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Abstract Background There is a strong, bi-directional link between tuberculosis (TB) and undernutrition: TB often causes undernutrition, and undernourished people are more likely to contract TB and experience worse outcomes. Globally, several TB nutritional support programmes exist; however, evidence on their effectiveness is limited and contested. This study evaluates the effect of a nutritional support programme implemented for people with TB in the Atsimo-Andrefana region, Madagascar in 2022. Within this programme, undernourished people with TB [with a body mass index (BMI) of

Background/Objectives: The previous literature has identified increased work-related stress among healthcare workers (HCWs) during the COVID-19 pandemic. This study analyzes work-related perceived stress experienced by therapists during the COVID-19 pandemic in Germany to identify potential for supporting this crucial group of HCWs in future health crises. Methods: Survey data on stress, measured through the Perceived Stress Scale 4, among HCWs (therapists n = 612, nurses n = 501, and doctors n = 461) were analyzed using descriptive statistics, and data from four semi-structured interviews and seven focus group discussions with therapists were analyzed using thematic content analysis. Data were collected from March to September 2022. Results: Therapists reported similar stress levels to other HCWs, with the reporting of perceived stress differing between work contexts. Eight stressors were identified through the thematic analysis: (1) concerns about maintaining the quality of care, (2) uncertainty about the future, (3) workload, (4) interactions with colleagues and patients, (5) PPE, (6) the risk of infection, (7) insufficient information flow, and (8) the lack of public and political recognition. Conclusions: This study emphasizes the distinct challenges that therapists experienced during the COVID-19 pandemic. By identifying the factors that contributed to the stress experienced, the study can inform targeted support strategies which can enhance therapists’ work, ultimately contributing to sustaining essential healthcare services during public health crises.

Context There is a substantial lack of inter-facility referral systems for emergency obstetrical and neonatal care in rural areas of sub-Saharan Africa. Data on the costs and cost-effectiveness of such systems that reduce preventable maternal and neonatal deaths are scarce.Setting We aimed to determine the cost-effectiveness of a non-governmental organisation (NGO)-run inter-facility referral system for emergency obstetrical and neonatal care in rural Southern Madagascar by analysing the characteristics of cases referred through the intervention as well as its costs.Design We used secondary NGO data, drawn from an NGO’s monitoring and financial administration database, including medical and financial records.Outcome measures We performed a descriptive and a cost-effectiveness analysis, including a one-way deterministic sensitivity analysis.Results 1172 cases were referred over a period of 4 years. The most common referral reasons were obstructed labour, ineffective labour and eclampsia. In total, 48 neonates were referred through the referral system over the study period. Estimated cost per referral was US$336 and the incremental cost-effectiveness ratio (ICER) was US$70 per additional life-year saved (undiscounted, discounted US$137). The sensitivity analysis showed that the intervention was cost-effective for all scenarios with the lowest ICER at US$99 and the highest ICER at US$205 per additional life-year saved. When extrapolated to the population living in the study area, the investment costs of the programme were US$0.13 per person and annual running costs US$0.06 per person.Conclusions In our study, the inter-facility referral system was a very cost-effective intervention. Our findings may inform policies, decision-making and implementation strategies for emergency obstetrical and neonatal care referral systems in similar resource-constrained settings.

BackgroundSeveral sub-Saharan African countries use digital financial services to improve health financing, especially for maternal and child health. In cooperation with the Malagasy Ministry of Health, the NGO Doctors for Madagascar is implementing a mobile health wallet for maternal health care in public-sector health facilities in Madagascar. Our aim was to explore the enabling and limiting factors related to the usability and acceptance of the Mobile Maternal Health Wallet (MMHW) intervention during its implementation.MethodsWe conducted a cross-sectional, mixed methods study with mothers and pregnant women and facility- (FBHWs) and community-based (CHWs) health workers from public-sector health facilities in three districts of the Analamanga region in Madagascar. We used a convergent design in collecting and analyzing quantitative and qualitative data. We performed one-stage proportional sampling of women who had signed up for the MMHW. All FBHWs and CHWs at primary care facilities in the intervention area were eligible to participate.Results and significance314 women, 76 FBHWs, and 52 CHWs were included in the quantitative survey. Qualitative data were extracted from in-depth interviews with 12 women and 12 FBHWs and from six focus group discussions with 39 CHWSs. The MMHW intervention was accepted and used by health workers and women from different socioeconomic backgrounds. Main motivations for women to enroll in the intervention were the opportunity to save money for health (30.6%), electronic vouchers for antenatal ultrasound (30.2%), and bonus payments upon reaching a savings goal (27.9%). Main motivation for health workers was enabling pregnant women to save for health, thus encouraging facility-based deliveries (57.9%). Performance-based payments had low motivational value for health workers. Key facilitators were community sensitization, strong women-health worker relationship, decision making at the household level, and repetitive training on the use of the MMHW. Key barriers included limited phone ownership, low level of digital literacy, disinformation concerning the effects of the intervention, and technical problems like slow payout processes.

