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PURPOSE: There is considerable variation in incremental circulating 25-hydroxyvitamin D (25OHD) levels on vitamin D supplements, even when similar age groups and identical vitamin D doses are compared. We therefore aimed to investigate the importance of body weight for the dose–response relation in circulating 25OHD. METHODS: We performed a systematic review of randomized placebo-controlled vitamin D supplementation trials in all age groups ≥10 years to clarify the influence of body weight and other parameters on incremental circulating 25OHD levels (difference between baseline and in-study values) in vitamin D-deficient and non-deficient individuals. RESULTS: We included 144 cohorts from 94 independent studies, published from 1990 to November 2012, in our systematic review. There was a logarithmic association between vitamin D dose per kg body weight per day and increment in circulating 25OHD. In multivariable regression analysis, vitamin D dose per kg body weight per day could explain 34.5 % of variation in circulating 25OHD. Additional significant predictors were type of supplement (vitamin D₂ or vitamin D₃), age, concomitant intake of calcium supplements and baseline 25OHD, explaining 9.8, 3.7, 2.4 and 1.9 %, respectively, of the variation in circulating 25OHD. CONCLUSIONS: This systematic review demonstrates that body weight is an important predictor of variation in circulating 25OHD in cohorts on vitamin D supplements. Our model provides an estimate of the daily vitamin D dose that is necessary for achieving adequate circulating 25OHD levels in vitamin D-insufficient or vitamin D-deficient individuals/cohorts with different body weights and ages.

The traditional description of cardiac development involves progression from a cardiac crescent to a linear heart tube, which in the phase of transformation into a mature heart forms a cardiac loop and is divided with the septa into individual cavities. Cardiac morphogenesis involves numerous types of cells originating outside the initial cardiac crescent, including neural crest cells, cells of the second heart field origin, and epicardial progenitor cells. The development of the fetal heart and circulatory system is subject to regulatation by both genetic and environmental processes. The etiology for cases with congenital heart defects (CHDs) is largely unknown, but several genetic anomalies, some maternal illnesses, and prenatal exposures to specific therapeutic and non-therapeutic drugs are generally accepted as risk factors. New techniques for studying heart development have revealed many aspects of cardiac morphogenesis that are important in the development of CHDs, in particular transposition of the great arteries.

A high number of SARS-CoV-2 infections are mild, often even asymptomatic. Because of high specificity and sensitivity, RT-PCR is considered the gold-standard for COVID-19 testing. The technology played a key role in detecting sources of infection at an early stage and therefore preventing larger outbreaks. This was especially important in case of critical infrastructure, such as hospitals. Until now, comprehensive studies concerning the impact of high-frequency PCR-testing in German tertiary care hospitals during the COVID-19 pandemic are lacking. We therefore analyzed about 285.000 oral swab probes of 3.421 healthcare-workers concerning SARS-CoV-2 RNA positivity between November 2020 and February 2023. Our data show that frequent PCR-testing is a useful tool concerning SARS-CoV-2 surveillance. Due to the longitudinal character of the study, we were able to observe SARS-CoV-2 variant-specific differences. For example, the omicron-variant led to high reinfection-rates as well as lower Ct-values. Nevertheless, reinfection rates in our hospital are much lower compared to other analyzed healthcare-worker cohorts described in the literature, which is again attributable to the frequent testing-regime implemented in the early phase of the pandemic. Our data further reveal a longer infection-duration in elderly compared to younger individuals.

Background Propensity score matching has become a popular method for estimating causal treatment effects in non-randomized studies. However, for time-to-event outcomes, the estimation of hazard ratios based on propensity scores can be challenging if omitted or unobserved covariates are present. Not accounting for such covariates could lead to treatment estimates, differing from the estimate of interest. However, researchers often do not know whether (and, if so, which) covariates will cause this divergence. Methods To address this issue, we extended a previously described method, Dynamic Landmarking , which was originally developed for randomized trials. The method is based on successively deletion of sorted observations and gradually fitting univariable Cox models. In addition, the balance of observed, but omitted covariates can be measured by the sum of squared z-differences. Results By simulation we show, that Dynamic Landmarking provides a good visual tool for detecting and distinguishing treatment effect estimates underlying built-in selection or confounding bias. We illustrate the approach with a data set from cardiac surgery and provide some recommendations on how to use and interpret Dynamic Landmarking in propensity score matched studies. Conclusion Dynamic Landmarking is a useful post-hoc diagnosis tool for visualizing whether an estimated hazard ratio could be distorted by confounding or built-in selection bias.

