Benchmarking of Coatings for Cathode Active Materials in Solid-State Batteries Using Surface Analysis and Reference Electrodes.

Fast and reliable evaluation of degradation and performance of cathode active materials (CAMs) for solid-state batteries (SSBs) is crucial to help better understand these systems and enable the synthesis of well-performing CAMs. However, there is a lack of well-thought-out procedures to reliably evaluate CAMs in SSBs. Current approaches often rely on X-ray photoelectron spectroscopy (XPS) for the evaluation of degradation. Unfortunately, XPS sensitivity is not very high, and minor but relevant degradation products may not be detected and distinguished. Furthermore, degradation caused by the current collector (CC) itself is usually not distinguished from CAM-induced degradation. This study uses a modified CC, which allows us to separate electrochemical degradation caused by the CC from degradation at the CAM itself. Using this CC, we present an approach using time-of-flight secondary ions mass spectrometry (ToF-SIMS) that offers high sensitivity and reliability. Principal component analysis (PCA) is applied to differentiate secondary ions as well as identify those mass fragments that correlate with degradation products. This approach also enables distinguishing between different pathways of degradation. To evaluate the kinetic performance of the samples, three-electrode rate tests are performed. Electrochemical characterization evaluates the kinetic performance of the samples under investigation. The samples are finally rated with a score that allows a reliable comparison between the different materials and offers a complete picture of the materials' characteristics in terms of electrochemical performance and degradation.

Measuring appropriateness of diagnostic imaging: a scoping review.

In radiology, the justification of diagnostic imaging is a key performance indicator. To date, specific recommendations on the measurement of appropriateness in diagnostic imaging are missing. To map the study literature concerning the definition, measures, methods and data used for analyses of appropriateness in research of diagnostic imaging. We conducted a scoping review in Medline, EMBASE, Scopus and the Cochrane Central Register of Controlled Trials. Two independent reviewers undertook screening and data extraction. After screening 6021 records, we included 50 studies. National guidelines (n = 22/50) or American College of Radiology Appropriateness Criteria (n = 23/50) were used to define and rate appropriateness. 22/50 studies did not provide methodological details about the appropriateness assessment. The included studies varied concerning modality, amount of reviewed examinations (88-13,941) and body regions. Computed tomography (27 studies, 27,168 examinations) was the most frequently analyzed modality, followed by magnetic resonance imaging (17 studies, 6559 examinations) and radiography (10 studies, 7095 examinations). Heterogeneous appropriateness rates throughout single studies (0-100%), modalities, and body regions (17-95%) were found. Research on pediatric and outpatient imaging was sparse. Multicentric, methodologically robust and indication-oriented studies would strengthen appropriateness research in diagnostic imaging and help to develop reliable key performance indicators.

Effect of clinical peer review on mortality in patients ventilated for more than 24 hours: a cluster randomised controlled trial.

BACKGROUND: Although clinical peer review is a well-established instrument for improving quality of care, clinical effectiveness is unclear. METHODS: In a pragmatic cluster randomised controlled trial, we randomly assigned 60 German Initiative Qualitätsmedizin member hospitals with the highest mortality rates in ventilated patients in 2016 to intervention and control groups. The primary outcome was hospital mortality rate in patients ventilated fore more than 24 hours. Clinical peer review was conducted in intervention group hospitals only. We assessed the impact of clinical peer review on mortality using a difference-in-difference approach by applying weighted least squares (WLS) regression to changes in age-adjusted and sex-adjusted standardised mortality ratios (SMRs) 1 year before and 1 year after treatment. Recommendations for improvement from clinical peer review and hospital survey data were used for impact and process analysis. RESULTS: We analysed 12 058 and 13 016 patients ventilated fore more than 24 hours in the intervention and control hospitals within the 1-year observation period. In-hospital mortality rates and SMRs were 40.6% and 1.23 in intervention group and 41.9% and 1.28 in control group hospitals in the preintervention period, respectively. The groups showed similar hospital (bed size, ownership) and patient (age, sex, mortality, main indications) characteristics. WLS regression did not yield a significant difference between intervention and control groups regarding changes in SMRs (estimate=0.04, 95% CI= -0.05 to 0.13, p=0.38). Mortality remained high in both groups (intervention: 41.8%, control: 42.1%). Impact and process analysis indicated few perceived outcome improvements or implemented process improvements following the introduction of clinical peer review. CONCLUSIONS: This study did not provide evidence for reductions in mortality in patients ventilated for more than 24 hours due to clinical peer review. A stronger focus on identification of structures and care processes related to mortality is required to improve the effectiveness of clinical peer review.

