Trends in antidiabetes medication use among hospitalised patients with type 2 diabetes: a retrospective single-centre cohort study.

OBJECTIVES: Novel antidiabetes medications with proven cardiovascular or renal benefit, such as sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA), have been introduced to the market. This study explored the 4-year trends of antidiabetes medication use among medical hospitalisations with type 2 diabetes (T2D). DESIGN: Retrospective cohort study. SETTING: Tertiary care hospital in Switzerland. PARTICIPANTS: 4695 adult hospitalisations with T2D and prevalent or incident use of one of the following antidiabetes medications (metformin, dipeptidyl peptidase-4 inhibitors (DPP-4i), sulfonylureas, GLP-1 RA, SGLT-2i, short-acting insulin or long-acting insulin), identified using electronic health record data. Quarterly trends in use of antidiabetes medications were plotted overall and stratified by cardiovascular disease (CVD) and chronic kidney disease (CKD). RESULTS: We observed a stable trend in the proportion of hospitalisations with T2D who received any antidiabetes medication (from 77.6% during 2019 to 78% in 2022; p for trend=0.97). In prevalent users, the largest increase in use was found for SGLT-2i (from 7.4% in 2019 to 21.8% in 2022; p for trend <0.01), the strongest decrease was observed for sulfonylureas (from 11.4% in 2019 to 7.2% in 2022; p for trend <0.01). Among incident users, SGLT-2i were the most frequently newly prescribed antidiabetes medication with an increase from 26% in 2019 to 56.1% in 2022 (p for trend <0.01). Between hospital admission and discharge, SGLT-2i also accounted for the largest increase in prescriptions (+5.1%; p<0.01). CONCLUSIONS: These real-world data from 2019 to 2022 demonstrate a significant shift in antidiabetes medications within the in-hospital setting, with decreased use of sulfonylureas and increased prescriptions of SGLT-2i, especially in hospitalisations with CVD or CKD. This trend aligns with international guidelines and indicates swift adaptation by healthcare providers, signalling a move towards more effective diabetes management.

CrossFit®: 'Unknowable' or Predictable?-A Systematic Review on Predictors of CrossFit® Performance.

The functional fitness training program CrossFit® is experiencing fast-growing and widespread popularity with day-to-day varying 'Workouts of the Day' (WOD). Even among tactical athletes, the training program is widely applied. Nevertheless, there is a lack of data on which parameters influence CrossFit® performance. For this reason, the purpose of this study is to conduct a systematic review of the existing literature to identify and summarize predictors of CrossFit® performance and performance enhancement. In accordance with the PRISMA guidelines, a systematic search of the following databases was conducted in April 2022: PubMed, SPORTDiscus, Scopus, and Web of Science. Using the keyword 'CrossFit', 1264 entries are found, and 21 articles are included based on the eligibility criteria. In summary, the studies show conflicting results, and no specific key parameter was found that predicts CrossFit® performance regardless of the type of WOD. In detail, the findings indicate that physiological parameters (in particular, body composition) and high-level competitive experience have a more consistent influence than specific performance variables. Nevertheless, in one-third of the studies, high total body strength (i.e., CrossFit® Total performance) and trunk strength (i.e., back squat performance) correlate with higher workout scores. For the first time, this review presents a summary of performance determinants in CrossFit®. From this, a guiding principle for training strategies may be derived, suggesting that a focus on body composition, body strength, and competition experience may be recommended for CrossFit® performance prediction and performance enhancement.

Physiological effects of regular CrossFit® training and the impact of the COVID-19 pandemic-A systematic review.

CrossFit® is a functional fitness training program known for its day-to-day varying "Workouts of the Day" (WOD). In accordance with the 'CrossFit® Level 1 Training Guide', regular CrossFit® training sessions consist of Warm-up, Mobility, Skill/Power training, WOD, and Cool-down. Despite the fast-growing and widespread popularity, data on the practical implementation of the training program based on scientific evidence are rare. Therefore, the purpose of this study is to systematically review the existing literature on the physiological effects of regular CrossFit® training in full extent instead of stand-alone WODs and to examine the impact of the COVID-19 pandemic on the training behavior of CrossFit® athletes. A systematic search was conducted following the PRISMA guidelines in April 2022 and updated in July 2022 using the following databases: PubMed, SPORTDiscus, Scopus, and Web of Science. Using the keyword "CrossFit", 1,264 records were found. Based on the eligibility criteria, 12 studies are included and separated by topics: acute-short term physiological response (n = 8), and impact of the COVID-19 pandemic (n = 4). The results show that studies of regular training sessions were rarely conducted and contradicted the existing knowledge of the physiological demands [e.g., heart rate (HR)] of CrossFit®. In detail, included studies demonstrate that training sessions last 30-60 min and provide a progressive increase in cardiovascular load up to maximal effort activity (>90% HRmax), differing from stand-alone WODs exclusively at high-intensity. Also, scarce research exists on COVID-19-pandemic-induced effects on training behavior, and studies are of moderate to low quality. There is still a lack of comprehensive analyses on the acute physiological effects of regular training sessions and the consequences of the COVID-19 pandemic in the scientific literature. Moreover, the inconsistent terminology used in CrossFit® research complicates generalized conclusions. Therefore, future research on the training methodology of CrossFit® needs to overcome terminological inequalities and examine scientifically the implementation of the concept by considering regular training sessions under practical settings.

