A DNA-dependent protease involved in DNA-protein crosslink repair.

Toxic DNA-protein crosslinks (DPCs) arise by ionizing irradiation and UV light, are particularly caused by endogenously produced reactive compounds such as formaldehyde, and also occur during compromised topoisomerase action. Although nucleotide excision repair and homologous recombination contribute to cell survival upon DPCs, hardly anything is known about mechanisms that target the protein component of DPCs directly. Here, we identify the metalloprotease Wss1 as being crucial for cell survival upon exposure to formaldehyde and topoisomerase 1-dependent DNA damage. Yeast mutants lacking Wss1 accumulate DPCs and exhibit gross chromosomal rearrangements. Notably, in vitro assays indicate that substrates such as topoisomerase 1 are processed by the metalloprotease directly and in a DNA-dependent manner. Thus, our data suggest that Wss1 contributes to survival of DPC-harboring cells by acting on DPCs proteolytically. We propose that DPC proteolysis enables repair of these unique lesions via downstream canonical DNA repair pathways.

Simple blood tests to diagnose compensated advanced chronic liver disease and stratify the risk of clinically significant portal hypertension.

BACKGROUND AND AIMS: Compensated advanced chronic liver disease (cACLD) identifies patients at risk for clinically significant portal hypertension (CSPH), and thus, for liver-related complications. The limited availability of liver stiffness measurements (LSM) impedes the identification of patients at risk for cACLD/CSPH outside of specialized clinics. We aimed to develop a blood-based algorithm to identify cACLD by fibrosis-4 (FIB-4) and CSPH by von Willebrand factor/platelet count ratio (VITRO). APPROACH AND RESULTS: Patients with (suspected) compensated chronic liver disease undergoing FIB-4+LSM were included in the LSM/FIB-4 cohorts from Vienna and Salzburg. The HVPG/VITRO cohorts included patients undergoing HVPG-measurement + VITRO from Vienna and Bern.LSM/FIB-4-derivation-cohort: We included 6143 patients, of whom 211 (3.4%) developed hepatic decompensation. In all, 1724 (28.1%) had LSM ≥ 10 kPa, which corresponded to FIB-4 ≥ 1.75. Importantly, both LSM (AUROC:0.897 [95% CI:0.865-0.929]) and FIB-4 (AUROC:0.914 [95% CI:0.885-0.944]) were similarly accurate in predicting hepatic decompensation within 3 years. FIB-4 ≥ 1.75 identified patients at risk for first hepatic decompensation (5 y-cumulative incidence:7.6%), while in those <1.75, the risk was negligible (0.3%).HVPG/VITRO-derivation cohort: 247 patients of whom 202 had cACLD/FIB-4 ≥ 1.75 were included. VITRO exhibited an excellent diagnostic performance for CSPH (AUROC:0.889 [95% CI:0.844-0.934]), similar to LSM (AUROC:0.856 [95% CI:0.801-0.910], p = 0.351) and the ANTICIPATE model (AUROC:0.910 [95% CI:0.869-0.952], p = 0.498). VITRO < 1.0/ ≥ 2.5 ruled-out (sensitivity:100.0%)/ruled-in (specificity:92.4%) CSPH. The diagnostic performance was comparable to the Baveno-VII criteria.LSM/FIB-4-derivation cohort findings were externally validated in n = 1560 patients, while HVPG/VITRO-derivation-cohort findings were internally (n = 133) and externally (n = 55) validated. CONCLUSIONS: Simple, broadly available laboratory tests (FIB-4/VITRO) facilitate cACLD detection and CSPH risk stratification in patients with (suspected) liver disease. This blood-based approach is applicable outside of specialized clinics and may promote early intervention.

Prognostic performance of non-invasive tests for portal hypertension is comparable to that of hepatic venous pressure gradient.

