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Sepsis is a life-threatening organ failure resulting from a poorly regulated infection response. Organ dysfunction includes hepatic involvement, weakening the immune system due to excretory liver failure, and metabolic dysfunction, increasing the death risk. Although experimental studies correlated excretory liver functionality with immune performance and survival rates in sepsis, the proteins and pathways involved remain unclear. This study identified protein kinase C-α (PKCα) as a novel target for managing excretory liver function during sepsis. Using a preclinical murine sepsis model, we found that both PKCα knockout and the use of a PKCα-inhibitor midostaurin successfully restored liver function without hindering the host's response or ability to clear the pathogen, highlighting PKCα's vital role in excretory liver failure. In septic animals, both approaches significantly boosted survival rates. Midostaurin is the clinically approved active pharmaceutical ingredient in Rydapt, approved for the adjuvant treatment of FTL3-mutated AML. Here, it reduced plasma bile acids and related inflammation in those patients, opening a translational avenue for therapeutics in sepsis. Conclusively, our research underscores the significance of PKCα in controlling excretory liver function during inflammation. This suggests that targeting this protein could restore liver function without compromising the immune system, thereby decreasing sepsis mortality and supporting the recent paradigm that the liver is a hub for the host response to infection that might, in the future, result in novel host-directed therapies supporting the current state-of-the-art intensive care medicine in patients with sepsis-associated liver failure., Competing Interests: Declaration of Competing Interest I have included a section, Conflict-of-Interest Statement, in the manuscript (required even if just to state there are no disclosures)., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Recent studies have revealed that many mosquito species regularly engage in high-altitude windborne migration, but its epidemiological significance was debated. The hypothesis that high-altitude mosquitoes spread pathogens over large distances has not been directly tested. Here, we report for the first time that high-altitude windborne mosquitoes are commonly infected with arboviruses, protozoans, and helminths affecting vertebrates and humans, and provide the first description of this pathogen-vector aerial network. A total of 1,017 female mosquitoes (81.4%, N=1,249) intercepted on nets suspended from helium balloons at altitudes of 120-290 m above ground over Mali and Ghana were screened for infection with arboviruses, plasmodia, and filariae, using pan-genus qPCR analyses followed by sequencing of positive samples. The mosquito fauna collected at altitude comprised 61 species, across 9 genera, dominated by Culex , Aedes, and Anopheles . Infection and infectiousness rates of high-altitude migrant mosquitoes were 7.2% and 4.4% with plasmodia, 1.6% and 0.6% with filariae, 3.5% and 1.1% with flaviviruses, respectively. Nineteen mosquito-borne pathogens were identified, including three arboviruses: dengue, West Nile and M'Poko viruses, 13 putative plasmodia species including Plasmodium matutinum and P. relictum , three filariids, including Pelecitus spp., 27 insect-specific viruses and 5 non-mosquito-borne pathogens (e.g., Trypanosoma theileri ). Confirmed head-thorax (disseminated) infections of multiple pathogens in multiple mosquito species, eg., Culex perexiguus , Coquilletidia metallica , Mansonia uniformis , and Anopheles squamosus provides evidence that pathogens carried by high-altitude windborne mosquitoes are infectious and likely capable of infecting naïve hosts far from their starting location. This traffic of sylvatic pathogens may be key to their maintenance among foci as well as initiating outbreaks away from them.

Background: Effective healthcare delivery in today's diverse society necessitates healthcare providers' adeptness in navigating cultural and religious nuances in patient care. However, the integration of cultural competence training into medical education remains inadequate, particularly concerning the care of Muslim patients. In response, we introduce a novel educational intervention aimed at enhancing intercultural proficiency among medical students, emphasizing care for Muslim patients., Methods: The intervention comprised interactive seminars and simulated patient sessions. With a bespoke and the Cross-Cultural Competence of Healthcare Professionals (CCCHP-27) questionnaire the pre- and post-course intercultural competencies of n = 31 medical students of the Medical Faculty of Jena University were assessed. Additionally, there was a control group consisting of 34 students. Statistical analyses including descriptive statistics, paired samples t-tests, Wilcoxon tests, correlation analysis, Mann-Whitney U-tests, and multiple regression analysis were employed for data analysis., Results: Results of the bespoke questionnaire reveal significant improvements in intercultural knowledge (median pre 1.0 (0.6 - 1.6), median post 2.2 (2.4-2.8), p < 0.001) and in knowledge regarding Muslim patients (median pre 1.0 (0.5 - 1.5), median post 2.5 (2-3), p < 0.001) following the course. Regarding the CCCHP-27, students demonstrated a significant improvement in their skills, with pre-assessment score of 4.10 (± 0.47) and post-assessment score of 4.38 (± 0.40), p = 0.001. Female participants and those with limited prior experience demonstrated greater gains (p = 0.005 and p = 0.053). Notably, the incorporation of a session with a simulated patient garnered favorable feedback, affirming the efficacy of practical application in consolidating learning outcomes., Discussion: Our study emphasizes the importance of integrating intercultural competencies training into medical education and our findings underscore the efficacy of targeted educational interventions in enhancing intercultural competencies among medical students. For the assessment of intercultural competence, our bespoke questionnaire serves as a valuable addition to the German healthcare system., Conclusion: Implementation of similar interventions into medical curricula nationwide is imperative to address the needs of diverse patient populations effectively., Competing Interests: Declarations. Ethics approval and consent to participate: All procedures performed in the study were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments. This study was conducted with approval from the local ethics committee of the University Hospital Jena, registered under the reference number 2022–2857-Bef. Informed consent was obtained from all participants. Consent for publication: The participants consented to the publication of data. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Diabetic polyneuropathy (DPN) shares overlapping clinical and electrodiagnostic features with chronic inflammatory demyelinating polyneuropathy (CIDP), which complicates the differential diagnosis of CIDP in diabetic patients. 32 patients with diabetes mellitus and CIDP, 68 patients with CIDP without diabetes, 83 patients with DPN, and 28 diabetic patients without polyneuropathy were examined using clinical scores (Overall Neuropathy Limitation Scale (ONLS), Neuropathy Symptom Score, Neuropathy Deficit Score), nerve conduction studies, and nerve ultrasound (Ultrasound Pattern Sum Score (UPSS)). The ONLS was significantly higher in the CIDP patients with diabetes than in DPN (median [interquartile range]: 4.0 [3.0] vs. 0 [1.0], p < 0.001) as well as the UPSS (4.0 [6.0] vs. 0 [2.9], p < 0.001). Multiple binary logistic regression revealed UPSS and ONLS as statistically significant predictors to differentiate between CIDP with diabetes and DPN. Receiver operating characteristic curve analysis showed the ONLS with an area under the curve (AUC) of 0.918 (95% CI: 0.868-0.0.967, p < 0.001). The UPSS total score had an AUC of 0.826 (95% CI: 0.743-0.909, p < 0.001). An UPSS ≥ 2.5 had a sensitivity of 77.4% and a specificity of 68.7% to detect CIDP. An ONLS ≥ 1.5 had a sensitivity of 87.1% and a specificity of 81.9% to detect CIDP. ROC curve analysis of a composite score of ONLS and UPSS revealed an AUC of 0.959 (95% CI: 0.928-0.991, p < 0.001). CIDP is an important differential diagnosis in people with diabetes mellitus. This study reports that the UPSS is well suited to differentiate between DPN and CIDP., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: This study was approved by the ethics committees of our institutions (Jena: project number 2022–2790 Daten and project number 2019-1416-BO, Tübingen: project number 099/2022BO2) and was performed in accordance with the ethics guidelines of our institutions for clinical studies and the Helsinki Declaration. Data collection was declared in accordance with the General Data Protection Regulation (no. 20190403113200), as required for the retrospective collection of routine care data. Patient consent for publication: Written informed consent was obtained from all prospectively examined patients of the diabetes cohort., (© 2024. The Author(s).)