Abstract Background Mobile money—a service enabling users to receive, store, and send electronic money using mobile phones—has been widely adopted across low- and middle-income economies to pay for a variety of services, including healthcare. However, evidence on its effects on healthcare access and health outcomes are scarce and the possible implications of using mobile money for financing and payment of maternal healthcare services—which generally require large one-time out-of-pocket payments—have not yet been systematically assessed in low-resource settings. The aim of this study is to determine the impact on health outcomes, cost-effectiveness, feasibility, acceptability, and usefulness of mobile phone-based savings and payment service, the Mobile Maternal Health Wallet (MMHW), for skilled healthcare during pregnancy and delivery among women in Madagascar. Methods This is a hybrid effectiveness-implementation type-1 trial, determining the effectiveness of the intervention while evaluating the context of its implementation in Madagascar’s Analamanga region, containing the capital, Antananarivo. Using a stratified cluster randomized design, 61 public-sector primary-care health facilities were randomized within 6 strata to either receive the intervention or not (29 intervention vs. 32 control facilities). The strata were defined by a health facility’s antenatal care visit volume and its capacity to offer facility-based deliveries. The registered pre-specified primary outcomes are (i) delivery at a health facility, (ii) antenatal care visits, and (iii) total healthcare expenditure during pregnancy, delivery, and neonatal period. The registered pre-specified secondary outcomes include additional health outcomes, economic outcomes, and measurements of user experience and satisfaction. Our estimated enrolment number is 4600 women, who completed their pregnancy between July 1, 2020, and December 31, 2021. A series of nested mixed-methods studies will elucidate client and provider perceptions on feasibility, acceptability, and usefulness of the intervention to inform future implementation efforts. Discussion A cluster-randomized, hybrid effectiveness-implementation design allows for a robust approach to determine whether the MMHW is a feasible and beneficial intervention in a resource-restricted public healthcare environment. We expect the results of our study to guide future initiatives and health policy decisions related to maternal and neonatal health and universal healthcare coverage through technology in Madagascar and other countries in sub-Saharan Africa. Trial registration This trial was registered on March 12, 2021: Deutsches Register Klinischer Studien (German Clinical Trials Register), identifier: DRKS00014928 . For World Health Organization Trial Registration Data Set see Additional file 1.

We report an outbreak of coronavirus disease with 74 cases related to a nightclub in Germany in March 2020. Staff members were particularly affected (attack rate 56%) and likely caused sustained viral transmission after an event at the club. This outbreak illustrates the potential for superspreader events and corroborates current club closures.

Financial barriers are a major obstacle to accessing maternal health care services in low-resource settings. In Madagascar, less than half of live births are attended by skilled health staff. Although mobile money-based savings and payment systems are often used to pay for a variety of services, including health care, data on the implications of a dedicated mobile money wallet restricted to health-related spending during pregnancy-a mobile health wallet (MHW)-are not well understood. In cooperation with the Madagascan Ministry of Health, this study aims to elicit the perceptions, experiences, and recommendations of key stakeholders in relation to a MHW amid a pilot study in 31 state-funded health care facilities. We conducted a two-stage qualitative study using semi-structured in-depth interviews with stakeholders (N = 21) representing the following groups: community representatives, health care providers, health officials and representatives from phone provider companies. Interviews were conducted in Atsimondrano and Renivohitra districts, between November and December of 2017. Data was coded thematically using inductive and deductive approaches, and found to align with a social ecological model. Key facilitators for successful implementation of the MHW, include (i) close collaboration with existing communal structures and (ii) creation of an incentive scheme to reward pregnant women to save. Key barriers to the application of the MHW in the study zone include (i) disruption of informal benefits for health care providers related to the current cash-based payment system, (ii) low mobile phone ownership, (iii) illiteracy among the target population, and (iv) failure of the MHW to overcome essential access barriers towards institutional health care services such as fear of unpredictable expenses. The MHW was perceived as a potential solution to reduce disparities in access to maternal health care. To ensure success of the MHW, direct demand-side and provider-side financial incentives merit consideration.

