Search

Zusammenfassung Hintergrund Die Blut-Kammerwasser-Schranke (BKS) grenzt immunprivilegiertes Gewebe des Auges von der Blutzirkulation ab. Die Störung der BKS stellt somit einen Risikofaktor für Abstoßungsreaktionen nach Keratoplastik dar. Ziel der Arbeit Die vorliegende Arbeit bietet eine Übersicht der Arbeiten unserer und anderer Arbeitsgruppen zu BKS-Störungen bei perforierender (PKPL) und posteriorer lamellärer Keratoplastik sowie deren Implikationen für das klinische Ergebnis. Methoden Es erfolgte eine PubMed-Literaturrecherche zur Erstellung einer Übersichtsarbeit. Ergebnis Die Laser-Flare-Photometrie bietet ein objektives und reproduzierbares Verfahren zur Beurteilung der Integrität der BKS. Untersuchungen des Flares nach perforierender und posteriorer lamellärer Keratoplastik belegen eine im postoperativen Verlauf meist rückläufige Störung der BKS, die in Ausmaß und Dauer durch multiple Faktoren beeinflusst wird. Persistierend erhöhte Flare-Werte oder ein Anstieg des Flares nach zunächst postoperativer Regeneration können dabei auf ein erhöhtes Abstoßungsrisiko hinweisen. Diskussion Bei persistierend oder im postoperativen Verlauf rezidivierend erhöhten Flare-Werten nach Keratoplastik ist eine intensivierte (lokale) Immunsuppression möglicherweise sinnvoll. Dies könnte zukünftig, insbesondere beim Monitoring von Patienten nach Hochrisiko-Keratoplastik, Bedeutung erlangen. Ob ein Anstieg des Laser-Flares ein reliabler Frühindikator einer drohenden Immunreaktion nach PKPL oder posteriorer lamellärer Keratoplastik ist, müssen jedoch prospektive Studien zeigen.

BackgroundSeveral long-term chronic illnesses are known to be associated with an increased risk of dementia independently, but little is known how combinations or clusters of potentially interacting chronic conditions may influence the risk of developing dementia.Methods447 888 dementia-free participants of the UK Biobank cohort at baseline (2006–2010) were followed-up until 31 May 2020 with a median follow-up duration of 11.3 years to identify incident cases of dementia. Latent class analysis (LCA) was used to identify multimorbidity patterns at baseline and covariate adjusted Cox regression was used to investigate their predictive effects on the risk of developing dementia. Potential effect moderations by C reactive protein (CRP) and Apolipoprotein E (APOE) genotype were assessed via statistical interaction.ResultsLCA identified four multimorbidity clusters representingMental health,Cardiometabolic,Inflammatory/autoimmuneandCancer-related pathophysiology, respectively. Estimated HRs suggest that multimorbidity clusters dominated byMental health(HR=2.12, pCardiometabolicconditions (2.02, pInflammatory/autoimmunecluster was intermediate (1.56, pCancercluster was least pronounced (1.36, pConclusionsEarly identification of older adults at higher risk of accumulating multimorbidity of specific pathophysiology and tailored interventions to prevent or delay the onset of such multimorbidity may help prevention of dementia.

El género Brachymyrmex es originario de la Región Neotropical donde incluye aproximadamente 30 especies, de las cuales 26 se han citado para la Argentina. Fue establecido para B. patagonicus (Mayr 1868). Santschi (1923) hizo la única revisión sistemática completa del género existente hasta la fecha, pero restan ambigüedades en la identificación de algunas especies. En este trabajo se redescriben la especie tipo del género, B. patagonicus, como asimismo B. bruchi y B. oculatus. Se acompañan las descripciones de las diferentes castas (obrera, reina y macho) con ilustraciones de los principales caracteres morfológicos utilizados en la identificación. Se designa lectotipo para B. oculatus. El material estudiado pertenece al Museo Argentino de Ciencias Naturales “B. Rivadavia”, al Naturhistorisches Museum Wien, y al Museo de La Plata.

ZusammenfassungDer akute Hydrops bezeichnet ein plötzliches Hornhautödem, das durch den Einriss der Descemet-Membran (DM) häufig bei fortschreitender Keratektasie verursacht wird. Er führt zu einer plötzlichen Visusminderung, Schmerzen und Fremdkörpergefühl sowie zu einem gesteigerten Blendungsempfinden. In der Regel heilt der akute Hydrops innerhalb von Monaten narbig ab, jedoch kann es auch zu Komplikationen wie Hornhautperforation, infektiöser Keratitis und Hornhautvaskularisationen kommen. Die Prävalenz bei Keratokonuspatienten liegt bei 2,6 – 2,8%. Risikofaktoren sind die Keratoconjunctivitis vernalis, die atopische Dermatitis, hohe Keratometriewerte, männliches Geschlecht sowie Augenreiben. Eine Keratoplastik sollte in der akuten Phase vermieden werden. Die Prognose des Transplantates ist reduziert und nach narbiger Abheilung des Hydrops kann das Tragen von Kontaktlinse oder Brille u. U. wieder möglich sein. Eine alleinige konservative Therapie mit benetzenden und entquellenden Tropfen, prophylaktischen antibiotischen Augentropfen zur Vermeidung einer Superinfektion und topischen Steroiden galt lange Zeit als die einzig mögliche Behandlungsform. Die narbige Abheilung und Entquellung unter konservativer Therapie dauert im Mittel jedoch über 100 Tage. Mittlerweile gibt es unterschiedliche chirurgische Strategien, die die Heilungs- und damit die Leidensphase der Patienten bis auf wenige Tage rapide verkürzen. Bei Lösung der DM ohne Spannung kann eine simple Gaseingabe in die Vorderkammer bereits zur Wiederanlage und damit zur fast sofortigen Entquellung der Hornhaut führen. Wenn die DM unter Spannung steht, kann durch prädescemetale Nähte in Kombination mit einer Gaseingabe in die Vorderkammer ein Abflachen der Hornhaut und eine Wiederanlage der DM erreicht werden. Die Mini-Descemet Membrane Endothelial Keratoplasty (Mini-DMEK) erlaubt den nahtfreien Verschluss des DM-Defektes durch Transplantation eines kleinen (

Crystal- melt separation has been invoked as a mechanism that generates compositional variabil-ities in magma reservoirs hosted within the Earth's crust. However, the way phase separation occurs within such reservoirs is still debated. The San Gabriel pluton of central Chile is a composite pluton (12.82 +/- 0.19 Ma) with wide textural/compositional variation (52- 67 wt% SiO2) and presents a great natural laboratory for studying processes that occur in upper crustal magma reservoirs. Geochemical and geochronological data supported by numerical models reveals that shallow magma differentiation via crystal- melt separation occurred in magma with intermediate composition and generated high-silica magmas and cumulate residues that were redistributed within the reservoir.The pluton is composed of three units: (1) quartz-monzonites representing the main hosting unit, (2) a porphyritic monzogranite located at the lowest exposed levels, and (3) coarse-grained quartz-monzodiorites with cumulate textures at the middle level of the intrusive. Calculations of mass balance and thermodynamic modeling of major and trace elements indicate that, Geosphere, 19 (2), ISSN:1553-040X

