Sub-optimal therapy of patients with primary biliary cholangitis (PBC) in the real-life stetting of the German PBC cohort.

Real-world data on the management of patients with primary biliary cholangitis (PBC) are so far scarce in Germany. Therefore, we aimed to establish a nationwide registry and describe the clinical characteristics and therapy of PBC patients.Three different cohorts defined as ursodeoxycholic acid (UDCA) responders, as inadequate responders according to Paris II criteria, and as newly diagnosed patients were prospectively recruited.This manuscript includes the baseline data of the project.In total, 33/77 (43%) contacted centres (58% of university hospitals, 38% of non-university hospitals, and 24% of private practices) recruited 515 patients including 204 UDCA responders, 221 inadequate responders to UDCA, and 90 newly diagnosed patients.All patients were treated with UDCA; however, a UDCA dosage below the recommended dosage of 13 mg/kg/d was observed in 38.5% of individuals after 12 months of treatment. UDCA dosages were lower in nonacademic compared to academic centres.Only 75/219 (38.5%) of inadequate responders to UDCA received a second-line therapy with obeticholic acid (OCA) and/or bezafibrate (BZF). OCA (13% vs. 4.5%) and BZF (14% vs. 6.5%) were significantly more often prescribed by academic vs. nonacademic centres.Pruritus (27% vs. 15.5%), fatigue (23% vs. 4.5%), and sicca syndrome (14% vs. 1%) were significantly more often reported by academic centres.The German PBC registry could be established, which indicates suboptimal therapy in a relevant proportion of patients and shows significant differences between academic and nonacademic centres. Results are fundamental to improving clinical management at different levels of care.

Long-term impact of scheduled regular endoscopic interventions for patients with primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is associated with biliary obstructions that can require endoscopic retrograde cholangiopancreatography (ERCP). While the beneficial effects of ERCP are well documented, follow-up interventional strategies are less defined, and their long-term impact is debated. METHODS: We evaluated the outcome of a scheduled program of ERCP-guided interventions that have been developed and implemented at our tertiary liver center for more than 20 years. Within our center, follow-up ERCPs were performed at regular intervals to treat previously detected morphological stenosis independent of clinical symptoms. We calculated the transplant-free survival (TFS) of patients who were enrolled in the scheduled ERCP program and compared it to patients who received follow-up ERCPs only on clinical demand. Moreover, we documented the occurrence of hepatic decompensation, recurrent cholangitis episodes, hepatobiliary malignancies, and endoscopy-related adverse events. RESULTS: In our retrospective study, we included 201 patients with PSC who all received an ERCP. In all, 133 patients received scheduled follow-up ERCPs and 68 received follow-up ERCPs only on demand. The rates of TFS since initial diagnosis (median TFS: 17 vs. 27 y; P = 0.020) and initial presentation (median TFS: 16 vs. 11 y; P = 0.002) were higher in patients receiving scheduled versus on-demand ERCP. Subgroup analysis revealed that progression in cholangiographic findings between the first and second ERCP was associated with a poorer outcome compared to patients without progression (17 y vs. undefined; P = 0.021). CONCLUSION: In conclusion, we report the outcome data of a scheduled follow-up ERCP program for patients with PSC in an experienced high-volume endoscopy center. Our data suggest the initiation of multicenter randomized controlled prospective trials to explore the full potential of regular endoscopic follow-up treatment as a strategy to prevent disease progression in patients with PSC.

Plant infection by the necrotrophic fungus Botrytis requires actin-dependent generation of high invasive turgor pressure.

