pan) compound (IC50 = 18.32±0.03 nM). Moreover, mechanistically, both Pan-containing formulations induced acetylation of H3 histone and apoptosis. Flow cytometry and immunofluorescence analysis of intracellular uptake of rhodamine-labeled liposome formulations in CLBL-1 cells confirmed cellular internalization of PEG-Lip and FA-PEG-Lip formulations and higher uptake profile for the latter. Biodistribution studies of both radiolabeled formulations in CD1 and SCID mice revealed a rapid clearance from the major organs and a 1.6-fold enhancement of tumor uptake at 24 h for 111In-FA-PEG-Pan-Lip (2.2 ± 0.1 %ID/g of tumor) compared to 111In-PEG-Pan-Lip formulation (1.2±0.2 %ID/g of tumor).DiscussionIn summary, our results provide new data validating Pan-loaded folate liposomes as a promising targeted drug delivery system for the treatment of canine B-cell lymphoma and open innovative perspectives for comparative oncology.

Objective To assess risk of adverse pregnancy, fetal, and neonatal outcomes after a third dose (first booster dose) of covid-19 vaccine during pregnancy among individuals who had completed both doses of primary covid-19 vaccine series before pregnancy.Design Population based, retrospective cohort study.Setting Ontario, Canada, from 20 December 2021 to 31 August 2022.Participants Individuals were included if they were pregnant with an expected date of delivery from 20 December 2021 (start date of third dose eligibility for everyone ≥18 years) to 31 August 2022, who had completed the two doses of primary covid-19 messenger RNA vaccine series before pregnancy, and became eligible for a third dose (≥six months since dose two) before the end of pregnancy.Main outcome measures Pregnancy outcomes included hypertensive disorders of pregnancy, placental abruption, caesarean delivery, chorioamnionitis, and postpartum hemorrhage. Fetal and neonatal outcomes included stillbirth, preterm birth, admission to neonatal intensive care unit for >24 h, newborn 5 min Apgar score

Understanding the spatial and temporal frameworks of species diversification is fundamental in evolutionary biology. Assessing the geographic origin and dispersal history of highly diverse lineages of rapid diversification can be hindered by the lack of appropriately sampled, resolved, and strongly supported phylogenetic contexts. The use of currently available cost-efficient sequencing strategies allows for the generation of a substantial amount of sequence data for dense taxonomic samplings, which together with well-curated geographic information and biogeographic models allow us to formally test the mode and tempo of dispersal events occurring in quick succession. Here, we assess the spatial and temporal frameworks for the origin and dispersal history of the expanded clade K, a highly diverse Tillandsia subgenus Tillandsia (Bromeliaceae, Poales) lineage hypothesized to have undergone a rapid radiation across the Neotropics. We assembled full plastomes from Hyb-Seq data for a dense taxon sampling of the expanded clade K plus a careful selection of outgroup species and used them to estimate a time- calibrated phylogenetic framework. This dated phylogenetic hypothesis was then used to perform biogeographic model tests and ancestral area reconstructions based on a comprehensive compilation of geographic information. The expanded clade K colonized North and Central America, specifically the Mexican transition zone and the Mesoamerican dominion, by long-distance dispersal from South America at least 4.86 Mya, when most of the Mexican highlands were already formed. Several dispersal events occurred subsequently northward to the southern Nearctic region, eastward to the Caribbean, and southward to the Pacific dominion during the last 2.8 Mya, a period characterized by pronounced climate fluctuations, derived from glacial–interglacial climate oscillations, and substantial volcanic activity, mainly in the Trans-Mexican Volcanic Belt. Our taxon sampling design allowed us to calibrate for the first time several nodes, not only within the expanded clade K focal group but also in other Tillandsioideae lineages. We expect that this dated phylogenetic framework will facilitate future macroevolutionary studies and provide reference age estimates to perform secondary calibrations for other Tillandsioideae lineages.

Objectives To examine how sales of sexual and reproductive health (SRH) products varied among pharmacies in Kenya using administrative data, leveraging natural variation in the COVID-19 pandemic and accompanying policy restrictions between 2019 and 2021.Design and setting Ecological study of pharmacies in Kenya.Participants 761 pharmacies using the Maisha Meds product inventory management system (capturing 572 916 products sold).Outcomes Sales quantity, price and revenue of SRH products sold per pharmacy per week.Results COVID-19 deaths were associated with a −2.97% (95% CI −3.82%, −2.11%) decrease in sales quantity, a 1.09% (95% CI 0.44%, 1.72%) increase in sales price and a −1.89% (−1.00%, −2.79%) decrease in revenues per pharmacy per week. Results were similar when considering new COVID-19 cases (per 1000) and the Average Policy Stringency Index. Results differed substantially between individual SRH products—a large decrease in sales quantity in pregnancy tests, injectables and emergency contraception, a modest decrease in condoms and no change in oral contraception. Sales price increases were similarly varied; four of the five most sold products were revenue neutral.Conclusions We found a robust negative association between SRH sales at pharmacies in Kenya and COVID-19 reported cases, deaths and policy restriction. Although our data cannot definitively point to reduced access, existing evidence from Kenya regarding unchanged fertility intentions, increases in unintended pregnancies and reported reasons for non-use of contraceptives during COVID-19 suggests a prominent role of reduced access. While policymakers may have a role in sustaining access, their role may be limited by broader macroeconomic problems, such as global supply chain disruptions and inflation, during supply shocks.