Impact of the Chlorination of Lithium Argyrodites on the Electrolyte/Cathode Interface in Solid-State Batteries.

Lithium argyrodite-type electrolytes are regarded as promising electrolytes due to their high ionic conductivity and good processability. Chemical modifications to increase ionic conductivity have already been demonstrated, but the influence of these modifications on interfacial stability remains so far unknown. In this work, we study Li6 PS5 Cl and Li5.5 PS4.5 Cl1.5 to investigate the influence of halogenation on the electrochemical decomposition of the solid electrolyte and the chemical degradation mechanism at the cathode interface in depth. Electrochemical measurements, gas analysis and time-of-flight secondary ion mass spectrometry indicate that the Li5.5 PS4.5 Cl1.5 shows pronounced electrochemical decomposition at lower potentials. The chemical reaction at higher voltages leads to more gaseous degradation products, but a lower fraction of solid oxygenated phosphorous and sulfur species. This in turn leads to a decreased interfacial resistance and thus a higher cell performance.

[Recommendations for the Utilization of Claims Data During a Pandemic: Lessons Learned from the Project EgePan-Unimed of the Netzwerk Universitätsmedizin (NUM)]. / Potentiale von und Empfehlungen zur Nutzung von GKV Routinedaten in einer pandemischen Versorgungslage ­ Erfahrungen aus dem Projekt egePan-Unimed des Netzwerk Universitätsmedizin (NUM).

For appropriate response to the COVID-19 pandemic, and for obtaining answers to various relevant research questions, empirical data are required. Claims data of health insurances are a valid data source in such a situation. Within the project egePan-Unimed of the Netzwerk Universitätsmedizin (NUM) we investigated five COVID-19-related research questions using German claims data of statutory health insurances. We studied the prevalence and relevance of risk factors for a severe course of COVID-19, the background incidence of cerebral venous sinus thrombosis and myocarditis, the frequency and symptoms of post-COVID as well as the care of people with a psychiatric condition during the COVID-19 pandemic. Based on these cases, context-specific recommendations regarding the use of German claims data for future pandemics or other public health emergencies were derived, namely that the utilization of established and interdisciplinary project teams enables a timely project start and furthermore, meta-analytic methods are a valuable way to pool aggregated results of claims data analyses when data protection regulations do not allow a consolidation of data sets from different statutory health insurances. Under these circumstances, claims data are a readily available and valid data source of empirical evidence base necessary for public health measures during a pandemic.

A Ziegler-type spherical cap model reveals early stage ethylene polymerization growth versus catalyst fragmentation relationships.

Polyolefin catalysts are characterized by their hierarchically complex nature, which complicates studies on the interplay between the catalyst and formed polymer phases. Here, the missing link in the morphology gap between planar model systems and industrially relevant spherical catalyst particles is introduced through the use of a spherical cap Ziegler-type catalyst model system for the polymerization of ethylene. More specifically, a moisture-stable LaOCl framework with enhanced imaging contrast has been designed to support the TiCl4 pre-active site, which could mimic the behaviour of the highly hygroscopic and industrially used MgCl2 framework. As a function of polymerization time, the fragmentation behaviour of the LaOCl framework changed from a mixture of the shrinking core (i.e., peeling off small polyethylene fragments at the surface) and continuous bisection (i.e., internal cleavage of the framework) into dominantly a continuous bisection model, which is linked to the evolution of the estimated polyethylene volume and the fraction of crystalline polyethylene formed. The combination of the spherical cap model system and the used advanced micro-spectroscopy toolbox, opens the route for high-throughput screening of catalyst functions with industrially relevant morphologies on the nano-scale.

Value of Clinical Information on Radiology Reports in Oncological Imaging.