The devastating pathogen Botrytis cinerea infects a broad spectrum of host plants, causing great socio-economic losses. The necrotrophic fungus rapidly kills plant cells, nourishing their wall and cellular contents. To this end, necrotrophs secrete a cocktail of cell wall degrading enzymes, phytotoxic proteins and metabolites. Additionally, many fungi produce specialized invasion organs that generate high invasive pressures to force their way into the plant cell. However, for most necrotrophs, including Botrytis, the biomechanics of penetration and its contribution to virulence are poorly understood. Here, we use a combination of quantitative micromechanical imaging and CRISPR-Cas-guided mutagenesis to show that Botrytis uses substantial invasive pressure, in combination with strong surface adherence, for penetration. We found that the fungus establishes a unique mechanical geometry of penetration that develops over time during penetration events, and which is actin cytoskeleton dependent. Furthermore, interference of force generation by blocking actin polymerization was found to decrease Botrytis virulence, indicating that also for necrotrophs, mechanical pressure is important in host colonization. Our results demonstrate for the first time mechanistically how a necrotrophic fungus such as Botrytis employs this 'brute force' approach, in addition to the secretion of lytic proteins and phytotoxic metabolites, to overcome plant host resistance.

Simultaneous Stereo Matching and Confidence Estimation Network.

In this paper, we present a multi-task model that predicts disparities and confidence levels in deep stereo matching simultaneously. We do this by combining its successful model for each separate task and obtaining a multi-task model that can be trained with a proposed loss function. We show the advantages of this model compared to training and predicting disparity and confidence sequentially. This method enables an improvement of 15% to 30% in the area under the curve (AUC) metric when trained in parallel rather than sequentially. In addition, the effect of weighting the components in the loss function on the stereo and confidence performance is investigated. By improving the confidence estimate, the practicality of stereo estimators for creating distance images is increased.

[Prolonged weaning after long-term ventilation due to SARS-CoV-2 infection: a multicenter retrospective analysis]. / Prolongierte Entwöhnung nach Langzeitbeatmung aufgrund einer SARS-CoV-2-Infektion ­ eine multizentrische retrospektive Analyse.

Some of the patients with SARS-CoV-2 infection (COVID-19) received invasive ventilation during inpatient care. Weaning from ventilation was difficult for some patients (so-called prolonged weaning). PATIENTS: Patients (n=751) with prolonged weaning (reason for ventilation "pneumonia" and "acute respiratory failure") from four centers for the period 2011-23 from the "WeanNet" registry were used as a matched group. RESULTS: The median duration of intensive medical care was 39 (25-68) days. In 19% (37/193) of patients, ECMO support was necessary for a median of 27 (18-51) days. In-hospital mortality was 8.3% (2.7% with vs. 9.6% without ECMO) and 6.8% died in the comparison group. At discharge, 84% (vs. 77% in the control group) were completely weaned and 2.6% (vs. 17.6% in the control group) of patients received non-invasive treatment. Invasive ventilation was still necessary in 7.8% (control group 15.7%). In the observation period of 6 months after discharge, 22.4% of patients required inpatient care and a further 14.1% after 12 months. The overall mortality at 12-month follow-up was 20,6% (5.6% with vs. 24.6% without ECMO). DISCUSSION: The mortality rate of ventilated patients with COVID-19 was very low at 8.3% in the four weaning centers studied. The mortality rate of patients with ECMO treatment was only 2.7%. The mortality rate in the control group was 7.3%. The lower mortality of patients with ECMO treatment was also evident at follow-up of up to 12 months.Patients with prolonged weaning who received invasive ventilation due to COVID-19 showed comparable results in terms of successful weaning and mortality compared to a control group from the WeanNet registry. The long-term results with a survival of more than 80% for the first year after discharge were encouraging.

Age-related and species-specific methylation changes in the protein-coding marmoset sperm epigenome.