BACKGROUND & AIMS: Non-invasive tests to assess the probability of clinically significant portal hypertension (CSPH) - including the ANTICIPATE±NASH models based on liver stiffness measurement and platelet count±BMI, and the von Willebrand factor antigen to platelet count ratio (VITRO) - have fundamentally changed the management of compensated advanced chronic liver disease (cACLD). However, their prognostic utility has not been compared head-to-head to the gold standard for prognostication in cACLD, i.e. the hepatic venous pressure gradient (HVPG). METHODS: Patients with cACLD (liver stiffness measurement ≥10 kPa) who underwent advanced characterization via same-day HVPG/non-invasive test assessment from 2007-2022 were retrospectively included. Long-term follow-up data on hepatic decompensation was recorded. RESULTS: Four hundred and twenty patients with cACLD of varying etiologies, with a CSPH prevalence of 67.6%, were included. The cumulative incidence of hepatic decompensation at 1 and 2 years was 4.7% and 8.0%, respectively. HVPG, VITRO, and ANTICIPATE±NASH-CSPH-probability showed similar time-dependent prognostic value (AUROCs 0.683-0.811 at 1 year and 0.699-0.801 at 2 years). In competing risk analyses adjusted for MELD score and albumin, HVPG (adjusted subdistribution hazard ratio [aSHR] 1.099 [95% CI 1.054-1.150] per mmHg; p <0.001), or VITRO (aSHR 1.134 [95% CI 1.062-1.211] per unit; p <0.001), or ANTICIPATE±NASH-CSPH-probability (aSHR 1.232 [95% CI 1.094-1.387] per 10%; p <0.001) all predicted first decompensation during follow-up. Previously proposed cut-offs (HVPG ≥10 mmHg vs. <10 mmHg, VITRO ≥2.5 vs. <2.5, and ANTICIPATE-CSPH probability ≥60% vs. <60%) all accurately discriminated between patients at negligible risk and those at substantial risk of hepatic decompensation. CONCLUSIONS: The prognostic performance of ANTICIPATE±NASH-CSPH-probability and VITRO is comparable to that of HVPG, supporting their utility for identifying patients who may benefit from medical therapies to prevent first hepatic decompensation. IMPACT AND IMPLICATIONS: Non-invasive tests have revolutionized the diagnosis and management of clinically significant portal hypertension in patients with compensated advanced chronic liver disease (cACLD). However, limited data exists regarding the prognostic utility of non-invasive tests in direct comparison to the gold standard for prognostication in cACLD, i.e. the hepatic venous pressure gradient. In our study including 420 patients with cACLD, the ANTICIPATE±NASH model and VITRO yielded similar AUROCs to hepatic venous pressure gradient for hepatic decompensation within 1 to 2 years. Thus, non-invasive tests should be applied and updated in yearly intervals in clinical routine to identify patients at short-term risk, thereby identifying patients who may benefit from treatment aimed at preventing hepatic decompensation.

Validation of Baveno VII criteria and other non-invasive diagnostic algorithms for clinically significant portal hypertension in hepatitis delta.

BACKGROUND & AIMS: Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH) require validation in patients with hepatitis D virus (HDV)-related compensated advanced chronic liver disease (cACLD). Therefore, we aimed to validate existing NIT algorithms for CSPH in this context. METHODS: Patients with HDV-cACLD (LSM ≥10 kPa or histological METAVIR F3/F4 fibrosis) who underwent paired HVPG and NIT assessment at Medical University of Vienna or Hannover Medical School between 2013 and 2023 were retrospectively included. Liver stiffness measurement (LSM), von Willebrand factor to platelet count ratio (VITRO), and spleen stiffness measurement (SSM) were assessed. Individual CSPH risk was calculated according to previously published models (ANTICIPATE, 3P/5P). The diagnostic performance of Baveno VII criteria and refined algorithms (Baveno VII-VITRO, Baveno VII-SSM) was evaluated. The prognostic utility of NITs was investigated in the main cohort and an independent, multicenter, validation cohort. RESULTS: Fifty-one patients (HVPG ≥10 mmHg/CSPH prevalence: 62.7%, varices: 42.2%) were included. Patients with CSPH had significantly higher LSM (25.8 [17.2-31.0] vs. 14.0 [10.5-19.8] kPa; p < 0.001), VITRO (n = 31, 3.5 [2.7-4.5] vs. 1.3 [0.6-2.0] %/[G/L]; p < 0.001), and SSM (n = 20, 53.8 [41.7-75.5] vs. 24.0 [17.0-33.9] kPa; p < 0.001). Composite CSPH risk models yielded excellent AUROCs (ANTICIPATE: 0.885, 3P: 0.903, 5P: 0.912). Baveno VII criteria ruled out CSPH with 100% sensitivity and ruled in CSPH with 84.2% specificity. The Baveno VII 'grey zone' (41.1%) was significantly reduced by Baveno VII-VITRO or Baveno VII-SSM algorithms, which maintained diagnostic accuracy. Hepatic decompensation within 2 years only occurred in patients who had CSPH or met Baveno VII rule-in criteria. The prognostic value of NITs was confirmed in the validation cohort comprising 92 patients. CONCLUSIONS: Standalone and composite NIT/diagnostic algorithms are useful for CSPH diagnosis in patients with HDV-cACLD. Thus, NITs may be applied to identify and prioritize patients with CSPH for novel antiviral treatments against chronic hepatitis D. IMPACT AND IMPLICATIONS: Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH) have been developed to identify patients with compensated advanced chronic liver disease (cACLD) at risk of decompensation, but conflicting data has been published regarding the accuracy of liver stiffness measurement (LSM) for the staging of fibrosis in patients infected with hepatitis D virus (HDV). In our study, including 51 patients with HDV-cACLD, LSM- and lab-based NITs yielded high AUROCs for CSPH. Moreover, only patients with CSPH or high non-invasively assessed CSPH risk were at risk of decompensation within 2 years, with the prognostic value of NITs confirmed in a validation cohort. Thus, NITs should be applied and updated in yearly intervals in clinical routine to identify patients with HDV-cACLD at short-term risk of clinical events; NITs may also guide prioritization for novel antiviral treatment options.