Despite the commendable progress made in addressing global health challenges and threats such as child mortality, HIV/AIDS, and Tuberculosis, many global health organizations still exhibit a Global North supremacy attitude, evidenced by their choice of leaders and executors of global health initiatives in low- and middle-income countries (LMICs). While efforts by the Global North to support global health practice in LMICs have led to economic development and advancement in locally led research, current global health practices tend to focus solely on intervention outcomes, often neglecting important systemic factors such as intellectual property ownership, sustainability, diversification of leadership roles, and national capacity development. This has resulted in the implementation of practices and systems informed by high-income countries (HICs) to the detriment of knowledge systems in LMICs, as they are deprived of the opportunity to generate local solutions for local problems. From their unique position as international global health fellows located in different African countries and receiving graduate education from a HIC institution, the authors of this viewpoint article assess how HIC institutions can better support LMICs. The authors propose several strategies for achieving equitable global health practices; 1) allocating funding to improve academic and research infrastructures in LMICs; 2) encouraging effective partnerships and collaborations with Global South scientists who have lived experiences in LMICs; 3) reviewing the trade-related aspects of intellectual property Rights (TRIPS) agreement; and 4) achieving equity in global health funding and education resources.

The nearby type II supernova, SN 2023ixf in M101 exhibits signatures of early time interaction with circumstellar material in the first week postexplosion. This material may be the consequence of prior mass loss suffered by the progenitor, which possibly manifested in the form of a detectable presupernova outburst. We present an analysis of long-baseline preexplosion photometric data in the g , w , r , i , z , and y filters from Pan-STARRS as part of the Young Supernova Experiment, spanning ∼5000 days. We find no significant detections in the Pan-STARRS preexplosion light curves. We train a multilayer perceptron neural network to classify presupernova outbursts. We find no evidence of eruptive presupernova activity to a limiting absolute magnitude of −7 mag. The limiting magnitudes from the full set of gwrizy (average absolute magnitude ≈ −8 mag) data are consistent with previous preexplosion studies. We use deep photometry from the literature to constrain the progenitor of SN 2023ixf, finding that these data are consistent with a dusty red supergiant progenitor with luminosity $\mathrm{log}\left(L/{L}_{\odot }\right)$ ≈ 5.12 and temperature ≈ 3950 K, corresponding to a mass of 14–20 M _⊙ .

Antecedentes: El cáncer de células pequeñas (CPCP) representa el 13-15% del total de neoplasias primarias de pulmón. Se caracteriza por su rapidez en la tasa de crecimiento y en el desarrollo de metástasis a distancia. Objetivos: Orientar y estandarizar el tratamiento del CPCP enfermedad extensa en México basado en evidencia clínica nacional e internacional. Material y métodos: Este documento se desarrolló como una colaboración del Instituto Nacional de Cancerología y la Sociedad Mexicana de Oncología en cumplimiento con estándares internacionales. Se integró un grupo conformado por oncólogos médicos, cirujanos oncólogos, cirujanos de tórax, radio-oncólogos y metodólogos con experiencia en revisiones sistemáticas de la literatura y guías de práctica clínica. Resultados: Se consensaron, por el método Delphi y en reuniones a distancia, las recomendaciones en CPCP enfermedad extensa, producto de preguntas de trabajo. Se identificó y evaluó la evidencia científica que responde a cada una de dichas preguntas clínicas antes de incorporarla al cuerpo de la guía. Conclusión: Esta guía proporciona recomendaciones clínicas para el manejo de la enfermedad extensa del CPCP y durante el proceso de toma de decisiones de los clínicos involucrados con su manejo en nuestro país para mejorar la calidad de la atención clínica para estos pacientes.