The sperm epigenome is thought to affect the developmental programming of the resulting embryo, influencing health and disease in later life. Age-related methylation changes in the sperm of old fathers may mediate the increased risks for reproductive and offspring medical problems. The impact of paternal age on sperm methylation has been extensively studied in humans and, to a lesser extent, in rodents and cattle. Here, we performed a comparative analysis of paternal age effects on protein-coding genes in the human and marmoset sperm methylomes. The marmoset has gained growing importance as a non-human primate model of aging and age-related diseases. Using reduced representation bisulfite sequencing, we identified age-related differentially methylated transcription start site (ageTSS) regions in 204 marmoset and 27 human genes. The direction of methylation changes was the opposite, increasing with age in marmosets and decreasing in humans. None of the identified ageTSS was differentially methylated in both species. Although the average methylation levels of all TSS regions were highly correlated between marmosets and humans, with the majority of TSS being hypomethylated in sperm, more than 300 protein-coding genes were endowed with species-specifically (hypo)methylated TSS. Several genes of the glycosphingolipid (GSL) biosynthesis pathway, which plays a role in embryonic stem cell differentiation and regulation of development, were hypomethylated (<5%) in human and fully methylated (>95%) in marmoset sperm. The expression levels and patterns of defined sets of GSL genes differed considerably between human and marmoset pre-implantation embryo stages and blastocyst tissues, respectively.

Comparison of veterinarians and a deep learning tool in the diagnosis of equine ophthalmic diseases.

BACKGROUND/OBJECTIVES: The aim was to compare ophthalmic diagnoses made by veterinarians to a deep learning (artificial intelligence) software tool which was developed to aid in the diagnosis of equine ophthalmic diseases. As equine ophthalmology is a very specialised field in equine medicine, the tool may be able to help in diagnosing equine ophthalmic emergencies such as uveitis. STUDY DESIGN: In silico tool development and assessment of diagnostic performance. METHODS: A deep learning tool which was developed and trained for classification of equine ophthalmic diseases was tested with 40 photographs displaying various equine ophthalmic diseases. The same data set was shown to different groups of veterinarians (equine, small animal, mixed practice, other) using an opinion poll to compare the results and evaluate the performance of the programme. Convolutional Neural Networks (CNN) were trained on 2346 photographs of equine eyes, which were augmented to 9384 images. Two hundred and sixty-one separate unmodified images were used to evaluate the trained network. The trained deep learning tool was used on 40 photographs of equine eyes (10 healthy, 12 uveitis, 18 other diseases). An opinion poll was used to evaluate the diagnostic performance of 148 veterinarians in comparison to the software tool. RESULTS: The probability for the correct answer was 93% for the AI programme. Equine veterinarians answered correctly in 76%, whereas other veterinarians reached 67% probability for the correct diagnosis. MAIN LIMITATIONS: Diagnosis was solely based on images of equine eyes without the possibility to evaluate the inner eye. CONCLUSIONS: The deep learning tool proved to be at least equivalent to veterinarians in assessing ophthalmic diseases in photographs. We therefore conclude that the software tool may be useful in detecting potential emergency cases. In this context, blindness in horses may be prevented as the horse can receive accurate treatment or can be sent to an equine hospital. Furthermore, the tool gives less experienced veterinarians the opportunity to differentiate between uveitis and other ocular anterior segment disease and to support them in their decision-making regarding treatment.

GABA does not regulate stomatal CO2 signalling in Arabidopsis.

Optimal stomatal regulation is important for plant adaptation to changing environmental conditions and for maintaining crop yield. The guard-cell signal GABA is produced from glutamate by Glutamate Decarboxylase (GAD) during a reaction that generates carbon dioxide (CO2) as a by-product. Here, we investigated a putative connection between GABA signalling and the more clearly defined CO2 signalling pathway in guard cells. The GABA-deficient mutant lines gad2-1, gad2-2 and gad1/2/4/5 were examined for stomatal sensitivity to various CO2 concentrations. Our findings show a phenotypical discrepancy between the allelic mutant lines gad2-1 and gad2-2 - a weakened CO2 response in gad2-1 (GABI_474_E05) in contrast to a wild-type response in gad2-2 (SALK_028819) and gad1/2/4/5. Through transcriptomic and genomic investigation, we traced the response of gad2-1 to a deletion of full-length Mitogen-activated protein kinase 12 (MPK12) in the GABI-KAT line, thereafter as renamed gad2-1*. Guard cell-specific complementation of MPK12 restored the gad2-1* CO2 phenotype, which confirms the proposed importance of MPK12 to CO2 sensitivity. Additionally, we found that stomatal opening under low atmospheric CO2 occurs independently of the GABA-modulated opening-channel ALMT9. Our results confirm that GABA has a role in modulating the rate of stomatal opening and closing - but not in response to CO2  per se.

