Engrailed 1 deficiency induces changes in ciliogenesis during human neuronal differentiation.

A key pathological feature of Parkinson's Disease (PD) is the progressive degeneration of dopaminergic neurons (DAns) in the substantia nigra pars compacta. Considering the major role of EN1 in the development and maintenance of these DAns and the implications from En1 mouse models, it is highly interesting to study the molecular and protective effect of EN1 also in a human cellular model. Therefore, we generated EN1 knock-out (ko) human induced pluripotent stem cell (hiPSCs) lines and analyzed these during neuronal differentiation. Although the EN1 ko didn't interfere with neuronal differentiation and generation of tyrosine hydroxylase positive (TH+) neurons per se, the neurons exhibited shorter neurites. Furthermore, mitochondrial respiration, as well as mitochondrial complex I abundance was significantly reduced in fully differentiated neurons. To understand the implications of an EN1 ko during differentiation, we performed a transcriptome analysis of human neuronal precursor cells (hNPCs) which unveiled alterations in cilia-associated pathways. Further analysis of ciliary morphology revealed an elongation of primary cilia in EN1-deficient hNPCs. Besides, also Wnt signaling pathways were severely affected. Upon stimulating hNPCs with Wnt which drastically increased EN1 expression in WT lines, the phenotypes concerning mitochondrial function and cilia were exacerbated in EN1 ko hNPCs. They failed to enhance the expression of the complex I subunits NDUFS1 and 3, and now displayed a reduced mitochondrial respiration. Furthermore, Wnt stimulation decreased ciliogenesis in EN1 ko hNPCs but increased ciliary length even further. This further highlights the relevance of primary cilia next to mitochondria for the functionality and correct maintenance of human DAns and provides new possibilities to establish neuroprotective therapies for PD.

[CF Lung Disease - a German S3 Guideline: Pseudomonas aeruginosa]. / S3-Leitlinie: Lungenerkrankung bei Mukoviszidose ­ Pseudomonas aeruginosa.

Cystic Fibrosis (CF) is the most common autosomal recessive genetic multisystemic disease. In Germany, it affects at least 8000 people. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the airway epithelial lining fluid which leads to reduction of the mucociliary clearance.Even if highly effective, CFTR modulator therapy has been available for some years and people with CF are getting much older than before, recurrent and chronic infections of the airways as well as pulmonary exacerbations still occur. In adult CF life, Pseudomonas aeruginosa (PA) is the most relevant pathogen in colonisation and chronic infection of the lung, leading to further loss of lung function. There are many possibilities to treat PA-infection.This is a S3-clinical guideline which implements a definition for chronic PA-infection and demonstrates evidence-based diagnostic methods and medical treatment in order to give guidance for individual treatment options.

Potential of Assistive Robots in Clinical Nursing: An Observational Study of Nurses' Transportation Tasks in Rural Clinics of Bavaria, Germany.

Transportation tasks in nursing are common, often overlooked, and directly impact patient care time in the context of staff shortages and an aging society. Current studies lack a specific focus on transportation tasks, a gap our research aims to fill. By providing detailed data on transportation needs in nursing, our study establishes a crucial foundation for the development and integration of assistive robots in clinical settings. In July and September 2023, we conducted weekly observations of nurses to assess clinical transportation needs. We aim to understand the economic impact and the methods nurses use for transportation tasks. We conducted a participant observation using a standardized app-based form over a seven-day observation period in two rural clinics. N = 1830 transports were made by nurses and examined by descriptive analysis. Non-medical supplies account for 27.05% (n = 495) of all transports, followed by medical supplies at 17.32% (n = 317), pharmacotherapy at 14.10% (n = 258) and other other categories like meals or drinks contributing 12.68% (n = 232). Most transports had a factual transport time of under a minute, with patient transport and lab samples displaying more variability. In total, 77.15% of all transports were made by hand. Requirements to collect items or connect transports with patient care were included in 5% of all transports. Our economic evaluation highlighted meals as the most costly transport, with 9596.16 € per year in the observed clinics. Budget-friendly robots would amortize these costs over one year by transporting meals. We support understanding nurses' transportation needs via further research on assistive robots to validate our findings and determine the feasibility of transport robots.

Simplifying radiologic reports with natural language processing: a novel approach using ChatGPT in enhancing patient understanding of MRI results.