Radiological reporting errors have a direct negative impact on patient treatment. The purpose of this study was to investigate the contribution of clinical information (CI) in radiological reporting of oncological imaging and the dependence on the radiologists' experience level (EL). Sixty-four patients with several types of carcinomas and twenty patients without tumors were enrolled. Computed tomography datasets acquired in primary or follow-up staging were independently analyzed by three radiologists (R) with different EL (R1: 15 years; R2: 10 years, R3: 1 year). Reading was initially performed without and 3 months later with CI. Overall, diagnostic accuracy and sensitivity for primary tumor detection increased significantly when receiving CI from 77% to 87%; p = 0.01 and 73% to 83%; p = 0.01, respectively. All radiologists benefitted from CI; R1: 85% vs. 92%, p = 0.15; R2: 77% vs. 83%, p = 0.33; R3: 70% vs. 86%, p = 0.02. Overall, diagnostic accuracy and sensitivity for detecting lymphogenous metastases increased from 80% to 85% (p = 0.13) and 42% to 56% (p = 0.13), for detection of hematogenous metastases from 85% to 86% (p = 0.61) and 46% to 60% (p = 0.15). Specificity remained stable (>90%). Thus, CI in oncological imaging seems to be essential for correct radiological reporting, especially for residents, and should be available for the radiologist whenever possible.

Relationships between multiple patient safety outcomes and healthcare and hospital-related risk factors in colorectal resection cases: cross-sectional evidence from a nationwide sample of 232 German hospitals.

OBJECTIVES: Studies analysing colorectal resections usually focus on a specific outcome (eg, mortality) and/or specific risk factors at the individual (eg, comorbidities) or hospital (eg, volume) level. Comprehensive evidence across different patient safety outcomes, risk factors and patient groups is still scarce. Therefore the aim of this analysis was to investigate consistent relationships between multiple patient safety outcomes, healthcare and hospital risk factors in colorectal resection cases. DESIGN: Cross-sectional study. SETTING: German inpatient routine care data of colorectal resections between 2016 and 2018. PARTICIPANTS: We analysed 54 168 colon resection and 20 395 rectum resection cases treated in German hospitals. The German Inpatient Quality Indicators were used to define colon resections and rectum resections transparently. PRIMARY OUTCOME MEASURES: Additionally to in-hospital death, postoperative respiratory failure, renal failure and postoperative wound infections we included multiple patient safety outcomes as primary outcomes/dependent variables for our analysis. Healthcare (eg, weekend surgery), hospital (eg, volume) and case (eg, age) characteristics served as independent covariates in a multilevel logistic regression model. The estimated regression coefficients were transferred into ORs. RESULTS: Weekend surgery, emergency admissions and transfers from other hospitals were significantly associated (ORs ranged from 1.1 to 2.6) with poor patient safety outcome (ie, death, renal failure, postoperative respiratory failure) in colon resections and rectum resections. Hospital characteristics showed heterogeneous effects. In colon resections hospital volume was associated with insignificant or adverse associations (postoperative wound infections: OR 1.168 (95% CI 1.030 to 1.325)) to multiple patient safety outcomes. In rectum resections hospital volume was protectively associated with death, renal failure and postoperative respiratory failure (ORs ranged from 0.7 to 0.8). CONCLUSIONS: Transfer from other hospital and emergency admission are constantly associated with poor patient safety outcome. Hospital variables like volume, ownership or localisation did not show consistent relationships to patient safety outcomes. TRIAL REGISTRATION NUMBER: ISRCTN10188560.

Prediction of inpatient pressure ulcers based on routine healthcare data using machine learning methodology.

Despite the relevance of pressure ulcers (PU) in inpatient care, the predictive power and role of care-related risk factors (e.g. anesthesia) remain unclear. We investigated the predictability of PU incidence and its association with multiple care variables. We included all somatic cases between 2014 and 2018 with length of stay ≥ 2d in a German university hospital. For regression analyses and prediction we used Bayesian Additive Regression Trees (BART) as nonparametric modeling approach. To assess predictive accuracy, we compared BART, random forest, logistic regression (LR) and least absolute shrinkage and selection operator (LASSO) using area under the curve (AUC), confusion matrices and multiple indicators of predictive performance (e.g. sensitivity, specificity, F1, positive/ negative predictive value) in the full dataset and subgroups. Analysing 149,006 cases revealed high predictive variable importance and associations between incident PU and ventilation, age, anesthesia (≥ 1 h) and number of care-involved wards. Despite high AUCs (range 0.89-0.90), many false negative predictions led to low sensitivity (range 0.04-0.10). Ventilation, age, anesthesia and number of care-involved wards were associated with incident PU. Using anesthesia as a proxy for immobility, an hourly repositioning is indicated. The low sensitivity indicates major challenges for correctly predicting PU based on routine data.