Synthetic co-culture in an interconnected two-compartment bioreactor system: violacein production with recombinant E. coli strains.

The concept of modular synthetic co-cultures holds considerable potential for biomanufacturing, primarily to reduce the metabolic burden of individual strains by sharing tasks among consortium members. However, current consortia often show unilateral relationships solely, without stabilizing feedback control mechanisms, and are grown in a shared cultivation setting. Such 'one pot' approaches hardly install optimum growth and production conditions for the individual partners. Hence, novel mutualistic, self-coordinating consortia are needed that are cultured under optimal growth and production conditions for each member. The heterologous production of the antibiotic violacein (VIO) in the mutually interacting E. coli-E. coli consortium serves as an example of this new principle. Interdependencies for growth control were implemented via auxotrophies for L-tryptophan and anthranilate (ANT) that were satisfied by the respective partner. Furthermore, VIO production was installed in the ANT auxotrophic strain. VIO production, however, requires low temperatures of 20-30 °C which conflicts with the optimum growth temperature of E. coli at 37 °C. Consequently, a two-compartment, two-temperature level setup was used, retaining the mutual interaction of the cells via the filter membrane-based exchange of medium. This configuration also provided the flexibility to perform individualized batch and fed-batch strategies for each co-culture member. We achieved maximum biomass-specific productivities of around 6 mg (g h)-1 at 25 °C which holds great promise for future applications.

Sex differences and age-related changes in vertebral body volume and volumetric bone mineral density at the thoracolumbar spine using opportunistic QCT.

Objectives: To quantitatively investigate the age- and sex-related longitudinal changes in trabecular volumetric bone mineral density (vBMD) and vertebral body volume at the thoracolumbar spine in adults. Methods: We retrospectively included 168 adults (mean age 58.7 ± 9.8 years, 51 women) who received ≥7 MDCT scans over a period of ≥6.5 years (mean follow-up 9.0 ± 2.1 years) for clinical reasons. Level-wise vBMD and vertebral body volume were extracted from 22720 thoracolumbar vertebrae using a convolutional neural network (CNN)-based framework with asynchronous calibration and correction of the contrast media phase. Human readers conducted semiquantitative assessment of fracture status and bony degenerations. Results: In the 40-60 years age group, women had a significantly higher trabecular vBMD than men at all thoracolumbar levels (p<0.05 to p<0.001). Conversely, men, on average, had larger vertebrae with lower vBMD. This sex difference in vBMD did not persist in the 60-80 years age group. While the lumbar (T12-L5) vBMD slopes in women only showed a non-significant trend of accelerated decline with age, vertebrae T1-11 displayed a distinct pattern, with women demonstrating a significantly accelerated decline compared to men (p<0.01 to p<0.0001). Between baseline and last follow-up examinations, the vertebral body volume slightly increased in women (T1-12: 1.1 ± 1.0 cm3; L1-5: 1.0 ± 1.4 cm3) and men (T1-12: 1.2 ± 1.3 cm3; L1-5: 1.5 ± 1.6 cm3). After excluding vertebrae with bony degenerations, the residual increase was only small in women (T1-12: 0.6 ± 0.6 cm3; L1-5: 0.7 ± 0.7 cm3) and men (T1-12: 0.7 ± 0.6 cm3; L1-5: 1.2 ± 0.8 cm3). In non-degenerated vertebrae, the mean change in volume was <5% of the respective vertebral body volumes. Conclusion: Sex differences in thoracolumbar vBMD were apparent before menopause, and disappeared after menopause, likely attributable to an accelerated and more profound vBMD decline in women at the thoracic spine. In patients without advanced spine degeneration, the overall volumetric changes in the vertebral body appeared subtle.

Virtual reality roleplays for patients with depression: A user experience evaluation.