PURPOSE: The aim of this prospective cohort study was to assess the factual accuracy, completeness of medical information, and potential harmfulness of incorrect conclusions by medical professionals in automatically generated texts of varying complexity (1) using ChatGPT, Furthermore, patients without a medical background were asked to evaluate comprehensibility, information density, and conclusion possibilities (2). METHODS: In the study, five different simplified versions of MRI findings of the knee of different complexity (A: simple, B: moderate, C: complex) were each created using ChatGPT. Subsequently, a group of four medical professionals (two orthopedic surgeons and two radiologists) and a group of 20 consecutive patients evaluated the created reports. For this purpose, all participants received a group of simplified reports (simple, moderate, and severe) at intervals of 1 week each for their respective evaluation using a specific questionnaire. Each questionnaire consisted of the original report, the simplified report, and a series of statements to assess the quality of the simplified reports. Participants were asked to rate their level of agreement with a five-point Likert scale. RESULTS: The evaluation of the medical specialists showed that the findings produced were consistent in quality depending on their complexity. Factual correctness, reproduction of relevant information and comprehensibility for patients were rated on average as "Agree". The question about possible harm resulted in an average of "Disagree". The evaluation of patients also revealed consistent quality of reports, depending on complexity. Simplicity of word choice and sentence structure was rated "Agree" on average, with significant differences between simple and complex findings (p = 0.0039) as well as between moderate and complex findings (p = 0.0222). Participants reported being significantly better at knowing what the text was about (p = 0.001) and drawing the correct conclusions the more simplified the report of findings was (p = 0.013829). The question of whether the text informed them as well as a healthcare professional was answered as "Neutral" across all findings. CONCLUSION: By using ChatGPT, MRI reports can be simplified automatically with consistent quality so that the relevant information is understandable to patients. However, a report generated in this way does not replace a thorough discussion between specialist and patient.

Do the enantiomers of ketamine bind enantioselectively to human serum albumin?

The binding of drugs to plasma proteins is an important process in the human body and has a significant influence on pharmacokinetic parameter. Human serum albumin (HSA) has the most important function as a transporter protein. The binding of ketamine to HSA has already been described in literature, but only of the racemate. The enantiomerically pure S-ketamine is used as injection solution for induction of anesthesia and has been approved by the Food and Drug Administration for the therapy of severe depression as a nasal spray in 2019. The question arises if there is enantioselective binding to HSA. Hence, the aim of this study was to investigate whether there is enantioselective binding of S-and R-ketamine to HSA or not. Ultrafiltration (UF) followed by chiral capillary electrophoretic analysis was used to determine the extent of protein binding. Bound fraction to HSA was 71.2 % and 64.9 % for enantiomerically pure R- and S-ketamine, respectively, and 66.5 % for the racemate. Detailed binding properties were studied by Saturation Transfer Difference (STD)-, waterLOGSY- and Carr-Purcell-Meiboom-Gill (CPMG)-NMR spectroscopy. With all three methods, the aromatic ring and the N-methyl group could be identified as the structural moieties most strongly involved in binding of ketamine to HSA. pKaff values determined using UF and NMR indicate that ketamine is a weak affinity ligand to HSA and no significant differences in binding behavior were found between the individual enantiomers and the racemate.

A reversible state of hypometabolism in a human cellular model of sporadic Parkinson's disease.

Sporadic Parkinson's Disease (sPD) is a progressive neurodegenerative disorder caused by multiple genetic and environmental factors. Mitochondrial dysfunction is one contributing factor, but its role at different stages of disease progression is not fully understood. Here, we showed that neural precursor cells and dopaminergic neurons derived from induced pluripotent stem cells (hiPSCs) from sPD patients exhibited a hypometabolism. Further analysis based on transcriptomics, proteomics, and metabolomics identified the citric acid cycle, specifically the α-ketoglutarate dehydrogenase complex (OGDHC), as bottleneck in sPD metabolism. A follow-up study of the patients approximately 10 years after initial biopsy demonstrated a correlation between OGDHC activity in our cellular model and the disease progression. In addition, the alterations in cellular metabolism observed in our cellular model were restored by interfering with the enhanced SHH signal transduction in sPD. Thus, inhibiting overactive SHH signaling may have potential as neuroprotective therapy during early stages of sPD.