PurposeThe aim of the study was to analyze early mortality after continuous-flow left ventricular assist device (LVAD) implantation which remains high.MethodsWe analyzed consecutive (n = 2689) patients from the European Registry for Patients with Mechanical Circulatory Support (EUROMACS) undergoing continuous-flow LVAD implantation. The primary outcome was early (< 90 days) mortality. Secondary outcomes were differential causes of early post-operative death following LVAD implantation.ResultsUnivariable and multivariable analysis as well as regression analysis were used to examine determinants and differential causes of early (< 90 days) mortality after LVAD implantation. During the first 90 days, 2160 (80%) patients were alive with ongoing LVAD support, 40(2%) patients underwent heart transplantation, and 487(18%) deceased. The main causes of early death were MOF (36%), sepsis (28%), cardiopulmonary failure (CPF; 10%), CVA (9%), and right-sided heart failure (RHF, 8%). Furthermore, MOF and sepsis are 70% of causes of death in the first week. Independent clinical predictors of early death were age, female sex, INTERMACS profile 1 to 3, and ECMO. Laboratory predictors included elevated serum creatinine, total bilirubin, lactate, and low hemoglobin. Furthermore, hemodynamic predictors included elevated RA-to-PCWP ratio, pulmonary vascular resistance, and low systemic vascular resistance. Longer total implantation time was also independent predictor of early mortality. A simple model of 12 variables predicts early mortality following LVAD implantation with a good discriminative power with area under the curve of 0.75.ConclusionsIn the EUROMACS registry, approximately one out of five patients die within 90 days after LVAD implantation. Early mortality is primarily dominated by multiorgan failure followed by sepsis. A simple model identifies important parameters which are associated with early mortality following LVAD implantation.

Many patients with end-stage heart disease die because of the scarcity of donor hearts. A total artificial heart (TAH), an implantable machine that replaces the heart, has so far been successfully used in over 1,700 patients as a temporary life-saving technology for bridging to heart transplantation. However, after more than six decades of research on TAHs, a TAH that is suitable for destination therapy is not yet available. High complication rates, bulky devices, poor durability, poor biocompatibility and low patient quality of life are some of the major drawbacks of current TAH devices that must be addressed before TAHs can be used as a destination therapy. Quickly emerging innovations in battery technology, wireless energy transmission, biocompatible materials and soft robotics are providing a promising opportunity for TAH development and might help to solve the drawbacks of current TAHs. In this Review, we describe the milestones in the history of TAH research and reflect on lessons learned during TAH development. We summarize the differences in the working mechanisms of these devices, discuss the next generation of TAHs and highlight emerging technologies that will promote TAH development in the coming decade. Finally, we present current challenges and future perspectives for the field.In this Review, Kluin and colleagues describe the historical milestones and lessons learned in the development of total artificial hearts (TAHs), discuss the current generation of TAHs and their working mechanisms, and highlight challenges and future perspectives for the field, including new technologies that will promote TAH development in the coming decade.

Heart transplantation is the gold-standard in the treatment of terminal heart failure. The shortage of donor hearts represents the major obstacle in patient care and necessitates the creation of waiting lists and allocation algorithms. The Transplantation Act regulates donor heart allocation according to the urgency and the prospects of success. Donor hearts can be implanted following the classical biatrial or the modern bicaval valve implantation technique with a slightly lower spectrum of complications. Modern mechanical perfusion systems enable extended transport times. After heart transplantation rejection reactions must be controlled by an individually adjusted immunosuppression to guarantee long-term survival with as few complications as possible.