Abstract Background People incarcerated in US prisons have been disproportionately harmed by the COVID-19 pandemic. That prisons are such efficient superspreading environments can be attributed to several known factors: small, communal facilities where people are confined for prolonged periods of time; poor ventilation; a lack of non-punitive areas for quarantine/medical isolation; and staggeringly high numbers of people experiencing incarceration, among others. While health organizations have issued guidance on preventing and mitigating COVID-19 infection in carceral settings, little is known about if, when, and how recommendations have been implemented. We examined factors contributing to containment of one of the first California prison COVID-19 outbreaks and remaining vulnerabilities using an adapted multi-level determinants framework to systematically assess infectious disease risk in carceral settings. Methods Case study employing administrative data; observation; and informal discussions with: people incarcerated at the prison, staff, and county public health officials. Results Outbreak mitigation efforts were characterized by pre-planning (e.g., designation of ventilated, single-occupancy quarantine) and a quickly mobilized inter-institutional response that facilitated systematic, voluntary rapid testing. However, several systemic- and institutional-level vulnerabilities were unaddressed hindering efforts and posing significant risk for future outbreaks, including insufficient decarceration, continued inter-facility transfers, incomplete staff cohorting, and incompatibility between built environment features (e.g., dense living conditions) and public health recommendations. Conclusions Our adapted framework facilitates systematically assessing prison-based infectious disease outbreaks and multi-level interventions. We find implementing some recommended public health strategies may have contributed to outbreak containment. However, even with a rapidly mobilized, inter-institutional response, failure to decarcerate created an overreliance on chance conditions. This left the facility vulnerable to future catastrophic outbreaks and may render standard public health strategies - including the introduction of effective vaccines - insufficient to prevent or contain those outbreaks.

Abstract Single domain antibodies (VHHs) are potentially disruptive therapeutics, with important biological value for treatment of several diseases, including neurological disorders. However, VHHs have not been widely used in the central nervous system (CNS), largely because of their restricted blood–brain barrier (BBB) penetration. Here, we propose a gene transfer strategy based on BBB‐crossing adeno‐associated virus (AAV)‐based vectors to deliver VHH directly into the CNS. As a proof‐of‐concept, we explored the potential of AAV‐delivered VHH to inhibit BACE1, a well‐characterized target in Alzheimer’s disease. First, we generated a panel of VHHs targeting BACE1, one of which, VHH‐B9, shows high selectivity for BACE1 and efficacy in lowering BACE1 activity in vitro. We further demonstrate that a single systemic dose of AAV‐VHH‐B9 produces positive long‐term (12 months plus) effects on amyloid load, neuroinflammation, synaptic function, and cognitive performance, in the AppNL‐G‐F Alzheimer’s mouse model. These results constitute a novel therapeutic approach for neurodegenerative diseases, which is applicable to a range of CNS disease targets.

The global trend of rising (male) infertility is concerning, and the unidentifiable causes in half of the cases, the so-called unknown origin male infertility (UOMI), demands a better understanding and assessment of both external/internal factors and mechanisms potentially involved. In this work, it was our aim to obtain new insight on UOMI, specifically on idiopathic (ID) and Unexplained male infertility (UMI), relying on a detailed evaluation of the male gamete, including functional, metabolic and proteomic aspects. For this purpose, 1114 semen samples, from males in couples seeking infertility treatment, were collected at the Reproductive Medicine Unit from the Centro Hospitalar e Universitário de Coimbra (CHUC), from July 2018–July 2022. Based on the couples’ clinical data, seminal/hormonal analysis, and strict eligibility criteria, samples were categorized in 3 groups, control (CTRL), ID and UMI. Lifestyle factors and anxiety/depression symptoms were assessed via survey. Sperm samples were evaluated functionally, mitochondrially and using proteomics. The results of Assisted Reproduction Techniques were assessed whenever available. According to our results, ID patients presented the worst sperm functional profile, while UMI patients were similar to controls. The proteomic analysis revealed 145 differentially expressed proteins, 8 of which were specifically altered in ID and UMI samples. Acrosin (ACRO) and sperm acrosome membrane-associated protein 4 (SACA4) were downregulated in ID patients while laminin subunit beta-2 (LAMB2), mannose 6-phosphate isomerase (MPI), ATP-dependent 6-phosphofructokinase liver type (PFKAL), STAR domain-containing protein 10 (STA10), serotransferrin (TRFE) and exportin-2 (XPO2) were downregulated in UMI patients. Using random forest analysis, SACA4 and LAMB2 were identified as the sperm proteins with a higher chance of distinguishing ID and UMI patients, and their function and expression variation were in accordance with the functional results. No alterations were observed in terms of lifestyle and psychological factors among the 3 groups. These findings obtained in an experimental setting based on 3 well-defined groups of subjects, might help to validate new biomarkers for unknown origin male infertility (ID and UMI) that, in the future, can be used to improve diagnostics and treatments.