Post-treatment LSM rather than change during treatment predicts decompensation in patients with cACLD after HCV cure.

BACKGROUND & AIMS: Baveno VII has defined a clinically significant (i.e., prognostically meaningful) decrease in liver stiffness measurement (LSM) in cACLD as a decrease of ≥20% associated with a final LSM <20 kPa or any decrease to <10 kPa. However, these rules have not yet been validated against direct clinical endpoints. METHODS: We retrospectively analysed patients with cACLD (LSM ≥10 kPa) with paired liver stiffness measurement (LSM) before (BL) and after (FU) HCV cure by interferon-free therapies from 15 European centres. The cumulative incidence of hepatic decompensation was compared according to these criteria, considering hepatocellular carcinoma and non-liver-related death as competing risks. RESULTS: A total of 2,335 patients followed for a median of 6 years were analysed. Median BL-LSM was 16.6 kPa with 37.1% having ≥20 kPa. After HCV cure, FU-LSM decreased to a median of 10.9 kPa (<10 kPa: 1,002 [42.9%], ≥20 kPa: 465 [19.9%]) translating into a median LSM change of -5.3 (-8.8 to -2.4) kPa corresponding to -33.9 (-48.0 to -15.9) %. Patients achieving a clinically significant decrease (65.4%) had a significantly lower risk of hepatic decompensation (subdistribution hazard ratio: 0.12, 95% CI 0.04-0.35, p <0.001). However, these risk differences were primarily driven by a negligible risk in patients with FU-LSM <10 kPa (5-year cumulative incidence: 0.3%) compared to a high risk in patients with FU-LSM ≥20 kPa (16.6%). Patients with FU-LSM 10-19.9 kPa (37.4%) also had a low risk of hepatic decompensation (5-year cumulative incidence: 1.7%), and importantly, the risk of hepatic decompensation did not differ between those with/without an LSM decrease of ≥20% (p = 0.550). CONCLUSIONS: FU-LSM is key for risk stratification after HCV cure and should guide clinical decision making. LSM dynamics do not hold significant prognostic information in patients with FU-LSM 10-19.9 kPa, and thus, their consideration is not of sufficient incremental value in the specific context of HCV cure. IMPACT AND IMPLICATIONS: Liver stiffness measurement (LSM) is increasingly applied as a prognostic biomarker and commonly decreases in patients with compensated advanced chronic liver disease achieving HCV cure. Although Baveno VII proposed criteria for a clinically significant decrease, little is known about the prognostic utility of LSM dynamics (changes through antiviral therapy). Interestingly, in those with a post-treatment LSM of 10-19.9 kPa, LSM dynamics did not provide incremental information, arguing against the consideration of LSM dynamics as prognostic criteria. Thus, post-treatment LSM should guide the management of patients with compensated advanced chronic liver disease achieving HCV cure.

[Neurorehabilitation after epilepsy surgery in the temporal lobe in patients with specific neurocognitive risk profiles]. / Anforderungen an die Neurorehabilitation nach epilepsiechirurgischen Eingriffen im linken Temporallappen bei Patienten mit neurokognitivem Risikoprofil.

INTRODUCTION: In case of pharmacoresistant focal epilepsy, surgery is often the only way to achieve seizure freedom. These operations may result in cognitive deficits, especially with surgery in the left temporal lobe. The aim of this study was to determine whether patients operated in the left or right temporal lobe, respectively, have different cognitive outcomes. Furthermore, it was investigated if there was a positive influence of occupational therapy on neurorehabilitation in epilepsy patients. METHODS: In all patients cognitive performance was assessed preoperatively and six months postoperatively. Patient groups with surgery in the right and left temporal lobe were compared. Additionally, single cases of patients who had undergone extensive pre- and postoperative occupational therapy were analyzed. RESULTS: There was a significantly better cognitive outcome in patients who underwent surgery in their right temporal lobe. Occupational therapy was highly beneficial in patients after left temporal lobe surgery. CONCLUSION: Occupational therapy after left temporal lobe surgery is adapted to find individual solutions for the patient's problems and to implement effective cognitive training strategies.