Objectives: This study investigates the relationship between the cerebro-placental ratio (CPR) measured at 40+0 weeks' gestation and perinatal outcomes to determine a CPR cut-off that may justify induction of labor at term in appropriately grown fetuses (AGA). Although CPR is used for monitoring growth-restricted fetuses, its role in guiding labor induction decisions for AGA pregnancies at term remains unclear., Methods: A retrospective cohort study was conducted using data from 491 singleton pregnancies with intended vaginal deliveries between 2015 and 2021. CPR was assessed at the actual estimated date of delivery (40+0 weeks' gestation). Adverse Pregnancy Outcome (APO) as the primary endpoint was defined by admission to neonatal intensive care unit (NICU), umbilical cord blood pH<7.1, 5-min APGAR<7 or interventions-due-to-fetal-distress during labor (IDFD=vaginal-operative delivery or emergency caesarean section)., Results: APO nearly doubled (adjOR 1.7; CI 1.007-2.905) when CPR was below our calculated cut-off of 1.269 (18.4 vs. 32.3 %, p=0.002) and NICU admissions (4.8 vs. 11.1 %, p=0.020) and IDFD (12.5 vs. 21.2 %, p=0.027) significantly increased. The positive predictive value for the presence of APO using our cut-off was 32.4 %, and the negative predictive value 81.6 %., Conclusions: Our data confirm a predictive value of a reduced CPR at term with impaired perinatal outcome. The cut-off of CPR<1.269 may guide decision-making regarding induction of labor. Further prospective studies are needed to confirm these findings., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Surface Functional Electrical Stimulation (FES) is a well-studied intervention for multiple muscular disorders. However, it is still controversially discussed as a complementary therapy for complete facial paralysis. The aim of this intervention is to test a daily home-based ES concept as a pilot study regarding safety, feasibility, and effects on facial functionality and symmetry. In a prospective single-centre pilot study, 10 patients (median 61 years, denervation 130 d) with complete peripheral facial paralysis performed home-based FES of the affected lateral mouth region Stimulation parameters, facial paralysis scores and standardised photographs were assessed in monthly follow-ups. No serious adverse events appeared. Stimulation parameters could be constantly increased indicating effective muscle training while subjectively perceived functionality of the face improved. Thus, smile angle of the paralysed side improved as well. FES is a safe therapy model for application in facial nerve paralysis patients. A feasible stimulation protocol could be applied, which improved the functionality and symmetry of the stimulated facial region. A future controlled, randomised and double-blind follow-up study is needed to investigate these initial results in a further evolved replicable setting.

Functional Electrical Stimulation (FES) is an established intervention for a range of muscular and neurological disorders that has already been studied in numerous publications. However, its application to Peripheral Facial nerve Paralysis (PFP) still needs to be sufficiently investigated. As the first approach known to the authors, this study examines the effect of FES on the facial muscles in complete PFP using ultrasonography as a means of observation. In a prospective single-center observational pilot study, ten patients with complete PFP, confirmed by needle-electromyography (EMG), performed FES of the affected lateral mouth region at home twice daily for 20 minutes. The facial muscles' Cross-Sectional Area (CSA) was regularly assessed using sonographic quantification. While the CSA of most non-stimulated muscles decreased considerably during ongoing paralysis, a significant CSA increase of the Zygomaticus Muscle (ZYG), which was regularly subjected to FES, could be demonstrated. FES can halt the atrophy of denervated ZYG and potentially other facial muscles. Further investigations with a more significant patient collective are recommended. From now on, FES could be established as an additive method in the non-invasive treatment of PFP.

Preliminary evidence suggests perturbations of the kynurenine pathway (KP) of tryptophan metabolism in infants with single ventricle heart disease (SVHD). In 72 infants with SVHD undergoing stage 2 palliation (S2P) and 41 controls, we quantified serum KP metabolite concentrations via tandem mass spectroscopy pre-S2P and post-S2P at 2, 24, and 48 h and assessed metabolite relationships with post-S2P outcomes (length of stay, hypoxemia burden, and intubation duration). Pre-S2P, SVHD infants had lower tryptophan and serotonin levels and higher kynurenic acid, 3-hydroxykynurenine, and picolinic acid levels than controls. Post-S2P, metabolites peaked at 2 h, with return to baseline by 48 h for all except kynurenic acid, which remained elevated. Metabolite concentrations pre-S2P were poorly associated with outcomes. A lower serotonin peak 2 h post-S2P was associated with longer length of stay and intubation duration. Multiple metabolites at 24 and 48 h correlated with outcomes; notably, elevated kynurenic acid was associated with worse results for all three outcomes. Our results confirm that interstage SVHD infants have altered KP activity compared to controls. Further, the link between outcomes and KP metabolites post-S2P-but not at baseline-demonstrates that acute, perioperative changes in tryptophan catabolism may be more important to tolerating S2P physiology than chronic interstage changes., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: Women developing preeclampsia (PE) or fetal growth restriction (FGR) during pregnancy are at higher risk for cardiovascular diseases (CVD) later in life. We aimed to analyse cardiovascular health of women 10-20 years after affected pregnancies in comparison to women after uneventful pregnancies. In addition, we assessed a potential long-term effect of the NO-donor pentaerythrityl tetranitrate (PETN)., Methods: Women 10-20 years after severe PE, including women receiving PETN during pregnancy and matched controls were recruited and assessed for baseline clinical data and cardiovascular function by transthoracic echocardiography, VICORDER and USCOM. SPSS was used for statistical analysis., Results: 53 participants after PE/FGR (13 with former PETN intake) and 51 controls were recruited for follow-up at an average of 14 years after index pregnancies. Compared to controls, women after PE/FGR had a significantly higher incidence of arterial hypertension (13.7% vs. 41.5%, p<0.001), and were more likely to be hypertensive (41.2% vs. 67.30%, p = 0.008). There were no differences in cardiovascular function observed. Affected women with PETN intake during pregnancy showed lower mean values for right atrial area and ventricle in comparison to controls and also to affected women without former medication., Conclusions: In conclusion, our study results confirm that the risk of CVD is increased in women after PE/FGR compared to women after uneventful pregnancies. Contrary to our expectations, no major cardiovascular changes were observed in our cohort 10-20 years post pregnancy. The observed differences found in right heart dimensions were within reference ranges, and should be interpreted with caution., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lößner et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Football is one of the most played sports in the world and kicking with adequate accuracy increases the likelihood of winning a competition. Although studies with different target-directed movements underline the role of distinctive cortical activity on superior accuracy, little is known about cortical dynamics associated with kicking. Mobile electroencephalography is a popular tool to investigate cortical modulations during movement, however, inherent and artefact-related pitfalls may obscure the reliability of functional sources and their activity. The purpose of this study was therefore to describe consistent cortical dynamics underlying target-directed pass-kicks based on test-retest reliability estimates. Eleven participants performed a target-directed kicking task at two different sessions within one week. Electroencephalography was recorded using a 65-channel mobile system and behavioural data were collected including motion range, acceleration and accuracy performance. Functional sources were identified using independent component analysis and clustered in two steps with the components of first and subsequently both sessions. Reliability estimates of event-related spectral perturbations were computed pixel-wise for participants contributing with components of both sessions. The parieto-occipital and frontal clusters were reproducible for the same majority of the sample at both sessions. Their activity showed consistent alpha desyhronization and theta sychnronisation patterns with substantial reliability estimates revealing visual and attentional demands in different phases of kicking. The findings of our study reveal prominent cortical demands during the execution of a target-directed kick which may be considered in practical implementations and provide promising academic prospects in the comprehension and investigation of cortical activity associated with target-directed movements., Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-024-10094-0., Competing Interests: Conflict of interestAll authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript., (© The Author(s) 2024.)