ObjectiveTo assess the main characteristics and result reporting of registered COVID-19 interventional trials of traditional Chinese medicine and traditional Indian medicine.Materials and methodsWe assessed design quality and result reporting of COVID-19 trials of traditional Chinese medicine (TCM) and traditional Indian medicine (TIM) registered before 10 February 2021, respectively, on Chinese Clinical Trial Registry (ChiCTR) and Clinical Trial Registry-India (CTRI). Comparison groups included registered COVID-19 trials of conventional medicine conducted in China (WMC), India (WMI), and in other countries (WMO). Cox regression analysis was used to assess the association between time from trial onset to result reporting and trial characteristics.ResultsThe proportion of COVID-19 trials investigating traditional medicine was 33.7% (130/386) among trials registered on ChiCTR, and 58.6% (266/454) on CTRI. Planned sample sizes were mostly small in all COVID-19 trials (median 100, IQR: 50–200). The proportion of trials that were randomized was 75.4 and 64.8%, respectively, for the TCM and TIM trials. Blinding measures were used in 6.2% of the TCM trials, and 23.6% of the TIM trials. Cox regression analysis revealed that planned COVID-19 clinical trials of traditional medicine were less likely to have results reported than trials of conventional medicine (hazard ratio 0.713, 95% confidence interval: 0.541–0.939; p = 0.0162).ConclusionThere were considerable between-country and within-country differences in design quality, target sample size, trial participants, and reporting of trial results. Registered COVID-19 clinical trials of traditional medicine were less likely to report results than trials of conventional medicine.

Many volcanoes show transitions between explosive and effusive eruptive styles both through the history of the volcano as a whole and occasionally within the course of a single eruption. These differing eruptive styles have vastly different implications for hazard assessments in surrounding regions and so understanding such changes is important. Here, we investigate the intercalated lavas and ignimbrites of the Miocene Fataga Group on the island of Gran Canaria, Spain. Ignimbrites reflect the products of explosive events from the Tejeda caldera, while lavas found within the pyroclastic succession were erupted from extra-caldera sources some 5–10 km from the caldera margin. The ignimbrites exhibit textural complexity containing both crystal-poor juvenile pyroclasts and late erupted crystal-rich juvenile clasts interpreted to reflect interaction between cumulates and recharge magmas. The lavas meanwhile are almost phenocryst-free, with the exception of few large (cm-scale), unzoned sanidine crystals. Despite their textural differences, the lavas are geochemically similar (in terms of bulk rock and feldspar compositions) to the crystal-poor juveniles in the ignimbrites. Oxygen and lead isotopic compositions of the lavas and surrounding ignimbrites reveal that the magmas shared a deeper source and that petrographic variability is imprinted upon the magmas at shallow levels. We interpret the lavas as originating from peripheral magmatic pockets, on the edges of the main caldera-feeding reservoir. These peripheral magma chambers felt the effects of recharge only as slight thermal fluctuations that fostered the production of the large sanidine crystals. Our findings highlight the potential for storage of magmas aside from the main magmatic system that may represent an underappreciated hazard at volcanoes worldwide., Chemical Geology, 616, ISSN:0009-2541, ISSN:1872-6836

Survival analysis is routinely used to assess differences between groups in relapse prevention and treatment discontinuation studies involving people with long-term psychiatric conditions. The actual outcome in survival analysis is ‘time to event’, yet, in the mental health field, there has been little consideration of whether a temporary delay to relapse is clinically relevant in a condition that can last for decades. Moreover, in psychiatric drug trials, a pattern of elevated early relapses following randomisation to placebo or no treatment is common. This may be the result of the withdrawal of previous treatment leading to physiological withdrawal effects, which may be mistaken for relapse, or genuine relapse precipitated by the process of withdrawal. Such withdrawal effects typically produce converging survival curves eventually. They inevitably lead to differences in time to relapse, even when there is little or no difference in the cumulative risk of relapse at final follow-up. Therefore, statistical tests based on survival analyses can be misleading because they obscure these withdrawal effects. We illustrate these difficulties in a trial of antipsychotic reduction versus maintenance, and a trial of prophylactic esketamine in people with treatment-resistant depression. Both illustrate withdrawal-related effects that underline the importance of long-term follow-up and question the use of tests based on time to event. Further discussion of the most relevant outcome and appropriate approach to analysis, and research on patient and carer preferences is important to inform the design of future trials and interpretation of existing ones.

Background The latest research clearly indicates that diet plays an important role in the onset and course of inflammatory bowel diseases (IBD). But especially data on gender specific aspects of diet in IBD patients are still lacking even though we know from the general population that gender matters in case of diet. Methods We hypothesised an interaction of gender and diet in IBD patients and that this is linked to disease behaviour. In a subgroup analysis of a previously published prospective trial (Wiestler M. et al., Clinical and Translational Gastroenterology, 2019) 91 IBD patients were stratified into 4 groups (Crohn’s disease - CD [n=50] and ulcerative colitis – UC [n=41], female and male, respectively) to compare nutritional behaviour by sex and diagnosis. We evaluated disease-specific quality of life (IBDQ), physical activity (accelerometery), body composition (bioelectrical impedance analysis (BIA)), as well as clinical (HBI, SCCAI) and biochemical (CRP, faecal calprotectin) parameters of disease activity in comparison to nutritional behaviour (food frequency questionnaire (FFQ)). Results The nutritional behaviour of CD patients showed significant gender-related trends and differences in correlation with disease activity (Spearman correlation analysis). In male CD patients HBI significantly negatively correlated with the amount of fish (p=0.005, r=-0.612) and meat consumed per month (p=0.023, r=-0.519). In female CD patients the amount of fish consumed per month significantly negatively correlated with the IBDQ score (p=0.029, r=-0.438). The nutritional behaviour of UC patients showed significant gender-related trends and differences in correlation with disease activity as well. In female patients SCCAI significantly negatively correlated with the amount of cake, pie/ sweet baked goods (p= Conclusion In this subgroup analysis of a cross-sectional study, nutritional behaviour of IBD patients showed significant gender-related differences in correlation with disease activity and disease related quality of life. Due to the close correlation between IBD and nutrition and the different nutritional needs according to disease activity, our results illustrate the importance of gender-sensitive collection of a nutritional history as well as the need for gender-sensitive nutritional recommendations in IBD patients to further optimize individual patient care.