Carvedilol Achieves Higher Hemodynamic Response and Lower Rebleeding Rates Than Propranolol in Secondary Prophylaxis.

BACKGROUND & AIMS: Carvedilol induces stronger decreases in hepatic venous pressure gradient (HVPG) than conventional nonselective ß-blockers (ie, propranolol). Limited data exist on the efficacy of carvedilol in secondary prophylaxis of variceal bleeding. METHODS: Patients undergoing paired HVPG measurements for guiding secondary prophylaxis with either carvedilol or propranolol were included in this retrospective analysis. All patients also underwent band ligation. Changes in HVPG and systemic hemodynamics were compared between the 2 groups. Long-term follow-up data on rebleeding, acute kidney injury, nonbleeding decompensation, and liver-related death were analyzed applying competing risk regression. RESULTS: Eighty-seven patients (carvedilol/propranolol, n = 45/42) were included in our study. The median baseline HVPG was 21 mm Hg (interquartile range, 18-24 mm Hg), and 39.1%/48.3%/12.6% had Child-Turcotte-Pugh A/B/C cirrhosis, respectively. Upon nonselective ß-blocker initiation, HVPG decreased more strongly in carvedilol users (median relative decrease, -20% [interquartile range: -29% to -10%] vs -11% [-22% to -5%] for propranolol; P = .027), who also achieved chronic HVPG response more often (53.3% vs 28.6%; P = .034). Cumulative incidences for rebleeding (Gray test, P = .027) and liver-related death (P = .036) were significantly lower in patients taking carvedilol compared with propranolol. Notably, ascites development/worsening also was observed less commonly in carvedilol patients (P = .012). Meanwhile, acute kidney injury rates did not differ between the 2 groups (P = .255). Stratifying patients by HVPG response status yielded similar results. The prognostic value of carvedilol intake was confirmed in competing risk regression models. CONCLUSIONS: Carvedilol induces more marked reductions in HVPG than propranolol in secondary prophylaxis of variceal bleeding, and thus is associated with lower rates of rebleeding, liver-related death, and further nonbleeding decompensation.

Endovascular Repair of Penetrating Thoracic Aortic Ulcers Using Tubular Stent Grafts Versus Stent Grafts With a Proximal Scallop.

PURPOSE: In penetrating aortic ulcers (PAUs), limited data support tubular thoracic endovascular aortic repair (TEVAR) as a viable treatment option. For treatment of more proximal PAUs, hybrid approaches and-more recently-scalloped TEVAR (scTEVAR) have been advocated. Outcomes of scTEVAR specifically for PAUs have not yet been reported. This study reports long-term outcomes for tubular and scTEVAR in PAUs and compares the safety profile in both cohorts regarding the significantly more proximal landing zone (LZ) for scTEVAR. MATERIALS AND METHODS: This single-center retrospective cohort study includes all nonacute patients treated for complicated PAU with scTEVAR and tubular TEVAR. Patient and PAU characteristics as well as procedural success, complication and reintervention rates, and all-cause and aortic mortality were analyzed. RESULTS: Of 212 TEVAR procedures reviewed, 21 patients with tubular TEVAR and 19 patients with scTEVAR were included. Patient and PAU characteristics were similar, and LZ was significantly more proximal in the scTEVAR cohort (p=0.0001), with similar number and types of supra-aortic revascularization procedures. Clinical success was reached in all 40 patients (100%), and reintervention rate was 2/21 (9.5%) and 1/19 (5.3%), respectively. Over the mean follow-up of 63 (TEVAR) and 53 (scTEVAR) months, clinical success was stable in all patients with one (abdominal) aortic-related mortality in the scTEVAR cohort. CONCLUSION: Treatment of complicated PAUs with TEVAR as well as scTEVAR provides excellent and similar clinical success, stability of clinical success, and aortic survival with acceptable complication and reintervention rates. Scalloped TEVAR safely lengthens the proximal sealing zone to address more proximal pathologies. CLINICAL IMPACT: Treatment of asymptomatic complicated penetrating aortic ulcers (PAUs) with thoracic endovascular aortic repair (TEVAR) provides excellent clinical success and acceptable complication and reintervention rates. More patients become amenable to endovascular treatment by including scalloped TEVAR (scTEVAR) as a means to safely lengthen the proximal sealing zone to address more proximal pathologies.

