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Background While the majority of the German population was fully vaccinated at the time (about 65%), COVID-19 incidence started growing exponentially in October 2021 with about 41% of recorded new cases aged twelve or above being symptomatic breakthrough infections, presumably also contributing to the dynamics. So far, it remained elusive how significant this contribution was and whether targeted non-pharmaceutical interventions (NPIs) may have stopped the amplification of the crisis. <br /> Methods We develop and introduce a contribution matrix approach based on the nextgeneration matrix of a population-structured compartmental infectious disease model to derive contributions of respective inter- and intragroup infection pathways of unvaccinated and vaccinated subpopulations to the effective reproduction number and new infections, considering empirical data of vaccine efficacies against infection and transmission. <br /> Results Here we show that about 61%-76% of all new infections were caused by unvaccinated individuals and only 24%-39% were caused by the vaccinated. Furthermore, 32%-51% of new infections were likely caused by unvaccinated infecting other unvaccinated. Decreasing the transmissibility of the unvaccinated by, e. g. targeted NPIs, causes a steeper decrease in the effective reproduction number R than decreasing the transmissibility of vaccinated individuals, potentially leading to temporary epidemic control. Reducing contacts between vaccinated and unvaccinated individuals serves to decrease R in a similar manner as increasing vaccine uptake. <br /> Conclusions A minority of the German population-the unvaccinated-is assumed to have caused the majority of new infections in the fall of 2021 in Germany. Our results highlight the importance of combined measures, such as vaccination campaigns and targeted contact reductions to achieve temporary epidemic control.
Analysis of physicians' probability estimates of a medical outcome based on a sequence of events
(2022)
A basic law of probability is that the probability of a conjunction of 2 independent events is the product of both components and cannot exceed the likelihood of either component. When this basic law is violated, it is known as the conjunction fallacy. In clinical practice, the conjunction fallacy may arise when physicians estimate the probability of the overall outcome that requires >= 2 steps to be successful. For example, if a successful procedure requires the success of step A and step B, then the probability of overall success of the procedure cannot exceed the likelihood of success of either step A or step B. The aim of this study was to determine whether physicians could correctly estimate the overall probability of success from 2 independent events. <br /> This was a 3-part, Internet-based survey study designed to evaluate the presence of the conjunction fallacy in 2 separate obstetric contexts and 1 pulmonary context. Respondents were board-certified or board-eligible physicians in obstetrics and gynecology and pulmonary, recruited from a commercial survey service. In each context, physicians were presented with scenarios related to their medical specialty and asked to judge the probability of the overall outcome, or conjunction, and of the 2 individual events, or conjuncts. <br /> The first substudy, conducted April 2-4, 2021, described a delivery in brow presentation discovered during labor. To assess the overall probability of a successful spontaneous vaginal delivery, an obstetrician must consider the likelihood of the brow presentation converting to a deliverable position and the likelihood of vaginal delivery from the converted position. The second substudy, conducted November 2-11, 2021, described the diagnostic evaluation of pulmonary nodule discovered incidentally. To assess the overall probability that a biopsy reveals cancer, the physician must consider the likelihood that the nodule is cancerous and the likelihood that the biopsy successfully and accurately detects cancer. The third study, conducted May 13-19, 2021, modified the first substudy and asked responding obstetricians to consider the likelihood of the individual conjuncts before estimating the overall probability of successful vaginal delivery. <br /> The survey included responses from 215 physicians: 66% were male and 34% were female with a mean (SD) age of 53.6 (9.5) years and mean time since obtaining a medical degree of 27.5 (10.6) years. Overall, 78.1% of physicians committed the conjunction fallacy, estimating that the overall probability of success was greater than the likelihood of at least 1 of the 2 conjuncts. In the first substudy, 74.6% of 67 obstetricians committed the conjunction fallacy; respondents overestimated the combined probability by 12.8% (95% confidence interval [CI], 9.6%-16.1%), compared with the product of the 2 estimated conjuncts with statistically significant deviation (t66 = 7.94; P < 0.001; Cohen d = 0.97 [95% CI, 0.68-1.26]). In the second substudy, 86.9% of 84 pulmonologists committed the conjunction fallacy; respondents overestimated the combined probability by 19.8% (95% CI, 16.6%-23.0%), with statistically significant deviation of (t83 = 7.94; P < 0.001; Cohen d = 1.34 [95% CI, 1.04-1.64]). In the third substudy, 70.3% of 64 committed the conjunction fallacy; respondents overestimated the combined probability by 18.0% (95% CI, 13.4%-22.5%) with statistically significant deviation (t63 = 7.89; P < 0.001; Cohen d = 0.99 [95% CI, 0.68-1.28]). <br /> In this study, it was common for seasoned obstetricians and pulmonologists to commit the conjunction fallacy. Given that physicians often need to estimate the successful outcome of a multistep procedure, they may be doing so in a flawed manner that may negatively impact decision-making.