Background Despite progress towards End TB Strategy targets for reducing tuberculosis (TB) incidence and deaths by 2035, South Africa remains among the top ten high-burden tuberculosis countries globally. A large challenge lies in how policies to improve detection, diagnosis and treatment completion interact with social and structural drivers of TB. Detailed understanding and theoretical development of the contextual determinants of problems in TB care is required for developing effective interventions. This article reports findings from the pre-implementation phase of a study of TB care in South Africa, contributing to HeAlth System StrEngThening in Sub-Saharan Africa (ASSET)—a five-year research programme developing and evaluating health system strengthening interventions in sub-Saharan Africa. The study aimed to develop hypothetical propositions regarding contextual determinants of problems in TB care to inform intervention development to reduce TB deaths and incidence whilst ensuring the delivery of quality integrated, person-centred care. Methods Theory-building case study design using the Context and Implementation of Complex Interventions (CICI) framework to identify contextual determinants of problems in TB care. Between February and November 2019, we used mixed methods in six public-sector primary healthcare facilities and one public-sector hospital serving impoverished urban and rural communities in the Amajuba District of KwaZulu-Natal Province, South Africa. Qualitative data included stakeholder interviews, observations and documentary analysis. Quantitative data included routine data on sputum testing and TB deaths. Data were inductively analysed and mapped onto the seven CICI contextual domains. Results Delayed diagnosis was caused by interactions between fragmented healthcare provision; limited resources; verticalised care; poor TB screening, sputum collection and record-keeping. One nurse responsible for TB care, with limited integration of TB with other conditions, and policy focused on treatment adherence contributed to staff stress and limited consideration of patients’ psychosocial needs. Patients were lost to follow up due to discontinuity of information, poverty, employment restrictions and limited support for treatment side-effects. Infection control measures appeared to be compromised by efforts to integrate care. Conclusions Delayed diagnosis, limited psychosocial support for patients and staff, patients lost to follow-up and inadequate infection control are caused by an interaction between multiple interacting contextual determinants. TB policy needs to resolve tensions between treating TB as epidemic and individually-experienced social problem, supporting interventions which strengthen case detection, infection control and treatment, and also promote person-centred support for healthcare professionals and patients. Graphic abstract

Herein we report the development of a new periodate-based reactive assay system for the fluorescent detection of the cis-diol metabolites produced by Rieske dioxygenases. This sensitive and diastereoselective assay system successfully evaluates the substrate scope of Rieske dioxygenases and determines the relative activity of a rationally designed Rieske dioxygenase variant library. The high throughput capacity of the assay system enables rapid and efficient substrate scope investigations and screening of large dioxygenase variant libraries.

Natural products constitute and significantly impact many current anti-cancer medical interventions. A subset of natural products induces injury processes in malignant cells that recruit and activate host immune cells to produce an adaptive anti-cancer immune response, a process known as immunogenic cell death. However, a challenge in the field is to delineate forms of cell death and injury that best promote durable antitumor immunity. Addressing this with a single-cell chemical biology natural product discovery platform, like multiplex activity metabolomics, would be especially valuable in human leukemia, where cancer cells are heterogeneous and may react differently to the same compounds. Herein, a new ten-color, fluorescent cell barcoding-compatible module measuring six immunogenic cell injury signaling readouts are as follows: DNA damage response (γH2AX), apoptosis (cCAS3), necroptosis (p-MLKL), mitosis (p-Histone H3), autophagy (LC3), and the unfolded protein response (p-EIF2α). A proof-of-concept screen was performed to validate functional changes in single cells induced by secondary metabolites with known mechanisms within bacterial extracts. This assay was then applied in multiplexed activity metabolomics to reveal an unexpected mammalian cell injury profile induced by the natural product narbomycin. Finally, the functional consequences of injury pathways on immunogenicity were compared with three canonical assays for immunogenic hallmarks, ATP, HMGB1, and calreticulin, to correlate secondary metabolite-induced cell injury profiles with canonical markers of immunogenic cell death. In total, this work demonstrated a new phenotypic screen for discovery of natural products that modulate injury response pathways that can contribute to cancer immunogenicity.

Herein, we report novel formic acid-mediated rearrangements of dearomatized acylphloroglucinols to access a structurally diverse group of synthetic acylphloroglucinol scaffolds (SASs). Density functional theory (DFT)-optimized orbital and stereochemical analyses shed light on the mechanism of these rearrangements. Products were evaluated by multiplexed activity profiling (MAP), an unbiased platform which determines multiple biological readouts simultaneously at single-cell resolution for markers of cell signaling and can aid in distinguishing genuine activity from assay interference. Using MAP, we identified a number of SASs that suppressed pS6 (Ser235/236), a marker for activation of the mTOR and ERK signaling pathways. These results illustrate how biomimetic synthesis and multiplexed activity profiling can reveal the pharmacological potential of novel chemotypes via diversity-oriented synthesis.

Everninomicins are orthoester oligosaccharide antibiotics with potent activity against multidrug-resistant bacterial pathogens. Everninomicins act by disrupting ribosomal assembly in a distinct region in comparison to clinically prescribed drugs. We employed microporous intergeneric conjugation with Escherichia coli to manipulate Micromonospora for targeted gene-replacement studies of multiple putative methyltransferases across the octasaccharide scaffold of everninomicin effecting the A1 , C, F, and H rings. Analyses of gene-replacement and genetic complementation mutants established the mutability of the everninomicin scaffold through the generation of 12 previously unreported analogues and, together with previous results, permitted assignment of the ten methyltransferases required for everninomicin biosynthesis. The in vitro activity of A1 - and H-ring-modifying methyltransferases demonstrated the ability to catalyze late-stage modification of the scaffold on an A1 -ring phenol and H-ring C-4' hydroxy moiety. Together these results establish the potential of the everninomicin scaffold for modification through mutagenesis and in vitro modification of advanced biosynthetic intermediates.

ZusammenfassungDie COVID-19-Pandemie ist ein weltweiter Ausbruch von neu aufgetretenen Infektionen mit dem SARS-CoV-2-Virus, von denen weltweit derzeit mehr als 10.670.000 Menschen erkrankt sind bzw. waren. In Deutschland leiden ca. 450.000 Patienten an einer chronisch entzündlichen Darmerkrankung; diese Patienten benötigen in der Regel eine kontinuierliche und kompetente Betreuung. Vor dem Hintergrund eines rasch zunehmenden Wissenszuwachses haben 68 Experten, die die derzeit gültigen Leitlinien der DGVS zum Morbus Crohn und zur Colitis ulcerosa erstellt haben, im Rahmen einer virtuellen Konferenz aktuelle und praxisnahe Empfehlungen formuliert, um die Versorgung von CED-Patienten zu verbessern. Diese adressieren das Infektionsrisiko einschließlich des Risikos für besondere Gruppen, den möglichen Verlauf der Erkrankung und die Konsequenzen für die medikamentöse und die operative Therapie der Grunderkrankung sowie allgemeine Maßnahmen zur Infektionsprävention und adjuvante Präventions- und Therapiemöglichkeiten.

Congenital corneal opacities are comparatively rare diseases with high amblyogenic potential.The present work provides an overview of the diagnostics, clinical aspects and genetics of congenital corneal opacities.A literature search was carried out to compile an overview and illustration with own clinical case examples.Differentiated diagnostics are of high importance in the treatment of patients with congenital corneal opacities. A close cooperation between the medical departments involved and also the parents is absolutely essential. The structured classification of congenital corneal opacities provides the basis for a targeted treatment.The causes and the clinical symptoms of congenital corneal opacities are manifold. The correct diagnosis should be made early and in an interdisciplinary manner. Based on this, conservative and surgical treatment measures can be planned and an impending development of amblyopia can be specifically counteracted.HINTERGRUND: Kongenitale Hornhauttrübungen sind vergleichsweise seltene Erkrankungen mit hohem amblyogenem Potenzial.Die vorliegende Arbeit gibt eine Übersicht der Diagnostik, Klinik und Genetik kongenitaler Hornhauttrübungen.Es erfolgte eine Literaturrecherche zur Erstellung einer Übersichtsarbeit und Illustration mit eigenen Fallbeispielen.Eine differenzierte Diagnostik ist von hoher Bedeutung bei der Behandlung von Patienten mit kongenitaler Hornhauttrübung. Dabei ist eine enge Zusammenarbeit zwischen den beteiligten medizinischen Fachbereichen und auch den Eltern unbedingt erforderlich. Die strukturierte Einteilung der kongenitalen Hornhauttrübungen bietet die Grundlage für eine gezielte Therapie.Die Ursachen und die Klinik der kongenitalen Hornhauttrübungen sind vielfältig. Die korrekte Diagnose sollte frühzeitig und interdisziplinär gestellt werden. Darauf aufbauend können konservative und operative therapeutische Maßnahmen geplant werden, und es kann einer drohenden Amblyopieentwicklung gezielt entgegengewirkt werden.