The presence of a guard vicariously drives split sex ratios in a facultatively social bee.

Split sex ratios provide broad insights into how reproductive strategies evolve, and historically have special relevance to the evolution of eusociality. Yet almost no attention has been directed to situations where split sex ratios may potentially decrease the payoffs for worker-like behaviour, increasing selective thresholds for eusociality. We examined sex ratios in a facultatively social colletid bee, Amphylaeus morosus. Sex ratios in this bee vary strongly with the presence of a nest guard and in a pattern that does not conform to assumptions of previous models in which split sex ratios facilitate altruism. While the production of daughters was constant across social and solitary nests, mothers produced more brood when a non-reproductive guard was present, but these extra brood were all male. This leads to split sex ratios, vicariously driven by guards that are unable to manipulate sex ratios in their favour. Importantly, if guarding becomes more common in a population this would lead to an excess of males and lower the genetic value of these extra males to guards, effectively putting a brake on selection for worker-like behaviour.

[Patient Preferences for Exercise Therapy in People with Severe Mental Illness in Germany]. / Der subjektive Stellenwert von Bewegungs- und Sporttherapie bei Menschen mit schwerer psychischer Erkrankung in Deutschland.

PURPOSE: Assessing the experience with and the attitudes towards exercise therapy in persons with severe mental illness (SMI). Furthermore, potential variables of high preference towards exercise therapy are investigated. METHODS: Cross-sectional observational study of SMI patients aged between 18 and 65 years (n=385). Patients were interviewed by trained staff using standardised instruments. Potential variables were analysed using a hierarchic binary logistic regression model. RESULTS: 84,4% of SMI patients had a high preference for exercise therapy; of these, 44,1% exercised regularly. Among patients with severe mental illness especially a higher value in the GAF-assessment (p=0,041) and living in a metropolitan area (p=0,011) predict a high preference for exercise therapy. CONCLUSION: Most of the patients with severe mental illness interviewed in this study place a surprisingly high value on sports and exercise therapy. Due to the increasing evidence with regard to positive effects of these therapies, it may be an excellent starting point to expand sports and exercise therapy as part of a comprehensive treatment plan. At the same time, strategies for everyday transfer need to be implemented more rigorously.

Association of Intraventricular Fibrinolysis With Clinical Outcomes in Intracerebral Hemorrhage: An Individual Participant Data Meta-Analysis.

BACKGROUND: In patients with intracerebral hemorrhage (ICH), the presence of intraventricular hemorrhage constitutes a promising therapeutic target. Intraventricular fibrinolysis (IVF) reduces mortality, yet impact on functional disability remains unclear. Thus, we aimed to determine the influence of IVF on functional outcomes. METHODS: This individual participant data meta-analysis pooled 1501 patients from 2 randomized trials and 7 observational studies enrolled during 2004 to 2015. We compared IVF versus standard of care (including placebo) in patients treated with external ventricular drainage due to acute hydrocephalus caused by ICH with intraventricular hemorrhage. The primary outcome was functional disability evaluated by the modified Rankin Scale (mRS; range: 0-6, lower scores indicating less disability) at 6 months, dichotomized into mRS score: 0 to 3 versus mRS: 4 to 6. Secondary outcomes included ordinal-shift analysis, all-cause mortality, and intracranial adverse events. Confounding and bias were adjusted by random effects and doubly robust models to calculate odds ratios and absolute treatment effects (ATE). RESULTS: Comparing treatment of 596 with IVF to 905 with standard of care resulted in an ATE to achieve the primary outcome of 9.3% (95% CI, 4.4-14.1). IVF treatment showed a significant shift towards improved outcome across the entire range of mRS estimates, common odds ratio, 1.75 (95% CI, 1.39-2.17), reduced mortality, odds ratio, 0.47 (95% CI, 0.35-0.64), without increased adverse events, absolute difference, 1.0% (95% CI, -2.7 to 4.8). Exploratory analyses provided that early IVF treatment (≤48 hours) after symptom onset was associated with an ATE, 15.2% (95% CI, 8.6-21.8) to achieve the primary outcome. CONCLUSIONS: As compared to standard of care, the administration of IVF in patients with acute hydrocephalus caused by intracerebral and intraventricular hemorrhage was significantly associated with improved functional outcome at 6 months. The treatment effect was linked to an early time window <48 hours, specifying a target population for future trials.