Exploring relationships between in-hospital mortality and hospital case volume using random forest: results of a cohort study based on a nationwide sample of German hospitals, 2016-2018.

BACKGROUND: Relationships between in-hospital mortality and case volume were investigated for various patient groups in many empirical studies with mixed results. Typically, those studies relied on (semi-)parametric statistical models like logistic regression. Those models impose strong assumptions on the functional form of the relationship between outcome and case volume. The aim of this study was to determine associations between in-hospital mortality and hospital case volume using random forest as a flexible, nonparametric machine learning method. METHODS: We analyzed a sample of 753,895 hospital cases with stroke, myocardial infarction, ventilation > 24 h, COPD, pneumonia, and colorectal cancer undergoing colorectal resection treated in 233 German hospitals over the period 2016-2018. We derived partial dependence functions from random forest estimates capturing the relationship between the patient-specific probability of in-hospital death and hospital case volume for each of the six considered patient groups. RESULTS: Across all patient groups, the smallest hospital volumes were consistently related to the highest predicted probabilities of in-hospital death. We found strong relationships between in-hospital mortality and hospital case volume for hospitals treating a (very) small number of cases. Slightly higher case volumes were associated with substantially lower mortality. The estimated relationships between in-hospital mortality and case volume were nonlinear and nonmonotonic. CONCLUSION: Our analysis revealed strong relationships between in-hospital mortality and hospital case volume in hospitals treating a small number of cases. The nonlinearity and nonmonotonicity of the estimated relationships indicate that studies applying conventional statistical approaches like logistic regression should consider these relationships adequately.

Regional responsibility and coordination of appropriate inpatient care capacities for patients with COVID-19 - the German DISPENSE model.

As of late 2019, the COVID-19 pandemic has been a challenge to health care systems worldwide. Rapidly rising local COVID-19 incidence rates, result in demand for high hospital and intensive care bed capacities on short notice. A detailed up-to-date regional surveillance of the dynamics of the pandemic, precise prediction of required inpatient capacities of care as well as a centralized coordination of the distribution of regional patient fluxes is needed to ensure optimal patient care. In March 2020, the German federal state of Saxony established three COVID-19 coordination centers located at each of its maximum care hospitals, namely the University Hospitals Dresden and Leipzig and the hospital Chemnitz. Each center has coordinated inpatient care facilities for the three regions East, Northwest and Southwest Saxony with 36, 18 and 29 hospital sites, respectively. Fed by daily data flows from local public health authorities capturing the dynamics of the pandemic as well as daily reports on regional inpatient care capacities, we established the information and prognosis tool DISPENSE. It provides a regional overview of the current pandemic situation combined with daily prognoses for up to seven days as well as outlooks for up to 14 days of bed requirements. The prognosis precision varies from 21% and 38% to 12% and 15% relative errors in normal ward and ICU bed demand, respectively, depending on the considered time period. The deployment of DISPENSE has had a major positive impact to stay alert for the second wave of the COVID-19 pandemic and to allocate resources as needed. The application of a mathematical model to forecast required bed capacities enabled concerted actions for patient allocation and strategic planning. The ad-hoc implementation of these tools substantiates the need of a detailed data basis that enables appropriate responses, both on regional scales in terms of clinic resource planning and on larger scales concerning political reactions to pandemic situations.

[The role of university hospitals in regional health care management for coping with the COVID-19 pandemic]. / Die Rolle der Universitätskliniken im regionalen medizinischen Versorgungsmanagement zur Bewältigung der COVID-19 Pandemie.