Incoherence and the balance of evidential reasons.

Eva Schmidt argues that facts about incoherent beliefs can be non-evidential epistemic reasons to suspend judgment. In this commentary, I argue that incoherence-based reasons to suspend are epistemically superfluous: if the subjects in Schmidt's cases ought to suspend judgment, then they should do so merely on the basis of their evidential reasons. This suggests a more general strategy to reduce the apparent normativity of coherence to the normativity of evidence. I conclude with some remarks on the independent interest that reasons-first epistemology might have within an evidentialist framework.

[On the Effectiveness of Digital Workplace Health Promotion in Times of Home Office: A Systematic Review]. / Zur Wirksamkeit der digitalen betrieblichen Gesundheitsförderung in Zeiten von Home-Office: Eine systematische Übersichtsarbeit.

BACKGROUND: In the face of an increasingly aging, multimorbid, chronically ill workforce, company health promotion (BGF) is an important instrument for promoting and maintaining the health of employees in the workplace. Due to digitization and the increasing possibilities of working from home, digital offers for workplace health promotion (dBGF) are being used increasingly in organizations. The portfolio of offers ranges from fitness trackers, online platforms, and health apps to so-called wearables, so that a broad, individual selection is possible for both organizations and employees. THE AIM OF THE STUDY: The aim of the study was to identify and analyze randomized controlled trials (RCT) with regard to the health-promoting effectiveness of dBGF. MATERIAL AND METHODS: A systematic literature search was carried out in relevant specialist databases (PubMed, Livivo, Cochrane Library). The identified studies were selected, evaluated and then descriptively presented by several people systematically and independently. RESULTS: 17 relevant contributions could be identified and analyzed. Above all, measures to promote physical activity and programs to improve mental health were identified in the RCT studies that were carried out. The results of the studies carried out indicate that dBGF can promote health in a variety of ways and support organizations in providing a health-promoting working environment. DISCUSSION: The effectiveness of dBGF could be proven on the basis of the studies identified, whereby the effects are undoubtedly influenced and determined by the employees, above all by their health competence. In order to ensure the long-term effectiveness of dBGF, it will be necessary in the future to increase the interest and motivation of employees with regard to personal health promotion and illness prevention.

A Novel Sensor-Based Application for Home-Based Rehabilitation Can Objectively Measure Postoperative Outcomes following Anterior Cruciate Ligament Reconstruction.

In order to successfully implement individualized patient rehabilitation and home-based rehabilitation programs, the rehabilitation process should be objectifiable, monitorable and comprehensible. For this purpose, objective measurements are required in addition to subjective measurement tools. Thus, the aim of this prospective, single-center clinical trial is the clinical validation of an objective, digital medical device (DMD) during the rehabilitation after anterior cruciate ligament reconstruction (ACLR) with regards to an internationally accepted measurement tool. Sixty-seven patients planned for primary ACLR (70:30% male-female, aged 25 years [21-32], IKDC-SKF 47 [31-60], Tegner Activity Scale 6 [4-7], Lysholm Score 57 [42-72]) were included and received physical therapy and the DMD after surgery. For clinical validation, combined measures of range of motion (ROM), coordination, strength and agility were assessed using the DMD in addition to patient-reported outcome measures (PROMs) at three and six months after ACLR. Significant correlations were detected for ROM (rs = 0.36-0.46, p < 0.025) and strength/agility via the single-leg vertical jump (rs = 0.43, p = 0.011) and side hop test (rs = 0.37, p = 0.042), as well as for coordination via the Y-Balance test (rs = 0.58, p ≤ 0.0001) regarding the IKDC-SKF at three months. Additionally, DMD test results for coordination, strength and agility (Y-Balance test (rs = 0.50, p = 0.008), side hop test (rs = 0.54, p = 0.004) and single-leg vertical jump (rs = 0.44, p = 0.018)) correlate significantly with the IKDC-SKF at six months. No adverse events related to the use of the sensor-based application were reported. These findings confirm the clinical validity of a DMD to objectively quantify knee joint function for the first time. This will have further implications for clinical and therapeutic decision making, quality control and monitoring of rehabilitation measures as well as scientific research.

Eulertigs: minimum plain text representation of k-mer sets without repetitions in linear time.