Purchasing behavior and use of digital sports offers by CrossFit® and weightlifting athletes during the first SARS-CoV-2 lockdown in Germany.

BACKGROUND: To combat the spread of SARS-CoV-2, CrossFit® training centers, and fitness studios were closed during the first lockdown in Germany from mid-March until June 2020, and as a result, CrossFit® (CFA) or weightlifting athletes (WLA) faced a major challenge for the first time. Therefore, this study aimed to investigate the impact of the first lockdown on the training behavior and to analyze the way the athletes dealt with the new situation. In detail, we focus on habits of purchase and examine the acceptance of digital sports offers between CFA and WLA in response to the restrictions of the nationwide lockdown. METHODS: An online survey was used to characterize the purchasing behavior and use of digital sports offers of CFA and WLA. In total, 484 volunteers (192 women, 290 men, 2 diverse) responded to the online questionary, allowing us to identify changes in training behavior and differences between the sports disciplines. RESULTS: Our data shows both CFA and WLA purchase new equipment for a home gym and the use of digital sports increased significantly across all age groups. A comparison during the lockdown even showed that within the CFA, one group (n = 142) reported losing 5 kg or more of body mass, while the value of the WLA remained constant. On the one hand, the results indicate that despite the restrictions during the lockdown, CFA were may able to enhance health aspects by improving their body composition. On the other hand, this study shows that the training habits of both groups of athletes have changed significantly with the use of digital sports offers. CONCLUSIONS: We suppose that the great openness and the expansion of online sports offers during the first lockdown may change the sports industry in the future.

Determination of a CrossFit® Benchmark Performance Profile.

In the trend sport CrossFit®, international competition is held at the CrossFit® Games, known worldwide as the definitive fitness test. Since American athletes are the best in the world regarding CrossFit®, there might be influencing factors on international competition performance. Here, we characterize the benchmark performance profile of American and German CrossFit® athletes (n = 162). To collect the common benchmark performance by questionnaire, 66 male and 96 female CrossFit® athletes (32.6 ± 8.2 years) participated in our survey in both nations. By comparing the individual performance variables, only a significant difference in total power lift performance by males was identified between the nations (p = 0.034). No other significant differences were found in the Olympic lift, running, or the "Girl" Workout of the Day (Fran, Grace, Helen) performance. Very large to extremely large (r = 0.79-0.99, p < 0.01) positive correlations were found between the power lift and Olympic lift variables. Further linear regression analysis predicted the influence of back squat performance on performance in the Olympic lifts, snatch (R2 = 0.76) and clean and jerk (R2 = 0.84). Our results suggested a dominant role of back squat performance in the assessment of physical fitness of CrossFit® athletes.

Chronic senescent human mesenchymal stem cells as possible contributor to the wound healing disorder after exposure to the alkylating agent sulfur mustard.

Wound healing is a complex process, and disturbance of even a single mechanism can result in chronic ulcers developing after exposure to the alkylating agent sulfur mustard (SM). A possible contributor may be SM-induced chronic senescent mesenchymal stem cells (MSCs), unable to fulfil their regenerative role, by persisting over long time periods and creating a proinflammatory microenvironment. Here we show that senescence induction in human bone marrow derived MSCs was time- and concentration-dependent, and chronic senescence could be verified 3 weeks after exposure to between 10 and 40 µM SM. Morphological changes, reduced clonogenic and migration potential, longer scratch closure times, differences in senescence, motility and DNA damage response associated genes as well as increased levels of proinflammatory cytokines were revealed. Selective removal of these cells by senolytic drugs, in which ABT-263 showed initial potential in vitro, opens the possibility for an innovative treatment strategy for chronic wounds, but also tumors and age-related diseases.

Expanding the spectrum of SMAD3-related phenotypes to agnathia-otocephaly.