Abstract Background Patients with steroid-refractory acute graft-versus-host disease (aGvHD) not tolerating/responding to ruxolitinib (RR-aGvHD) have a dismal prognosis. Methods We retrospectively assessed real-world outcomes of RR-aGvHD treated with the random-donor allogeneic MSC preparation MSC-FFM, available via Hospital Exemption in Germany. MSC-FFM is provided as frozen cell dispersion for administration as i.v. infusion immediately after thawing, at a recommended dose of 1–2 million MSCs/kg body weight in 4 once-weekly doses. 156 patients, 33 thereof children, received MSC-FFM; 5% had Grade II, 40% had Grade III, and 54% had Grade IV aGvHD. Median (range) number of prior therapies was 4 (1–10) in adults and 7 (2–11) in children. Results The safety profile of MSC-FFM was consistent with previous reports for MSC therapies in general and MSC-FFM specifically. The overall response rate at Day 28 was 46% (95% confidence interval [CI] 36–55%) in adults and 64% (45–80%) in children; most responses were durable. Probability of overall survival at 6, 12 and 24 months was 47% (38–56%), 35% (27–44%) and 30% (22–39%) for adults, and 59% (40–74%), 42% (24–58%) and 35% (19–53%) for children, respectively (whole cohort: median OS 5.8 months). Conclusion A recent real-world analysis of outcomes for 64 adult RR-aGvHD patients not treated with MSCs reports survival of 20%, 16% and 10% beyond 6, 12 and 24 months, respectively (median 28 days). Our data thus suggest effectiveness of MSC-FFM in RR-aGvHD.

Objective: Beta cell dysfunction and death are critical steps in the development of both type 1 and type 2 diabetes (T1D and T2D), but the underlying mechanisms are incompletely understood. Activation of the essential tumor suppressor and transcription factor P53 (also known as TP53 and Trp53 in mice) was linked to beta cell death in vitro and has been reported in several diabetes mouse models and beta cells of humans with T2D. In this article, we set out to determine the beta cell specific role of P53 in beta cell dysfunction, cell death and development of diabetes in vivo. Methods: We generated beta cell specific P53 knockout (P53BKO) mice and used complementary genetic, dietary and pharmacological models of glucose intolerance, beta cell dysfunction and diabetes development to evaluate the functional role of P53 selectively in beta cells. We further analyzed the effect of P53 ablation on beta cell survival in isolated pancreatic islets exposed to diabetogenic stress inducers ex vivo by flow cytometry. Results: Beta cell specific ablation of P53/Trp53 failed to ameliorate glucose tolerance, insulin secretion or to increase beta cell numbers in genetic, dietary and pharmacological models of diabetes. Additionally, loss of P53 in beta cells did not protect against streptozotocin (STZ) induced hyperglycemia and beta cell death, although STZ-induced activation of classical pro-apoptotic P53 target genes was significantly reduced in P53BKO mice. In contrast, Olaparib mediated PARP1 inhibition protected against acute ex vivo STZ-induced beta cell death and islet destruction. Conclusions: Our study reveals that ablation of P53 specifically in beta cells is unexpectedly unable to attenuate beta cell failure and death in vivo and ex vivo. While during development and progression of diabetes, P53 and P53-regulated pathways are activated, our study suggests that P53 signaling is not essential for loss of beta cells or beta cell dysfunction. P53 in other cell types and organs may predominantly regulate systemic glucose homeostasis.

The processing of metaphors and idioms has been the subject of neuroscientific research for several decades. However, results are often contradictory, which can be traced back to inconsistent terminology and stimulus control. In this systematic review of research methods, we analyse linguistic aspects of 116 research papers which used EEG, fMRI, PET, MEG, or NIRS to investigate the neural processing of the two figurative subtypes metaphor and idiom. We critically examine the theoretical foundations as well as stimulus control by performing a systematic literature synthesis according to the PRISMA guidelines. We explicitly do not analyse the findings of the studies but instead focus on four primary aspects: definitions of figurative language and its subtypes, linguistic theory behind the studies, control for factors influencing figurative language processing, and the relationship between theoretical and operational definitions. We found both a lack and a broad variety in existing definitions and operationalisation, especially in regard to familiarity and conventionality. We identify severe obstacles in the comparability and validation potential of the results of the papers in our review corpus. We propose the development of a consensus in fundamental terminology and more transparency in the reporting of stimulus design in the research on figurative language processing.

