ABSTRACT
In their daily practice, health care workers (HCWs) experience the effects of tensions between professional ethos and work realities, which can lead to ethical dilemmas. We aim to explore the ethical dilemmas that affected HCWs in Germany during the COVID-19 pandemic and to understand these in the context of the German health system. Between April and December 2022, we interviewed HCWs from various levels of care and key informants responsible for decisions related to HCWs in Germany. Three themes were identified in the data analyzed from 78 participants. The first highlighted the potency of pre-existing health system problems during the COVID-19 pandemic. The second captured the ethical dilemmas that were described as having arisen due to the tension between professional ethos and structural constraints. The third included factors related to increasing or diminishing the implications of ethical dilemmas. A lack of opportunities for HCWs to participate in political and managerial decisions was suggested to result in policies that do not meet the needs of HCWs and patients. Positive interpersonal interactions were described as helpful when coping with dilemmatic decision-making situations. In order to avoid negative consequences caused by unresolved ethical dilemmas, including moral distress, among HCWs, staff shortages and decision-making in the German health system urgently need to be addressed. HCWs' working conditions regularly evoke ethical dilemmas, particularly during public health emergencies. Together with HCWs, decision-makers must develop new models for working in health care settings that are in line with HCWs' professional ethos.
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.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Child , Adult , Humans , Mesenchymal Stem Cell Transplantation/adverse effects , Retrospective Studies , Acute Disease , Hematopoietic Stem Cell Transplantation/adverse effects , Graft vs Host Disease/drug therapyABSTRACT
PURPOSE: The aim of this study was to establish the rate at which routine postoperative renal ultrasonography is able to detect urinary tract injury following gynecological surgery. METHODS: A retrospective analysis was carried out for the study period 2015-2019 of all patients who had undergone subtotal or total hysterectomy, or radical hysterectomy or salpingectomy, salpingo-oophorectomy, or oophorectomy, and subsequently had a urinary tract injury. RESULTS: In a total of 2068 patients, 25 urinary tract injuries occurred (1.21%), including 21 urinary bladder lesions (1.02%) and four ureteral injuries (0.19%). The incidence of urinary tract injuries was 3% in oncologic procedures and 0.86% in procedures for benign disease. Nineteen injuries (76%) were diagnosed intraoperatively, and six injuries (24%) were clinically diagnosed after surgery. All of the patients had uneventful postoperative renal ultrasound examinations. CONCLUSION: Routine postoperative renal ultrasonography was not capable of diagnosing urinary tract injuries after gynecologic surgery. Routine postoperative renal ultrasound examinations should, therefore, not be performed after gynecologic operations.
Subject(s)
Ureter , Urinary Tract , Female , Gynecologic Surgical Procedures , Humans , Hysterectomy , Ovariectomy , Retrospective Studies , Ureter/diagnostic imaging , Urinary Tract/diagnostic imagingABSTRACT
Internal states, e.g., emotions, cognitive states, or desires, are often verbalized by figurative means, in particular by embodied metaphors involving human senses, such as touch, taste, and smell. The present paper presents a database for German metaphorical expressions conveying internal states with human senses as their source domains. 168 metaphorical expressions from the source domains of vision, hearing, smell, taste, touch, and temperature combined with literal equivalents were collected and rated by 643 adults. The agreement between the metaphor and an equivalent literal expression, as well as emotional valence, arousal, and familiarity values were assessed using a 7-point Likert scale. Between the metaphorical expressions and their equivalents, familiarity, but not valence or arousal differed significantly while agreement ratings indicated high similarity in meaning. The novel database offers carefully controlled stimuli that can be used in both empirical metaphor research and research on internal state language. Using part of the stimuli in a sentence completion experiment revealed a significant preference for literal over metaphorical expressions that cannot be attributed to higher familiarity levels.
