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Abstract Human monoclonal antibodies (mAbs) against the central repeat and junction domain of Plasmodium falciparum circumsporozoite protein (PfCSP) have been studied extensively to guide malaria vaccine design compared to antibodies against the PfCSP C terminus. Here, we describe the molecular characteristics and protective potential of 73 germline and mutated human mAbs against the highly immunogenic PfCSP C‐terminal domain. Two mAbs recognized linear epitopes in the C‐terminal linker with sequence similarity to repeat and junction motifs, whereas all others targeted conformational epitopes in the α‐thrombospondin repeat (α‐TSR) domain. Specificity for the polymorphic Th2R/Th3R but not the conserved RII+/CS.T3 region in the α‐TSR was associated with IGHV3‐21/IGVL3‐21 or IGLV3‐1 gene usage. Although the C terminus specific mAbs showed signs of more efficient affinity maturation and class‐switching compared to anti‐repeat mAbs, live sporozoite binding and inhibitory activity was limited to a single C‐linker reactive mAb with cross‐reactivity to the central repeat and junction. The data provide novel insights in the human anti‐C‐linker and anti‐α‐TSR antibody response that support exclusion of the PfCSP C terminus from malaria vaccine designs.

Abstract Single‐cell RNA sequencing (scRNA‐seq) enables characterizing the cellular heterogeneity in human tissues. Recent technological advances have enabled the first population‐scale scRNA‐seq studies in hundreds of individuals, allowing to assay genetic effects with single‐cell resolution. However, existing strategies to analyze these data remain based on principles established for the genetic analysis of bulk RNA‐seq. In particular, current methods depend on a priori definitions of discrete cell types, and hence cannot assess allelic effects across subtle cell types and cell states. To address this, we propose the Cell Regulatory Map (CellRegMap), a statistical framework to test for and quantify genetic effects on gene expression in individual cells. CellRegMap provides a principled approach to identify and characterize genotype–context interactions of known eQTL variants using scRNA‐seq data. This model‐based approach resolves allelic effects across cellular contexts of different granularity, including genetic effects specific to cell subtypes and continuous cell transitions. We validate CellRegMap using simulated data and apply it to previously identified eQTL from two recent studies of differentiating iPSCs, where we uncover hundreds of eQTL displaying heterogeneity of genetic effects across cellular contexts. Finally, we identify fine‐grained genetic regulation in neuronal subtypes for eQTL that are colocalized with human disease variants.

Pragmatic measures of evidence-based practice (EBP) implementation can support and evaluate implementation efforts. We examined the predictive validity of therapist reports of EBP strategy delivery for children's mental health outcomes. Data were obtained from 1,380 sessions with 248 children delivered by 76 therapists in two county systems. Children (Mage=11.8 years, SD = 3.7) presented with internalizing (52%), externalizing (27%), trauma (16%), and other (5%) concerns. Therapists reported their delivery of EBP strategies on a revised version of the EBP Concordant Care Assessment (ECCA; Brookman-Frazee, et al., Administration and Policy in Mental Health and Mental Health Services Research, 48, 155–170, 2021) that included 25 content (e.g., parenting, cognitive behavioral) and 12 technique strategies (e.g., modeling, practice/role-play). On average, 5.6 ECCA session reports (SD = 2.3) were obtained for each client, and caregivers reported symptoms on the Brief Problem Checklist (Chorpita, et al., Journal of Consulting and Clinical Psychology, 78(4), 526–536, 2010) at baseline, weekly over two months, and again at four months. Multilevel models examined whether the mean extensiveness of each EBP strategy predicted trajectories of child outcomes. More individual technique (6 of 12) than content strategies (1 of 25) were associated with outcome trajectories. For techniques, more extensive use of Performance Feedback and Live Coaching and less extensive use of Addressing Barriers were associated with greater declines in total symptoms, and more extensive use of Establishing/Reviewing Goals, Tracking/Reviewing Progress, and Assigning/Reviewing Homework was associated with declines in externalizing symptoms. For content, more extensive use of Cognitive Restructuring was associated with declines in total symptoms. In addition, higher average extensiveness ratings of the top content strategy across sessions was associated with greater declines in total and externalizing symptoms. Therapist-reported delivery of some EBP strategies showed evidence of predictive validity and may hold utility in indexing quality of care. [ABSTRACT FROM AUTHOR]