Mafic and ultramafic plutonic rocks are often considered to be crystal cumulates (i.e., they are melt-depleted), but such a classification is much more contentious for intermediate to silicic gran-itoids (e.g., tonalite, granodiorite, granite, and syenite). Whether or not a given plutonic rock has lost melt to feed shallower subvolcanic intrusive bodies or volcanic edifices has key implications for understanding igneous processes occurring within the crust throughout the evolution of the Earth. We use statistical analyses of a global vol-canic and plutonic rock database to show that most mafic to felsic plutonic rock compositions can be interpreted as melt-depleted (i.e., most of the minerals analyzed are more evolved than their bulk-rock compositions would allow). To illustrate the application of the method to natural samples (from the Tertiary Adamello Batholith in the south-ern Alps), we estimate the degree of melt depletion using a combination of magmatic textures, bulk-rock chemistry, modal mineralogy, distributions of plagioclase composition (using scanning electron microscope phase mapping/electron microprobe analyses), and thermodynamic modeling. We find that melt depletion correlates with the magmatic foliation and is accompanied by bulk depletion in incompatible elements, low amounts of near-sol-idus minerals, and mineral compositions that are too evolved (i.e., depleted in Ca or Mg, depend-ing on the mineral) to be in equilibrium with their bulk-rock chemistry. The analytical and modeling workflow proposed in this study provides a path to quantifying melt depletion in any plutonic samples., Geosphere, 18 (3), ISSN:1553-040X

Since the onset of plate tectonics, continents have evolved through a balance between crustal growth, reworking, and recycling at convergent plate margins. The term “reworking” involves the re-insertion of crustal material into pre-existing crustal volumes, while crustal growth and recycling respectively represent gains from and losses to the mantle. Reworking that occurs in the mantle wedge (“source” contamination from slab material) or within the upper plate (“path” contamination), will have contrasting effects on crustal evolution. However, due to limited access to deep crustal and mantle rocks, quantifying source vs. path contamination remains challenging. Based on the 4-dimensional record of the fossil (Ordovician) Famatinian continental arc (Argentina), we demonstrate that source contamination plays a dominant role in imprinting mafic to granitic rocks with crustal oxygen-hafnium (O-Hf) isotopic compositions. We argue that source contamination at convergent plate margins significantly increased the diversity of O-Hf isotopic signatures of continents over geologic time. Our interpretation implies that crustal evolution models attributing this isotopic diversity dominantly to intra-crustal reworking may be over-simplistic and may underestimate continental growth in the last 2.5 billion years., Earth and Planetary Science Letters, 595, ISSN:0012-821X, ISSN:1385-013X

Background Although HIV continues to have a high prevalence among adults in sub-Saharan Africa (SSA), the burden of noncommunicable diseases (NCD) such as diabetes and hypertension is increasing rapidly. There is an urgent need to expand the capacity of healthcare systems in SSA to provide NCD services and scale up existing chronic care management pathways. The aim of this study was to identify key components, outcomes, and best practice in integrated service provision for the prevention, identification and treatment of HIV, hypertension and diabetes. Methods An international, multi stakeholder e-Delphi consensus study was conducted over two successive rounds. In Round 1, 24 participants were asked to score 27 statements, under the headings ‘Service Provision’ and ‘Benefits of Integration’, by importance. In Round 2, the 16 participants who completed Round 1 were shown the distribution of scores from other participants along with the score that they attributed to an outcome and were asked to reflect on the score they gave, based on the scores of the other participants and then to rescore if they wished to. Nine participants completed Round 2. Results Based on the Round 1 ranking, 19 of the 27 outcomes met the 70% threshold for consensus. Four additional outcomes suggested by participants in Round 1 were added to Round 2, and upon review by participants, 22 of the 31 outcomes met the consensus threshold. The five items participants scored from 7 to 9 in both rounds as essential for effective integrated healthcare delivery of health services for chronic conditions were improved data collection and surveillance of NCDs among people living with HIV to inform integrated NCD/HIV programme management, strengthened drug procurement systems, availability of equipment and access to relevant blood tests, health education for all chronic conditions, and enhanced continuity of care for patients with multimorbidity. Conclusions This study highlights the outcomes which may form key components of future complex interventions to define a model of integrated healthcare delivery for diabetes, hypertension and HIV in sub-Saharan Africa.

Introduction HIV programmes in sub-Saharan Africa are well funded but programmes for diabetes and hypertension are weak with only a small proportion of patients in regular care. Healthcare provision is organised from stand-alone clinics. In this cluster randomised trial, we are evaluating a concept of integrated care for people with HIV infection, diabetes or hypertension from a single point of care. Methods and analysis 32 primary care health facilities in Dar es Salaam and Kampala regions were randomised to either integrated or standard vertical care. In the integrated care arm, services are organised from a single clinic where patients with either HIV infection, diabetes or hypertension are managed by the same clinical and counselling teams. They use the same pharmacy and laboratory and have the same style of patient records. Standard care involves separate pathways, that is, separate clinics, waiting and counselling areas, a separate pharmacy and separate medical records. The trial has two primary endpoints: retention in care of people with hypertension or diabetes and plasma viral load suppression. Recruitment is expected to take 6 months and follow-up is for 12 months. With 100 participants enrolled in each facility with diabetes or hypertension, the trial will provide 90% power to detect an absolute difference in retention of 15% between the study arms (at the 5% two-sided significance level). If 100 participants with HIV infection are also enrolled in each facility, we will have 90% power to show non-inferiority in virological suppression to a delta=10% margin (ie, that the upper limit of the one-sided 95% CI of the difference between the two arms will not exceed 10%). To allow for lost to follow-up, the trial will enrol over 220 persons per facility. This is the only trial of its kind evaluating the concept of a single integrated clinic for chronic conditions in Africa. Ethics and dissemination The protocol has been approved by ethics committee of The AIDS Support Organisation, National Institute of Medical Research and the Liverpool School of Tropical Medicine. Dissemination of findings will be done through journal publications and meetings involving study participants, healthcare providers and other stakeholders. Trial registration number NCT43896688.