A fundamental operation in computational genomics is to reduce the input sequences to their constituent k-mers. For maximum performance of downstream applications it is important to store the k-mers in small space, while keeping the representation easy and efficient to use (i.e. without k-mer repetitions and in plain text). Recently, heuristics were presented to compute a near-minimum such representation. We present an algorithm to compute a minimum representation in optimal (linear) time and use it to evaluate the existing heuristics. Our algorithm first constructs the de Bruijn graph in linear time and then uses a Eulerian-cycle-based algorithm to compute the minimum representation, in time linear in the size of the output.

Matchtigs: minimum plain text representation of k-mer sets.

We propose a polynomial algorithm computing a minimum plain-text representation of k-mer sets, as well as an efficient near-minimum greedy heuristic. When compressing read sets of large model organisms or bacterial pangenomes, with only a minor runtime increase, we shrink the representation by up to 59% over unitigs and 26% over previous work. Additionally, the number of strings is decreased by up to 97% over unitigs and 90% over previous work. Finally, a small representation has advantages in downstream applications, as it speeds up SSHash-Lite queries by up to 4.26× over unitigs and 2.10× over previous work.

[Strengthening the Role of Public Health Service: a Comparison of the Public Health Service Quota Selection Procedures in Germany]. / Die Rolle des Öffentlichen Gesundheitsdiensts stärken ­ ein Vergleich der ÖGD-Quotenauswahlverfahren in Deutschland.

To combat the shortage of skilled workers in the Public Health Service sector, the federal states of Bavaria, Hesse, Rhineland-Palatinate, and Saxony-Anhalt have a study placement system for students of Public Health Service. A comparison of the selection procedures showed that three out of the four federal states (Bavaria, Hesse, and Rhineland-Palatinate) used a two-step procedure. In the second step, eligibility for was determined based on interviews to assess social and communication skills as well as personal aptitude of the applicants to study and work in the Public Health Service. To find out whether the role of the Public Health Service and public health care is strengthened by the quotas, a nationwide comparison of the selection procedures including evaluation is necessary.

Combination of organic acids benzoate, butyrate, caprylate, and sorbate provides a novel antibiotics-independent treatment option in the combat of acute campylobacteriosis.

Introduction: The food-borne Gram-negative bacterial pathogen Campylobacter jejuni may cause the acute enterocolitis syndrome campylobacteriosis in infected humans. Given that human C. jejuni infections are rising globally which hold also true for resistance rates against antibiotic compounds such as macrolides and fluoroquinolones frequently prescribed for the treatment of severe infectious enteritis, novel antibiotics-independent therapeutic strategies are needed. Distinct organic acids are well known for their health-beneficial including anti-microbial and immunomodulatory properties. In our present study, we investigated potential pathogen-lowering and anti-inflammatory effects of benzoic acid, butyric acid, caprylic acid, and sorbic acid either alone or in combination during acute murine campylobacteriosis. Methods: Therefore, secondary abiotic IL-10-/- mice were perorally infected with C. jejuni strain 81-176 and subjected to a 4-day-course of respective organic acid treatment. Results and discussion: On day 6 post-infection, mice from the combination cohort displayed slightly lower pathogen loads in the duodenum, but neither in the stomach, ileum nor large intestine. Remarkably, the clinical outcome of C. jejuni induced acute enterocolitis was significantly improved after combined organic acid treatment when compared to the placebo control group. In support, the combinatory organic acid treatment dampened both, macroscopic and microscopic inflammatory sequelae of C. jejuni infection as indicated by less colonic shrinkage and less pronounced histopathological including apoptotic epithelial cell changes in the colon on day 6 post-infection. Furthermore, mice from the combination as compared to placebo cohort exhibited lower numbers of innate and adaptive immune cells such as neutrophilic granulocytes, macrophages, monocytes, and T lymphocytes in their colonic mucosa and lamina propria, respectively, which also held true for pro-inflammatory cytokine secretion in the large intestines and mesenteric lymph nodes. Notably, the anti-inflammatory effects were not restricted to the intestinal tract, but could also be observed systemically given pro-inflammatory mediator concentrations in C. jejuni infected mice from the combination organic acid treatment that were comparable to basal values. In conclusion, our in vivo study provides first evidence that an oral application of distinct organic acids in combination exhibits pronounced anti-inflammatory effects and hence, constitutes a promising novel antibiotics-independent therapeutic strategy in the combat of acute campylobacteriosis.