Background: Virtual reality (VR) has been used successfully and effectively in psychotherapy for a variety of disorders. In the field of depression, there are only a few VR interventions and approaches. Although simple social interactions have been successfully modeled in VR for several mental disorders, there has been no transfer to the field of depression therapy. VR may be employed for psychodynamic psychotherapy to work on interpersonal conflict patterns. In this study, we developed and evaluated a VR intervention for the simulation of roleplay situations in the context of supportive-expressive therapy. Methods: We conducted a clinical user experience (UX) study at a psychotherapeutic clinic in Düsseldorf, Germany. Eight inpatients with depression and four therapists were included. Semi-structured interviews and qualitative content analysis were used to identify UX issues of the developed VR intervention. Usability questionnaires and technical usage data were also considered. The VR intervention consisted of two therapist-controlled roleplay scenarios designed to support work on the core conflictual relationship theme by allowing patients to interact in typical problematic social situations. Recorded VR roleplays allow for therapeutic debriefing with a change of perspective. Therapists were given the option of using the roleplay in multiple sessions. Results: All therapists conducted one session per patient with the VR intervention. From the patient interviews, 26 UX issues were extracted, of which one technical malfunction and two unclarities in the interaction with the VR agent were rated as major problems. From the therapist interviews, 14 UX issues were extracted, of which five were rated as major problems related to the interface in the dialog control or the complex system setup. Conclusion: The main problem was designing a dialog structure that allows both complex conversational flows and a clear control interface. In principle, VR roleplays could be integrated well and safely into therapy. The VR intervention shows promise for providing an emotional experience of interpersonal conflict patterns in the context of psychotherapy. Additionally, other roleplay situations involving various social problem areas must be created and evaluated in terms of the fit to the patients' core conflictual relationship themes.

Measuring facial mimicry: Affdex vs. EMG.

Facial mimicry is the automatic imitation of the facial affect expressions of others. It serves as an important component of interpersonal communication and affective co-experience. Facial mimicry has so far been measured by Electromyography (EMG), which requires a complex measuring apparatus. Recently, software for measuring facial expressions have become available, but it is still unclear how well it is suited for measuring facial mimicry. This study investigates the comparability of the automated facial coding software Affdex with EMG for measuring facial mimicry. For this purpose, facial mimicry was induced in 33 subjects by presenting naturalistic affect-expressive video sequences (anger, joy). The response of the subjects is measured simultaneously by facial EMG (corrugator supercilii muscle, zygomaticus major muscle) and by Affdex (action units lip corner puller and brow lowerer and affects joy and anger). Subsequently, the correlations between the measurement results of EMG and Affdex were calculated. After the presentation of the joy stimulus, there was an increase in zygomaticus muscle activity (EMG) about 400 ms after stimulus onset and an increase in joy and lip corner puller activity (Affdex) about 1200 ms after stimulus onset. The joy and the lip corner puller activity detected by Affdex correlate significantly with the EMG activity. After presentation of the anger stimulus, corrugator muscle activity (EMG) also increased approximately 400 ms after stimulus onset, whereas anger and brow lowerer activity (Affdex) showed no response. During the entire measurement interval, anger activity and brow lowerer activity (Affdex) did not correlate with corrugator muscle activity (EMG). Using Affdex, the facial mimicry response to a joy stimulus can be measured, but it is detected approximately 800 ms later compared to the EMG. Thus, electromyography remains the tool of choice for studying subtle mimic processes like facial mimicry.

Separating the wheat from the chaff: How to measure hospital quality in routine data?