Soluble Aβ1–42 oligomers (AβO) are formed in the early stages of Alzheimer’s disease (AD) and were previously shown to trigger enhanced Ca2+ levels and mitochondrial dysfunction via the activation of N-methyl-D-aspartate receptors (NMDAR). Src kinase is a ubiquitous redox-sensitive non-receptor tyrosine kinase involved in the regulation of several cellular processes, which was demonstrated to have a reciprocal interaction towards NMDAR activation. However, little is known about the early-stage mechanisms associated with AβO-induced neurodysfunction involving Src. Thus, in this work, we analysed the influence of brief exposure to oligomeric Aβ1–42 on Src activation and related mechanisms involving mitochondria and redox changes in mature primary rat hippocampal neurons. Data show that brief exposure to AβO induce H2O2-dependent Src activation involving different cellular events, including NMDAR activation and mediated intracellular Ca2+ rise, enhanced cytosolic and subsequent mitochondrial H2O2 levels, accompanied by mild mitochondrial fragmentation. Interestingly, these effects were prevented by Src inhibition, suggesting a feedforward modulation. The current study supports a relevant role for Src kinase activation in promoting the loss of postsynaptic glutamatergic synapse homeostasis involving cytosolic and mitochondrial ROS generation after brief exposure to AβO. Therefore, restoring Src activity can constitute a protective strategy for mitochondria and related hippocampal glutamatergic synapses.

Abstract Anti-CD20 therapies have revolutionized the treatment of B-cell malignancies. Despite these advances, relapsed and refractory disease remains a major treatment challenge. The optimization of CD20-targeted immunotherapies is considered a promising strategy to improve current therapies. However, research has been limited by the scarcity of preclinical models that recapitulate the complex interaction between the immune system and cancers. The addition of the canine lymphoma (cNHL) model in the development of anti-CD20 therapies may provide a clinically relevant approach for the translation of improved immunotherapies. Still, an anti-CD20 therapy for cNHL has not been established stressing the need of a comprehensive target characterization. Herein, we performed an in-depth characterization on canine CD20 mRNA transcript and protein expression in a cNHL biobank and demonstrated a canine CD20 overexpression in B-cell lymphoma samples. Moreover, CD20 gene sequencing analysis identified six amino acid differences in patient samples (C77Y, L147F, I159M, L198V, A201T and G273E). Finally, we reported the use of a novel strategy for the generation of anti-CD20 mAbs, with human and canine cross-reactivity, by exploring our rabbit derived single-domain antibody platform. Overall, these results support the rationale of using CD20 as a target for veterinary settings and the development of novel therapeutics and immunodiagnostics.

Background: Recipients of a related haploidentical stem cell transplant (haplo-SCT) can have preformed antibodies to HLA donor’s antigens. Objective: The aim of the study was to evaluate the engraftment rate and major clinical associations of anti-HLA donor-specific antibodies (DSA) at two mean fluorescence intensity (MFI) thresholds in recipients of an outpatient haplo-SCT. Methods: Seventy haplo-HCT recipients were analyzed. A virtual crossmatch was performed using the donor HLA typing and the recipient’s anti-HLA DSA test results. Data for anti-HLA-A, -B, -C, and -DR were analyzed. Recipients with DSA ≥ 500 MFI were considered positive, and those with < 500 were considered negative; the same was adopted for MFI ≥ 1000. Results: Post-transplant infection was higher in recipients with DSA ≥ 500 MFI (84.6%, p = 0.041). First-year mortality was higher in DSA-positive patients ≥ 500 MFI, p = 0.004, and DSA ≥ 1000 MFI, p = 0.022, than in DSA-negative recipients. Graft failure in the first 100 days was not associated with DSA ≥ 500 or ≥ 1000 MFI. There was no difference in acute (a-GVHD) or chronic (c-GVHD) graft versus host disease between DSA-positive and negative patients. Conclusions: There was no association of anti-HLA DSA at MFI ≥ 500 and ≥ 1000 with graft failure, however, increased infection and 1st-year mortality were documented in related haplo-HCT at the MFI cutoffs studied.

Abstract Introduction: Several studies have found that most patients with severe mental illness (SMI) and comorbid (physical) conditions are partially or wholly nonadherent to their medication regimens. Nonadherence to treatment is a serious concern, affecting the successful management of patients with SMIs. Psychiatric disorders tend to worsen and persist in nonadherent patients, worsening their overall health. The study described herein aimed to develop and validate a scale (the Ralat Adherence Scale) to measure nonadherence behaviors in a culturally sensitive way. Materials and Methods: Guided by a previous study that explored the primary reasons for nonadherence in Puerto Rican patients, we developed a pool of 147 items linked to the concept of adherence. Nine experts reviewed the meaning, content, clarity, and relevance of the individual items, and a content validity ratio was calculated for each one. Forty items remained in the scale’s first version. This version was administered to 160 patients (21–60 years old). All the participants had a diagnosis of bipolar disorder, major depressive disorder, or schizoaffective disorder. The STROBE checklist was used as the reporting guideline. Results: The scale had very good internal consistency (Cronbach’s alpha = 0.812). After a factor analysis, the scale was reduced to 24 items; the new scale had a Cronbach’s alpha of 0.900. Conclusions: This adherence scale is a self-administered instrument with very good psychometric properties; it has yielded important information about nonadherence behaviors. The scale can help health professionals and researchers to assess patient adherence or nonadherence to a medication regimen.