Background: Breastfeeding has numerous health benefits for patients and their infants. There are inconsistencies in how anesthesia providers care for lactating patients undergoing anesthesia. Providers may be cautious and have patients "pump and dump" instead of following current evidence-based recommendations. Video-based education provides a novel reference for health care providers in their fast-paced work environments. This project evaluated the effectiveness of an online video module and resources accessed at the bedside for anesthesia providers caring for lactating patients. Materials and Methods: A preintervention survey was sent to anesthesia providers at a large academic institution to assess baseline knowledge of current recommendations for caring for lactating patients having anesthesia. A quick response code-linked video module and references were created and disseminated to all anesthesia providers. A postsurvey was sent to assess knowledge and satisfaction with the educational approach. Postsurvey data were compared with presurvey data. Results: All who watched the educational video found the education helpful to care for lactating patients undergoing surgery. In the posteducation group, 93% of providers selected the correct recommendation to continue breastfeeding or pumping after general anesthesia or sedation once the patient is awake and alert, compared with 48% in the pre-education group. After education, 92% would recommend preoperative feeding or pumping prior to transport to the operating room, compared with the 50% in the pre-education group. Conclusions: Video-based, just-in-time education is an effective way to deliver updated information to anesthesia providers. This format is conducive to just-in-time delivery, and there may be implications for other patient populations that present infrequently but require population-specific care.

Immunoglobulins for intravenous use (IVIgs) and subcutaneous use (SCIgs) can prevent recurrent and severe infections in patients with secondary antibody deficiencies that are frequently linked to haematological/oncological malignancies as well as other clinical conditions and their respective treatments. Even so, as IVIgs and SCIgs are costly and their supply is limited, their clinical use must be optimised. The aim of this position paper is to provide structured practical guidance on the optimal use of IVIgs and SCIgs in secondary antibody deficiencies, particularly in haematological and oncological practice. The authors agree that the occurrence of severe infections is a prerequisite for the use of IVIgs. Serum IgG levels in general as well as IgG subclass levels can be additional indicators of whether a patient could benefit from IVIgs. Responsiveness to vaccines can help to identify immunodeficiency. Patients with chronic lymphocytic leukaemia or multiple myeloma who are receiving respective treatment, especially B-cell depletion therapy, but also some patients with autoimmune diseases are prone to antibody deficiencies and need IVIgs. For the optimal use of IVIgs and to maximise their potential benefit, the indication must be individually assessed for each patient. As a primary treatment goal, the authors define a sufficient prophylaxis of severe infections, which can be supported by normalising IgG levels. If the initiated treatment is insufficient or linked to intolerable adverse reactions, switching the product within the class of IVIgs or changing to a different batch of the same product can be considered. Pausing treatment can also be considered if there are no infections, which happens more frequently in summer, but treatment needs to be resumed once infections return. These structured recommendations for IVIg treatment in patients with secondary antibody deficiency may provide guidance for clinical practice and therefore help to allocate IVIgs to those who will benefit the most, without overusing valuable resources.

This multicentre, prospective cohort study measured the effect of romosozumab for 12 months on bone mineral density, taking into account prior therapies. Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip., Introduction: In Switzerland, romosozumab is administered to high-risk osteoporosis patients. Our study aimed to assess the effect of romosozumab on bone mineral density (BMD), taking into account prior therapies., Methods: This multicentre, prospective cohort study measured the effect of romosozumab for 12 months in patients in a nationwide Swiss osteoporosis registry. BMD and bone turnover marker (P1NP and CTX) changes were measured and compared between pre-treated and treatment naïve patients., Results: Ninety-nine patients (92 women and 7 men, median age 71 years [65, 76]) were enrolled from January 2021 to December 2023. Among them, 22 had no prior treatment before romosozumab, while 77 had previous therapy (including 23 with a history of prior teriparatide therapy), with a median duration of 6 years [4, 11] of cumulative antiresorptive treatment. Over 12 months, romosozumab led to BMD changes of 10.3% [7.5, 15.5] at the lumbar spine, 3.1% [1.1, 5.8] at the total hip and 3.1% [0.5, 5.3] at the femoral neck, indicating notable variability. Significantly lower BMD responses were observed in pre-treated patients, with the duration of prior antiresorptive therapy inversely associated with BMD increases at the lumbar spine and hip. Other predictors of BMD changes at the total hip included baseline T-scores at the hip, body mass index and baseline CTX level, while the BMD response at the lumbar spine was associated with the lumbar spine T-score at baseline, age and baseline CTX level., Conclusion: Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip., (© 2024. The Author(s).)

Fracture prediction is essential in managing patients with osteoporosis and is an integral component of many fracture prevention guidelines. We aimed to identify the most relevant clinical fracture risk factors in contemporary populations by training and validating short- and long-term fracture risk prediction models in 2 cohorts. We used traditional and machine learning survival models to predict risks of vertebral, hip, and any fractures on the basis of clinical risk factors, T-scores, and treatment history among participants in a nationwide Swiss Osteoporosis Registry (N = 5944 postmenopausal women, median follow-up of 4.1 yr between January 2015 and October 2022; a total of 1190 fractures during follow-up). The independent validation cohort comprised 5474 postmenopausal women from the UK Biobank with 290 incident fractures during follow-up. Uno's C-index and the time-dependent area under the receiver operating characteristics curve were calculated to evaluate the performance of different machine learning models (Random survival forest and eXtreme Gradient Boosting). In the independent validation set, the C-index was 0.74 [0.58, 0.86] for vertebral fractures, 0.83 [0.7, 0.94] for hip fractures, and 0.63 [0.58, 0.69] for any fractures at year 2, and these values further increased for longer estimations of up to 7 yr. In comparison, the 10-yr fracture probability calculated with FRAX Switzerland was 0.60 [0.55, 0.64] for major osteoporotic fractures and 0.62 [0.49, 0.74] for hip fractures. The most important variables identified with Shapley additive explanations values were age, T-scores, and prior fractures, while number of falls was an important predictor of hip fractures. Performances of both traditional and machine learning models showed similar C-indices. We conclude that fracture risk can be improved by including the lumbar spine T-score, trabecular bone score, numbers of falls and recent fractures, and treatment information has a significant impact on fracture prediction., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Improved pass accuracy is a prominent determinant of success in football. It demands an effective interaction of complex behavioral and cortical dynamics. Exploring differences in the ability to sustain an accurate pass behavior in a stable setting and the associated cortical dynamics at different expertise levels may provide an insight into skilled strategies contributing to superior accuracy in football. The aim of this study is to compare trial-to-trial variability of pass biomechanics and the corresponding cortical dynamics during short-distance passes between novices and experienced football players. Thirty participants (15 novices, 15 football players) performed 90 short-distance passes. The intertrial variability of pass biomechanics (foot acceleration, range of hip flexion, knee flexion and foot rotation) was assessed by means of multiscale entropy. The task-related cortical dynamics were analyzed via source-derived event-related spectral perturbations. Experienced players demonstrated higher accuracy and overall lower entropy values across multiple time scales which was significant for hip flexion. The electroencephalography data revealed group differences in parieto-occipital alpha desynchronization and frontal theta synchronization in successive phases of passes. The current findings suggest that experienced football players may show a skilled ability to recruit and retain pass biomechanics promoting higher accuracy, whereas novices may show an explorative behavior with higher spatial variability. This difference may be associated with distinctive visuospatial and attentional strategies acquired with expertise in football. Our study provides an insight into expertise-specific behavioral and cortical dynamics of superior accuracy in football and a basis for its prospective investigation in enriched contexts., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Preterm birth and fetal growth restriction are the main determinants of perinatal mortality. In the absence of therapeutic interventions, management is restricted to the observation of fetal growth and fetoplacental perfusion to determine the timing of delivery. Fetal circulatory redistribution, known as "brain sparing," represents a sign of fetal hypoxia and has been implemented in algorithms for when to deliver. In the absence of any other option, the nitric oxide donor pentaerythrityl tetranitrate (PETN), which has been shown to improve fetoplacental flow and reduce preterm birth in high-risk patients, is offered to patients as a personal therapy attempt. The aim of this study was to evaluate determinants related to pregnancy, including PETN intake during pregnancy, on immediate neonatal outcomes in a cohort of growth-restricted infants born before 32 completed weeks of gestation., Methods: We performed a retrospective cohort study of 98 infants born with a birth weight below the 10th percentile before 32 completed weeks of gestation at our tertiary care center between 2010 and 2019. PETN was offered to all mothers with a history of severe adverse pregnancy outcomes who were at high risk of developing fetal growth restriction as an individual therapy attempt., Results: The mean gestational age at birth was 188.5 days, and the mean birth weight was 549 g, corresponding to a median percentile of three. In 73 (79.3%) cases, brain sparing occurred during pregnancy. A total of 22 (22.4%) neonates were stillborn, 20 died postnatally, and 37.3% developed a severe complication. Multivariable analysis revealed birth weight percentile, gestational age at birth, and gestational age when brain sparing first occurred to be robust predictors of mortality or severe neonatal morbidity. In 39 neonates of mothers taking PETN, this impact of brain sparing was not observed., Conclusion: Our study is the first to demonstrate a significant association between the early occurrence of brain-sparing and severe neonatal outcomes in a cohort of very early preterm, growth-restricted newborns. The data suggest that PETN intake may ameliorate the effect of brain sparing in the affected neonates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Köber, Heimann, Lehmann, Schleußner, Proquitté and Groten.)