INTRODUCTION: The complex and dynamic situation in the current pandemic requires a regionally coordinated and interconnected cooperation between the different stakeholders within the health care system, such as the inpatient sector or the public health service. The aim of this study is to analyze health care management during the COVID-19 pandemic in 2020 with a focus on regional networking and communication structures. METHODS: As part of the BMBF-funded project "egePan Unimed", an online questionnaire on pandemic management was sent to the boards of all 35 German university hospitals in November 2020. The questionnaire focused on the core topics of regional networking, crisis management, data exchange, and communication with political stakeholders. The questionnaire consisted of 37 closed and three open-ended questions. After piloting, the invitation to the survey was extended three times by mail and once by telephone. RESULTS: The results (n=25, response 71.4%) show that 68% of the clinics surveyed were connected to representatives from the inpatient sector and 86% to representatives from the public health service. Networking with representatives from the outpatient sector was less common (26%). Of the university hospitals surveyed, 84% had a leadership role in a regional COVID-19 pandemic management effort. Data exchange with regional hospitals in the course of pandemic management took place at 75% of the participating university hospitals and with supra-regional hospitals at 67% of the clinics surveyed. CONCLUSION: To manage regional medical care during the COVID-19 pandemic in 2020, university hospitals often assumed a coordinating role in the complex pandemic care process. There were often structured collaborations with regional clinics and health departments and comparatively few cooperations with the outpatient care sector. However, this cooperation has the potential to prevent overcrowding in hospitals.

A mechanistic investigation of the Li10GeP2S12|LiNi1-x-yCoxMnyO2 interface stability in all-solid-state lithium batteries.

All-solid-state batteries are intensively investigated, although their performance is not yet satisfactory for large-scale applications. In this context, the combination of Li10GeP2S12 solid electrolyte and LiNi1-x-yCoxMnyO2 positive electrode active materials is considered promising despite the yet unsatisfactory battery performance induced by the thermodynamically unstable electrode|electrolyte interface. Here, we report electrochemical and spectrometric studies to monitor the interface evolution during cycling and understand the reactivity and degradation kinetics. We found that the Wagner-type model for diffusion-controlled reactions describes the degradation kinetics very well, suggesting that electronic transport limits the growth of the degradation layer formed at the electrode|electrolyte interface. Furthermore, we demonstrate that the rate of interfacial degradation increases with the state of charge and the presence of two oxidation mechanisms at medium (3.7 V vs. Li+/Li < E < 4.2 V vs. Li+/Li) and high (E ≥ 4.2 V vs. Li+/Li) potentials. A high state of charge (>80%) triggers the structural instability and oxygen release at the positive electrode and leads to more severe degradation.

Are birth outcomes in low risk birth cohorts related to hospital birth volumes? A systematic review.

BACKGROUND: There is convincing evidence that birth in hospitals with high birth volumes increases the chance of healthy survival in high-risk infants. However, it is unclear whether this is true also for low risk infants. The aim of this systematic review was to analyze effects of hospital's birth volume on mortality, mode of delivery, readmissions, complications and subsequent developmental delays in all births or predefined low risk birth cohorts. The search strategy included EMBASE and Medline supplemented by citing and cited literature of included studies and expert panel highlighting additional literature, published between January/2000 and February/2020. We included studies which were published in English or German language reporting effects of birth volumes on mortality in term or all births in countries with neonatal mortality < 5/1000. We undertook a double-independent title-abstract- and full-text screening and extraction of study characteristics, critical appraisal and outcomes in a qualitative evidence synthesis. RESULTS: 13 retrospective studies with mostly acceptable quality were included. Heterogeneous volume-thresholds, risk adjustments, outcomes and populations hindered a meta-analysis. Qualitatively, four of six studies reported significantly higher perinatal mortality in lower birth volume hospitals. Volume-outcome effects on neonatal mortality (n = 7), stillbirths (n = 3), maternal mortality (n = 1), caesarean sections (n = 2), maternal (n = 1) and neonatal complications (n = 1) were inconclusive. CONCLUSION: Analyzed studies indicate higher rates of perinatal mortality for low risk birth in hospitals with low birth volumes. Due to heterogeneity of studies, data synthesis was complicated and a meta-analysis was not possible. Therefore international core outcome sets should be defined and implemented in perinatal registries. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42018095289.