HCC risk stratification after cure of hepatitis C in patients with compensated advanced chronic liver disease.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality in patients with advanced chronic liver disease (ACLD) caused by chronic hepatitis C who have achieved sustained virologic response (SVR). We developed risk stratification algorithms for de novo HCC development after SVR and validated them in an independent cohort. METHODS: We evaluated the occurrence of de novo HCC in a derivation cohort of 527 patients with pre-treatment ACLD and SVR to interferon-free therapy, in whom alpha-fetoprotein (AFP) and non-invasive surrogates of portal hypertension including liver stiffness measurement (LSM) were assessed pre-/post-treatment. We validated our results in 1,500 patients with compensated ACLD (cACLD) from other European centers. RESULTS: During a median follow-up (FU) of 41 months, 22/475 patients with cACLD (4.6%, 1.45/100 patient-years) vs. 12/52 decompensated patients (23.1%, 7.00/100 patient-years, p <0.001) developed de novo HCC. Since decompensated patients were at substantial HCC risk, we focused on cACLD for all further analyses. In cACLD, post-treatment-values showed a higher discriminative ability for patients with/without de novo HCC development during FU than pre-treatment values or absolute/relative changes. Models based on post-treatment AFP, alcohol consumption (optional), age, LSM, and albumin, accurately predicted de novo HCC development (bootstrapped Harrel's C with/without considering alcohol: 0.893/0.836). Importantly, these parameters also provided independent prognostic information in competing risk analysis and accurately stratified patients into low- (~2/3 of patients) and high-risk (~1/3 of patients) groups in the derivation (algorithm with alcohol consumption; 4-year HCC-risk: 0% vs. 16.5%) and validation (3.3% vs. 17.5%) cohorts. An alternative approach based on alcohol consumption (optional), age, LSM, and albumin (i.e., without AFP) also showed a robust performance. CONCLUSIONS: Simple algorithms based on post-treatment age/albumin/LSM, and optionally, AFP and alcohol consumption, accurately stratified patients with cACLD based on their risk of de novo HCC after SVR. Approximately two-thirds were identified as having an HCC risk <1%/year in both the derivation and validation cohort, thereby clearly falling below the cost-effectiveness threshold for HCC surveillance. LAY SUMMARY: Simple algorithms based on age, alcohol consumption, results of blood tests (albumin and α-fetoprotein), as well as liver stiffness measurement after the end of hepatitis C treatment identify a large proportion (approximately two-thirds) of patients with advanced but still asymptomatic liver disease who are at very low risk (<1%/year) of liver cancer development, and thus, might not need to undergo 6-monthly liver ultrasound.

Extreme reproductive skew at the dawn of sociality is consistent with inclusive fitness theory but problematic for routes to eusociality.

To understand the earliest stages of social evolution, we need to identify species that are undergoing the initial steps into sociality. Amphylaeus morosus is the only unambiguously known social species in the bee family Colletidae and represents an independent origin of sociality within the Apoidea. This allows us to investigate the selective factors promoting the transition from solitary to social nesting. Using genome-wide SNP genotyping, we infer robust pedigree relationships to identify maternity of brood and intracolony relatedness for colonies at the end of the reproductive season. We show that A. morosus forms both matrifilial and full-sibling colonies, both involving complete or almost complete monopolization over reproduction. In social colonies, the reproductive primary was also the primary forager with the secondary female remaining in the nest, presumably as a guard. Social nesting provided significant protection against parasitism and increased brood survivorship in general. We show that secondary females gain large indirect fitness benefits from defensive outcomes, enough to satisfy the conditions of inclusive fitness theory, despite an over-production of males in social colonies. These results suggest an avenue to sociality that involves high relatedness and, very surprisingly, extreme reproductive skew in its earliest stages and raises important questions about the evolutionary steps in pathways to eusociality.

Characterization of hepatic zonation in mice by mass-spectrometric and antibody-based proteomics approaches.

Periportal and perivenous hepatocytes show zonal heterogeneity in metabolism and signaling. Here, hepatic zonation in mouse liver was analyzed by non-targeted mass spectrometry (MS) and by the antibody-based DigiWest technique, yielding a comprehensive overview of protein expression in periportal and perivenous hepatocytes. Targeted immunoaffinity-based proteomics were used to substantiate findings related to drug metabolism. 165 (MS) and 82 (DigiWest) zonated proteins were identified based on the selected criteria for statistical significance, including 7 (MS) and 43 (DigiWest) proteins not identified as zonated before. New zonated proteins especially comprised kinases and phosphatases related to growth factor-dependent signaling, with mainly periportal localization. Moreover, the mainly perivenous zonation of a large panel of cytochrome P450 enzymes was characterized. DigiWest data were shown to complement the MS results, substantially improving possibilities to bioinformatically identify zonated biological processes. Data mining revealed key regulators and pathways preferentially active in either periportal or perivenous hepatocytes, with ß-catenin signaling and nuclear xeno-sensing receptors as the most prominent perivenous regulators, and several kinase- and G-protein-dependent signaling cascades active mainly in periportal hepatocytes. In summary, the present data substantially broaden our knowledge of hepatic zonation in mouse liver at the protein level.