Purpose Methods Results Conclusion Level of Evidence To describe knee reinjuries and surgeries within 2 years after an acute anterior cruciate ligament (ACL) injury, in patients treated with or without ACL reconstruction (ACLR).Two years follow‐up of 275 patients (52% females, mean age 25.2 [SD 7.0] years) about knee reinjuries and surgeries were analysed from the prospective NACOX cohort study, aiming to describe recovery after an acute ACL injury treated according to clinical routine. Knee reinjury was defined as increase or new symptoms due to new trauma. At 2 years after injury, 169 (61%) had undergone an ACLR. Results are presented with descriptive statistics and risk ratios (RR).Thirty‐two patients sustained reinjuries within 2 years; 6 in the non‐ACLR group, and 26 in the ACLR group (7 before and 19 after ACLR). Twelve patients in the ACLR group sustained a graft rupture and three did an ACL revision. Patients with non‐ACLR, aged 21–25 years, had a 5.9‐fold higher risk for reinjury than those aged 15–20 years (RR 5.9 [1.3–26.9]; p = 0.012). Twenty‐four patients had surgery in the non‐ACLR group and 36 patients in the ACLR group (excluding primary ACLR), where six were before ACLR and 30 were after ACLR.Twelve percent sustained a knee reinjury and 21% underwent knee surgery within 2 years after the index ACL injury. There was a higher reinjury incidence in the ACLR group, but no difference in incidence of surgeries. Thus, ACLR did not reduce the risk of traumatic reinjuries or surgeries, which is important for treatment decision considerations.Level I. [ABSTRACT FROM AUTHOR]

Introduction: The American Association for the Surgery of Trauma (AAST) renal trauma grading leads to a variable management of patients with high-grade renal injuries. For a better prediction of the risk for bleeding interventions, Keihani et al. introduced the multi-institutional genito-urinary trauma study (MiGUTS) renal trauma nomogram in 2019. The aim of this study was to conduct an external validation and generalization for all kidney trauma cases of the nomogram with a European cohort of a Swiss level 1 trauma center. Methods: We collected data from the clinical information system of the Kantonsspital Graubünden, Chur, Switzerland. All patients ≥ 18 years of age from 01.01.2008 to 01.12.2020 with a renal trauma who underwent computed tomography imaging of the abdomen were included. The descriptive analysis was performed by a t-test/Wilcoxon signed-rank test and a Chi-square test. The predictions of the nomogram were analysed by the Pearson correlation coefficient. The threshold of prediction of a bleeding intervention was optimized by a ROC analysis. Results: Overall, 166 patients were included. Most patients were male (80.7%) with a median age of 44 years. Using the prediction from the MiGUTS nomogram developed by Keihani et al. we were able to identify a threshold with a sensitivity of 1.00, specificity of 0.87, positive predictive value of 0.44, negative predictive value of 1.00 and accuracy of 0.88. Conclusion: The MiGUTS nomogram by Keihani et al. demonstrated to be reliable in the prediction of an intervention for bleeding control in our validation study in a European cohort. [ABSTRACT FROM AUTHOR]

Text-matching software (TMS) is a standard part of efforts to prevent and detect plagiarism in upper secondary and higher education. While there are many studies on the potential benefits of using this technology, few studies look into potential unintended side effects. These side effects include students worrying about being accused of plagiarism due to TMS output, even though they did not intentionally plagiarise. Although such worries are frequently mentioned in the literature, little is known about how prevalent they are, why they occur and how students react to them. This paper aims to fill this knowledge gap. The data for the study comprise 36 interviews with upper secondary and Bachelor students from three European countries combined with survey data from 3,424 students from seven European countries representing a broad range of disciplines. The study found that a substantial proportion of the two groups of students – 47% of upper secondary and 55% of Bachelor students – had experienced TMS-related worries during their current studies. Furthermore, there were substantial differences across countries. Students worry partly because they have a poor understanding of how TMS is used in their institution, and partly because they know that plagiarism is taken very seriously. The study shows that TMS-related worries can lead students to become very focused on not being caught plagiarising, to such an extent that some adopt citation practices that they believe are suboptimal. The paper concludes that institutions using TMS should always combine it with training for students and teachers. Students should be clearly informed about how TMS is used and should develop an understanding of plagiarism and good citation practice that goes beyond the narrow focus on any overlap between texts elicited by the software. [ABSTRACT FROM AUTHOR]

