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On September 1, 2022, CDC recommended an updated (bivalent) COVID-19 vaccine booster to help restore waning protection conferred by previous vaccination and broaden protection against emerging variants for persons aged ≥12 years (subsequently extended to persons aged ≥6 months).* To assess the impact of original (monovalent) COVID-19 vaccines and bivalent boosters, case and mortality rate ratios (RRs) were estimated comparing unvaccinated and vaccinated persons aged ≥12 years by overall receipt of and by time since booster vaccination (monovalent or bivalent) during Delta variant and Omicron sublineage (BA.1, BA.2, early BA.4/BA.5, and late BA.4/BA.5) predominance. During the late BA.4/BA.5 period, unvaccinated persons had higher COVID-19 mortality and infection rates than persons receiving bivalent doses (mortality RR = 14.1 and infection RR = 2.8) and to a lesser extent persons vaccinated with only monovalent doses (mortality RR = 5.4 and infection RR = 2.5). Among older adults, mortality rates among unvaccinated persons were significantly higher than among those who had received a bivalent booster (65-79 years; RR = 23.7 and ≥80 years; 10.3) or a monovalent booster (65-79 years; 8.3 and ≥80 years; 4.2). In a second analysis stratified by time since booster vaccination, there was a progressive decline from the Delta period (RR = 50.7) to the early BA.4/BA.5 period (7.4) in relative COVID-19 mortality rates among unvaccinated persons compared with persons receiving who had received a monovalent booster within 2 weeks-2 months. During the early BA.4/BA.5 period, declines in relative mortality rates were observed at 6-8 (RR = 4.6), 9-11 (4.5), and ≥12 (2.5) months after receiving a monovalent booster. In contrast, bivalent boosters received during the preceding 2 weeks-2 months improved protection against death (RR = 15.2) during the late BA.4/BA.5 period. In both analyses, when compared with unvaccinated persons, persons who had received bivalent boosters were provided additional protection against death over monovalent doses or monovalent boosters. Restored protection was highest in older adults. All persons should stay up to date with COVID-19 vaccination, including receipt of a bivalent booster by eligible persons, to reduce the risk for severe COVID-19.

Most antidiabetic drugs treat disease symptoms rather than adipose tissue dysfunction as a key pathogenic cause in the metabolic syndrome and type 2 diabetes. Pharmacological targeting of adipose tissue through the nuclear receptor PPARg, as exemplified by glitazone treatments, mediates efficacious insulin sensitization. However, a better understanding of the context‐specific PPARg responses is required for the development of novel approaches with reduced side effects. Here, we identified the transcriptional cofactor Cited4 as a target and mediator of rosiglitazone in human and murine adipocyte progenitor cells, where it promoted specific sets of the rosiglitazone‐dependent transcriptional program. In mice, Cited4 was required for the proper induction of thermogenic expression by Rosi specifically in subcutaneous fat. This phenotype had high penetrance in females only and was not evident in beta‐adrenergically stimulated browning. Intriguingly, this specific defect was associated with reduced capacity for systemic thermogenesis and compromised insulin sensitization upon therapeutic rosiglitazone treatment in female but not male mice. Our findings on Cited4 function reveal novel unexpected aspects of the pharmacological targeting of PPARg. Synopsis The identification of the Cited4 cofactor as a sex‐, tissue‐ and signal‐specific mediator of transcriptional responses to glitazones in adipocyte progenitors reveals unexpected aspects of therapeutic PPARg targeting for insulin sensitization in type 2 diabetes and prediabetes. Cited4 is a glitazone target in human and murine adipocyte progenitors promoting the induction of beige adipocyte differentiation. Cited4 is required for rosiglitazone‐mediated but not beta‐adrenergic induction of thermogenic expression in subcutaneous fat in a sex‐biased manner. Systemic energy expenditure and maximal beta‐adrenergic adipocyte respiration are reduced in Cited4‐deficient female mice under rosiglitazone treatment. Reduced thermogenic expression in subcutaneous fat is associated with compromised insulin sensitization upon therapeutic rosiglitazone treatment specifically in female mice. Graphical Abstract The identification of the Cited4 cofactor as a sex‐, tissue‐ and signal‐specific mediator of transcriptional responses to glitazones in adipocyte progenitors reveals unexpected aspects of therapeutic PPARg targeting for insulin sensitization in type 2 diabetes and prediabetes.