[Characteristics of Innovation Fund-supported Intervention Studies: Review and Document Analysis of Study Protocols, Publications and Final Reports]. / Charakteristika von durch den Innovationsfonds geförderten Interventionsstudien: Review und Dokumentenanalyse von Studienprotokollen, Publikationen und Abschlussberichten.

This prospectively registered review characterizes 50 intervention studies from the 1st wave of the Innovation Fund based on study protocols or original articles, among other sources. The mainly (randomized) controlled intervention studies included predominantly adults/seniors in ambulatory care without a regional focus and analyzed treatment processes, clinical and patient outcomes as outcomes. The substantial lack of study protocols and methodological details (e. g., sample size planning) reveals (avoidable) methodological problems regarding the scientific quality of the funded studies.

Patient-Level and Hospital-Level Risk Factors for In-Hospital Mortality in Patients Ventilated for More Than 24 Hours: Results of a Nationwide Cohort Study.

BACKGROUND: Prolonged ventilation is associated with a high risk of death. This study investigated both patient-level and hospital-level risk factors for in-hospital mortality in patients ventilated for more than 24 hours. METHODS: The analyses were conducted in the framework of a German national multicenter retrospective cohort study. Patient and hospital characteristics were examined using descriptive statistics. Risk factors of in-hospital mortality were analyzed using multilevel robust Poisson regressions for binary outcomes. Potential effect modifications were examined by stratified analyses. RESULTS: The sample includes 95 672 cases of patients ventilated >24 hours in 163 hospitals covering the period 2016 to 2017. According to the results of multilevel Poisson regressions, main patient-level risk factors for in-hospital mortality were age (per year relative risk [RR] = 1.021, 95% CI = 1.020-1.023), stroke (RR = 1.459; 95% CI = 1.361-1.563), emergency case admission (RR = 1.273, 95% CI = 1.156-1.403), and transfer from another hospital (RR = 1.169, 95% CI = 1.084-1.261). The individual risk of in-hospital death was positively associated with hospital size (RR of hospitals with 600-799 beds vs <100 beds = 1.412, 95% CI = 1.095-1.820) and negatively related to cumulated ventilation patient time (per 1000 days RR = 0.995, 95% CI = 0.993-0.996). University hospital status was identified as an effect modifier, particularly with regard to the patients' admission reasons. The RR of in-hospital death in patients admitted after transfer from another hospital was higher in university hospitals (RR = 1.456, 95% CI = 1.298-1.634) compared to nonuniversity hospitals (RR = 1.077, 95% CI = 1.019-1.139). Likewise, patients admitted as emergency case had a higher relative risk in university hospitals (RR = 1.619, 95% CI = 1.359-1.929) than in nonuniversity hospitals (RR = 1.141, 95% CI = 1.080-1.205). CONCLUSION: By providing evidence on multiple patient-level and hospital-level risk factors for in-hospital mortality in patients ventilated for more than 24 hours, this large multicenter study has main implications for quality assessment of clinical care and the adequate specification of risk adjustment models. The revealed effect modifications indicate the relevance of stratified analyses.

Implementing longitudinal integrated curricula: Systematic review of barriers and facilitators.

PURPOSE: The increase of longitudinal integrated curricula in medical schools worldwide represents the shift towards an outcome-oriented education. This novel model allows comprehensive student-patient interactions over time and integrates the educational content across disciplines. According to quantitative research, students, patients, doctors and communities benefit from this educational model in terms of participant satisfaction, learning outcomes and clinician recruitment. However, quantitative research does not provide detailed information on programme implementation processes. Therefore, this review aims to summarise facilitators and barriers of programme implementation reported in qualitative and mixed methods studies. METHOD: The authors reviewed the literature about facilitators and barriers for the implementation of longitudinal integrated curricula in undergraduate medical education programmes. The systematic search was conducted in MEDLINE, Embase and PsycINFO on 2 December 2019. The authors used the CASP checklist for qualitative research for the critical appraisal and summarised the results across studies using thematic content analysis. RESULTS: The authors screened 1682 reports. Twenty studies examining 17 different curricula met the inclusion criteria. Most curricula were implemented in the United States (n = 6/17), Australia (n = 5/17) or Canada (n = 4/17). Programme implementation is facilitated and hampered by its educational components (eg continuity of supervision, safe learning environments), organisational structures (eg community involvement) and participating students' and staff' motivation and personality. The critical appraisal revealed that several studies lacked transparent documentation and adequate reflection on the researcher-participant relationship (n = 20/20), data collection instruments (n = 12/20) and recruitment strategy (n = 4/20). CONCLUSIONS: The authors derived practical recommendations for the implementation of undergraduate, patient-centred, integrated medical curricula. Programme managers need to define and communicate common objectives with all participants. They should clarify the implementation of the objectives in all processes in a transparent and structured manner. Considering reporting guidelines, future studies in this field should document more transparently the methods used to gain qualitative insights and the researchers' personal involvement.