Microphthalmia-associated transcription factor (MITF) is a master regulator of melanocyte function, development and plays a significant role in melanoma pathogenesis. MITF genomic amplification promotes melanoma development, and it can facilitate resistance to multiple therapies. Here, we show that MITF regulates a global antioxidant program that increases survival of melanoma cell lines by protecting the cells from reactive oxygen species (ROS)-induced damage. In addition, this redox program is correlated with MITF expression in human melanoma cell lines and patient-derived melanoma samples. Using a zebrafish melanoma model, we show that MITF decreases ROS-mediated DNA damage in vivo. Some of the MITF target genes involved, such as IDH1 and NNT, are regulated through direct MITF binding to canonical enhancer box (E-BOX) sequences proximal to their promoters. Utilizing functional experiments, we demonstrate the role of MITF and its target genes in reducing cytosolic and mitochondrial ROS. Collectively, our data identify MITF as a significant driver of the cellular antioxidant state. [ABSTRACT FROM AUTHOR]

Postoperative fluid overload (FO) after cardiac surgery is common and affects recovery. Predicting FO could help optimize fluid management. This post-hoc analysis of the HERACLES randomized controlled trial evaluated the predictive value of MR-proADM for FO post-cardiac surgery. MR-proADM levels were measured at four different timepoints in 33 patients undergoing elective cardiac surgery. Patients were divided into FO (> 5% weight gain) and no-FO at ICU discharge. The primary outcome was the predictive power of MR-proADM at ICU admission for FO at discharge. Secondary outcomes included the predictive value of MR-proADM for FO on day 6 post-surgery and changes over time. The association between MR-proADM and FO at ICU discharge or day 6 post-surgery was not significant (crude odds ratio (cOR): 4.3 (95% CI 0.5–40.9, p = 0.201) and cOR 1.1 (95% CI 0.04–28.3, p = 0.954)). MR-proADM levels over time did not differ significantly between patients with and without FO at ICU discharge (p = 0.803). MR-proADM at ICU admission was not associated with fluid overload at ICU discharge in patients undergoing elective cardiac surgery. MR-proADM levels over time were not significantly different between groups, although elevated levels were observed in patients with FO. [ABSTRACT FROM AUTHOR]

Long-term metal remediation in wetland treatment systems (WTSs) involves facilitating dissimilatory sulfate reduction to produce sulfide and mineralize metals in deep sediments. We evaluated seasonal sulfur cycling in two constructed wetlands (Maintained WTS constructed in 2007, and the Unmaintained WTS constructed in 2000) on the Savannah River Site in Aiken, South Carolina, USA. Significant interactions in sulfide concentration were observed between sediment depth, season, and wetland (F = 4.64, df = 11, P = 3.28 × 10 − 5). In the Maintained WTS, dissimilatory sulfate reduction dominated the surface sediments during the warm season (0–2 cm depth, t=-2.66, P = 9.70 × 10 − 3), unlike the Unmaintained system. Sulfate concentrations in pore waters increased in the warm season (F = 7.84, df = 1, P = 6.50 × 10 − 3), contrary to expectations. Sulfur limitation in the Unmaintained WTS during the warm season correlated with increased sulfur assimilation in giant bulrush. Lower sulfide concentrations in surface sediments of the Unmaintained WTS illustrated aging effects. The Maintained WTS shows potential for managing erosion, pH reduction, and sulfur limitation observed in the older Unmaintained WTS. [ABSTRACT FROM AUTHOR]

Diclofenac is a non-steroidal anti-inflammatory drug (NSAID). Here, we use double electron–electron resonance (DEER, also known as PELDOR) to study the interaction of spin-labeled diclofenac (diclofenac-SL) with three types of model membranes consisting of palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), an equimolar mixture of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and this mixture with the addition of 20 mol% cholesterol. The results suggest that lipid-mediated lateral clustering of diclofenac-SL molecules occurs in all cases. For the POPC bilayer, alternative clustering takes place in two opposite leaflets, with random distribution of the molecules within the clusters. For DOPC/DPPC and DOPC/DPPC/cholesterol bilayers, diclofenac-SL molecules are separated by a distance of at least 1.4 nm. DOPC/DPPC/cholesterol bilayers are known to form nanoscale liquid disordered and liquid ordered lateral structures, the latter called lipid rafts. For this case, diclofenac-SL molecules were found to be captured by lipid rafts, forming a quasi-regular two-dimensional substructure in them with a "superlattice" parameter of ~ 3.0 nm. [ABSTRACT FROM AUTHOR]