Diabetic foot ulcer (DFU) is a severe complication of diabetes and a challenging medical condition. Conventional treatments for DFU have not been effective enough to reduce the amputation rates, which urges the need for additional treatment. Stem cell-based therapy for DFU has been investigated over the past years. Its therapeutic effect is through promoting angiogenesis, secreting paracrine factors, stimulating vascular differentiation, suppressing inflammation, improving collagen deposition, and immunomodulation. It is controversial which type and origin of stem cells, and which administration route would be the most optimal for therapy. We reviewed the different types and origins of stem cells and routes of administration used for the treatment of DFU in clinical and preclinical studies. Diabetes leads to the impairment of the stem cells in the diseased patients, which makes it less ideal to use autologous stem cells, and requires looking for a matching donor. Moreover, angioplasty could be complementary to stem cell therapy, and scaffolds have a positive impact on the healing process of DFU by stem cell-based therapy. In short, stem cell-based therapy is promising in the field of regenerative medicine, but more studies are still needed to determine the ideal type of stem cells required in therapy, their safety, proper dosing, and optimal administration route.
Nudix hydrolase NUDT19 regulates mitochondrial function and ATP production in murine hepatocytes
(2022)
Changes in intracellular CoA levels are known to contribute to the development of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes (T2D) in human and rodents. However, the underlying genetic basis is still poorly understood.
Due to their diverse susceptibility towards metabolic diseases, mouse inbred strains have been proven to serve as powerful tools for the identification of novel genetic factors that underlie the patho-physiology of NAFLD and diabetes. Transcriptome analysis of mouse liver samples revealed the nucleoside diphosphate linked moiety X-type motif Nudt19 as novel candidate gene responsible for NAFLD and T2D development. Knockdown (KD) of Nudt19 increased mitochondrial and glycolytic ATP production rates in Hepa 1-6 cells by 41% and 10%, respectively.
The enforced utilization of glutamine or fatty acids as energy substrate reduced uncoupled respiration by 41% and 47%, respectively, in non-target (NT) siRNA transfected cells.
This reduction was prevented upon Nudt19 KD. Furthermore, incubation with palmitate or oleate respectively increased mitochondrial ATP production by 31% and 20%, and uncoupled respiration by 23% and 30% in Nudt19 KD cells, but not in NT cells.
The enhanced fatty acid oxidation in Nudt19 KD cells was accompanied by a 1.3-fold increased abundance of Pdk4.
This study is the first to describe Nudt19 as regulator of hepatic lipid metabolism and potential mediator of NAFLD and T2D development.
Background
In cystic fibrosis (CF), acute respiratory exacerbations critically enhance pulmonary destruction. Since these mainly occur outside regular appointments, they remain unexplored. We previously elaborated a protocol for home-based upper airway (UAW) sampling obtaining nasal-lavage fluid (NLF), which, in contrast to sputum, does not require immediate processing. The aim of this study was to compare UAW inflammation and pathogen colonization during stable phases and exacerbations in CF patients and healthy controls.
Methods
Initially, we obtained NLF by rinsing 10 ml of isotonic saline/nostril during stable phases. During exacerbations, subjects regularly collected NLF at home. CF patients directly submitted one aliquot for microbiological cultures. The remaining samples were immediately frozen until transfer on ice to our clinic, where PCR analyses were performed and interleukin (IL)-1 beta/IL-6/IL-8, neutrophil elastase (NE), matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1 were assessed.
Results
Altogether, 49 CF patients and 38 healthy controls (HCs) completed the study, and 214 NLF samples were analyzed. Of the 49 CF patients, 20 were at least intermittently colonized with P. aeruginosa and received azithromycin and/or inhaled antibiotics as standard therapy. At baseline, IL-6 and IL-8 tended to be elevated in CF compared to controls. During infection, inflammatory mediators increased in both cohorts, reaching significance only for IL-6 in controls (p=0.047). Inflammatory responses tended to be higher in controls [1.6-fold (NE) to 4.4-fold (MMP-9)], while in CF, mediators increased only moderately [1.2-1.5-fold (IL-6/IL-8/NE/TIMP-1/MMP-9)]. Patients receiving inhalative antibiotics or azithromycin (n=20 and n=15, respectively) revealed lower levels of IL-1 beta/IL-6/IL-8 and NE during exacerbation compared to CF patients not receiving those antibiotics. In addition, CF patients receiving azithromycin showed MMP-9 levels significantly lower than CF patients not receiving azithromycin at stable phase and exacerbation. Altogether, rhinoviruses were the most frequently detected virus, detected at least once in n=24 (49.0%) of the 49 included pwCF and in n=26 (68.4%) of the 38 healthy controls over the 13-month duration of the study. Remarkably, during exacerbation, rhinovirus detection rates were significantly higher in the HC group compared to those in CF patients (65.8% vs. 22.4%; p<0.0001).
Conclusion
Non-invasive and partially home-based UAW sampling opens new windows for the assessment of inflammation and pathogen colonization in the unified airway system.