The oxidation-induced DNA modification 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) was recently implicated in the activation and repression of gene transcription. We aimed at a systematic characterisation of the impacts of 8-oxodG on the activity of a GC box placed upstream from the RNA polymerase II core promoter. With the help of reporters carrying single synthetic 8-oxodG residues at four conserved G:C base pairs (underlined) within the 5′-TGGGCGGAGC-3′ GC box sequence, we identified two modes of interference of 8-oxodG with the promoter activity. Firstly, 8-oxodG in the purine-rich (but not in the pyrimidine-rich) strand caused direct impairment of transcriptional activation. In addition, and independently of the first mechanism, 8-oxodG initiated a decline of the gene expression, which was mediated by the specific DNA glycosylase OGG1. For the different 8-oxodG positions, the magnitude of this effect reflected the excision preferences of OGG1. Thus, 8-oxodG seeded in the pyrimidine-rich strand was excised with the highest efficiency and caused the most pronounced decrease of the promoter activity. Conversely, 8-oxodG in the symmetric position within the same CpG dinucleotide, was poorly excised and induced no decline of the gene expression. Of note, abasic lesions caused gene silencing in both positions. By contrast, an uncleavable apurinic lesion in the pyrimidine-rich strand enhanced the GC box activity, suggesting that the AP endonuclease step provides a switch between the active versus repressed promoter states during base excision repair.

Abstract Background New treatment options are needed to prevent relapses following failed antibiotic therapies of Clostridium difficile infections (CDI) in humans. The concomitant therapy with an anti-C. difficile IgA containing whey protein concentrate can support the sustainable recovery of CDI patients. For 31 weeks, nine dairy cows were continuously vaccinated with several anti-C. difficile vaccines by certain routes of administration to produce anti-C. difficile IgA enriched milk. The study aimed at finding decisive differences between low responder (LR) and high responder (HR) cows (> 8.0 µg ml−1 total milk C. difficile specific IgA) concerning their immune response to vaccination on cellular and molecular biological levels. Results The results of total and differential cell counting (DCC) in blood and milk and the outcomes of the gene expression analysis of selected immune factors were assessed relating to the usage of two vaccine batches for injection (MucoCD-I batch A and B), marking two immunization (IM) periods, and compared to a control group (Ctr). The MucoCD-I batch A caused short-term leukopenia followed by leukocytosis in the blood of LR and HR. The total somatic cell counts in milk were not altered by the treatment. The DCC revealed that the leukocytes of the treated groups were partly impaired by the treatment. The gene expression analysis exposed cumulative and sustainable differences (p

Pancreatic beta cell death is a hallmark of type 1 and 2 diabetes (T1D/T2D), but the underlying molecular mechanisms are incompletely understood. Key proteins of the DNA damage response (DDR), including tumor protein P53 (P53, also known as TP53 or TRP53 in rodents) and Ataxia Telangiectasia Mutated (ATM), a kinase known to act upstream of P53, have been associated with T2D. Here we test and compare the effect of ATM and P53 ablation on beta cell survival in the rat beta cell line Ins1E. We demonstrate that ATM and P53 differentially regulate beta cell apoptosis induced upon fundamentally different types of diabetogenic beta cell stress, including DNA damage, inflammation, lipotoxicity and endoplasmic reticulum (ER) stress. DNA damage induced apoptosis by treatment with the commonly used diabetogenic agent streptozotocin (STZ) is regulated by both ATM and P53. We show that ATM is a key STZ induced activator of P53 and that amelioration of STZ induced cell death by inhibition of ATM mainly depends on P53. While both P53 and ATM control lipotoxic beta cell apoptosis, ATM but not P53 fails to alter inflammatory beta cell death. In contrast, tunicamycin induced (ER stress associated) apoptosis is further increased by ATM knockdown or inhibition, but not by P53 knockdown. Our results reveal differential roles for P53 and ATM in beta cell survival in vitro in the context of four key pathophysiological types of diabetogenic beta cell stress, and indicate that ATM can use P53 independent signaling pathways to modify beta cell survival, dependent on the cellular insult.