Background: Infants with single ventricle heart disease (SVHD) suffer morbidity from insufficient pulmonary blood flow, which may be related to impaired arginine metabolism. No prior study has reported quantitative mapping of arginine metabolites to evaluate the relationship between circulating metabolite levels and outcomes., Methods: Prospective cohort study of 75 SVHD cases peri-Stage 2 and 50 healthy controls. We targeted pre- and post-op absolute serum quantification of 9 key members of the arginine metabolism pathway by tandem mass spectrometry. Primary outcomes were length of stay (LOS) and post-Stage 2 hypoxemia., Results: Pre-op cases showed alteration in 6 metabolites including decreased arginine and increased asymmetric dimethyl arginine (ADMA) levels compared to controls. Post-op cases demonstrated decreased arginine and citrulline levels persisting through 48 h. Adjusting for clinical variables, lower pre-op and 2 h post-op concentrations of multiple metabolites, including arginine and citrulline, were associated with longer post-op LOS (p < 0.01). Increased ADMA at 24 h was associated with greater post-op hypoxemia burden (p < 0.05)., Conclusion: Arginine metabolism is impaired in interstage SVHD infants and is further deranged following Stage 2 palliation. Patients with greater metabolite alterations experience greater post-op morbidity. Decreased arginine metabolism may be an important driver of pathology in SVHD., Impact: Interstage infants with SVHD have significantly altered arginine-nitric oxide metabolism compared to healthy children with deficiency of multiple pathway intermediates persisting through 48 h post-Stage 2 palliation. After controlling for clinical covariates and classic catheterization-derived predictors of Stage 2 readiness, both lower pre-operation and lower post-operation circulating metabolite levels were associated with longer post-Stage 2 LOS while increased post-Stage 2 ADMA concentration was associated with greater post-op hypoxemia. Arginine metabolism mapping offers potential for development using personalized medicine strategies as a biomarker of Stage 2 readiness and therapeutic target to improve pulmonary vascular health in infants with SVHD., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Targeted protein degradation is an innovative therapeutic strategy to selectively eliminate disease-causing proteins. Exemplified by proteolysis-targeting chimeras (PROTACs), they have shown promise in overcoming drug resistance and targeting previously undruggable proteins. However, PROTACs face challenges, such as low oral bioavailability and limited selectivity. The recently published PROxAb Shuttle technology offers a solution enabling the targeted delivery of PROTACs using antibodies fused with PROTAC-binding domains derived from camelid single-domain antibodies (VHHs). Here, a modular approach to quickly generate PROxAb Shuttles by enzymatically coupling PROTAC-binding VHHs to off-the-shelf antibodies was developed. The resulting conjugates retained their target binding and internalization properties, and incubation with BRD4-targeting PROTACs resulted in formation of defined PROxAb-PROTAC complexes. These complexes selectively induced degradation of the BRD4 protein, resulting in cytotoxicity specifically to cells expressing the antibody's target. The chemoenzymatic approach described herein provides a versatile and efficient solution for generating antibody-VHH conjugates for targeted protein degradation applications, but it could also be used to combine antibodies and VHH binders to generate bispecific antibodies for further applications.