In this article, we present findings from a three-year comparative longitudinal and ethnographic study of how schools in two cities, Buffalo and Denver, have taken up STEM education reform, including the idea of \"inclusive STEM-focused schools,\" to address weaknesses in urban high schools with majority low-income and minority students. Although introduced with great fanfare, the data indicate that well-meaning efforts toward expanding opportunities in STEM-focused schools for low-income underrepresented minorities quickly dissolved. We focus on mechanisms that seem to underlie this dissolution and consider its contributions to short- and long-term inequalities.

In light of the accumulating evidence, awareness and urgency to act upon the three planetary crises - climate change, biodiversity loss, and pollution - the concept of Planetary Health underscores their profound implications for health and promotes actionable solutions to advance both wellbeing and ecological sustainability. Despite (inter)national calls to integrate Planetary Health into health workers' curricula, the current status of Planetary Health Education in undergraduate medical education in Germany is unclear. This study therefore aimed (a) to assess the current implementation of Planetary Health in undergraduate medical education in Germany and (b) to explore its characteristics as a foundation to develop evidence-informed recommendations for mainstreaming Planetary Health Education in medical schools in Germany. The study comprised structured interviews followed by an online survey, both targeting all 39 medical schools in Germany. In 2021, structured interviews were conducted with students, educators and deanery staff at medical schools. In 2023, educators and deanery staff participated in an online survey based on the findings from the interviews. In total, 80% of the 39 medical schools participated in the interviews, while 90% took part in the online survey. Based on integrated findings, 35 medical schools (90%) offered Planetary Health Education, with a median of two educational activities, including both stand-alone courses and lectures integrated into other courses. Despite an overall increase since winter semester 2021/2022, most educational activities were electives and not part of the mandatory curriculum. Innovative educational approaches and learning objectives differed significantly between mandatory and elective formats. In contrast to mandatory educational activities, student involvement was reported for the majority of electives and was significantly associated with transformative learning objectives. Despite a steady rise in teaching activities, mandatory Planetary Health Education remains insufficiently integrated into undergraduate medical education in Germany. Key criteria defining high-quality Planetary Health Education, such as innovative educational approaches, practical skills, and transformative learning, were primarily reflected in electives, that reach only a minority of students. To adequately equip the future healthcare workforce, the current barriers to successfully integrating Planetary Health into medical education must be systematically addressed and overcome.

Cachexia is a major cause of morbidity and mortality in individuals with cancer and is characterized by weight loss due to adipose and muscle tissue wasting. Hallmarks of white adipose tissue (WAT) remodeling, which often precedes weight loss, are impaired lipid storage, inflammation and eventually fibrosis. Tissue wasting occurs in response to tumor-secreted factors. Considering that the continuous endothelium in WAT is the first line of contact with circulating factors, we postulated whether the endothelium itself may orchestrate tissue remodeling. Here, we show using human and mouse cancer models that during precachexia, tumors overactivate Notch1 signaling in distant WAT endothelium. Sustained endothelial Notch1 signaling induces a WAT wasting phenotype in male mice through excessive retinoic acid production. Pharmacological blockade of retinoic acid signaling was sufficient to inhibit WAT wasting in a mouse cancer cachexia model. This demonstrates that cancer manipulates the endothelium at distant sites to mediate WAT wasting by altering angiocrine signals.