BACKGROUND: Agnathia-otocephaly is a rare and lethal anomaly affecting craniofacial structures derived from the first pharyngeal arch. It is characterized by agnathia, microstomia, aglossia, and abnormally positioned auricles with or without associated anomalies. Variants affecting function of OTX2 and PRRX1, which together regulate the neural crest cells and the patterning of the first pharyngeal arch as well as skeletal and limb development, were identified to be causal for the anomaly in a few patients. METHODS: Family-based exome sequencing (ES) on a fetus with severe agnathia-otocephaly, cheilognathopalatoschisis, laryngeal hypoplasia, fused lung lobes and other organ abnormalities and mRNA expression analysis were performed. RESULTS: Exome sequencing detected a de novo SMAD3 missense variant in exon 6 (c.860G>A) associated with decreased mRNA expression. Variants in SMAD3 cause Loeys-Dietz syndrome 3 presenting with craniofacial anomalies such as mandibular hypoplasia, micro- or retro-gnathia, bifid uvula and cleft palate as well as skeletal anomalies and arterial tortuosity. The SMAD3 protein acts as a transcriptional regulator in the transforming growth factor ß (TGFB) and bone morphogenetic (BMP) signaling pathways, which play a key role in the development of craniofacial structures originating from the pharyngeal arches. CONCLUSION: Agnathia-otocephaly with or without associated anomalies may represent the severe end of a phenotypic spectrum related to variants in genes in the interacting SMAD/TGFB/BMP/SHH/FGF developmental pathways.

Reasons for Prehospital Delay in Acute Ischemic Stroke.

Background Prehospital delay reduces the proportion of patients with stroke treated with recanalization therapies. We aimed to identify novel and modifiable risk factors for prehospital delay. Methods and Results We included patients with an ischemic stroke confirmed by diffusion-weighted magnetic resonance imaging, symptom onset within 24 hours and hospitalized in the Stroke Center of the University Hospital Basel, Switzerland. Trained study nurses interviewed patients and proxies along a standardized questionnaire. Prehospital delay was defined as >4.5 hours between stroke onset-or time point of wake-up-and admission. Overall, 336 patients were enrolled. Prehospital delay was observed in 140 patients (42%). The first healthcare professionals to be alarmed were family doctors for 29% of patients (97/336), and a quarter of these patients had a baseline National Institute of Health Stroke Scale score of 4 or higher. The main modifiable risk factor for prehospital delay was a face-to-face visit to the family doctor (adjusted odds ratio, 4.19; 95% CI, 1.85-9.46). Despite transport by emergency medical services being associated with less prehospital delay (adjusted odds ratio, 0.41; 95% CI, 0.24-0.71), a minority of patients (39%) who first called their family doctor were transported by emergency medical services to the hospital. The second risk factor was lack of awareness of stroke symptoms (adjusted odds ratio, 4.14; 95% CI, 2.36-7.24). Conclusions Almost 1 in 3 patients with a diffusion-weighted magnetic resonance imaging-confirmed ischemic stroke first called the family doctor practice. Face-to-face visits to the family doctor quadrupled the odds of prehospital delay. Efforts to reduce prehospital delay should address family doctors and their staffs as important partners in the prehospital pathway. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02798770.

Exome sequencing of fetal anomaly syndromes: novel phenotype-genotype discoveries.

The monogenic etiology of most severe fetal anomaly syndromes is poorly understood. Our objective was to use exome sequencing (ES) to increase our knowledge on causal variants and novel candidate genes associated with specific fetal phenotypes. We employed ES in a cohort of 19 families with one or more fetuses presenting with a distinctive anomaly pattern and/or phenotype recurrence at increased risk for lethal outcomes. Candidate variants were identified in 12 families (63%); in 6 of them a definite diagnosis was achieved including known or novel variants in recognized disease genes (MKS1, OTX2, FGFR2, and RYR1) and variants in novel disease genes describing new fetal phenotypes (CENPF, KIF14). We identified variants likely causal after clinical and functional review (SMAD3, KIF4A, and PIGW) and propose novel candidate genes (PTK7, DNHD1, and TTC28) for early human developmental disease supported by functional and cross-species phenotyping evidence. We describe rare and novel fetal anomaly syndromes and highlight the diagnostic utility of ES, but also its contribution to discovery. The diagnostic yield of the future application of prenatal ES will depend on our ability to increase our knowledge on the specific phenotype-genotype correlations during fetal development.

Development of a cyclosporin A derivative with excellent anti-hepatitis C virus potency.

Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand. Identification of advanced crystalline intermediates enabled practical supply of key intermediates. Finally, macrocyclization was carried out at 10% weight concentration by a general and unconventional "slow release" concept.

Genetic control of courtship behavior in the housefly: evidence for a conserved bifurcation of the sex-determining pathway.

In Drosophila melanogaster, genes of the sex-determination hierarchy orchestrate the development and differentiation of sex-specific tissues, establishing sex-specific physiology and neural circuitry. One of these sex-determination genes, fruitless (fru), plays a key role in the formation of neural circuits underlying Drosophila male courtship behavior. Conservation of fru gene structure and sex-specific expression has been found in several insect orders, though it is still to be determined whether a male courtship role for the gene is employed in these species due to the lack of mutants and homologous experimental evidence. We have isolated the fru ortholog (Md-fru) from the common housefly, Musca domestica, and show the gene's conserved genomic structure. We demonstrate that male-specific Md-fru transcripts arise by conserved mechanisms of sex-specific splicing. Here we show that Md-fru, is similarly involved in controlling male courtship behavior. A male courtship behavioral function for Md-fru was revealed by the behavioral and neuroanatomical analyses of a hypomorphic allele, Md-tra(man) , which specifically disrupted the expression of Md-fru in males, leading to severely impaired male courtship behavior. In line with a role in nervous system development, we found that expression of Md-fru was confined to neural tissues in the brain, most prominently in optic neuropil and in peripheral sensory organs. We propose that, like in Drosophila, overt sexual differentiation of the housefly depends on a sex-determining pathway that bifurcates downstream of the Md-tra gene to coordinate dimorphic development of non-neuronal tissues mediated by Md-dsx with that of neuronal tissues largely mediated by Md-fru.

Molecular characterization of the key switch F provides a basis for understanding the rapid divergence of the sex-determining pathway in the housefly.

The housefly, Musca domestica, is an excellent model system to study the diversification of the pathway that specifies the sexual fate. A number of different mechanisms have been described in the housefly, which reflects in part the broad diversity of sex-determining strategies used in insects. In this study we present the molecular identification and characterization of F, which acts as the master switch in the housefly pathway. We provide evidence that F corresponds to the transformer ortholog in Musca (Mdtra), which, as a result of alternative processing, expresses functional products only in individuals committed to the female fate. We demonstrate that, once activated, a self-sustaining feedback loop will maintain the female-promoting functions of Mdtra. Absence of Mdtra transcripts in eggs of Arrhenogenic (Ag) mutant females suggests that maternally deployed Mdtra activity initiates this self-sustaining loop in the zygote. When an M factor is paternally transmitted to the zygote, the establishment of the loop is prevented at an early stage before cellularization and splicing of Mdtra shifts irreversibly to the male nonproductive mode. On the basis of the analysis of two mutant alleles we can explain the different sex-determining systems in the housefly largely as deviations at the level of Mdtra regulation. This plasticity in the housefly pathway may provide a suitable framework to understand the evolution of sex-determining mechanisms in other insect species. For instance, while sex determination in a close relative, the tsetse fly Glossina morsitans, differs at the level of the instructive signal, we find that its tra ortholog, Gmtra, is regulated in a mode similar to that of Mdtra.

Template synthesis of benzannulated N-heterocyclic carbene ligands.

The reaction of 2-azidophenyl isocyanide (7) with [M(CO)(5)(thf)] (M=Cr, W) yields the isocyanide complexes [M(CO)(5)(7)] (M=Cr 8, M=W 9). Complexes 8 and 9 react with tertiary phosphines such as triphenylphosphane at the azido function of the isocyanide ligand to give the 2-triphenylphosphiniminophenyl isocyanide complexes 10 (M=Cr) and 11 (M=W). The polar triphenylphosphiniminophenyl function in complexes 10 and 11 can be hydrolyzed with H(2)O/HBr to afford triphenylphosphane oxide and the complexes containing the unstable 2-aminophenyl isocyanide ligand. This ligand spontaneously cyclizes by intramolecular nucleophilic attack of the primary amine at the isocyanide carbon atom to yield the 2,3-dihydro-1H-benzimidazol-2-ylidene complexes 12 (M=Cr) and 13 (M=W). Double deprotonation of the cyclic NH,NH-carbene ligands in 12 and 13 with KOtBu and reaction with two equivalents of allyl bromide yields the N,N'-dialkylated benzannulated N-heterocyclic carbene complexes 14 (M=Cr) and 15 (M=W). The molecular structures of complexes 9 and 11-15 were confirmed by X-ray diffraction studies.