The study aims to compare outcomes after deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty (PK) in keratoconic eyes with or without previous hydrops.Retrospective analysis of 211 eyes who received PK (group 1, n = 74 [history of hydrops: n = 33]) or DALK (group 2, n = 137 [history of hydrops: n = 9]) from 2012 to 2019 at the Department of Ophthalmology, University of Cologne, Germany. Analysis included best spectacle-corrected visual acuity (BSCVA), complications, immune reactions, graft survival and keratometry, and subgroup analyses for subjects with or without previous hydrops.Follow-up was 34.0 ± 23.6 months in group 1 and 30.7 ± 22.5 months in group 2. No significant difference was found in the course of BSCVA between groups 1 and 2 (p = 0.182) and in postoperative BSCVA between eyes with and without previous hydrops, regardless of the surgical method (p = 0.768). Endothelial immune reactions occurred exclusively in group 1 and did not occur more frequently in eyes with previous hydrops (p = 0.377). A higher risk of complications for eyes with previous hydrops was observed (p = 0.022). There was no difference in astigmatism and maximum keratometry (KThe prognosis for visual outcome after keratoplasty including visual acuity, astigmatism, and K

Background Integration of health services might be an efficient strategy for managing multiple chronic conditions in sub-Saharan Africa, considering the scope of treatments and synergies in service delivery. Proven to promote compliance, integration may lead to increased economies-of-scale. However, evidence on the socio-economic consequences of integration for providers and patients is lacking. We assessed the clinical resource use, staff time, relative service efficiency and overall societal costs associated with integrating HIV, diabetes and hypertension services in single one-stop clinics where persons with one or more of these conditions were managed. Methods 2273 participants living with HIV infection, diabetes, or hypertension or combinations of these conditions were enrolled in 10 primary health facilities in Tanzania and Uganda and followed-up for up to 12 months. We collected data on resources used from all participants and on out-of-pocket costs in a sub-sample of 1531 participants, while a facility-level costing study was conducted at each facility. Health worker time per participant was assessed in a time-motion morbidity-stratified study among 228 participants. The mean health service cost per month and out-of-pocket costs per participant visit were calculated in 2020 US$ prices. Nested bootstrapping from these samples accounted for uncertainties. A data envelopment approach was used to benchmark the efficiency of the integrated services. Last, we estimated the budgetary consequences of integration, based on prevalence-based projections until 2025, for both country populations. Results Their average retention after 1 year service follow-up was 1911/2273 (84.1%). Five hundred and eighty-two of 2273 (25.6%) participants had two or all three chronic conditions and 1691/2273 (74.4%) had a single condition. During the study, 84/2239 (3.8%) participants acquired a second or third condition. The mean service costs per month of managing two conditions in a single participant were $39.11 (95% CI 33.99, 44.33), $32.18 (95% CI 30.35, 34.07) and $22.65 (95% CI 21.86, 23.43) for the combinations of HIV and diabetes and of HIV and hypertension, diabetes and hypertension, respectively. These costs were 34.4% (95% CI 17.9%, 41.9%) lower as compared to managing any two conditions separately in two different participants. The cost of managing an individual with all three conditions was 48.8% (95% CI 42.1%, 55.3%) lower as compared to managing these conditions separately. Out-of-pocket healthcare expenditure per participant per visit was $7.33 (95% CI 3.70, 15.86). This constituted 23.4% (95% CI 9.9, 54.3) of the total monthly service expenditure per patient and 11.7% (95% CI 7.3, 22.1) of their individual total household income. The integrated clinics’ mean efficiency benchmark score was 0.86 (range 0.30–1.00) suggesting undercapacity that could serve more participants without compromising quality of care. The estimated budgetary consequences of managing multi-morbidity in these types of integrated clinics is likely to increase by 21.5% (range 19.2–23.4%) in the next 5 years, including substantial savings of 21.6% on the provision of integrated care for vulnerable patients with multi-morbidities. Conclusion Integration of HIV services with diabetes and hypertension control reduces both health service and household costs, substantially. It is likely an efficient and equitable way to address the increasing burden of financially vulnerable households among Africa’s ageing populations. Additional economic evidence is needed from longer-term larger-scale implementation studies to compare extended integrated care packages directly simultaneously with evidence on sustained clinical outcomes.

Background: People with chronic general medical conditions who have comorbid depression experience poorer health outcomes. This problem has received scant attention in low- and middle-income countries. The aim of the ongoing study reported here is to refine and promote the scale-up of an evidence-based task-sharing collaborative care model, the Mental Health Integration (MhINT) program, to treat patients with comorbid depression and chronic disease in primary health care settings in South Africa. Methods: Adopting a learning-health-systems approach, this study uses an onsite, iterative observational implementation science design. Stage 1 comprises assessment of the original MhINT model under real-world conditions in an urban subdistrict in KwaZulu-Natal, South Africa, to inform refinement of the model and its implementation strategies. Stage 2 comprises assessment of the refined model across urban, semiurban, and rural contexts. In both stages, population-level effects are assessed by using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) evaluation framework with various sources of data, including secondary data collection and a patient cohort study (N=550). The Consolidated Framework for Implementation Research is used to understand contextual determinants of implementation success involving quantitative and qualitative interviews (stage 1, N=78; stage 2, N=282). Results: The study results will help refine intervention components and implementation strategies to enable scale-up of the MhINT model for depression in South Africa. Next steps: Next steps include strengthening ongoing engagements with policy makers and managers, providing technical support for implementation, and building the capacity of policy makers and managers in implementation science to promote wider dissemination and sustainment of the intervention.

Imaging the inventory of microbial small molecule interactions provides important insights into microbial chemical ecology and human medicine. Herein we demonstrate a new method for enhanced detection and analysis of metabolites present in interspecies interactions of microorganisms on surfaces. We demonstrate that desorption electrospray ionization-imaging mass spectrometry (DESI-IMS) using microporous membrane scaffolds (MMS) enables enhanced spatiochemical analyses of interacting microbes among tested sample preparation techniques. Membrane scaffolded DESI-IMS has inherent advantages compared to matrix-assisted laser desorption ionization (MALDI) and other IMS methods through direct IMS analyses of microbial chemistry in situ. This rapid imaging method yields sensitive MS analyses with unique m/z measurements when compared to liquid chromatography–electrospray ionization-mass spectrometry (LC–ESI-MS) via unmediated sampling by MMS DESI-IMS. Unsupervised segmentation imaging analysis of acquired DESI-IMS data reveals distinct chemical regions corresponding to intermicrobial phenomenon such as predation and communication. We validate the method by linking Myxovirescin A and DKxanthene-560 to their known biological roles of predation and phase variation, respectively. In addition to providing the first topographic locations of known natural products, we prioritize 54 unknown features using segmentation within the region of predation. Thus, DESI-IMS and unsupervised segmentation spatially annotates the known biology of myxobacteria and provides functional exploration of newly uncharacterized small molecules.