Antecedentes: El cáncer de células pequeñas (CPCP) representa el 13-15% del total de neoplasias primarias de pulmón. Se caracteriza por su rapidez en la tasa de crecimiento y en el desarrollo de metástasis a distancia. Objetivos: Orientar y estandarizar el tratamiento del CPCP, enfermedad limitada, en México, basado en evidencia clínica nacional e internacional. Material y métodos: Este documento se desarrolló como una colaboración entre el Instituto Nacional de Cancerología y la Sociedad Mexicana de Oncología en cumplimiento con estándares internacionales. Se integró un grupo conformado por oncólogos médicos, cirujanos oncólogos, cirujanos de tórax, radio-oncólogos y metodólogos con experiencia en revisiones sistemáticas de la literatura y guías de práctica clínica. Resultados: Se consensuaron, por el método Delphi y en reuniones a distancia, las recomendaciones en CPCP enfermedad limitada, producto de las preguntas de trabajo. Se identificó y evaluó críticamente la evidencia científica que responde a cada una de dichas preguntas clínicas, antes de incorporarla a la guía. Conclusión: Esta guía proporciona recomendaciones clínicas para el manejo de la enfermedad limitada del CPCP y durante el proceso de toma de decisiones de los clínicos involucrados con su manejo en nuestro país para mejorar la calidad de la atención clínica en estos pacientes.

Abstract Replacement orthopedic surgeries are among the most common surgeries worldwide, but clinically used passive implants cannot prevent failure rates and inherent revision arthroplasties. Optimized non-instrumented implants, resorting to preclinically tested bioactive coatings, improve initial osseointegration but lack long-term personalized actuation on the bone–implant interface. Novel bioelectronic devices comprising biophysical stimulators and sensing systems are thus emerging, aiming for long-term control of peri-implant bone growth through biointerface monitoring. These acting-sensing dual systems require high frequency (HF) operations able to stimulate osteoinduction/osteoconduction, including matrix maturation and mineralization. A sensing-compatible capacitive stimulator of thin interdigitated electrodes and delivering an electrical 60 kHz HF stimulation, 30 min/day, is here shown to promote osteoconduction in pre-osteoblasts and osteoinduction in human adipose-derived mesenchymal stem cells (hASCs). HF stimulation through this capacitive interdigitated system had significant effects on osteoblasts’ collagen-I synthesis, matrix, and mineral deposition. A proteomic analysis of microvesicles released from electrically-stimulated osteoblasts revealed regulation of osteodifferentiation and mineralization-related proteins (e.g. Tgfb3, Ttyh3, Itih1, Aldh1a1). Proteomics data are available via ProteomeXchange with the identifier PXD028551. Further, under HF stimulation, hASCs exhibited higher osteogenic commitment and enhanced hydroxyapatite deposition. These promising osteoinductive/conductive capacitive stimulators will integrate novel bioelectronic implants able to monitor the bone–implant interface and deliver personalized stimulation to peri-implant tissues.

Abstract Background Viral suppression is key to ending the HIV epidemic, yet only 58% of people living with HIV (PLHIV) in sub-Saharan Africa are suppressed. Cash transfers are an effective strategy to improve retention in care, but little is known about optimization of implementation; for example, designing effective programs that integrate into existing clinic workflows. We studied implementation of an mHealth system to deliver cash transfers to support retention. Methods We conducted a mixed-methods study assessing implementation of an mHealth cash transfer study. This was part of a larger, hybrid implementation-effectiveness randomized controlled trial evaluating cash transfers conditional on visit attendance for viral suppression among Tanzanian PLHIV initiating ART. An mHealth system using fingerprint identification and mobile payments was used to automatically disburse mobile money to eligible PLHIV. We used Proctor’s framework, assessing implementation of the mHealth system from the perspectives of PLHIV and clinicians. We analyzed mHealth system data and conducted surveys (n = 530) and in-depth interviews (n = 25) with PLHIV, clinic and pharmacy staff (n = 10), and structured clinic observations (n = 2293 visits). Results One thousand six hundred fifty-one cash transfers were delivered to 346 PLHIV in the cash arms, 78% through mobile money. Among those in the cash arms, 81% registered their mobile money account with the mHealth system by study end, signaling high adoption. While acceptability for fingerprinting and mobile payments was high among PLHIV, interviews revealed mixed views: some had privacy concerns while others felt the system was secure and accurate, and provided some legitimacy to the clinical visits. Pharmacists praised system efficiency, but concerns about duplicative recordkeeping and added work arose. Clinic staff voiced excitement for the system’s potential to bring the cash program to all patients and simplify workflows; yet concerns about multiple systems, staffing, and intermittent connectivity tempered enthusiasm, highlighting structural issues beyond program scope. Structured observations revealed a steep learning curve; repeat fingerprint scans and manual entry declined as the system improved. Conclusions Biometric identification and mobile payments were acceptable to most patients and staff. Fingerprinting encountered some feasibility limitations in the first months of testing; however, mobile payments were highly successful. Biometric identification and mobile payments may provide a scalable mechanism to improve patient tracking and efficiently implement financial incentives in low-resource settings. Trial registration Name of the registry: clinicaltrials.gov Trial registration number: NCT03351556 Date of registration: 11/24/2017 Checklists: StaRI (included with submission). Note CONSORT for cluster-randomized trials was used for the main trial but is not directly applicable to this manuscript.