Subject(s)
Language , Metaphor , Adult , Comprehension , Emotions , Humans , Psycholinguistics , Recognition, PsychologyABSTRACT
Myelodysplastic syndrome (MDS) with isolated deletion of chromosome 5q (MDS del5q) is a distinct subtype of MDS with quite favorable prognosis and excellent response to treatment with lenalidomide. Still, a relevant percentage of patients do not respond to lenalidomide and even experience progression to acute myeloid leukemia (AML). In this study, we aimed to investigate whether global DNA methylation patterns could predict response to lenalidomide. Genome-wide DNA methylation analysis using Illumina 450k methylation arrays was performed on n=51 patients with MDS del5q who were uniformly treated with lenalidomide in a prospective multicenter trial of the German MDS study group. To study potential direct effects of lenalidomide on DNA methylation, 17 paired samples pre- and post-treatment were analyzed. Our results revealed no relevant effect of lenalidomide on methylation status. Furthermore, methylation patterns prior to therapy could not predict lenalidomide response. However, methylation clustering identified a group of patients with a trend towards inferior overall survival. These patients showed hypermethylation of several interesting target genes, including genes of relevant signaling pathways, potentially indicating the evaluation of novel therapeutic targets.
Subject(s)
Antineoplastic Agents/therapeutic use , DNA Methylation/drug effects , Lenalidomide/therapeutic use , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/genetics , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/pharmacology , Chromosome Deletion , Chromosomes, Human, Pair 5/genetics , Female , Humans , Lenalidomide/pharmacology , Male , Middle Aged , Treatment OutcomeABSTRACT
BackgroundDetailed information on symptom duration and temporal course of patients with mild COVID-19 was scarce at the beginning of the COVID-19 pandemic.AimWe aimed to determine the longitudinal course of clinical symptoms in non-hospitalised COVID-19 patients in Berlin, Germany.MethodsBetween March and May 2020, 102 confirmed COVID-19 cases in home isolation notified in Berlin, Germany, were sampled using total population sampling. Data on 25 symptoms were collected during telephone consultations (a maximum of four consultations) with each patient. We collected information on prevalence and duration of symptoms for each day of the first 2 weeks after symptom onset and for day 30 and 60 after symptom onset.ResultsMedian age was 35 years (range 18-74), 57% (58/102) were female, and 37% (38/102) reported having comorbidities. During the first 2 weeks, most common symptoms were malaise (94%, 92/98), headache (71%, 70/98), and rhinitis (69%, 68/98). Malaise was present for a median of 11 days (IQR 7-14 days) with 35% (34/98) of cases still reporting malaise on day 14. Headache and muscle pain mostly occurred during the first week, whereas dysosmia and dysgeusia mostly occurred during the second week. Symptoms persisted in 41% (39/95) and 20% (18/88) of patients on day 30 and 60, respectively.ConclusionOur study shows that a significant proportion of non-hospitalised COVID-19 cases endured symptoms for at least 2 months. Further research is needed to assess the frequency of long-term adverse health effects in non-hospitalised COVID-19 patients.
Subject(s)
COVID-19 , Adolescent , Adult , Aged , Berlin , Female , Germany/epidemiology , Humans , Longitudinal Studies , Middle Aged , Pandemics , SARS-CoV-2 , Young AdultABSTRACT
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.
Subject(s)
CpG Islands , Cytosine/analogs & derivatives , DNA Damage , DNA Repair , Promoter Regions, Genetic , Thymine DNA Glycosylase/metabolism , DNA/metabolism , DNA Demethylation , DNA Methylation , Deoxyribonuclease (Pyrimidine Dimer) , Epigenesis, Genetic , HeLa Cells , HumansABSTRACT
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.