Impact of regionalisation and case-volume on neonatal and perinatal mortality: an umbrella review.

OBJECTIVE: This umbrella review summarises and critically appraises the evidence on the effects of regulated or high-volume perinatal care on outcome among very low birth weight/very preterm infants born in countries with neonatal mortality <5/1000 births. INTERVENTION/EXPOSITION: Perinatal regionalisation, centralisation, case-volume. PRIMARY OUTCOMES: Death. SECONDARY OUTCOMES: Disability, discomfort, disease, dissatisfaction. METHODS: On 29 November 2019 a systematic search in MEDLINE and Embase was performed and supplemented by hand search. Relevant systematic reviews (SRs) were critically appraised with A MeaSurement Tool to Assess systematic Reviews 2. RESULTS: The literature search revealed 508 hits and three SRs were included. Effects of perinatal regionalisation were assessed in three (34 studies) and case-volume in one SR (6 studies). Centralisation has not been evaluated. The included SRs reported effects on 'death' (eg, neonatal), 'disability' (eg, mental status), 'discomfort' (eg, maternal sensitivity) and 'disease' (eg, intraventricular haemorrhages). 'Dissatisfactions' were not reported. The critical appraisal showed a heterogeneous quality ranging from moderate to critically low. A pooled effect estimate was reported once and showed a significant favour of perinatal regionalisation in terms of neonatal mortality (OR 1.60, 95% CI 1.33-1.92). The qualitative evidence synthesis of the two SRs without pooled estimate suggests superiority of perinatal regionalisation in terms of different mortality and non-mortality outcomes. In one SR, contradictory results of lower neonatal mortality rates were reported in hospitals with higher birth volumes. CONCLUSIONS: Regionalised perinatal care seems to be a crucial care strategy to improve the survival of very low birth weight and preterm births. To overcome the low and critically low methodological quality and to consider additional clinical and patient-reported results that were not addressed by the SRs included, we recommend an updated SR. In the long term, an international, uniformly conceived and defined perinatal database could help to provide evidence-based recommendations on optimal strategies to regionalise perinatal care. PROSPERO REGISTRATION NUMBER: CRD42018094835.

Convergent Losses of TLR5 Suggest Altered Extracellular Flagellin Detection in Four Mammalian Lineages.

Toll-like receptors (TLRs) play an important role for the innate immune system by detecting pathogen-associated molecular patterns. TLR5 encodes the major extracellular receptor for bacterial flagellin and frequently evolves under positive selection, consistent with coevolutionary arms races between the host and pathogens. Furthermore, TLR5 is inactivated in several vertebrates and a TLR5 stop codon polymorphism is widespread in human populations. Here, we analyzed the genomes of 120 mammals and discovered that TLR5 is convergently lost in four independent lineages, comprising guinea pigs, Yangtze river dolphin, pinnipeds, and pangolins. Validated inactivating mutations, absence of protein-coding transcript expression, and relaxed selection on the TLR5 remnants confirm these losses. PCR analysis further confirmed the loss of TLR5 in the pinniped stem lineage. Finally, we show that TLR11, encoding a second extracellular flagellin receptor, is also absent in these four lineages. Independent losses of TLR5 and TLR11 suggest that a major pathway for detecting flagellated bacteria is not essential for different mammals and predicts an impaired capacity to sense extracellular flagellin.