Abstract Mitochondrial and autophagy dysfunction are mechanisms proposed to be involved in the pathogenesis of several neurodegenerative diseases. Huntington's disease (HD) is a progressive neurodegenerative disorder associated with mutant Huntingtin‐induced abnormalities in neuronal mitochondrial dynamics and quality control. Former studies suggest that the removal of defective mitochondria may be compromised in HD. Mitochondrial quality control (MQC) is a complex, well‐orchestrated pathway that can be compromised through mitophagy dysregulation or impairment in the mitochondria‐lysosomal axis. Another mitochondrial stress response is the generation of mitochondrial‐derived vesicles that fuse with the endolysosomal system and form multivesicular bodies that are extruded from cells as extracellular vesicles (EVs). In this work, we aimed to study the presence of mitochondrial components in human EVs and the relation to the dysfunction of both mitochondria and the autophagy pathway. We comprehensively characterized the mitochondrial and autophagy alterations in premanifest and manifest HD carriers and performed a proteomic and genomic EVs profile. We observed that manifest HD patients exhibit mitochondrial and autophagy impairment associated with enhanced EVs release. Furthermore, we detected mitochondrial DNA and proteins in EVs released by HD cells and in neuronal‐derived EVs including VDAC‐1 and alpha and beta subunits of ATP synthase F1. HD‐extracellular vesicles transport higher levels of mitochondrial genetic material in manifest HD patients, suggesting an alternative pathway for the secretion of reactive mitochondrial components. This study provides a novel framework connecting EVs enhanced release of mitochondrial components to mitochondrial and lysosomal dysfunction in HD.

Deficits in mitochondrial function and redox deregulation have been attributed to Huntington's disease (HD), a genetic neurodegenerative disorder largely affecting the striatum. However, whether these changes occur in early stages of the disease and can be detected in vivo is still unclear. In the present study, we analysed changes in mitochondrial function and production of reactive oxygen species (ROS) at early stages and with disease progression. Studies were performed in vivo in human brain by PET using [64Cu]-ATSM and ex vivo in human skin fibroblasts of premanifest and prodromal (Pre-M) and manifest HD carriers. In vivo brain [64Cu]-ATSM PET in YAC128 transgenic mouse and striatal and cortical isolated mitochondria were assessed at presymptomatic (3 month-old, mo) and symptomatic (6–12 mo) stages. Pre-M HD carriers exhibited enhanced whole-brain (with exception of caudate) [64Cu]-ATSM labelling, correlating with CAG repeat number. Fibroblasts from Pre-M showed enhanced basal and maximal respiration, proton leak and increased hydrogen peroxide (H2O2) levels, later progressing in manifest HD. Mitochondria from fibroblasts of Pre-M HD carriers also showed reduced circularity, while higher number of mitochondrial DNA copies correlated with maximal respiratory capacity. In vivo animal PET analysis showed increased accumulation of [64Cu]-ATSM in YAC128 mouse striatum. YAC128 mouse (at 3 months) striatal isolated mitochondria exhibited a rise in basal and maximal mitochondrial respiration and in ATP production, and increased complex II and III activities. YAC128 mouse striatal mitochondria also showed enhanced mitochondrial H2O2 levels and circularity, revealed by brain ultrastructure analysis, and defects in Ca2+ handling, supporting increased striatal susceptibility. Data demonstrate both human and mouse mitochondrial overactivity and altered morphology at early HD stages, facilitating redox unbalance, the latter progressing with manifest disease.