Subject(s)
COVID-19/epidemiology , COVID-19/transmission , Disease Outbreaks/statistics & numerical data , Disease Transmission, Infectious/statistics & numerical data , Food Services , Adolescent , Adult , COVID-19/virology , Child , Child, Preschool , Female , Germany/epidemiology , Humans , Male , Middle Aged , SARS-CoV-2 , Young AdultABSTRACT
Human aggression can be differentiated into reactive aggression (RA), displayed in face of a real or perceived threat and associated with high levels of anxiety, and proactive aggression (PA), displayed to achieve a certain goal and linked to lower anxiety levels. To study the origins of these aggression subtypes and their relation to anxiety, we tested if both subtypes can be distinguished in a nonhuman primate species, characterized their occurrence within the study group, and examined the link between aggression subtype and anxiety. Data were collected on 29 individuals of a semi-free ranging group of Barbary macaques (Macaca sylvanus) at Affenberg Salem, Germany, via focal animal (303 hr) and event sampling (1,222 agonistic events). Using a priori definitions, each aggressive event was classified as either reactive or proactive. We found both aggression types in our study population as well as individual differences in the proportion at which they occurred. The predominant use of one subtype of aggression was linked to the individual's dominance rank, age and sex, but not related to standard behavioral and physiological measures of anxiety. Our results suggest that reactive and proactive subtypes of aggression also exist in Barbary macaques, indicating a deeper evolutionary history of these aggression types observed in humans.
Subject(s)
Aggression/physiology , Behavior, Animal/physiology , Macaca/physiology , Animals , Female , MaleABSTRACT
BACKGROUND: In the care of people with dementia (PwD), occupational therapies and activities aiming at maintaining the quality of life of PwD, such as reminiscence therapy (RT), are taking on a more and more important role. Information and communication technology (ICT) has the potential to improve and to facilitate RT by facilitating access to and selection of biographical information and related contents or by providing novel multimodal interaction forms to trigger memories; however, interactive multimedia technology is barely used in practice. OBJECTIVES, MATERIALS AND METHODS: This article presents three exploratory field studies that evaluated different aspects of RT technology use for PwD in care homes, including the utilization of online movie databases, interactive surface touch computers as well as natural user interfaces allowing gestures and haptic interaction. In these studies, the usage of prototype systems was observed in occupational sessions by 5, 12 and 16 PwD. RESULTS AND CONCLUSION: The results indicate positive effects of technology use, e. g. in the form of verbally elicited reminiscence statements, expressed joy and playful interaction. Lessons learned for the design of technology-based RT interventions are presented and discussed.
Subject(s)
Alzheimer Disease/therapy , Communication , Information Technology , Mental Recall , Multimedia , Psychotherapy/methods , Aged , Aged, 80 and over , Alzheimer Disease/psychology , Computers, Handheld , Female , Germany , Humans , Interdisciplinary Communication , Intersectoral Collaboration , Male , Personhood , Photography , Video RecordingABSTRACT
Patients with monoclonal gammopathy of undetermined significance (MGUS) have a higher risk for the development of concomitant primary cancers such as multiple myeloma (MM) and myelodysplastic syndrome (MDS). We report the case of patient initially suffering from MGUS of the IgG lambda subtype for more than 10 yr, which evolved to MM and MDS with deletion (5q) with severe pancytopenia. Due to pancytopenia, he received dose-reduced treatment with lenalidomide and dexamethasone. He achieved an ongoing transfusion independency after about 1 month of treatment. Bone marrow taken 14 months after start of treatment showed a complete cytogenetic response of the del(5q) clone and a plasma cell infiltration below 5%. In contrast to the development of MM in MGUS patients, the subsequent occurrence of MDS after diagnosis of MGUS is infrequent. Moreover, the biological association of MDS with MGUS is not sufficiently understood, but the non-treatment-related occurrence supports the pathogenetic role of pre-existing alterations of stem cells. Here, we summarize data on concomitant MDS and MGUS/MM with particular emphasis on molecular aspects.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 5 , Monoclonal Gammopathy of Undetermined Significance/diagnosis , Monoclonal Gammopathy of Undetermined Significance/genetics , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/genetics , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow/pathology , Disease Progression , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/genetics , Male , Monoclonal Gammopathy of Undetermined Significance/therapy , Mutation , Myelodysplastic Syndromes/drug therapy , Repressor Proteins/geneticsABSTRACT
The major histocompatibility complex (MHC) plays an important role in the immune response and may thus crucially affect an individual's fitness, relevant also for studies on evolutionary ecology and wildlife conservation. Detailed knowledge on the genomic organization, polymorphism and diversity of the MHC has a narrow taxonomic focus though and among macaques is only available for rhesus and long-tailed macaques-the species most commonly kept for biomedical research. The lack of data on wild populations is largely due to the difficulty of obtaining blood or tissue samples necessary for genotyping approaches. Here, we aimed at analyzing MHC-DRB from non-invasively collected fecal samples in wild Assamese macaques (Macaca assamensis), utilizing the MHC-DRB-STR (D6S2878) microsatellite marker. Due to the fecal DNA source incomplete genotypes occurred, which may be improved in the future by method refinement. We detected 28 distinct DRB-STR lengths in 43 individuals with individual genotypes containing 1-9 MHC-DRB-STRs and defined four haplotypes segregating between families in Mendelian fashion. Our results indicate that variability and diversity of MHC-DRB in Assamese macaques is comparable to that of other macaque species and importantly, that fecal samples can be used for non-invasive analysis of MHC genes after refinement of the applied methods, opening a number of opportunities for MHC research on natural populations.