Objectives: Consensus regarding biomarkers for detection of infection-related organ dysfunction in the emergency department is lacking. We aimed to identify and validate biomarkers that could improve risk prediction for overt or incipient organ dysfunction when added to quick Sepsis-related Organ Failure Assessment (qSOFA) as a screening tool., Design: In a large prospective multicenter cohort of adult patients presenting to the emergency department with a qSOFA score greater than or equal to 1, admission plasma levels of C-reactive protein, procalcitonin, adrenomedullin (either bioavailable adrenomedullin or midregional fragment of proadrenomedullin), proenkephalin, and dipeptidyl peptidase 3 were assessed. Least absolute shrinkage and selection operator regression was applied to assess the impact of these biomarkers alone or in combination to detect the primary endpoint of prediction of sepsis within 96 hours of admission., Setting: Three tertiary emergency departments at German University Hospitals (Jena University Hospital and two sites of the Charité University Hospital, Berlin)., Patients: One thousand four hundred seventy-seven adult patients presenting with suspected organ dysfunction based on qSOFA score greater than or equal to 1., Interventions: None., Measurements and Main Results: The cohort was of moderate severity with 81% presenting with qSOFA = 1; 29.2% of these patients developed sepsis. Procalcitonin outperformed all other biomarkers regarding the primary endpoint (area under the curve for receiver operating characteristic [AUC-ROC], 0.86 [0.79-0.93]). Adding other biomarkers failed to further improve the AUC-ROC for the primary endpoint; however, they improved the model regarding several secondary endpoints, such as mortality, need for vasopressors, or dialysis. Addition of procalcitonin with a cutoff level of 0.25 ng/mL improved net (re)classification by 35.2% compared with qSOFA alone, with positive and negative predictive values of 60.7% and 88.7%, respectively., Conclusions: Biomarkers of infection and organ dysfunction, most notably procalcitonin, substantially improve early prediction of sepsis with added value to qSOFA alone as a simple screening tool on emergency department admission., Competing Interests: Drs. Bolanaki’s, Winning’s, Slagman’s, Kiehntopf’s, Stacke’s, and Möckel’s institutions received funding from the Federal Ministry of Education and Research (Germany) (Bundesministerium für Bildung und Forschung [BMBF]). Dr. Slagman reports research funds from the German Research Council (Deutsche Forschungsgemeinschaft), the Innovation Fonds (Gemeinsamer Bundesausschuss), Roche Diagnostics, and ThermoFisher BRAHMS. Dr. Bolanaki reports funds from the Roche Diagnostics and ThermoFisher BRAHMS. Dr. Reinhart reported research grants from the Innovation Fonds (Gemeinsamer Bundesausschuss) and holds shares of the InflaRx NV, Jena, Germany. Dr. Bauer participated in advisory boards of BRAHMS/ThermoFisher and Roche Diagnostics regarding the use of biomarkers to diagnose sepsis. Dr. Winning disclosed he is an employee of the Jena University Hospital (JUH) and at the Ernst-Abbe-Hochschule in Jena. Drs. Kiehntopf’s and Bauer’s institutions received funding from the BMBF (Grant No. 03ZZ0810B). Dr. Kiehntopf disclosed they are inventor of a patent covering a method for quantification of C-terminal peptides of α1-antitrypsin (applicant: JUH; EP22154836.5; status: application), and the inventor of other patents covering C-terminal AAT peptides in inflammation (applicant: JUH: Method for determining the origin of an infection; EP17719610.2 [application]; EP3239712 [granted]) and Diagnosis of Sepsis and Systemic Inflammatory Response Syndrome (CN104204808B, EP2592421, EP2780719, US10712350B2, JP6308946B2 [all granted]). Dr. Möckel’s institution received funding from Roche Molecular Diagnostics German Innovation Funds; he received funding from ThermoFisher BRAHMS GmbH, AstraZeneca, Abbott, Medtronic, Radiometer, and Sanofi; and he disclosed he is Editor-in-Chief of Biomarkers. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Invasive insects threaten ecosystem stability, public health, and food security. Documenting newly invasive species and understanding how they reach into new territories, establish populations, and interact with other species remain vitally important. Here, we report on the invasion of the South American leafhopper, Curtara insularis into Africa, where it has established populations in Ghana, encroaching inland at least 350 km off the coast. Importantly, 80% of the specimens collected were intercepted between 160 and 190 m above ground. Further, the fraction of this species among all insects collected was also higher at altitude, demonstrating its propensity to engage in high-altitude windborne dispersal. Its aerial densities at altitude translate into millions of migrants/km over a year, representing massive propagule pressure. Given the predominant south-westerly winds, these sightings suggest an introduction of C. insularis into at least one of the Gulf of Guinea ports. To assess the contribution of windborne dispersal to its spread in a new territory, we examine records of C. insularis range-expansion in the USA. Reported first in 2004 from central Florida, it reached north Florida (Panhandle) by 2008-2011 and subsequently spread across the southeastern and south-central US. Its expansion fits a "diffusion-like" process with 200-300 km long "annual displacement steps"-a pattern consistent with autonomous dispersal rather than vehicular transport. Most "steps" are consistent with common wind trajectories from the nearest documented population, assuming 2-8 hours of wind-assisted flight at altitude. Curtara insularis has been intercepted at US ports and on trucks. Thus, it uses multiple dispersal modalities, yet its rapid overland spread is better explained by its massive propagule pressure linked with its high-altitude windborne dispersal. We propose that high-altitude windborne dispersal is common yet under-appreciated in invasive insect species.

Brain/computer interfaces (BCIs) rely on the concurrent recording of many channels of electrical activity from excitable tissue. Traditionally such neural interfacing has been performed using cumbersome, channel-limited multielectrode arrays. We believe that BCIs can greatly benefit from using an optical approach based on simple yet powerful liquid-crystal based transducer technology. This approach potentially offers a technology platform that can sustain the necessary bandwidth, density of channels, responsivity, and conformability that are required for the long-term viability of such interfaces. In this paper we review the overall architecture of this approach, the challenges it faces, and the solutions that are being developed at UNSW Sydney.

Background: This is a follow-up study to the pentaerythrityl tetranitrate randomized controlled multicenter trial that reports neonatal outcome data of newborns admitted to neonatal intensive care units and outcome data of the offspring at 12 months of age., Objective: We present data on adverse events reported during the study to document the safety of pentaerythrityl tetranitrate treatment during pregnancy. To further evaluate the effects of pentaerythrityl tetranitrate on neonatal and long-term outcomes, we present follow up data from of 240 children at 12 months of age, including information on height, weight, head circumference, developmental milestones, and the presence of chronic disease and of 144 newborns admitted to the neonatal intensive care unit during the trial., Study Design: The pentaerythrityl tetranitrate trial was a randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of the nitric oxide-donor pentaerythrityl tetranitrate in the prevention of fetal growth restriction and perinatal death in pregnancies complicated by abnormal placental perfusion., Results: Results at 12 months demonstrated that significantly more children were age appropriately developed without impairments in the pentaerythrityl tetranitrate group (P=.018). In addition, the presence of chronic disease was lower in the pentaerythrityl tetranitrate group (P=.041). Outcome data of the 144 newborns admitted to the neonatal intensive care unit did not reveal differences between the treatment and placebo groups. There were no differences in the number or nature of reported adverse events between the study groups., Conclusion: The analysis shows that study children born in the pentaerythrityl tetranitrate cohort have a clear advantage compared with the placebo group at the age of 12 months, as evidenced by the increased incidence of normal development without the presence of chronic disease. Although safety has been proven, further follow-up studies are necessary to justify pentaerythrityl tetranitrate treatment during pregnancies complicated by impaired uterine perfusion., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Vocal production learning ("vocal learning") is a convergently evolved trait in vertebrates. To identify brain genomic elements associated with mammalian vocal learning, we integrated genomic, anatomical, and neurophysiological data from the Egyptian fruit bat ( Rousettus aegyptiacus ) with analyses of the genomes of 215 placental mammals. First, we identified a set of proteins evolving more slowly in vocal learners. Then, we discovered a vocal motor cortical region in the Egyptian fruit bat, an emergent vocal learner, and leveraged that knowledge to identify active cis-regulatory elements in the motor cortex of vocal learners. Machine learning methods applied to motor cortex open chromatin revealed 50 enhancers robustly associated with vocal learning whose activity tended to be lower in vocal learners. Our research implicates convergent losses of motor cortex regulatory elements in mammalian vocal learning evolution.