Amyotrophic lateral sclerosis (ALS) is a severe and incurable neurodegenerative disease characterized by the progressive death of motor neurons, leading to paralysis and death. It is a rare disease characterized by high patient-to-patient heterogeneity, which makes its study arduous and complex. Extracellular vesicles (EVs) have emerged as important players in the development of ALS. Thus, ALS phenotype-expressing cells can spread their abnormal bioactive cargo through the secretion of EVs, even in distant tissues. Importantly, owing to their nature and composition, EVs’ formation and cargo can be exploited for better comprehension of this elusive disease and identification of novel biomarkers, as well as for potential therapeutic applications, such as those based on stem cell-derived exosomes. This review highlights recent advances in the identification of the role of EVs in ALS etiopathology and how EVs can be promising new therapeutic strategies.

Full plastome sequences for land plants have become readily accessible thanks to the development of Next Generation Sequencing (NGS) techniques and powerful bioinformatic tools. Despite this vast amount of genomic data, some lineages remain understudied. Full plastome sequences from the highly diverse (>1,500 spp.) subfamily Tillandsioideae (Bromeliaceae, Poales) have been published for only three (i.e., Guzmania, Tillandsia, and Vriesea) out of 22 currently recognized genera. Here, we focus on core Tillandsioideae, a clade within subfamily Tillandsioideae, and explore the contribution of individual plastid markers and data categories to inform deep divergences of a plastome phylogeny. We generated 37 high quality plastome assemblies and performed a comparative analysis in terms of plastome structure, size, gene content and order, GC content, as well as number and type of repeat motifs. Using the obtained phylogenetic context, we reconstructed the evolution of these plastome attributes and assessed if significant shifts on the evolutionary traits’ rates have occurred in the evolution of the core Tillandsioideae. Our results agree with previously published phylogenetic hypotheses based on plastid data, providing stronger statistical support for some recalcitrant nodes. However, phylogenetic discordance with previously published nuclear marker-based hypotheses was found. Several plastid markers that have been consistently used to address phylogenetic relationships within Tillandsioideae were highly informative for the retrieved plastome phylogeny and further loci are here identified as promising additional markers for future studies. New lineage-specific plastome rearrangements were found to support recently adopted taxonomic groups, including large inversions, as well as expansions and contractions of the inverted repeats. Evolutionary trait rate shifts associated with changes in size and GC content of the plastome regions were found across the phylogeny of core Tillandsioideae.

Background In September 2017, hurricanes Irma and Maria affected Puerto Rico (PR) and the US Virgin Islands (USVI), causing major disruptions in basic services and health care. This study documented the stressors and experiences of patients with gynecologic cancer receiving oncology care in PR following these hurricanes. Methods We conducted 4 focus groups (December 2018-April 2019) among women aged ≥21 years from PR who were diagnosed with gynecological cancer between September 2016 and September 2018 (n = 24). Using the same eligibility criteria, we also interviewed patients from the USVI (n = 2) who were treated in PR. We also conducted key-informant interviews with oncology care providers and administrators (n = 23) serving gynecologic cancer patients in PR. Discussions were audio-recorded, transcribed verbatim, and coded to identify emergent themes using a constant comparison method. Results Analyses of focus group discussions and interviews allowed us to identify the following emergent themes: 1) disruptions in oncology care were common; 2) communication between oncology providers and patients was challenging before and after the hurricanes hit; 3) patient resilience was key to resume care; and 4) local communities provided much-needed social support and resources. Conclusions This study provides firsthand information about the disruptions in oncology care experienced by and the resiliency of women with gynecologic cancer following hurricanes Irma and Maria. Our findings underscore the need to incorporate oncology care in the preparedness and response plans of communities, health systems, and government agencies to maintain adequate care for cancer patients during and after disasters such as hurricanes.

Abstract Background Public health initiatives must look for ways to cost-effectively scale critical interventions to achieve high coverage. Private sector distribution channels, can potentially distribute preventive healthcare products to hard-to-reach populations, decongest public healthcare systems, and increase the sustainability of programs by getting customers to share costs. However, little is known about how sellers set prices for new products. By introducing a new product, HIV self-test kits, to local drug shops, we observed whether shops experimented with pricing, charged different buyers different prices, and whether prices converged within the local market over our study period. Methods From August to December 2019, we provided free HIV self-test kits, a new product, to 26 drug shops in Shinyanga, Tanzania to sell to the local community. We measured sales volume, price, customer age and sex using shop records. Using a multiple linear regression model, we conducted F-tests to determine whether shop, age, sex, and time (week) respectively were associated with price. We measured willingness-to-pay to restock test kits at the end of the study. Results 514 test kits were sold over 18 weeks; 69% of buyers were male, 40% were aged 25–34 and 32% aged 35–44. Purchase prices ranged from 1000 to 6000 Tsh (median 3000 Tsh; ~$1.30 USD). Within shops, prices were 11.3% higher for 25–34 and 12.7% higher for 45+ year olds relative to 15–19-year olds (p = 0.029) and 13.5% lower for men (p = 0.023) on average. Although prices varied between shops, prices varied little within shops over time, and did not converge over the study period or cluster geospatially. Mean maximum willingness-to-pay to restock was 2000 Tsh per kit. Conclusions Shopkeepers charged buyers different prices depending on buyers’ age and sex. There was limited variation in prices within shops over time and low demand among shopkeepers to restock at the end of the study. Given the subsidized global wholesale price ($2 USD or ~ 4600 Tsh), further demand creation and/or cost-reduction is required before HIV self-test kits can become commercially viable in drug shops in this setting. Careful consideration is needed to align the motivations of retailers with public health priorities while meeting their private for-profit needs.