To describe changes in prevalence of hypertension, diabetes, HIV and tuberculosis, and prevalence of comorbidity, and to investigate associations between each condition, and combinations of conditions, with self-reported general health and hospital admission.This study used data from a longitudinal population-based HIV and health surveillance cohort, conducted by the Africa Health Research Institute in Umkhanyakude district of rural KwaZulu-Natal, South Africa.Prevalence of hypertension, HIV and diabetes increased from 2009 to 2015, and prevalence of tuberculosis decreased. 81% of the 47 334 participants were female; hypertension and diabetes were the commonest conditions in people over age 50, whereas HIV was most common in those younger than 50 years. Comorbidity of communicable and non-communicable conditions was commonest in 40- to 60-year-olds. The adjusted odd ratios (OR) for better self-reported general health with multimorbidity were 0.53 (95% CI 0.51-0.56), 0.29 (95% CI 0.27-0.29), 0.25 (95% CI 0.21-0.37) and 0.21 (95% CI 0.12-0.37) for one, two, three and four conditions, respectively, vs. no conditions. Tuberculosis was most strongly and inversely associated with better general health (OR 0.34 (0.31-0.37) and most strongly associated with hospital admission (OR 3.26 (2.32-2.99)).The high prevalence of communicable and non-communicable conditions in this rural South African population is giving rise to a burden of multimorbidity, as increased access to antiretroviral treatment has reduced mortality in people with HIV. Healthcare systems must adapt by working towards integrated primary care for HIV/AIDS and non-communicable diseases.Décrire l’évolution de la prévalence de l'hypertension, du diabète, du VIH et de la tuberculose et de la prévalence de la comorbidité, et étudier les associations entre chaque affection et les combinaisons d'affections avec l’état de santé général et l'hospitalisation rapportés. MÉTHODES: Cette étude a utilisé les données d'une cohorte longitudinale de surveillance du VIH et de la santé basée sur la population, menée par l'Institut de Recherche sur la Santé en Afrique dans le district de Umkhanyakude, en zone rurale du KwaZulu-Natal, en Afrique du Sud. RÉSULTATS: La prévalence de l'hypertension, du VIH et du diabète a augmenté de 2009 à 2015 et la prévalence de la tuberculose a diminué. 81% des 47.334 participants étaient des femmes; l'hypertension et le diabète étaient les affections les plus courantes chez les personnes de plus de 50 ans, tandis que le VIH était plus répandu chez celles de moins de 50 ans. La comorbidité des maladies transmissibles et non transmissibles était plus fréquente chez les 40 à 60 ans. Les rapports de cotes ajustés (OR) pour une meilleure santé générale auto-déclarée avec une multimorbidité étaient de 0,53 (IC95%: 0,51-0,56), 0,29 (IC95%: 0,27-0,29), 0,25 (IC95%: 0,21-0,37) et 0,21 (IC95%: 0,12-0,37) pour une, deux, trois et quatre affections, respectivement, par rapport à l'absence d'affection. La tuberculose était le plus fortement et inversement associée à une meilleure santé générale (OR: 0,34 (0,31-0,37) et plus fortement associée à l'hospitalisation (OR: 3,26 (2,32-2,99)).La prévalence élevée des maladies transmissibles et non transmissibles dans cette population sud-africaine rurale entraine une augmentation de la charge de la multimorbidité,l'accès accru au traitement antirétroviral ayant réduit la mortalité chez les personnes vivant avec le VIH. Les systèmes de santé doivent s'adapter en œuvrant pour des soins primaires intégrés pour le VIH/SIDA et les maladies non transmissibles.

Purpose: To evaluate the course of corneal biomechanical properties (corneal hysteresis and corneal resistance factor) after Descemet membrane endothelial keratoplasty (DMEK) in patients with Fuchs endothelial dystrophy (FECD). Methods: In this prospective study, we consecutively included 49 patients with FECD with an indication for DMEK. Central corneal thickness, measured using the Oculus Pentacam, and corneal hysteresis (CH) and corneal resistance factor (CRF), both measured using the Reichert Ocular Response Analyzer, were examined preoperatively, 3 months, and 6 months after DMEK. Results: CH was significantly increased 6 months postoperatively (8.66 +/- 2.50 mm Hg) compared with preoperative baseline (7.43 +/- 1.56 mm Hg). Preoperative CRF (7.89 +/- 1.68 mm Hg) increased significantly 6 months after DMEK (8.49 +/- 1.71 mm Hg). Preoperative central corneal thickness showed a significant decrease from 629 +/- 58 mm to 550 +/- 40 mm after 3 months and 535 +/- 40 mm after 6 months postoperatively. Conclusions: DMEK affects both measured corneal biomechanical properties in patients with FECD: CH and CRF. This has to be taken into account for the accuracy of intraocular pressure measurements.

ZusammenfassungNach Hornhautchirurgie kommt es durch das mechanische Trauma, durch Fremdkörper wie z. B. Nähte oder Implantate oder durch Antigene bei Gewebetransplantation zu entzündlichen Reaktionen. Nach chirurgischen Eingriffen mit Abstand zum vaskularisierten Limbus verlaufen diese aufgrund des Immunprivilegs und des angiogenen Privilegs der Hornhaut in aller Regel sehr gedämpft. Hauptpfeiler in der Therapie und Prophylaxe von Entzündungen nach Hornhautchirurgie sind topische Glukokortikoide. Bei der Anwendung müssen die kataraktogene Wirkung bei Langzeitnutzung, die Möglichkeit einer steroidbedingten Augeninnendruckerhöhung als sogenannte Steroidresponse, die Erhöhung der Infektanfälligkeit und die Hemmung einer Epithelialisierung berücksichtigt werden. Die verfügbaren Glukokortikoide unterscheiden sich in ihrer Fähigkeit zur Penetration in das Auge (Prednisolon am besten), ihrer immunsuppressiven Wirkung (Dexamethason am besten) und im Risiko der Induktion einer Steroidresponse (Loteprednoletabonat und Fluorometholon am geringsten). Die unterschiedlichen Eigenschaften müssen bei der Wahl des „richtigen“ Glukokortikoids berücksichtigt werden: Bei Gefahr einer Epithelialisierungsstörung sollten topische Steroide möglichst vermieden bzw., falls zwingend erforderlich, konservierungsmittelfreies und phosphatfreies Dexamethason (Dexapos COMOD®) verwendet werden. Bei Bedarf einer Tiefenwirksamkeit, z. B. nach perforierender Keratoplastik, sollte Prednisolonacetat verwendet werden. Bei bekannter Steroidresponse sollten Loteprednoletabonat oder Fluorometholon verwendet werden. Wenn allogenes Gewebe transplantiert wird, ist eine langfristige topische Anwendung von Glukokortikoiden über 24 Monate und länger notwendig. Nach Hochrisikokeratoplastik mit allogenem Spendergewebe ist meist eine ergänzende systemische immunsuppressive Therapie mit Calcineurininhibitoren oder Mycophenolatmofetil über 6 – 12 Monate sinnvoll.

Objectives The aim of the article was to assess the appropriateness and rationales of subgroup analyses planned in protocols of randomized controlled trials and reported in subsequent corresponding trial publications. Study Design and Setting We searched PubMed to identify trial protocols published in journals during 2006–2017. From a total of 3,774 initially identified records, we included a random sample of 479 protocols and identified 280 trial publications corresponding to the included protocols. Results Subgroup analyses were specified in 19% of the protocols and reported in 21% of the trial publications. Of the 94 protocols with planned subgroup analyses, 32% mentioned testing for interaction, and only three considered statistical power. Subgroup analyses were not prespecified in 56% of the 59 trial publications with subgroup analyses. Subgroup analyses were stated as prespecified in nine trial publications, without support evidence from the corresponding protocols. Subgroup analyses were often reported insufficiently for assessing the consistency of subgroup effects across studies. Justifications for subgroup analyses were provided in only four trial protocols and seven trial publications. Conclusion Inappropriate specification and reporting of subgroup analyses remain problematic in protocols and reports of randomized controlled trials. Justifications or rationales for subgroup analyses were only rarely provided in trial protocols and reports.