Vitamin D has immunomodulatory properties and seems to reduce the risk of infections. Whether low vitamin D concentrations are independent risk factors for nosocomial postoperative infections in surgical patients remains to be studied in detail. In 3,340 consecutive cardiac surgical patients, we investigated the association of circulating 25-hydroxyvitamin D (25OHD; indicator of nutritional vitamin D status) and 1,25-dihydroxyvitamin D (1,25[OH]2D; active vitamin D hormone) with nosocomicial infections. The primary endpoint was a composite of thoracic wound infection, sepsis, and broncho-pulmonary infection. Vitamin D status was measured on the last preoperative day. Infections were assessed until discharge. Logistic regression analysis was used to examine the association between vitamin D metabolite concentrations and the composite endpoint. The primary endpoint was reached by 5.6% (n = 186). In patients who reached and did not reach the endpoint, in-hospital mortality was 13.4% and 1.5%, respectively (P<0.001). Median (IQR) 25OHD and 1,25(OH)2D concentrations were 43. 2 (29.7-61.9) nmol/l and 58.0 (38.5-77.5) pmol/l, respectively. Compared with the highest 1,25(OH)2D quintile (>81.0 pmol/l), the multivariable-adjusted odds ratio of infection was 2.57 (95%CI:1.47-4.49) for the lowest 1,25(OH)2D quintile (<31.5 pmol/l) and 1.85 (95%CI:1.05-3.25) for the second lowest quintile (31.5-49.0 pmol/l). There was no significant association between 25OHD concentrations and the primary endpoint. Our data indicate an independent association of low 1,25(OH)2D levels with the risk of postoperative infections in cardiac surgical patients. Future studies should pay more attention on the clinical relevance of circulating 1,25(OH)2D and its regulation.

Desmin is the major intermediate filament protein of all three muscle cell types, and connects different cell organelles and multi-protein complexes such as the cardiac desmosomes. Several pathogenic mutations in the DES gene cause different skeletal and cardiac myopathies. However, the significance of the majority of DES missense variants is currently unknown, since functional data are lacking. To determine whether desmin missense mutations within the highly conserved 1A coil domain cause a filament assembly defect, we generated a set of variants with unknown significance and systematically analyzed the filament assembly using confocal microscopy in transfected SW-13, H9c2 cells and cardiomyocytes derived from induced pluripotent stem cells. We found that mutations in the N-terminal part of the 1A coil domain affect filament assembly, leading to cytoplasmic desmin aggregation. In contrast, mutant desmin in the C-terminal part of the 1A coil domain forms filamentous structures comparable to wild-type desmin. Our findings suggest that the N-terminal part of the 1A coil domain is a hot spot for pathogenic desmin mutations, which affect desmin filament assembly. This study may have relevance for the genetic counselling of patients carrying variants in the 1A coil domain of the DES gene.

Preoperative anemia is considered an independent risk factor of poor clinical outcome in cardiac surgical patients. Low vitamin D status may increase anemia risk. We investigated 3,615 consecutive patients scheduled for cardiac surgery to determine the association between preoperative anemia (hemoglobin [Hb] <12.5 g/dL) and circulating levels of the vitamin D metabolites 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25[OH]2D). Of the study cohort, 27.8 % met the criteria for anemia. In patients with deficient 25OHD levels (<30 nmol/l) mean Hb concentrations were 0.5 g/dL lower than in patients with adequate 25OHD levels (50.0-125 nmol/l; P<0.001). Regarding 1,25(OH)2D, mean Hb concentrations were 1.2 g/dL lower in the lowest 1,25(OH)2D category (<40 pmol/l) than in the highest 1,25(OH)2D category (>70 pmol/l; P<0.001). In multivariable-adjusted logistic regression analyses, the odds ratios for anemia of the lowest categories of 25OHD and 1,25(OH)2D were 1.48 (95%CI:1.19-1.83) and 2.35 (95%CI:1.86-2.97), compared with patients who had adequate 25OHD levels and 1,25(OH)2D values in the highest category, respectively. Anemia risk was greatest in patients with dual deficiency of 25OHD and 1,25(OH)2D (multivariable-adjusted OR = 3.60 (95%CI:2.40-5.40). Prevalence of deficient 25OHD levels was highest in anemia of nutrient deficiency, whereas low 1,25(OH)2D levels were most frequent in anemia of chronic kidney disease. This cross-sectional study demonstrates an independent inverse association between vitamin D status and anemia risk. If confirmed in clinical trials, preoperative administration of vitamin D or activated vitamin D (in case of chronic kidney disease) would be a promising strategy to prevent anemia in patients scheduled for cardiac surgery.