OBJECTIVE: To measure hospital quality based on routine data available in many health care systems including the United States, Germany, the United Kingdom, Scandinavia, and Switzerland. DATA SOURCES AND STUDY SETTING: We use the Swiss Medical Statistics of Hospitals, an administrative hospital dataset of all inpatient stays in acute care hospitals in Switzerland for the years 2017-2019. STUDY DESIGN: We study hospital quality based on quality indicators used by leading agencies in five countries (the United States, the United Kingdom, Germany, Austria, and Switzerland) for two high-volume elective procedures: inguinal hernia repair and hip replacement surgery. We assess how least absolute shrinkage and selection operator (LASSO), a supervised machine learning technique for variable selection, and Mundlak corrections that account for unobserved heterogeneity between hospitals can be used to improve risk adjustment and correct for imbalances in patient risks across hospitals. DATA COLLECTION/EXTRACTION METHODS: The Swiss Federal Statistical Office collects annual data on all acute care inpatient stays including basic socio-demographic patient attributes and case-level diagnosis and procedure codes. PRINCIPAL FINDINGS: We find that LASSO-selected and Mundlak-corrected hospital random effects logit models outperform common practice logistic regression models used for risk adjustment. Besides the more favorable statistical properties, they have superior in- and out-of-sample explanatory power. Moreover, we find that Mundlak-corrected logits and the more complex LASSO-selected models identify the same hospitals as high or low-quality offering public health authorities a valuable alternative to standard logistic regression models. Our analysis shows that hospitals vary considerably in the quality they provide to patients. CONCLUSION: We find that routine hospital data can be used to measure clinically relevant quality indicators that help patients make informed hospital choices.

Pseudo-fermion functional renormalization group for spin models.

For decades, frustrated quantum magnets have been a seed for scientific progress and innovation in condensed matter. As much as the numerical tools for low-dimensional quantum magnetism have thrived and improved in recent years due to breakthroughs inspired by quantum information and quantum computation, higher-dimensional quantum magnetism can be considered as the final frontier, where strong quantum entanglement, multiple ordering channels, and manifold ways of paramagnetism culminate. At the same time, efforts in crystal synthesis have induced a significant increase in the number of tangible frustrated magnets which are generically three-dimensional in nature, creating an urgent need for quantitative theoretical modeling. We review the pseudo-fermion (PF) and pseudo-Majorana (PM) functional renormalization group (FRG) and their specific ability to address higher-dimensional frustrated quantum magnetism. First developed more than a decade ago, the PFFRG interprets a Heisenberg model Hamiltonian in terms of Abrikosov pseudofermions, which is then treated in a diagrammatic resummation scheme formulated as a renormalization group flow ofm-particle pseudofermion vertices. The article reviews the state of the art of PFFRG and PMFRG and discusses their application to exemplary domains of frustrated magnetism, but most importantly, it makes the algorithmic and implementation details of these methods accessible to everyone. By thus lowering the entry barrier to their application, we hope that this review will contribute towards establishing PFFRG and PMFRG as the numerical methods for addressing frustrated quantum magnetism in higher spatial dimensions.

Scoping review of climate change and mental health in Germany - Direct and indirect impacts, vulnerable groups, resilience factors.

Background: Climate change is a major threat to human health and has direct and indirect impacts on the human psyche. Methods: To assess the state of knowledge on the impact of climate change on mental health in Germany, a scoping review was conducted for the focus topics extreme weather events, temperature increase, intra-psychological processing, sociological aspects, and resilience factors. Ten studies met the inclusion criteria of the searches in the databases Academic Search Complete, CINAHL, PubPsych, PubMed, and PsychInfo. The majority of the studies looked at correlative relationships in a cross-sectional design. Results: There are indications of an accumulation of psychiatric disorders after extreme weather events; in addition, the risk of suicide increases with higher temperatures and it appears there is an increase in aggressive behaviour. The majority of people surveyed in Germany report concerns about the consequences of climate change, although these currently rarely lead to clinically significant impairments in mental health. Conclusions: Overall, the evidence for Germany must be classified as insufficient. In addition to the absolute priority of climate protection (mitigation) by reducing emissions, there is a particular need for additional research with a focus on vulnerable groups and possibilities for prevention and adaptation.

The influence of patient-centered teaching on medical students' stigmatization of the mentally ill.