Background: Rectal cancer (RC) occupies a leading position in the structure of oncological morbidity and mortality. Aberrant methylation of tumor-suppressor genes and hypomethylation of retrotransposons were shown to be detectable in cell-free DNA, circulating in the blood (cfDNA) of cancer patients, indicating the possibility to use them as diagnostic and prognosis markers. Purpose: Evaluation of the changes in the methylation level of LINE-1 elements and SEPTIN9 and IKZF1 genes in the cell-surface-bound cfDNA (csb-cfDNA) from the blood of RC patients after antitumor therapy at a long-term follow-up. Methods: Blood samples were obtained from RC patients (n = 25) before treatment, after preoperative chemotherapy (3 courses according to the XELOX scheme), 10–15 days after surgery, and every 3 months during 12 months of dynamic observation. The methylation level of LINE-1, SEPTIN9, and IKZF1 in the csb-cfDNA was evaluated by quantitative methyl-specific PCR. Results: The LINE-1 methylation level in the csb-cfDNA increased 1.6 times in RC patients after chemotherapy and 3 times after tumor resection versus methylation level before therapy. The SEPTIN9 gene methylation level in the csb-cfDNA decreased by 1.7 times in RC patients after chemotherapy and by 2.3 times after tumor resection compared with the values before the treatment. The IKZF1 gene methylation level decreased by 2 times in RC patients after combined therapy. Notably, all patients with relapses (n = 5) showed an increase in methylation level for the SEPTIN9 and IKZF1 genes and a decrease of methylation level for the LINE-1 elements by 2 times or more in comparison with the level 10–15 days after surgery. There were no changes in the circulating SEPTIN9, IKZF1, and LINE-1 methylation levels during the 12-month follow-up period after the combined therapy of RC patients (n = 20) without relapses. Conclusion: The results indicate that SEPTIN9, IKZF1, and LINE-1 methylation levels in the csb-cfDNA are potential markers of the effectiveness of antitumor therapy and early detection of relapse in RC patients. [ABSTRACT FROM AUTHOR]

Altruism is an enigmatic form of prosocial behavior, characterized by diverse motivations and significant interindividual differences. Studying neural mechanisms of altruism is crucial to identify objective markers of pro- and antisocial tendencies in behavior. This study was designed to delve into the mechanisms of altruism by analyzing EEG-based functional connectivity patterns within the framework of the network approach. To experimentally induce a situation of altruistic decision-making, we employed the Pain versus Gain (PvsG) task, which implies making choices concerning financial self-benefit and pain of the other. Our results reveal that the behavioral measure of altruism in the experiment correlated with emotional empathy, which is in line with the "empathy-altruism" hypothesis. Applying the network approach to EEG functional connectivity analysis, we discovered that the very process of decision-making in the PvsG is characterized by the synchronous activity of structures in the right hemisphere, which are involved in empathy for pain. The prosociality of decisions was reflected in functional connectivity between the rostral ACC and orbital IFG in the left hemisphere and the overall network centrality of the caudal ACC. This finding additionally points to the distinct functional roles of the ACC subregions in altruistic decision-making. The proposed neural mechanisms of altruism can further be used to identify neurophysiological markers of prosociality in behavior. [ABSTRACT FROM AUTHOR]

Abstract Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A‐priori identification of platinum resistance is therefore crucial to improve on standard first‐line carboplatin–paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum‐induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK‐compliant study of pre‐treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51‐High tumours had shorter progression‐free and overall survival compared to RAD51‐Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR‐proficient cancers (Myriad HRDscore

The ongoing worldwide effort to reduce animal numbers in research often omits the issue of pre-weaning mortality in mouse breeding. A conservative estimate of 20% mortality would mean approximately 1.1 M mice die annually in the EU before scientific use. We hypothesize that pre-weaning mortality in laboratory mouse breeding is associated with cage social and macro/micro-environment conditions. Here we count pups from 509 C57BL/6J litters daily for accurate detection of mortality, and monitor cage micro-environment for 172 C57BL/6J litters. Probability of pups to die increases with the increase in dam age, number and age of older pups in the cage (of overlapped/cohabitating litters), and in small (<6 pups) and large (>11 pups) focal litters. Higher temperatures (>23.6 °C) and nest scores (>3.75) compensate for some of the socially-associated risks for pup death. These findings can be implemented in strategies for reducing pre-weaning mouse mortality, a more welfare-friendly and sustainable approach for science. A laboratory mouse breeding study suggests that new pups born in the presence of older pups and older dams are more likely to die before weaning, but these social risks can be alleviated by proper thermal and light environment. [ABSTRACT FROM AUTHOR]