HCV hotline facilitates Hepatitis C elimination during the COVID-19 pandemic.

The COVID-19 pandemic necessitates healthcare restrictions that also affected ongoing hepatitis C virus (HCV) elimination efforts. We assessed the value of a physician-operated HCV hotline on treatment and cure rates throughout the pandemic. All HCV patients undergoing HCV therapy at the Vienna General Hospital from 2019 to 2021 were included. An HCV hotline was established in 2019 and provided services including phone calls, text messages and voicemails. Patients were stratified by date of HCV therapy: 2019 (pre-COVID) vs. 2020/2021 (during-COVID) and use of the HCV hotline: users vs. non-users. Overall, 220 patients were included (pre-COVID: n = 91 vs. during-COVID: n = 129). The prevalence of intravenous drug use (60.5%) and alcohol abuse (24.8%) was high during COVID. During COVID, the number of DAA treatment starts declined by 24.2% (n = 69) in 2020 and by 34.1% (n = 60) in 2021 vs. pre-COVID (n = 91, 100%). Significantly more patients used the HCV hotline during-COVID (95.3%) vs. pre-COVID (65.9%; p < .001). Sustained virologic response (SVR) was 84.6% pre-COVID and 86.0% during-COVID. HCV hotline users achieved higher SVR rates during-COVID (88.2% vs. 33.3%, p = .004), but also pre-COVID (96.7% vs. 61.3%, p < .001) compared with non-users. Considering only patients with completed DAA treatments, SVR rates remained similarly high during-COVID (96.9%) versus pre-COVID (98.1%). HCV treatment initiations decreased during-COVID but importantly, nearly all DAA-treated HCV patients used the HCV hotline during the COVID pandemic. Overall, the SVR rate remained at 88.2% during COVID and was particularly high in HCV phone users-most likely due to facilitation of adherence.

Glucocorticoid modulation of synaptic plasticity in the human temporal cortex of epilepsy patients: Does chronic stress contribute to memory impairment?

OBJECTIVE: Memory impairment is common in patients with temporal lobe epilepsy and seriously affects life quality. Chronic stress is a recognized cofactor in epilepsy and can also impair memory function. Furthermore, increased cortisol levels have been reported in epilepsy patients. Animal models have suggested that aggravating effects of stress on memory and synaptic plasticity were mediated via glucocorticoids. The aim of this study was, therefore, to investigate the effect of glucocorticoid receptor (GR) modulation on synaptic plasticity in the human cortex of epilepsy patients. METHODS: We performed field potential recordings in acute slices from the temporal neocortex of patients who underwent surgery for drug-resistant temporal lobe epilepsy. Synaptic plasticity was investigated by a theta-burst stimulation (TBS) protocol for induction of long-term potentiation (LTP) in the presence of GR modulators. RESULTS: LTP was impaired in temporal cortex from epilepsy patients. Pretreatment of the slices with the GR antagonist mifepristone (RU486) improved LTP induction, suggesting that LTP impairment was due to baseline GR activation in the human cortex. The highly potent GR agonist dexamethasone additionally weakened synaptic strength in an activity-dependent manner when applied after TBS. SIGNIFICANCE: Our results show a direct negative glucocorticoid effect on synaptic potentiation in the human cortex and imply chronic activation of GRs. Chronic stress may therefore contribute to memory impairment in patients with temporal lobe epilepsy. Furthermore, the activity-dependent acute inhibitory effect of dexamethasone suggests a mechanism of synaptic downscaling by which postictally increased cortisol levels may prevent pathologic plasticity upon seizures.

The role of migration in mental healthcare: treatment satisfaction and utilization.