Background: Long-term opioid use after surgery is a crucial healthcare problem in North America. Data from European hospitals are scarce and differentiation of chronic pain has rarely been considered., Methods: In a mixed surgical cohort of the PAIN OUT registry, opioid use and chronic pain were evaluated before surgery, and 6 and 12 months after surgery (M6/M12). Subgroups with or without opioid medication and pre-existing chronic pain were analysed. M12-chronic pain was categorised as chronic postsurgical pain (CPSP) meeting the ICD-11 definition, chronic pain related to surgery not meeting the ICD-11 definition, and chronic pain unrelated to surgery. Primary endpoint was the rate of M12 opioid users. Variables associated with M12 opioid use and patient-reported outcomes were evaluated., Results: Of 2326 patients, 5.5% were preoperative opioid users; 4.4% and 3.5% took opioids at M6 and M12 (P<0.001). Chronic pain before operation and at M6/M12 was reported by 41.2%, 41.8%, and 34.7% of patients, respectively (P<0.001). The rate of M12 opioid users was highest in group unrelated (22.3%; related 8.3%, CPSP 1.5%; P<0.001). New opioid users were 1.1% (unrelated 7.1%, related 2.3%, CPSP 0.7%; P<0.001). M12 opioid users reported more pain, pain-related physical and affective interference, and needed more opioids than non-users. The predominant variable associated with M12 opioids was preoperative opioid use (estimated odds ratio [95% confidence interval]: 28.3 [14.1-56.7], P<0.001)., Conclusions: Opioid use was low in patients with CPSP, and more problematic in patients with chronic pain unrelated to surgery. A detailed assessment of chronic pain unrelated or related to surgery or CPSP is necessary., Clinical Trial Registration: NCT02083835., (Copyright © 2023 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Objectives: Multi-organ failure is one of the leading causes of mortality after cardiac surgery for infective endocarditis (IE). Although the randomized evidence does not support the use of haemoadsorption during cardiac surgery for IE, observational studies suggest a beneficial effect in selected patient groups. Staphylococcus aureus is the most common pathogen, and its presence is an independent mortality predictor. We aimed to analyse the effect of haemoadsorption in patients with IE caused by S. aureus., Methods: This is a post hoc analysis of the REMOVE trial that randomized 288 patients with IE who underwent cardiac surgery with haemoadsorption using CytoSorb® or control. The primary outcome was ΔSequential Organ Failure Assessment (SOFA), defined as the difference between the mean total postoperative and baseline SOFA score within 24 h of surgery., Results: Among the total of 282 patients included in the modified intention-to-treat analysis of the REMOVE trial, 73 (25.9%) had S. aureus IE (38 patients in the haemoadsorption group and 35 patients in the control group). The overall ΔSOFA did not differ between the intervention groups in patients with S. aureus IE (mead difference = -0.4, 95% confidence interval -2.3 to 1.4, P = 0.66) and neither did 30-day mortality (hazard ratios = 1.32, 95% confidence interval 0.53-3.28, P = 0.55). No differences were observed with regard to any of the other secondary outcomes., Conclusions: Based on a post hoc analysis from REMOVE trial, the intraoperative use of haemoadsorption in patients with S. aureus IE was not associated with reduction of postoperative organ dysfunction, 30-day mortality or other major clinical end points., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Determination of the procedure-specific, risk-adjusted probability of nausea., Design: Cross-sectional analysis of clinical and patient-reported outcome data. We used a logistic regression model with type of operation, age, sex, preoperative opioids, antiemetic prophylaxis, regional anaesthesia, and perioperative opioids as predictors of postoperative nausea., Setting: Data from 152 German and Austrian hospitals collected in the Quality Improvement in Postoperative Pain Treatment (QUIPS) registry from 2013 to 2022. Participants completed a validated outcome questionnaire on the first postoperative day. Operations were categorised into groups of at least 100 cases., Participants: We included 78 231 of the 293 947 participants from the QUIPS registry. They were 18 years or older, willing and able to participate and could be assigned to exactly one operation group., Main Outcome Measures: Adjusted absolute risk of nausea on the first postoperative day for 72 types of operation., Results: The adjusted absolute risk of nausea ranged from 6.2% to 36.2% depending on the type of operation. The highest risks were found for laparoscopic bariatric operations (36.2%), open hysterectomy (30.4%), enterostoma relocation (29.8%), open radical prostatectomy (28.8%), laparoscopic colon resection (28.6%) and open sigmoidectomy (28%). In a logistic regression model, male sex (OR: 0.39, 95% CI 0.37 to 0.41, p<0.0001), perioperative nausea and vomiting prophylaxis (0.73, 0.7 to 0.76, p<0.0001), intraoperative regional anaesthesia (0.88, 0.83 to 0.93, p<0.0001) and preoperative opioids for chronic pain (0.74, 0.68 to 0.81, p<0.0001) reduced the risk of nausea. Perioperative opioid use increased the OR up to 2.38 (2.17 to 2.61, p<0.0001)., Conclusions: The risk of postoperative nausea varies considerably between surgical procedures. Patients undergoing certain types of operation should receive special attention and targeted prevention strategies. Adding these findings to known predictive tools may raise awareness of the still unacceptably high incidence of nausea in certain patient groups. This may help to further reduce the prevalence of nausea., Trial Registration Number: DRKS00006153; German Clinical Trials Register; https://drks.de/search/de/trial/DRKS00006153., Competing Interests: Competing interests: All authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years: PK received consulting fees and payment for lectures from TEVA Ratiopharm, Sintetica, Amicus Ltd., Fresenius Kabi, CSL Bering, Vifor and Pajunk; WM received consultation fees and payment for lectures from Mundipharma Int., Ethypharm, Grünenthal, Kyowa, Spectrum Therapeutics. His institution has received research funding from Pfizer, Grünenthal, Mundipharma Int. other relationships or activities that could appear to have influenced the submitted work: PK had leading roles in ESAIC Chairman of the Guideline Committee and PONV Consensus Conference Member (ASER, SAMBA)., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Despite children's right to a non-violent upbringing, they become daily victims of violence. Physical violence concerns mostly the head-especially the orofacial area. Therefore, dentists and paediatricians should be able to suspect possible abuse and to initiate child protection. This study aimed to record and compare the training situation and competencies of dental and medical students at Jena University Hospital regarding child abuse and neglect (CAN)., Materials and Methods: Using a three-part questionnaire about CAN, 123 medical and 77 dental students were surveyed anonymously after completing all courses on the topic. The question sets included as follows: (1) educational experiences, training content and satisfaction; (2) current knowledge regarding diagnostic, management and legal concerns; (3) self-evaluation, needs of further education and wishes. Reliability of the questionnaire was tested with kappa-statistics and assessed as good., Results: Dental and medical students' overall satisfaction with CAN-related training is low. Although medical students had more knowledge on CAN, all participants showed large deficits. Better diagnostic than management skills were reported in both groups. Only 1.3% dental and 16.3% medical students felt adequately prepared to deal with CAN. 7% of all study participants stated that they can report CAN without any help. 87.0% of medical and 79.2% of dental students expressed a desire for further education. To improve their knowledge, both courses prefer seminars, followed by expert talks, lectures and simulation-based training (SkillsLab)., Conclusion: Dental and medical students are inadequately prepared to suspect possible abuse and to deal with possible signs of CAN. Mandatory interdisciplinary courses and lectures addressing CAN are recommendable for both medical and dental curricula., (© 2023 The Authors. European Journal of Dental Education published by John Wiley & Sons Ltd.)

Background: The spread of SARS-CoV-2 cannot be well monitored and understood in areas without capacity for effective disease surveillance. Countries with a young population will have disproportionately large numbers of asymptomatic or pauci-symptomatic infections, further hindering detection of infection. Sero-surveillance on a country-wide scale by trained medical professionals may be limited in a resource-limited setting such as Mali. Novel ways of broadly sampling the human population in a non-invasive method would allow for large-scale surveillance at a reduced cost., Approach: Here we evaluate the collection of naturally blood-fed mosquitoes to test for human anti-SARS-CoV-2 antibodies in the laboratory and at five field locations in Mali., Results: Immunoglobulin-G antibodies to multiple SARS-CoV-2 antigens were readily detected in mosquito bloodmeals by bead-based immunoassay through at least 10 h after feeding [mean sensitivity of 0.92 (95% CI 0.78-1) and mean specificity of 0.98 (95% CI 0.88-1)], indicating that most blood-fed mosquitoes collected indoors during early morning hours (and likely to have fed the previous night) are viable samples for analysis. We found that reactivity to four SARS-CoV-2 antigens rose during the pandemic from pre-pandemic levels. The crude seropositivity of blood sampled via mosquitoes was 6.3% in October and November 2020 across all sites, and increased to 25.1% overall by February 2021, with the most urban site reaching 46.7%, consistent with independent venous blood-based sero-surveillance estimates., Conclusions: We have demonstrated that using mosquito bloodmeals, country-wide sero-surveillance of human diseases (both vector-borne and non-vector-borne) is possible in areas where human-biting mosquitoes are common, offering an informative, cost-effective, and non-invasive sampling option., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors (PED, JW, IZ) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2023 Krajacich, Samaké, Dao, Diallo, Sanogo, Yaro, Zeguime, Poudiougo, Cissé, Traoré, dit Assitoun, Faiman, Zaidi, Woodford, Duffy and Lehmann.)