The Earth System is warming due to anthropogenic greenhouse gas emissions which increases the risk of passing a tipping point in the Earth System, such as a collapse of the Atlantic Meridional Overturning Circulation (AMOC). An AMOC weakening can have large climate impacts which influences the marine and terrestrial carbon cycle and hence atmospheric pCO 2 . However, the sign and mechanism of this response are subject to uncertainty. Here, we use a state-of-the-art Earth System Model, the Community Earth System Model v2 (CESM2), to study the atmospheric pCO 2 response to an AMOC weakening under low (SSP1-2.6) and high (SSP5-8.5) emission scenarios over the years 2015–2100. A freshwater flux anomaly in the North Atlantic strongly weakens the AMOC, and we simulate a weak positive pCO 2 response of 0.45 and 1.3 ppm increase per AMOC decrease in Sv for SSP1-2.6 and SSP5-8.5, respectively. For SSP1-2.6 this response is driven by both the oceanic and terrestrial carbon cycles, whereas in SSP5-8.5 it is solely the ocean that drives the response. However, the spatial patterns of both the climate and carbon cycle response are similar in both emission scenarios over the course of the simulation period (2015–2100), showing that the response pattern is not dependent on cumulative CO 2 emissions up to 2100. Though the global atmospheric pCO 2 response might be small, locally large changes in both the carbon cycle and the climate system occur due to the AMOC weakening, which can have large detrimental effects on ecosystems and society. [ABSTRACT FROM AUTHOR]

Purpose: To elucidate the association between arterial and venous Doppler ultrasound parameters and the risk of secondary cesarean delivery for intrapartum fetal compromise (IFC) and neonatal acidosis in small-for-gestational-age (SGA) fetuses. Methods: This single-center, prospective, blinded, cohort study included singleton pregnancies with an estimated fetal weight (EFW) < 10th centile above 36 gestational weeks. Upon study inclusion, all women underwent Doppler ultrasound, including umbilical artery (UA) pulsatility index (PI), middle cerebral artery (MCA) PI, fetal aortic isthmus (AoI) PI, umbilical vein blood flow (UVBF), and modified myocardial performance index (mod-MPI). Primary outcome was defined as secondary cesarean section due to IFC. Results: In total, 87 SGA pregnancies were included, 16% of which required a cesarean section for IFC. Those fetuses revealed lower UVBF corrected for abdominal circumference (AC) (5.2 (4.5–6.3) vs 7.2 (5.5–8.3), p = 0.001). There was no difference when comparing AoI PI, UA PI, ACM PI, or mod-MPI. No association was found for neonatal acidosis. After multivariate logistic regression, UVBF/AC remained independently associated with cesarean section due to IFC (aOR 0.61 [0.37; 0.91], p = 0.03) and yielded an area under the curve (AUC) of 0.78 (95% CI, 0.67–0.89). A cut-off value set at the 50th centile of UVBF/AC reached a sensitivity of 86% and specificity of 58% for the occurrence of cesarean section due to IFC (OR 8.1; 95% CI, 1.7–37.8, p = 0.003). Conclusion: Low levels of umbilical vein blood flow (UVBF/AC) were associated with an increased risk among SGA fetuses to be delivered by cesarean section for IFC. [ABSTRACT FROM AUTHOR]

While significant advances have been made in understanding renal pathophysiology, less is known about the role of glycosphingolipid (GSL) metabolism in driving organ dysfunction. Here, we used a small molecule inhibitor of glucosylceramide synthase to modulate GSL levels in three mouse models of distinct renal pathologies: Alport syndrome (Col4a3 KO), polycystic kidney disease (Nek8jck), and steroid-resistant nephrotic syndrome (Nphs2 cKO). At the tissue level, we identified a core immune-enriched transcriptional signature that was shared across models and enriched in human polycystic kidney disease. Single nuclei analysis identified robust transcriptional changes across multiple kidney cell types, including epithelial and immune lineages. To further explore the role of GSL modulation in macrophage biology, we performed in vitro studies with homeostatic and inflammatory bone marrow-derived macrophages. Cumulatively, this study provides a comprehensive overview of renal dysfunction and the effect of GSL modulation on kidney-derived cells in the setting of renal dysfunction. This study identifies shared immune-related gene signatures across kidney cell types in three distinct mouse models of renal disease and examines the role of glycosphingolipid metabolism in renal dysfunction. [ABSTRACT FROM AUTHOR]