Aim: Stigmatization by healthcare workers poses a challenge to providing care to the mentally ill. Bedside teaching during undergraduate medical education offers students an opportunity to directly interact with patients with a range of psychiatric disorders and thereby gather reflective experience. The present study investigates if this supervised contact with mentally ill patients during a one-week clinical course on psychosomatic medicine leads to stigma reduction in medical students. The factors influencing stigmatization were also investigated. Method: This was a prospective, non-randomized, controlled interventional study done in the 2019/20 winter semester involving fourth-year medical students who attended a week-long practical block on psychosomatic medicine (intervention group). This group was compared to students who had attended a week-long practical block with a somatic focus during the same time period (control group). Stigmatization was measured before and immediately upon completion of the week using the MICA-4 scale. Data on age, sex, experience with the mentally ill, interest in psychiatry/psychosomatics, and sense of self-worth were also gathered prior to starting the practical block. Analysis of the sample of 143 students with a complete basic data set was carried out using mixed ANOVA, multiple linear regression and moderator analysis. Results: In the context of clinical teaching with psychiatric patients, the stigmatization of the mentally ill among medical students decreased significantly more in the intervention group compared to the students in the control group who received instruction on somatic topics (p=.019, η2p=.04). In addition, being female, having previous experience with the mentally ill and general interest in the subjects of psychiatry or psychosomatics at T0 associated with lower stigma. In contrast, stigmatization was increased at the beginning of the study in males and those with low self-esteem. A moderating effect of the factors on stigma reduction was not seen. Conclusion: Undergraduate clinical instruction that enables direct contact and reflective experiences with the mentally ill leads to a reduction in the stigmatizing attitudes held by medical students toward the mentally ill. This underscores the need to have practical clinical instruction using patients.

Sex-differences in the association of interleukin-10 and interleukin-12 variants with the progression of hepatitis B virus infection in Caucasians.

AIM: Interleukin (IL)-10 and IL-12 contribute to immune responses against hepatitis B virus (HBV) infection. Polymorphisms in the IL-10 and IL-12A genes might affect the clinical outcome of HBV infection. We evaluated the association of IL-10 rs1800896 and rs3024490, and IL-12A rs568408 and rs2243115 with the progression of HBV infection and development of severe liver disease stages in a white European population. METHOD: A total of 636 white European patients with chronic HBV infection, 239 individuals with spontaneous HBV surface antigen seroclearance, and 254 healthy controls were enrolled. The chronic HBV infection group included patients with hepatitis B envelope antigen (HBeAg) negative chronic hepatitis B (n = 255), with HBeAg positive chronic hepatitis B (n = 99) and with HBeAg negative HBV infection (n = 228). A total of 104 chronically infected patients were diagnosed with liver cirrhosis. Serum levels of cytokines were measured in patients with HBV infection (n = 195) and in healthy controls (n = 160). RESULTS: In adjusted multivariate analysis, the IL-10 rs1800896 AG/GG genotypes were significantly associated with an increased probability of HBV surface antigen seroclearance (OR = 1.75, 95% CI 1.04-2.94, p = 0.034), with an increased likelihood of HBeAg negative chronic infection (OR = 1.93, 95% CI 1.05-3.54, p = 0.034) and with increased serum cytokines levels in female patients. In contrast, the IL-12A rs568408 AG/AA genotypes were independently associated with an increased risk to develop liver cirrhosis, with an OR of 1.90 (95% CI 1.07-3.39, p = 0.029) in male patients. CONCLUSION: The current study shows a sex-related association of the IL-10 single-nucleotide polymorphism rs1800896 and IL-12A single-nucleotide polymorphism rs568408 with different stages of HBV infection and with HBV-related liver cirrhosis in white European patients.

Surgeon supply and healthcare quality: Are revision rates for hip and knee replacements lower in hospitals that employ more surgeons?

We study the link between department-wide surgeon supply and quality of care for two major elective medical procedures. Several countries have adopted policies to concentrate medical procedures in high-volume hospitals. While higher patient volumes might translate to higher quality, we provide evidence for a positive relationship between surgeon supply and hospital revision rates for hip and knee replacement surgery. Hence, hospital performance decreases with higher surgeon supply, and this finding holds conditional on patient volumes.