Subject(s)
Feces/chemistry , Genotype , HLA-DR beta-Chains/genetics , Macaca/genetics , Major Histocompatibility Complex/genetics , Animals , DNA/analysis , Haplotypes/genetics , Macaca/immunology , Microsatellite Repeats/genetics , Microsatellite Repeats/immunologyABSTRACT
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 < 18.5 kg/m2] receive 0.6 L of vegetable oil and 6.0 kg of a soy-wheat blend per month throughout their TB treatment. METHODS: We analysed secondary non-governmental organisation data collected between January and November 2022 in the Atsimo-Andrefana region, Southern Madagascar, including information on an individual's medical conditions (e.g., type of TB, treatment outcomes) and nutritional status measured prior to, during, and after completion of treatment (e.g., height, weight, mid-upper arm circumference). We conducted descriptive analyses of patient baseline characteristics and outcomes to assess the impact of the provided nutritional support on the BMI of people with TB. RESULTS: A total of 1310 people with TB were included in the study [9.9% (130) children under the age of 5, 32.1% (420) children between 5 and 18 years, 58.0% (760) adults]. 55.4% of children under 5, 28.1% of children between ages 5 and 18, and 81.3% of adults were undernourished at treatment initiation. 42.3% (55/130) of children under 5 experienced severe acute malnutrition at treatment uptake. While the average BMI of adults with TB receiving food support increased over time, from 17.1 kg/m2 (interquartile range: 15.8-18.3, range: 10.3-22.5) to 17.9 kg/m2 (interquartile range: 16.6-19.1, range: 11.9-24.1), most adults remained undernourished even after completing TB treatment. CONCLUSIONS: The current TB nutritional support programme falls short of sufficiently increasing the BMI of people with TB to overcome malnutrition. There is an urgent need to revise the nutritional support available for people with TB, particularly for children under 5.
Subject(s)
Malnutrition , Tuberculosis , Adult , Child , Humans , Cross-Sectional Studies , Madagascar/epidemiology , Nutritional Status , Malnutrition/epidemiology , Malnutrition/therapy , Tuberculosis/epidemiology , Tuberculosis/therapy , Tuberculosis/complications , Nutritional SupportABSTRACT
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.
Subject(s)
Labor, Obstetric , Obstetrics , Pregnancy , Infant, Newborn , Female , Humans , Cost-Effectiveness Analysis , Madagascar , Cost-Benefit AnalysisABSTRACT
BACKGROUND: Several 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. METHODS: We 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 SIGNIFICANCE: 314 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.
Subject(s)
Pregnant Women , Telemedicine , Child , Female , Humans , Pregnancy , Madagascar , Cross-Sectional Studies , Telemedicine/methods , Health Facilities , Qualitative Research , Community Health WorkersABSTRACT
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.