BackgroundLaparoscopic suturing and knot tying is essential for advanced laparoscopic procedures and requires training outside of the operating room. However, personal instruction by experienced surgeons is limitedly available. To address this, the concept of combining e-learning with practical training has become of interest. This study aims to investigate the influence of the first-person perspective in instructional videos, as well as the feasibility of a completely self-directed training curriculum for laparoscopic suturing and knot tying.Materials and methodsNinety-one laparoscopically naïve medical students were randomised into two groups training with e-learning videos in either the first-person perspective (combining endoscopic view and view of hands/instruments/forearm motion) or the endoscopic view only. Both groups trained laparoscopic suturing and knot tying in teams of two until reaching predefined proficiency levels. Blinded, trained raters regularly assessed the participants’ performance by using validated checklists. After training, participants filled out questionnaires regarding training experience and personal characteristics.ResultsAverage training time to reach proficiency did not differ between groups [first-person perspective (min): 112 ± 44; endoscopic view only (min): 109 ± 47; p = 0.746]. However, participants from both groups perceived the first-person perspective as useful for learning new laparoscopic skills. Both groups showed similar baseline performances and improved significantly after training [Objective Structured Assessment of Technical Skills (OSATS) (max. 37 points): first-person perspective: 30.3 ± 2.3; endoscopic view only: 30.8 ± 2.3]. All participants managed to reach proficiency, needing 8–43 attempts without differences between groups. Visuospatial abilities (mental rotation) seemed to enhance the learning curve.ConclusionModifying instructional videos to the first-person perspective did not translate into a better performance in this setting but was welcomed by participants. Completely self-directed training with the use of e-learning can be a feasible training approach to achieve technical proficiency in laparoscopic suturing and knot tying in a training setting.

MicroRNAs (miRs) appear to be major, yet poorly understood players in regulatory networks guiding cardiogenesis. We sought to identify miRs with unknown functions during cardiogenesis analyzing the miR-profile of multipotent Nkx2.5 enhancer cardiac progenitor cells (NkxCE-CPCs). Besides well-known candidates such as miR-1, we found about 40 miRs that were highly enriched in NkxCE-CPCs, four of which were chosen for further analysis. Knockdown in zebrafish revealed that only miR-128a affected cardiac development and function robustly. For a detailed analysis, loss-of-function and gain-of-function experiments were performed during in vitro differentiations of transgenic murine pluripotent stem cells. MiR-128a knockdown (1) increased Isl1, Sfrp5, and Hcn4 (cardiac transcription factors) but reduced Irx4 at the onset of cardiogenesis, (2) upregulated Isl1-positive CPCs, whereas NkxCE-positive CPCs were downregulated, and (3) increased the expression of the ventricular cardiomyocyte marker Myl2 accompanied by a reduced beating frequency of early cardiomyocytes. Overexpression of miR-128a (4) diminished the expression of Isl1, Sfrp5, Nkx2.5, and Mef2c, but increased Irx4, (5) enhanced NkxCE-positive CPCs, and (6) favored nodal-like cardiomyocytes (Tnnt2+, Myh6+, Shox2+) accompanied by increased beating frequencies. In summary, we demonstrated that miR-128a plays a so-far unknown role in early heart development by affecting the timing of CPC differentiation into various cardiomyocyte subtypes.

Clostridium thermocellum is one of the most efficient microorganisms for the deconstruction of cellulosic biomass. To achieve this high level of cellulolytic activity, C. thermocellum uses large multienzyme complexes known as cellulosomes to break down complex polysaccharides, notably cellulose, found in plant cell walls. The attachment of bacterial cells to the nearby substrate via the cellulosome has been hypothesized to be the reason for this high efficiency. The region lying between the cell and the substrate has shown great variation and dynamics that are affected by the growth stage of cells and the biomass used for growth. Here, we utilized both photoactivation localization microscopy (PALM) and stochastic optical reconstruction microscopy (STORM) in combination with Density-Based Spatial Clustering of Applications with Noise (DBSCAN) to study the distribution of C. thermocellum cellulosomes at different stages of growth when actively growing on soluble and insoluble substrates, providing a clearer picture of the dynamics of cellulosome populations at the enzyme microbe substrate interface. This research demonstrates the promising application of novel optical methodologies in tandem with targeted mutations within C. thermocellum to test the prevailing theories regarding the mechanisms of cellulosomes and their potential to shuttle onto the biomass for the attachment of C. thermocellum to improve biomass deconstruction.