We sought to investigate correlations between preoperative corneal backscatter with visual acuity results after Descemet membrane endothelial keratoplasty (DMEK) in eyes with corneal endothelial disorders.Retrospective interventional case series.The first 551 consecutive patients with DMEK at the Center of Ophthalmology, University of Cologne who had available preoperative corneal densitometry values (corneal light backscatter measured in gray scale units) measured with the Scheimpflug-based Oculus Pentacam corneal densitometry module were screened for eligibility. Best spectacle-corrected visual acuity (BSCVA) results were retrospectively correlated with densitometry data. Densitometry data were obtained in 4 corneal layers (ie, anterior, central, posterior, and total layers) and 4 annuli. Pre- and postoperative BSCVA results were correlated with densitometry data. Receiver operating characteristic analyses were performed.Four hundred twelve eyes were available for the analyses. Visual acuity results improved significantly after DMEK surgery at 3, 6, 12, and 24 months of follow-up (P.001). Corneal backscatter correlated moderately with preoperative BSCVA results. Moderate associations to postoperative BSCVA results could predominantly be found between densitometry values of the anterior and central layer more pronounced in the center of the cornea for all postoperative timepoints. The posterior layer correlated worst with postoperative gain in BSCVA. Receiver operating characteristic analyses revealed that the best predictive power of densitometry values was for the 2-6 mm annular zone of the cornea.Corneal backscatter in eyes with corneal endothelial disorders correlates with postsurgical BSCVA results after DMEK surgery. Therefore, early DMEK surgery seems to have a positive impact on long-term BSCVA results.

Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene transformed cells, yet their molecular mechanism remains uncertain. We used photoaffinity analogs of the apoptolidins to identify the F1 subcomplex of mitochondrial ATP synthase as the target of apoptolidin A. CryoEM of apoptolidin and ammocidin-ATP synthase complexes revealed a novel shared mode of inhibition that was confirmed by deep mutational scanning of the binding interface to reveal resistance mutations which were confirmed using CRISPR-Cas9. Ammocidin A was found to suppress leukemia progression in vivo at doses that were tolerated with minimal toxicity. The combination of cellular, structural, mutagenesis, and in vivo evidence define the mechanism of action of apoptolidin family glycomacrolides and establish a path to address OXPHOS-dependent cancers.

Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene-transformed cells, yet their molecular mechanism remains uncertain. We used photoaffinity analogs of the apoptolidins to identify the F1 subcomplex of mitochondrial ATP synthase as the target of apoptolidin A. Cryogenic electron microscopy (cryo-EM) of apoptolidin and ammocidin–ATP synthase complexes revealed a novel shared mode of inhibition that was confirmed by deep mutational scanning of the binding interface to reveal resistance mutations which were confirmed using CRISPR–Cas9. Ammocidin A was found to suppress leukemia progression in vivo at doses that were tolerated with minimal toxicity. The combination of cellular, structural, mutagenesis, and in vivo evidence defines the mechanism of action of apoptolidin family glycomacrolides and establishes a path to address oxidative phosphorylation-dependent cancers. Photoaffinity analogs of a family of glycosylated macrolides, apoptolidins, revealed the F1 subcomplex of mitochondrial ATP synthase as the target. Cryo-EM analysis of the apoptolidin–ATP synthase complex enabled identification of resistance mutations.

Descemet membrane endothelial keratoplasty (DMEK) is considered the gold standard for the treatment of corneal endothelial dysfunction and generally leads to good postoperative results. Recently, studies have also analyzed the outcome of DMEK in so-called high-risk eyes.The relevant literature and own data on DMEK for graft failure after penetrating keratoplasty and in vascularized high-risk eyes are presented and discussed.A DMEK for the treatment of transplant failure after penetrating keratoplasty can be considered for eyes without stromal scars and without high astigmatism. A retrospective analysis of 52 patients with failed penetrating grafts showed that DMEK leads to a significant increase in visual acuity, albeit to a lesser extent than after primary DMEK. Rejection and transplant failure rates seem to be similar those seen after penetrating re-keratoplasty and are thus higher than after primary DMEK. A DMEK might also be a feasible option for eyes with corneal neovascularization and stromal edema without stromal scars. A retrospective analysis of 24 eyes with at least 2 vascularized corneal quadrants demonstrated that DMEK leads to a significant improvement in visual acuity and regression of corneal neovascularization. The rejection rate in this cohort was 4.2% and is therefore slightly higher than after low-risk DMEK in eyes without corneal neovascularization but still much better compared to penetrating keratoplasty.Indications for DMEK are expanding and it can be a therapeutic option for transplant failure after penetrating keratoplasty with acceptable outcomes. Furthermore, DMEK seems to be a good option for the treatment of endothelial dysfunction in vascularized high-risk eyes without stromal scars.HINTERGRUND: Die „Descemet membrane endothelial keratoplasty“ (DMEK) als Goldstandard für die Behandlung von endothelialen Dysfunktionen führt in der Regel zu sehr guten postoperativen Ergebnissen. Inzwischen gibt es auch erste Erfahrungen zur DMEK in sog. „Hochrisikoaugen“.Es werden relevante Literatur und eigene Daten zur DMEK bei Transplantatversagen nach perforierender Keratoplastik und in vaskularisierten Hochrisikoaugen präsentiert und diskutiert.Eine DMEK zur Therapie des Transplantatversagens nach perforierender Keratoplastik kommt für Augen ohne stromale Narben und ohne hohen Astigmatismus infrage. Eine retrospektive Analyse von 52 Patienten aus dem eigenen Haus zeigte, dass eine DMEK in diesen Fällen zu einem signifikanten, im Vergleich zur primären DMEK allerdings verzögerten Visusanstieg führt. Die Abstoßungs- und Transplantatversagensraten scheinen ähnlich wie nach perforierender Re-Keratoplastik und damit deutlich höher als nach primärer DMEK zu sein. Eine DMEK kann auch für Augen mit Hornhautvaskularisationen ohne stromale Narben infrage kommen. Eine eigene retrospektive Analyse von 24 Augen mit mindestens 2 vaskularisierten Hornhautquadranten zeigte, dass eine DMEK in diesen Augen zu einer signifikanten Erholung der Sehschärfe und einem deutlichen Rückgang der Hornhautvaskularisationen führt. Die Abstoßungsrate in dieser Kohorte lag bei 4,2 % und ist damit geringgradig höher als nach „Niedrigrisiko“-DMEK in Augen ohne Hornhautvaskularisationen, aber deutlich unter dem Abstoßungsrisiko einer penetrierenden Hochrisikokeratoplastik.Das Indikationsspektrum der DMEK wird zunehmend breiter. So kann die DMEK bei Transplantatversagen nach perforierender Keratoplastik eine geeignete Therapieoption mit akzeptablen Ergebnissen und deutlich schnellerer und sicherer Visuserholung sein. Weiterhin scheint die DMEK eine gute Option zur Therapie der endothelialen Dysfunktion auch bei vaskularisierten Hochrisikoaugen ohne stromale Narben zu sein.