Subject(s)
Diabetes Mellitus, Type 2 , Insulin-Secreting Cells , Humans , Mice , Animals , Insulin-Secreting Cells/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Diabetes Mellitus, Type 2/metabolism , Insulin/metabolism , Glucose/metabolismABSTRACT
Impaired proinsulin-to-insulin processing in pancreatic ß-cells is a key defective step in both type 1 diabetes and type 2 diabetes (T2D) (refs. 1,2), but the mechanisms involved remain to be defined. Altered metabolism of sphingolipids (SLs) has been linked to development of obesity, type 1 diabetes and T2D (refs. 3-8); nonetheless, the role of specific SL species in ß-cell function and demise is unclear. Here we define the lipid signature of T2D-associated ß-cell failure, including an imbalance of specific very-long-chain SLs and long-chain SLs. ß-cell-specific ablation of CerS2, the enzyme necessary for generation of very-long-chain SLs, selectively reduces insulin content, impairs insulin secretion and disturbs systemic glucose tolerance in multiple complementary models. In contrast, ablation of long-chain-SL-synthesizing enzymes has no effect on insulin content. By quantitatively defining the SL-protein interactome, we reveal that CerS2 ablation affects SL binding to several endoplasmic reticulum-Golgi transport proteins, including Tmed2, which we define as an endogenous regulator of the essential proinsulin processing enzyme Pcsk1. Our study uncovers roles for specific SL subtypes and SL-binding proteins in ß-cell function and T2D-associated ß-cell failure.
Subject(s)
Diabetes Mellitus, Type 1 , Diabetes Mellitus, Type 2 , Insulin-Secreting Cells , Humans , Proinsulin/genetics , Proinsulin/metabolism , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Sphingolipids/metabolism , Diabetes Mellitus, Type 1/metabolism , Insulin/metabolism , Homeostasis , Carrier Proteins/metabolism , Glucose/metabolism , Insulin-Secreting Cells/metabolismABSTRACT
We explored the effects of resilience in the healthcare setting during the COVID-19 pandemic in Germany. Our study sheds light on the cross-level effects of resilience in hospitals and thus responds to calls to research this empirically. In a cross-sectional study design, the perceptions of resilience of employees in hospitals and of transformations at the individual, team, and organizational level were analyzed. An online survey was conducted in summer 2020 in Germany in which 1,710 healthcare workers completed a self-report questionnaire. Results indicate that resilience is both a highly interrelated construct on the individual and organizational level and also positively linked to perceptions of transformation as an indicator for demonstration of resilience. We also found a partial mediation effect of organizational resilience and team efficacy, respectively, on the relationship between individual resilience and perceived transformation on the individual and organizational level as well as a full mediation on the team level. The study highlights the interdependence of individual and organizational resilience (which is mediated by team efficacy) and its impact on perceived transformation in German hospitals during the COVID-19 pandemic. Whereas team efficacy is crucial for performance in regular work operations, during a pandemic the organizational level becomes more relevant. Theoretical and practical implications are discussed.
ABSTRACT
Despite a free TB care policy, access to TB care in rural Madagascar is limited due to a markedly underfunded health care system. The World Health Organization estimated the yearly TB incidence in Madagascar at 238 cases per 100,000 people in 2020; only half of the patients with TB are being notified and treated. We describe the development, implementation, and lessons learned of an intervention to improve TB care services in a remote, rural district in southern Madagascar. We involved national, regional, and local stakeholders in assessing the multifaceted challenges in a remote, rural area and codesigning activities to address them. The overarching principles of the intervention were to (1) promote national TB guidelines, (2) build on best practices, and (3) prioritize low-cost activities to enable scale-up. An in-depth assessment of challenges in accessing and delivering TB care resulted in the following prioritization of activities: (1) fostering community engagement, (2) decentralizing service provision, (3) improving quality of care, (4) providing nutritional support, and (5) ensuring staff support and supervision. The intervention was launched in September 2019 and is ongoing as of October 2022. During mobile TB clinics conducted between September 2019 and December 2020, 4,982 presumptive patients were screened and 1,706 (34.2%) have been diagnosed with TB. Based on 2010-2020 official TB notification data, we calculated trend-adjusted additional TB notifications during the intervention, resulting in a 2.6-fold increase in cases in 2019-2020. The intervention district's TB notification rate increased from 178 cases per 100,000 people in 2018 to 424 cases per 100,000 people in 2020. Involving stakeholders from all levels of care was perceived as a key to success. The unexpected increase in the number of patients with TB in the intervention district overburdened the current paper-based TB notification system and emphasized the need for expanded diagnostics and social support services.