Recent theories suggest a shift from model-based goal-directed to model-free habitual decision-making in obsessive-compulsive disorder (OCD). However, it is yet unclear, whether this shift in the decision process is heritable. We investigated 32 patients with OCD, 27 unaffected siblings (SIBs) and 31 healthy controls (HCs) using the two-step task. We computed behavioral and reaction time analyses and fitted a computational model to assess the balance between model-based and model-free control. 80 subjects also underwent structural imaging. We observed a significant ordered effect for the shift towards model-free control in the direction OCD>SIB>HC in our computational parameter of interest. However less directed analyses revealed no shift towards model-free control in OCDs. Nonetheless, we found evidence for reduced model-based control in OCDs compared to HCs and SIBs via 2nd stage reaction time analyses. In this measure SIBs also showed higher levels of model-based control than HCs. Across all subjects these effects were associated with the surface area of the left medial/right dorsolateral prefrontal cortex. Moreover, correlations between bilateral putamen/right caudate volumes and these effects varied as a function of group: they were negative in SIBs and OCDs, but positive in HCs. Associations between fronto-striatal regions and model-based reaction time effects point to a potential endophenotype for OCD.
Symptom Checker Applications (SCA) are mobile applications often designed for the end-user to assist with symptom assessment and self-triage. SCA are meant to provide the user with easily accessible information about their own health conditions.
However, SCA raise questions regarding ethical, legal, and social aspects (ELSA), for example, regarding fair access to this new technology.
The aim of this scoping review is to identify the ELSA of SCA in the scientific literature. A scoping review was conducted to identify the ELSA of SCA. Ten databases (e.g., Web of Science and PubMed) were used. Studies on SCA that address ELSA, written in English or German, were included in the review.
The ELSA of SCA were extracted and synthesized using qualitative content analysis. A total of 25,061 references were identified, of which 39 were included in the analysis. The identified aspects were allotted to three main categories: (1) Technology; (2) Individual Level; and (3) Healthcare system.
The results show that there are controversial debates in the literature on the ethical and social challenges of SCA usage. Furthermore, the debates are characterised by a lack of a specific legal perspective and empirical data.
The review provides an overview on the spectrum of ELSA regarding SCA. It offers guidance to stakeholders in the healthcare system, for example, patients, healthcare professionals, and insurance providers and could be used in future empirical research to investigate the perspectives of those affected, such as users.
Background
Depression is a leading cause of disability worldwide and a significant contributor to the global burden of disease. Altered leptin levels are known to be associated with depressive symptoms, however discrepancies in the results of increased or decreased levels exist. Due to various limitations associated with commonly used antidepressant drugs, alternatives such as exercise therapy are gaining more importance. Therefore, the current study investigates whether depressed patients have higher leptin levels compared to healthy controls and if exercise is efficient to reduce these levels.
Methods
Leptin levels of 105 participants with major depressive disorder (MDD; 45.7% female, age mean ± SEM: 39.1 ± 1.0) and 34 healthy controls (HC; 61.8% female, age mean ± SEM: 36.0 ± 2.0) were measured before and after a bicycle ergometer test. Additionally, the MDD group was separated into three groups: two endurance exercise intervention groups (EX) differing in their intensities, and a waiting list control group (WL). Leptin levels were measured pre and post a 12-week exercise intervention or the waiting period.
Results
Baseline data showed no significant differences in leptin levels between the MDD and HC groups. As expected, correlation analyses displayed significant relations between leptin levels and body weight (HC: r = 0.474, p = 0.005; MDD: r = 0.198, p = 0.043) and even more with body fat content (HC: r = 0.755, p < 0.001; MDD: r = 0.675, p < 0.001). The acute effect of the bicycle ergometer test and the 12-week training intervention showed no significant changes in circulating leptin levels.
Conclusion
Leptin levels were not altered in patients with major depression compared to healthy controls and exercise, both the acute response and after 12 weeks of endurance training, had no effect on the change in leptin levels.
Trial registration
The study was registered at the German register for clinical studies (DRKS) and the International Clinical Trials Registry Platform of the World Health Organization https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00008869 on 28/07/2015.
The ability to catalyze diverse reactions with relevance for chemical and pharmaceutical research and industry has led to an increasing interest in fungal enzymes.
There is still an enormous potential considering the sheer amount of new enzymes from the huge diversity of fungi.
Most of these fungal enzymes have not been characterized yet due to the lack of high throughput synthesis and analysis methods.
This bottleneck could be overcome by means of cell-free protein synthesis. In this study, cell-free protein synthesis based on eukaryotic cell lysates was utilized to produce a functional glycoside hydrolase (GH78) from the soft-rot fungus Xylaria polymorpha (Ascomycota).
The enzyme was successfully synthesized under different reaction conditions.
We characterized its enzymatic activities and immobilized the protein via FLAG-Tag interaction. Alteration of several conditions including reaction temperature, template design and lysate supplementation had an influence on the activity of cell-free synthesized GH78.
Consequently this led to a production of purified GH78 with a specific activity of 15.4 U mg? 1.
The results of this study may be foundational for future high throughput fungal enzyme screenings, including substrate spectra analysis and mutant screenings.