Abstract: The complement and coagulation cascades interact at multiple levels in thrombosis and inflammatory diseases. In venous thrombosis, complement factor 3 (C3) is crucial for platelet and tissue factor (TF) procoagulant activation dependent on protein disulfide isomerase (PDI). Furthermore, C5 selectively contributes to the exposure of leukocyte procoagulant phosphatidylserine (PS), which is a prerequisite for rapid activation of monocyte TF and fibrin formation in thrombosis. Here, we show that monoclonal cofactor-independent antiphospholipid antibodies (aPLs) rapidly activate TF on myelomonocytic cells. TF activation is blocked by PDI inhibitor and an anti-TF antibody interfering with PDI binding to TF, and requires C3 but unexpectedly not C5. Other prothrombotic, complement-fixing antibodies, for example, antithymocyte globulin, typically induce TF activation dependent on C5b-7–mediated PS exposure on the outer membrane of monocytes. We show that aPLs directly induce procoagulant PS exposure independent of C5. Accordingly, mice deficient in C3, but not mice deficient in C5, are protected from in vivo thrombus formation induced by cofactor-independent aPLs. Only immunoglobulin G (IgG) fractions with cofactor-independent anticardiolipin reactivity from patients with antiphospholipid syndrome (APS) induce complement-independent monocyte PS exposure and PDI-dependent TF activation. Neither a human monoclonal aPL directed against β2-glycoprotein I (β2GPI) nor patient IgG with selective reactivity to β2GPI rapidly activated monocyte TF. These results indicate that inhibitors of PDI and TF, but not necessarily clinically available drugs targeting C5, have therapeutic benefit in preventing thrombosis associated with APS caused by pathogenic aPLs primarily reactive with lipid, independent of β2GPI.

Stepwise oxidation of the epigenetic mark 5-methylcytosine and base excision repair (BER) of the resulting 5-formylcytosine (5-fC) and 5-carboxycytosine (5-caC) may provide a mechanism for reactivation of epigenetically silenced genes; however, the functions of 5-fC and 5-caC at defined gene elements are scarcely explored. We analyzed the expression of reporter constructs containing either 2′-deoxy-(5-fC/5-caC) or their BER-resistant 2′-fluorinated analogs, asymmetrically incorporated into CG-dinucleotide of the GC box cis-element (5′-TGGGCGGAGC) upstream from the RNA polymerase II core promoter. In the absence of BER, 5-caC caused a strong inhibition of the promoter activity, whereas 5-fC had almost no effect, similar to 5-methylcytosine or 5-hydroxymethylcytosine. BER of 5-caC caused a transient but significant promoter reactivation, succeeded by silencing during the following hours. Both responses strictly required thymine DNA glycosylase (TDG); however, the silencing phase additionally demanded a 5′-endonuclease (likely APE1) activity and was also induced by 5-fC or an apurinic/apyrimidinic site. We propose that 5-caC may act as a repressory mark to prevent premature activation of promoters undergoing the final stages of DNA demethylation, when the symmetric CpG methylation has already been lost. Remarkably, the downstream promoter activation or repression responses are regulated by two separate BER steps, where TDG and APE1 act as potential switches.

The objective of the present paper is to develop a validated numerical model of a water vortex power plant that serves as a digital twin for further studies such as assessments of the ethohydraulic characteristics or the performance of such devices. The reference for the validation process is a large-scale hydraulic installation equipped with a full-scale water vortex power plant prototype installed in Dresden (Germany), where flow field measurements were carried out using three-dimensional Acoustic Doppler Velocimetry. The numerical model was implemented within the software package Star-CCM+. The unsteady, two-phase flow was solved with the Reynolds-Averaged Navier–Stokes equations in a Eulerian Multiphase approach, deploying a Volume of Fluid method to describe the free-surface flow. Water level and flow velocities were systematically compared in key areas of the device, demonstrating that the simulation is in good agreement with experimental observations. Relative differences are limited to at most 4% regarding water height in the system, and even the much more challenging velocity fields are reproduced with typical relative errors of roughly 10%. This validates the ability of the model to model the challenging flow conditions found in a water vortex power plant, enabling subsequent studies of the characteristics of this power plant concerning fish migration.

Antiphospholipid antibodies (aPL) are a hallmark of the antiphospholipid syndrome (APS), which is the most commonly acquired thrombophilia. To date there is consensus that aPL cause the clinical manifestations of this potentially devastating disorder. However, there is good evidence that not all aPL are pathogenic. For instance, aPL associated with syphilis show no association with the manifestations of APS. While there has been intensive research on the pathogenetic role of aPL, comparably little is known about the origin and development of aPL. This review will summarize the current knowledge and understanding of the origin and development of aPL derived from animal and human studies.