Skeletal muscle optoacoustics reveals patterns of circulatory function and oxygen metabolism during exercise.

Imaging skeletal muscle function and metabolism, as reported by local hemodynamics and oxygen kinetics, can elucidate muscle performance, severity of an underlying disease or outcome of a treatment. Herein, we used multispectral optoacoustic tomography (MSOT) to image hemodynamics and oxygen kinetics within muscle during exercise. Four healthy volunteers underwent three different hand-grip exercise challenges (60s isometric, 120s intermittent isometric and 60s isotonic). During isometric contraction, MSOT showed a decrease of HbO2, Hb and total blood volume (TBV), followed by a prominent increase after the end of contraction. Corresponding hemodynamic behaviors were recorded during the intermittent isometric and isotonic exercises. A more detailed analysis of MSOT readouts revealed insights into arteriovenous oxygen differences and muscle oxygen consumption during all exercise schemes. These results demonstrate an excellent capability of visualizing both circulatory function and oxygen metabolism within skeletal muscle under exercise, with great potential implications for muscle research, including relevant disease diagnostics.

The omnitig framework can improve genome assembly contiguity in practice.

Despite the long history of genome assembly research, there remains a large gap between the theoretical and practical work. There is practical software with little theoretical underpinning of accuracy on one hand and theoretical algorithms which have not been adopted in practice on the other. In this paper we attempt to bridge the gap between theory and practice by showing how the theoretical safe-and-complete framework can be integrated into existing assemblers in order to improve contiguity. The optimal algorithm in this framework, called the omnitig algorithm, has not been used in practice due to its complexity and its lack of robustness to real data. Instead, we pursue a simplified notion of omnitigs, giving an efficient algorithm to compute them and demonstrating their safety under certain conditions. We modify two assemblers (wtdbg2 and Flye) by replacing their unitig algorithm with the simple omnitig algorithm. We test our modifications using real HiFi data from the Drosophilia melanogaster and the Caenorhabditis elegans genome. Our modified algorithms lead to a substantial improvement in alignment-based contiguity, with negligible computational costs and either no or a small increase in the number of misassemblies.

Eulertigs: minimum plain text representation of k-mer sets without repetitions in linear time.

A fundamental operation in computational genomics is to reduce the input sequences to their constituent k-mers. For maximum performance of downstream applications it is important to store the k-mers in small space, while keeping the representation easy and efficient to use (i.e. without k-mer repetitions and in plain text). Recently, heuristics were presented to compute a near-minimum such representation. We present an algorithm to compute a minimum representation in optimal (linear) time and use it to evaluate the existing heuristics. Our algorithm first constructs the de Bruijn graph in linear time and then uses a Eulerian-cycle-based algorithm to compute the minimum representation, in time linear in the size of the output.

Metabolic Control, Diabetic Complications and Drug Therapy in a Cohort of Patients with Type 1 and Type 2 Diabetes in Secondary and Tertiary Care between 2004 and 2019.

This paper studies the features of metabolic parameters, diabetic complications and drug therapy of a single-centre cohort of patients with type 1 diabetes (T1DM) or type 2 diabetes (T2DM) in secondary care and tertiary care over a 15-year period. METHODS: Retrospective cross-sectional analysis of four single-centre cohorts between 2004 and 2019. All patients with T1DM or T2DM in secondary care (n = 5571) or tertiary care (n = 2001) were included. Statistical analyses were performed using linear mixed models. RESULTS: Diabetes duration increased in both patients with T1DM and T2DM in secondary care and tertiary care (p < 0.001). Patients in secondary care consistently showed good glycaemic control, while patients in tertiary care showed inadequate glycaemic control. All four cross-sectional cohorts showed a significant increase in the prevalence of nephropathy over time and three out of four cohorts (T1DM and T2DM in secondary care and T2DM in tertiary care) showed an increase in the prevalence of neuropathy (all p < 0.001). The incidence of severe hypoglycaemia was consistently low. The use of insulin pumps and insulin analogues in the therapy of T1DM increased significantly. CONCLUSIONS: The increased prevalence of complications is likely due to older age and longer diabetes duration. Low rates of hypoglycaemia, lower limb amputations and good glycaemic control in secondary care patients indicate a good structure of patient care.