Abstract Background HIV risk remains high among adolescent girls and young women (AGYW, ages 15–24) in Tanzania. Many AGYW experience stigma and provider bias at health facilities, deterring their use of HIV prevention services. Privately-owned drug shops, ubiquitous in many communities, may be an effective and accessible channel to deliver HIV prevention products to AGYW, including oral pre-exposure prophylaxis (PrEP) and the dapivirine vaginal ring. Methods In July–August 2019, we enrolled 26 drug shops in Shinyanga, Tanzania in an ongoing study to create “girl-friendly” drug shops where AGYW can access HIV self-testing and contraception. At baseline, all shop dispensers were given basic information about oral PrEP and the dapivirine ring and were asked about their interest in stocking each. During the next 3–5 months, we surveyed AGYW (n = 56) customers about their interest in oral PrEP and the ring. Results Among dispensers, the median age was 42 years and 77% were female. Overall, 42% of dispensers had heard of a medication for HIV prevention. Almost all dispensers reported some interest in stocking oral PrEP (92%) and the dapivirine ring (96%). Most (85%) reported they would provide oral PrEP to AGYW who requested it. Among AGYW customers, the median age was 17 years; 29% of AGYW were married or had a steady partner and 18% had children. Only 20% of AGYW had heard of a medication to prevent HIV, yet 64% and 43% expressed some interest in using oral PrEP and the dapivirine ring, respectively, after receiving information about the products. PrEP interest was higher among AGYW who were partnered and had children. Conclusions Despite low prior awareness of PrEP among shop dispensers and AGYW, we found high levels of interest in oral PrEP and the dapivirine ring in both groups. Community-based drug shops represent a promising strategy to make HIV prevention more accessible to AGYW.

Theragnostics is a promising approach that integrates diagnostics and therapeutics into a single personalized strategy. To conduct effective theragnostic studies, it is essential to create an in vitro environment that accurately reflects the in vivo conditions. In this review, we discuss the importance of redox homeostasis and mitochondrial function in the context of personalized theragnostic approaches. Cells have several ways to respond to metabolic stress, including changes in protein localization, density, and degradation, which can promote cell survival. However, disruption of redox homeostasis can lead to oxidative stress and cellular damage, which are implicated in various diseases. Models of oxidative stress and mitochondrial dysfunction should be developed in metabolically conditioned cells to explore the underlying mechanisms of diseases and develop new therapies. By choosing an appropriate cellular model, adjusting cell culture conditions and validating the cellular model, it is possible to identify the most promising therapeutic options and tailor treatments to individual patients. Overall, we highlight the importance of precise and individualized approaches in theragnostics and the need to develop accurate in vitro models that reflect the in vivo conditions.

Efforts have been made to understand the physiological and pathological role of DJ-1, a Parkinson’s disease (PD)-associated protein, to provide new insights into PD pathophysiology. Such studies have revealed several neuroprotective roles of DJ-1, from which its ability to modulate signaling pathways seems to be of utmost importance for cell death regulation by DJ-1. Indeed, research on these topics has led to a higher number of publications disclosing a variety of mechanisms through which DJ-1 is able to modulate signaling pathways in distinct disease-related contexts. Thus, this graphical review presents the most relevant findings concerning the mechanisms through which DJ-1 exerts its regulatory activity on signaling cascades relevant for DJ-1 neuroprotective action, namely ERK1/2, PI3K/Akt, and ASK1 pathways, and Nrf2 and p53 transcription factors-related signaling. A greater focus was given to perform an overview of the research interests over the last years, especially in the most recent works, to highlight the current research lines in this topic, and point out future directions in the field. In addition, the impact of DJ-1 mutations causative of PD and the importance of the redox status of DJ-1’s cysteine residues for the action of DJ-1 on signaling modulation was also addressed to uncover the potential pathological mechanisms associated with loss of DJ-1 native function.