Introduction: Fetal growth restriction (FGR) is associated with impaired angiogenesis and chronic inflammation. MicroRNAs (miRs) are short noncoding RNAs that regulate gene expression at the post-transcriptional level by targeting messenger RNA (mRNA) for degradation or by suppressing translation. We hypothesize that dysregulation of miR-15b, an antiangiogenic miR, and miR-146a, an anti-inflammatory miR, are associated with the FGR's pathogenesis., Methods: Pregnant mice were provided ad libitum access to food between E1 and E8. From E9-E18, dams received either a 50% caloric restricted diet (FGR) or continued ad libitum access (controls). Placentas were harvested at E18.5 and total RNA was extracted. Gene expression levels of miRs and mRNAs were compared between FGR and control placentas., Results: Placentas affected by FGR demonstrated increased expression of miR-15b. Vascular endothelial growth factor alpha, which is downregulated in response to increased levels of miR-15b, was suppressed. The anti-inflammatory miR, miR-146a, was downregulated, resulting in upregulation of proinflammatory (IL-6, IL-8, and NFkB1) and oxidative stress (HIF-1α, SOD2, and Nox2) mediators., Conclusions: Aberrant angiogenesis and chronic inflammation seen in FGR appear to be associated with dysregulated miR-15b and miR-146a gene expression, respectively. This observation suggests these miRs play a post-transcriptional regulatory role in FGR, providing an insight into possible therapeutic targets., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study is to investigate the effect of treatment choice on survival, transfusion needs and hospitalizations in patients > 64 years old with newly diagnosed acute myeloid leukaemia (AML)., Material and Methods: This study retrospectively analysed patients over 64 years with AML diagnosed at a regional healthcare network in Switzerland between 2017 and 2020. Patients underwent four therapy groups: intensive chemotherapy (IC), hypomethylating agent in combination with the BCL2-Inhibitor venetoclax (HMA + VEN), hypomethylating agents alone (HMA) or best supportive care (BSC)., Results: Of 54 patients 12 (22%) were selected for IC, 13 (24%) for HMA + VEN, 17 (32%) for HMA and 12 (22%) for BSC. The median overall survival of the patients was 76 days, with a significant difference in the four therapy groups (IC 119 days, HMA + VEN 732 days, HMA monotherapy 73 days and BSC 12 days Log-Rank Test Chi2(2): p  < 0.001). Patients with HMA + VEN spent significantly less time in the hospital 6.8 days/month compared to IC (19.5 days/month), HMA (20.5 days/month) and BSC (10.5 days/month) ( p  = 0.005). Transfusion needs were the highest in IC (7.0 RBC/month, 8.0 PC/month) ( p  = 0.023), whereas there was no difference between HMA + VEN (2.5 RBC/month, 3.2 PC/month), HMA monotherapy (5.3 RBC/month, 6.2 PC/month) and BSC (3.0 RBC/month, 1.4 PC/month)., Conclusion: Our real-world data demonstrate superior OS rates of HMA + VEN when compared to IC, HMC or BSC, with a favourable side effect profile with regard to transfusion needs or hospitalization days., Abbreviations: AML, acute myeloid leukaemia; BCL2, B-cell leukaemia/lymphoma-2; BSC, best supportive care; CR, complete response; Cri, complete response with incomplete haematologic regeneration; FLT3, Fms Related Receptor Tyrosine Kinase 3; EKOS, Ethikkomission Ostschweiz; ELN, European Leukaemia Net; HMA, hypomethylating agent; IC, intensive chemotherapy; IDH, Isocitratdehydrogenase; LDAC, low-dose Cytarabine; NCCN, National Comprehensive Cancer Network; OS, overall survival; PC, platelet concentrate; RBC, red blood cell; RCT, randomized controlled trials; t-AML, therapy relative acute myeloid leukaemia'; VEN, venetoclax.

Mosquito-borne diseases (MBDs) threaten public health and food security globally. We provide the first biogeographic description of the African mosquito fauna (677 species) and the 151 mosquito-borne pathogens (MBPs) they transmit. While mosquito species richness agrees with expectations based on Africa's land surface, African arboviruses and mammalian plasmodia are more speciose than expected. Species assemblages of mosquitoes and MBPs similarly separate sub-Saharan Africa from North Africa, and those in West and Central Africa from eastern and southern Africa. Similarities between mosquitoes and MBPs in diversity and range size suggest that mosquitoes are key in delimiting the range of MBPs. With approximately 25% endemicity, approximately 50% occupying one to three countries and less than 5% occupying greater than 25 countries, the ranges of mosquitoes and MBPs are surprisingly small, suggesting that most MBPs are transmitted by a single mosquito species. Exceptionally widespread mosquito species feed on people and livestock, and most are high-altitude-windborne migrants. Likewise, widespread MBPs are transmitted among people or livestock by widespread mosquitoes, suggesting that adapting to people or livestock and to widespread mosquito species promote range expansion in MBPs. Range size may predict range expansion and emergence risk. We highlight key knowledge gaps that impede prediction and mitigation of future emergence of local and global MBDs.

Background: Renal oligohydramnios (ROH) describes an abnormally low volume of amniotic fluid (AF) during pregnancy. ROH is mostly caused by congenital fetal kidney anomalies. The ROH diagnosis frequently implies an increased risk of peri- and postnatal fetal mortality and morbidity. The present study aimed to evaluate the impact of ROH on pre-and postnatal development in children with congenital kidney anomalies., Methods: This retrospective study included 168 fetuses with anomalies in the kidney and urinary tract. Based on the amount of AF measured by ultrasound, patients were divided into three groups: normal amniotic fluid (NAF), amniotic fluid in the lower normal range (LAF), and ROH. These groups were compared with respect to prenatal sonographic parameters, perinatal outcomes, and postnatal outcomes., Results: Among the 168 patients with congenital kidney anomalies, 26 (15%) had ROH, 132 (79%) had NAF, and 10 (6%) had LAF. Of the 26 families affected by ROH, 14 (54%) decided to terminate pregnancy. Of 10 live-born children in the ROH group, 6 (60%) survived the observation time; of these, 5/6 presented with chronic kidney disease, stages I-III, at their last examination. The main differences in postnatal development between the ROH group and the NAF and LAF groups were: restricted height and weight gain, respiratory issues, complicated feeding, and the presence of extrarenal malformations., Conclusions: ROH is not a mandatory indicator of severe postnatal kidney function impairment. However, children with ROH have complicated peri-and postnatal periods, due to the presence of concomitant malformations, which must be considered in prenatal care. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s).)