Migration rates increase globally and require an adaption of national mental health services to the needs of persons with migration background. Therefore, we aimed to identify differences between persons with and without migratory background regarding (1) treatment satisfaction, (2) needed and received mental healthcare and (3) utilization of mental healthcare.In the context of a cross-sectional multicenter study, inpatients and day hospital patients of psychiatric settings in Southern Germany with severe affective and non-affective psychoses were included. Patients' satisfaction with and their use of mental healthcare services were assessed by VSSS-54 and CSSRI-EU; patients' needs were measured via CAN-EU.In total, 387 participants (migratory background: n = 72; 19%) provided sufficient responses for analyses. Migrant patients were more satisfied with the overall treatment in the past year compared to non-migrant patients. No differences between both groups were identified in met and unmet treatment needs and use of supply services (psychiatric, psychotherapeutic, and psychosocial treatment).Despite a comparable degree of met and unmet treatment needs and mental health service use among migrants and non-migrants, patients with migration background showed higher overall treatment satisfaction compared to non-migrants. The role of sociocultural and migrant-related factors may explain our findings.

Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver.

Activation of the constitutive androstane receptor (CAR) may induce adaptive but also adverse effects in rodent liver, including the induction of drug-metabolizing enzymes, transient hepatocellular proliferation, and promotion of liver tumor growth. Human relevance of CAR-related adverse hepatic effects is controversially debated. Here, we used the chimeric FRG-KO mouse model with livers largely repopulated by human hepatocytes, in order to study human hepatocytes and their response to treatment with the model CAR activator phenobarbital (PB) in vivo. Mice received an intraperitoneal injection with 50 mg/kg body weight PB or saline, and were sacrificed after 72-144 h. Non-repopulated FRG-KO mice were used as additional control. Comprehensive proteomics datasets were generated by merging data obtained by targeted as well as non-targeted proteomics approaches. For the first time, a novel proteomics workflow was established to comparatively analyze the effects of PB on human and murine proteins within one sample. Analysis of merged proteome data sets and bioinformatics data mining revealed comparable responses in murine and human hepatocytes with respect to nuclear receptor activation and induction of xenobiotic metabolism. By contrast, activation of MYC, a key regulator of proliferation, was predicted only for mouse but not human hepatocytes. Analyses of 5-bromo-2'-deoxyuridine incorporation confirmed this finding. In summary, this study for the first time presents a comprehensive proteomic analysis of CAR-dependent effects in human and mouse hepatocytes from humanized FRG-KO mice. The data support the hypothesis that PB does induce adaptive metabolic responses, but not hepatocellular proliferation in human hepatocytes in vivo.

MESA: automated assessment of synthetic DNA fragments and simulation of DNA synthesis, storage, sequencing and PCR errors.

SUMMARY: The development of de novo DNA synthesis, polymerase chain reaction (PCR), DNA sequencing and molecular cloning gave researchers unprecedented control over DNA and DNA-mediated processes. To reduce the error probabilities of these techniques, DNA composition has to adhere to method-dependent restrictions. To comply with such restrictions, a synthetic DNA fragment is often adjusted manually or by using custom-made scripts. In this article, we present MESA (Mosla Error Simulator), a web application for the assessment of DNA fragments based on limitations of DNA synthesis, amplification, cloning, sequencing methods and biological restrictions of host organisms. Furthermore, MESA can be used to simulate errors during synthesis, PCR, storage and sequencing processes. AVAILABILITY AND IMPLEMENTATION: MESA is available at mesa.mosla.de, with the source code available at github.com/umr-ds/mesa_dna_sim. CONTACT: dominik.heider@uni-marburg.de. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Holocene population expansion of a tropical bee coincides with early human colonization of Fiji rather than climate change.

There is substantial debate about the relative roles of climate change and human activities on biodiversity and species demographies over the Holocene. In some cases, these two factors can be resolved using fossil data, but for many taxa such data are not available. Inferring historical demographies of taxa has become common, but the methodologies are mostly recent and their shortcomings often unexplored. The bee genus Homalictus is developing into a tractable model system for understanding how native bee populations in tropical islands have responded to past climate change. We greatly expand on previous studies using sequences of the mitochondrial gene COI from 474 specimens and between 171 and 3928 autosomal (DArTSeq) single nucleotide polymorphism loci from 19 specimens of the native Fijian bee, Homalictus fijiensis, to explore its historical demography using coalescent and mismatch analyses. We ask whether past changes in demography were human- or climate-driven, while considering analytical assumptions. We show that inferred changes in population sizes are too recent to be explained by past climate change. Instead we find that a dramatic increase in population size for the main island of Viti Levu coincides with increasing occupation by humans and their modification of the environment. We found no corresponding change in bee population size for another major island, Kadavu, where human populations and agricultural activities have been historically very low. Our analyses indicate that molecular approaches can be used to disentangle the impacts of humans and climate change on a major tropical pollinator and that stringent analytical approaches are required for reliable interpretation of results.