ObjectiveTo assess the effect of lockdown during the 2020 COVID-19 pandemic on daily all-cause admissions, and by age and diagnosis subgroups, and the odds of all-cause mortality in a hospital in rural KwaZulu-Natal (KZN).DesignObservational cohort.SettingReferral hospital for 17 primary care clinics in uMkhanyakude District.ParticipantsData collected by the Africa Health Research Institute on all admissions from 1 January to 20 October: 5848 patients contributed to 6173 admissions.ExposureFive levels of national lockdown in South Africa from 27 March 2020, with restrictions decreasing from levels 5 to 1, respectively.Outcome measuresChanges and trends in daily all-cause admissions and risk of in-hospital mortality before and at each stage of lockdown, estimated by Poisson and logistic interrupted time series regression, with stratification for age, sex and diagnosis.ResultsDaily admissions decreased during level 5 lockdown for infants (incidence rate ratio (IRR) compared with prelockdown 0.63, 95% CI 0.44 to 0.90), children aged 1–5 years old (IRR 0.43, 95% CI 028 to 0.65) and respiratory diagnoses (IRR 0.57, 95% CI 0.36 to 0.90). From level 4 to level 3, total admissions increased (IRR 1.17, 95% CI 1.06 to 1.28), as well as for men >19 years (IRR 1.50, 95% CI 1.17 to 1.92) and respiratory diagnoses (IRR 4.26, 95% CI 2.36 to 7.70). Among patients admitted to hospital, the odds of death decreased during level 5 compared with prelockdown (adjusted OR 0.48, 95% CI 0.28 to 0.83) and then increased in later stages.ConclusionsLevel 5 lockdown is likely to have prevented the most vulnerable population, children under 5 years and those more severely ill from accessing hospital care in rural KZN, as reflected by the drop in admissions and odds of mortality. Subsequent increases in admissions and in odds of death in the hospital could be due to improved and delayed access to hospital as restrictions were eased.

Background The purpose of this trial was to test if the Norfolk Diabetes Prevention Study (NDPS) lifestyle intervention, recently shown to reduce the incidence of type 2 diabetes in high-risk groups, also improved glycaemic control in people with newly diagnosed screen-detected type 2 diabetes. Methods We screened 12,778 participants at high risk of type 2 diabetes using a fasting plasma glucose and glycosylated haemoglobin (HbA1c). People with screen-detected type 2 diabetes were randomised in a parallel, three-arm, controlled trial with up to 46 months of follow-up, with a control arm (CON), a group-based lifestyle intervention of 6 core and up to 15 maintenance sessions (INT), or the same intervention with additional support from volunteers with type 2 diabetes trained to co-deliver the lifestyle intervention (INT-DPM). The pre-specified primary end point was mean HbA1c compared between groups at 12 months. Results We randomised 432 participants (CON 149; INT 142; INT-DPM 141) with a mean (SD) age of 63.5 (10.0) years, body mass index (BMI) of 32.4 (6.4) kg/m2, and HbA1c of 52.5 (10.2) mmol/mol. The primary outcome of mean HbA1c at 12 months (CON 48.5 (9.1) mmol/mol, INT 46.5 (8.1) mmol/mol, and INT-DPM 45.6 (6.0) mmol/mol) was significantly lower in the INT-DPM arm compared to CON (adjusted difference −2.57 mmol/mol; 95% CI −4.5, −0.6; p = 0.007) but not significantly different between the INT-DPM and INT arms (−0.55 mmol/mol; 95% CI −2.46, 1.35; p = 0.57), or INT vs CON arms (−2.14 mmol/mol; 95% CI −4.33, 0.05; p = 0.07). Subgroup analyses showed the intervention had greater effect in participants p = 0.02). This effect was most significant in the INT-DPM arm (−6.01 mmol/mol; 95% CI −9.56, −2.46 age 65 years old; p = 0.007). The use of oral hypoglycaemic medication was associated with a significantly lower mean HbA1c but only within the INT-DPM arm compared to CON (−7.0 mmol/mol; 95% CI −11.5, −2.5; p = 0.003). Conclusion The NDPS lifestyle intervention significantly improved glycaemic control after 12 months in people with screen-detected type 2 diabetes when supported by trained peer mentors with type 2 diabetes, particularly those receiving oral hypoglycaemics and those under 65 years old. The effect size was modest, however, and not sustained at 24 months. Trial registration ISRCTN34805606. Retrospectively registered 14.4.16

Fluorescent cell barcoding (FCB) enables efficient collection of tens to hundreds of flow cytometry samples by covalently marking cells with varying concentration of spectrally distinct dyes. A key consideration in FCB is to balance the density of dye barcodes, the complexity of cells in the sample, and the desired accuracy of the debarcoding. Unfortunately, barcoding bench and computational methods have not benefited from the high dimensional revolution in cytometry due to a lack of automated computational tools that effectively balance these common cytometry needs. DebarcodeR addresses these unmet needs by providing a framework for computational debarcoding augmented by improvements to experimental methods. Adaptive regression modeling accounted for differential dye uptake between different cell types and Gaussian mixture modeling provided a robust method to probabilistically assign cells to samples. Assignment tolerance parameters are available to allow users to balance high cell recovery with accurate assignments. Improvements to experimental methods include: (1) inclusion of an "external standard" control where a pool of all cells was stained a single level of each barcoding dyes and (2) an "internal standard" where each cell is stained with a single level of a separate dye. DebarcodeR significantly improved speed, accuracy, and reproducibility of FCB while avoiding selective loss of unusual cell subsets when debarcoding microtiter plates of cell lines and heterogenous mixtures of primary cells. DebarcodeR is available on Github as an R package that works with flowCore and Cytoverse packages at github.com/cytolab/DebarcodeR.

Background We tested the real-world effectiveness of a collaborative task-sharing model on depressive symptom reduction in hypertensive Primary Health Care (PHC) patients in South Africa. Method A pragmatic parallel cluster randomised trial in 20 clinics in the Dr Kenneth Kaunda district, North West province. PHC clinics were stratified by sub-district and randomised in a 1:1 ratio. Control clinics received care as usual (CAU), involving referral to PHC doctors and/or mental health specialists. Intervention clinics received CAU plus enhanced mental health training and a lay counselling referral service. Participant inclusion criteria were ≥ 18 years old, Patient Health Questionnaire-9 (PHQ-9) score ≥ 9 and receiving hypertension medication. Primary superiority outcome was ≥ 50% reduction in PHQ-9 score at 6 months. Statistical analyses comprised mixed effects regression models and a non-inferiority analysis. Trial registration number: NCT 02425124. Results Between April 2015 and October 2015, 1043 participants were enrolled (504 intervention and 539 control); 82% were women; half were ≥ 55 years. At 6 and 12 months follow-up, 91% and 89% of participants were interviewed respectively. One control group participant committed suicide. There was no significant difference in the primary outcome between intervention (N=256/456) and control (N=232/492) groups (55.9% versus 50.9%; adjusted risk difference = -0.04 ([95% CI = -0.19; 0.11], p = 0.6). The difference in PHQ-9 scores was within the defined equivalence limits at 6 and 12 months for the non-inferiority analysis. Limitations The trial was limited by low exposure to depression treatment by trial participants and by observed co-intervention in control clinics Conclusions Incorporating lay counselling services within collaborative care models does not produce superior nor inferior outcomes to models with specialist only counselling services. Funding This work was supported by the UK Department for International Development [201446] as well as the National Institute of Mental Health, United States of America, grant number 1R01MH100470-01. Graham Thornicroft is supported by the National Institute for Health Research (NIHR) Applied Research Collaboration (ARC) South London at King's College London and King's College Hospital NHS Foundation Trust.