Purpose: Evaluating bleb morphology is crucial after glaucoma filtering surgery. Advances in anterior segment optical coherence tomography (AS-OCT) allow for objective assessment. While various parameters differentiate functional from failed blebs, limited information exists regarding variations within functional blebs. This study aimed to identify factors influencing morphology of functional blebs following implantation of Preserflo MicroShunt., Methods: Eyes with functional blebs after Preserflo were retrospectively included. Age, gender, lens status, preoperative intraocular pressure (pre-IOP) and number of glaucoma medications were documented along with biometric measurements as axial length (AL), white-to-white distance, and anterior chamber depth. Postoperative data included time elapsed since surgery (TaS) and postoperative IOP (post-IOP). Bleb dimensions were measured using AS-OCT including maximal bleb height (MBH), width, length (MBL), bleb wall thickness (BWT), and bleb distance to limbus (DtL) along with dimensions of episcleral lake (maximal height, width [MLW], and length). Linear regression models were applied to correlate these parameters with bleb dimensions., Results: Included were 50 eyes from 50 patients. Mean IOP decreased from 25.3 ± 10.0 to 11.9 ± 3.0 mm Hg after 278.5 ± 221.9 days after surgery. MBH correlated negatively with age (unstandardized coefficients [uSC] = -0.012) and TaS (uSC = -0.001, P = 0.008 for both). BWT correlated negatively with age (uSC = -0.013, P = 0.02), MBL with AL (uSC = -0.566, P = 0.01) and MLW with pre-IOP (uSC = -0.073, P = 0.02). DtL exhibited a positive correlation with post-IOP (uCS = 0.136, P = 0.02)., Conclusions: Morphology of functional blebs might be influenced by multiple factors such as age, TaS, AL, and pre- and post-IOP., Translational Relevance: Age, time after surgery, axial length, and preoperative and postoperative IOP could affect the morphology of a functional bleb; hence, these factors should be taken into consideration when making treatment decisions.

This registry-based study of 3068 patients with osteoporosis compared the anti-fracture effectiveness of denosumab versus bisphosphonates. Denosumab was associated with significantly greater risk reduction than alendronate or ibandronate for vertebral and any fractures. No difference in fracture risk reduction was found between zoledronate and denosumab., Purpose: To analyse the fracture risk of patients with osteoporosis receiving bisphosphonates or denosumab in a real-world setting., Methods: This registry-based cohort study evaluated patients taking denosumab, bisphosphonates or both sequentially. Fractures were analysed using rates, rate ratios and hazard ratios (HR), including both therapies as time-varying co-variates. Fracture risk hazards were adjusted (aHR) for baseline T-Scores and trabecular bone score (TBS) and were additionally analysed with inverse probability treatment weighting., Results: A total of 3068 patients (89% female; median age at treatment onset, 69 years [63 to 76]) received denosumab (median duration 2.8 years, [2.2 to 4.7]), bisphosphonates (3.4 years, [2.1 to 5.7]) or both sequentially. Thus, 11,078 subject-years were assessed for bisphosphonates (41% alendronate, 36% ibandronate, 23% zoledronate) and 4216 for denosumab. Moreover, 48,375 subject-years were observed before treatment onset, in addition to 2593 years of drug holidays. A total of 1481 vertebral fractures (435 under therapy), 1508 non-vertebral fractures (499 under therapy) and 202 hip fractures (67 under therapy) occurred after age 50. The risks of vertebral, non-vertebral and hip fractures were significantly lower under all bisphosphonates, denosumab and drug holidays than before treatment onset (all p < 0.001). After adjusting for age, baseline T-scores and TBS, denosumab was associated with lower risk than alendronate or ibandronate for vertebral fractures (aHR 0.47 (0.35 to 0.64) and 0.70 [0.53 to 0.91], p < 0.001 and p = 0.009, respectively) and any fractures (aHR 0.62 [0.51 to 0.76] and 0.77 [0.64 to 0.92], p < 0.001 and p = 0.004). With propensity weighting, denosumab was associated with a lower hip fracture risk compared to alendronate (HR 0.54 [0.29 to 0.98], p = 0.044). No difference in fracture risk reduction (vertebral, non-vertebral or hip) was found between zoledronate and denosumab., Conclusions: When adjusting for disease severity, denosumab was associated with significantly greater risk reduction than alendronate and ibandronate for vertebral fractures. No difference in fracture risk reduction was found between zoledronate and denosumab., (© 2023. The Author(s).)

Background: Multi-professional specialist palliative homecare (SPHC) teams care for palliative patients with complex symptoms. In Germany, the SPHC directive regulates care provision, but model contracts for each federal state are heterogeneous regarding staff requirements, cooperation with other healthcare providers, and financial reimbursement. The structural characteristics of SPHC teams also vary., Aim: We provide a structured overview of the existing model contracts, as well as a nationwide assessment of SPHC teams and their structural characteristics. Furthermore, we explore whether these characteristics serve to find specifc patterns of SPHC team models, based on empirical data., Methods: This study is part of the multi-methods research project "SAVOIR", funded by the German Innovations Fund. Most model contracts are publicly available. Structural characteristics (e.g. number, professions, and affiliations of team members, and external cooperation) were assessed via an online database ("Wegweiser Hospiz- und Palliativversorgung") based on voluntary information obtained from SPHC teams. All the data were updated by phone during the assessment process. Data were descriptively analysed regarding staff, cooperation requirements, and reimbursement schemes, while latent class analysis (LCA) was used to identify structural team models., Results: Model contracts have heterogeneous contract partners and terms related to staff requirements (number and qualifications) and cooperation with other services. Fourteen reimbursement schemes were available, all combining different payment models. Of the 283 SPHC teams, 196 provided structural characteristics. Teams reported between one and 298 members (mean: 30.3, median: 18), mainly nurses and physicians, while 37.8% had a psychosocial professional as a team member. Most teams were composed of nurses and physicians employed in different settings; for example, staff was employed by the team, in private practices/nursing services, or in hospitals. Latent class analysis identified four structural team models, based on the team size, team members' affiliation, and care organisation., Conclusion: Both the contractual terms and teams' structural characteristics vary substantially, and this must be considered when analysing patient data from SPHC. The identified patterns of team models can form a starting point from which to analyse different forms of care provision and their impact on care quality., (© 2023. The Author(s).)

Background: Nonadherence to medication is a major issue in patients with chronic disorders such as Parkinson's disease (PD). Many interventions for increasing adherence have been tested, and these have shown weak-to-moderate efficiency. Although the best methods to improve adherence remain unclear, it is reasonable to use tailored interventions instead of the "one-size-fits-all" approach., Methods: A randomized, controlled, triple-blinded trial in elderly patients with PD is conducted to test the efficacy of AdhCare, a tailored intervention to enhance adherence compared with that achieved with routine care (64 participants per arm). Motor function, quality of life, and adherence measures will be assessed at baseline and at 3 and 6 months of follow-up. The type of intervention depends on the main personal reason for nonadherence (e.g., forgetting to take the medication or poor knowledge about the medication)., Discussion: The results of this study will provide valuable information for health professionals and policymakers on the effectiveness of tailored interventions in elderly patients with PD., Trial Registration: German Clinical Trials Register DRKS00023655. Registered on 24 February 2021. Last update on 22 March 2023., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The main framework conditions for palliative care are set at the regional level. The scope of the forms of care used (outpatient, inpatient, general, specialized) varies widely. What is the quality of outcomes achieved by the palliative care provided on a federal states level? What are the associated costs of care?, Method: Retrospective observational study using BARMER claims data from 145,372 individuals who died between 2016 and 2019 and had palliative care in the last year of life. Regional comparison with regard to the following outcomes: proportion of palliative care patients who died in the hospital, potentially burdensome care in the last 30 days of life (ambulance calls, [intensive care] hospitalizations, chemotherapy, feeding tubes, parenteral nutrition), total cost of care (last three months), cost of palliative care (last year), and cost-effectiveness ratios. Calculation of patient/resident characteristic adjusted rates, costs, and ratios., Results: Federal states vary significantly with respect to the outcomes (also adjusted) of palliative care. Palliative care costs vary widely, most strongly for specialized outpatient palliative care (SAPV). Across all indicators and the cost-effectiveness ratio of total cost of care to at-home deaths, Westphalia-Lippe shows favorable results., Conclusion: Regions with better quality and more favorable cost (ratios) can provide guidance for other regions. The extent to which the new federal SAPV agreement can incorporate the empirical findings should be reviewed. Patient-relevant outcome parameters should be given greater weight than parameters aiming at structures of care., (© 2023. The Author(s).)