Emergence of resistance-associated variants during sofosbuvir treatment in chronically infected hepatitis E patients.

BACKGROUND AND AIMS: Chronic HEV infections remain a serious problem in immunocompromised patients, as specifically approved antiviral drugs are unavailable. In 2020, a 24-week multicenter phase II pilot trial was carried out, evaluating the nucleotide analog sofosbuvir by treating nine chronically HEV-infected patients with sofosbuvir (Trial Number NCT03282474). During the study, antiviral therapy reduced virus RNA levels initially but did not lead to a sustained virologic response. Here, we characterize the changes in HEV intrahost populations during sofosbuvir treatment to identify the emergence of treatment-associated variants. APPROACH AND RESULTS: We performed high-throughput sequencing on RNA-dependent RNA polymerase sequences to characterize viral population dynamics in study participants. Subsequently, we used an HEV-based reporter replicon system to investigate sofosbuvir sensitivity in high-frequency variants. Most patients had heterogenous HEV populations, suggesting high adaptability to treatment-related selection pressures. We identified numerous amino acid alterations emerging during treatment and found that the EC 50 of patient-derived replicon constructs was up to ~12-fold higher than the wild-type control, suggesting that variants associated with lower drug sensitivity were selected during sofosbuvir treatment. In particular, a single amino acid substitution (A1343V) in the finger domain of ORF1 could reduce susceptibility to sofosbuvir significantly in 8 of 9 patients. CONCLUSIONS: In conclusion, viral population dynamics played a critical role during antiviral treatment. High population diversity during sofosbuvir treatment led to the selection of variants (especially A1343V) with lower sensitivity to the drug, uncovering a novel mechanism of resistance-associated variants during sofosbuvir treatment.

Prevention of M2 polarization and temporal limitation of differentiation in monocytes by extracellular ATP.

BACKGROUND: Elevated levels of extracellular adenosine triphosphate (ATP) modulate immunologic pathways and are considered to be a danger signal in inflammation, lung fibrosis and cancer. Macrophages can be classified into two main types: M1 macrophages are classically activated, pro-inflammatory macrophages, whereas M2 macrophages are alternatively activated, pro-fibrotic macrophages. In this study, we examined the effect of ATP on differentiation of native human monocytes into these macrophage subtypes. We characterized M1 and M2 like macrophages by their release of Interleukin-1beta (IL-1ß) and Chemokine (C-C motif) ligand 18 (CCL18), respectively. RESULTS: Monocytes were stimulated with ATP or the P2X7 receptor agonist Benzoylbenzoyl-ATP (Bz-ATP), and the production of various cytokines was analyzed, with a particular focus on CCL18 and IL-1ß, along with the expression of different purinergic receptors. Over a 72 h period of cell culture, monocytes spontaneously differentiated to M2 like macrophages, as indicated by an increased release of CCL18. Immediate stimulation of monocytes with ATP resulted in a dose-dependent reduction in CCL18 release, but had no effect on the concentration of IL-1ß. In contrast, delayed stimulation with ATP had no effect on either CCL18 or IL-1ß release. Similar results were observed in a model of inflammation using lipopolysaccharide-stimulated human monocytes. Stimulation with the P2X7 receptor agonist Bz-ATP mimicked the effect of ATP on M2-macrophage differentiation, indicating that P2X7 is involved in ATP-induced inhibition of CCL18 release. Indeed, P2X7 was downregulated during spontaneous M2 differentiation, which may partially explain the ineffectiveness of late ATP stimulation of monocytes. However, pre-incubation of monocytes with PPADS, Suramin (unselective P2X- and P2Y-receptor blockers) and KN62 (P2X7-antagonist) failed to reverse the reduction of CCL18 by ATP. CONCLUSIONS: ATP prevents spontaneous differentiation of monocytes into M2-like macrophages in a dose- and time-dependent manner. These effects were not mediated by P2X and P2Y receptors.