Despite a significant accumulation of research, there has been little systemic implementation of evidence-based practices (EBP) in youth mental health care. The fragmentation of the evidence base complicates implementation efforts. In light of this challenge, we sought to pilot a system that consolidates and coordinates the entire evidence base in a single direct service model (i.e., Managing and Adapting Practice; MAP) in the context of a legal reform of psychotherapy training in Germany. This pilot study aimed to evaluate the feasibility of the implementation of MAP into the curriculum of the reformed German master's program. Eligible participants were students in the master's program at Philipps-University Marburg during the winter-term 2022/2023. Students first learned about MAP through introductions and role plays (seminar 1), followed by actively planning and conducting interventions using MAP resources for patients in a case seminar under supervision (seminar 2). A repeated-measures survey was conducted to investigate students' knowledge gains, perception of MAP and changes in their self-rated confidence to use EBP. Results indicated that students perceive MAP to be manageable to learn. Positive progress was achieved with regard to their knowledge and self-reported confidence to use EBP, although interpretation and generalization of the results are limited by small and homogeneous samples, lack of statistical power and missing comparison groups. The feasibility of the implementation and suitability of measures are discussed. Important implications could be drawn with regard to future investigations. [ABSTRACT FROM AUTHOR]

Despite its high prevalence, the determinants of smelling impairment in COVID-19 remain not fully understood. In this work, we aimed to examine the association between olfactory bulb volume and the clinical trajectory of COVID-19-related smelling impairment in a large-scale magnetic resonance imaging (MRI) analysis. Data of non-vaccinated COVID-19 convalescents recruited within the framework of the prospective Hamburg City Health Study COVID Program between March and December 2020 were analyzed. At baseline, 233 participants underwent MRI and neuropsychological testing as well as a structured questionnaire for olfactory function. Between March and April 2022, olfactory function was assessed at follow-up including quantitative olfactometric testing with Sniffin' Sticks. This study included 233 individuals recovered from mainly mild to moderate SARS-CoV-2 infections. Longitudinal assessment demonstrated a declining prevalence of self-reported olfactory dysfunction from 67.1% at acute infection, 21.0% at baseline examination and 17.5% at follow-up. Participants with post-acute self-reported olfactory dysfunction had a significantly lower olfactory bulb volume at baseline than normally smelling individuals. Olfactory bulb volume at baseline predicted olfactometric scores at follow-up. Performance in neuropsychological testing was not significantly associated with the olfactory bulb volume. Our work demonstrates an association of long-term self-reported smelling dysfunction and olfactory bulb integrity in a sample of individuals recovered from mainly mild to moderate COVID-19. Collectively, our results highlight olfactory bulb volume as a surrogate marker that may inform diagnosis and guide rehabilitation strategies in COVID-19. [ABSTRACT FROM AUTHOR]

The second decade of the 20th century saw the beginning of the Great Migration of African Americans to cities such as Chicago. The city's existing African American community expressed concern for the welfare of girls and women coming to a strange, potentially dangerous, new place and worked to ease their transition to life there. This article employs a "documentary archaeology" approach, using texts from the period to understand material conditions experienced by members of "the Race," especially women, in Chicago ca. 1920. It includes a special emphasis on space, how people moved through it, and how it was used in struggles for domination and equality. A rumored spatial transgression was the spark for Chicago's "riot" of 1919. During the violence, Black spaces were decimated. The events, including many deaths, were so shocking that a commission was established at the time to study the Great Migration and its consequences for Chicago. That commission's report is at the center of the archive consulted for the analysis presented here. Reflecting the ideologies of the era, its analyses emphasized race over gender as a determining factor in the life experiences of female members of the Race. I argue that the spatial distribution of racialized risk was different for women than for men, and, furthermore, that the dangers women faced were chronic rather than acute. [ABSTRACT FROM AUTHOR]

Background: Fluid accumulation (FA) is known to be associated with acute kidney injury (AKI) during intensive care unit (ICU) stay but data on mid-term renal outcome is scarce. The aim of this study was to investigate the association between FA at ICU day 3 and major adverse kidney events in the first 30 days after ICU admission (MAKE30). Methods: Retrospective, single-center cohort study including adult ICU patients with sufficient data to compute FA and MAKE30. We defined FA as a positive cumulative fluid balance greater than 5% of bodyweight. The association between FA and MAKE30, including its sub-components, as well as the serum creatinine trajectories during ICU stay were examined. In addition, we performed a sensitivity analysis for the stage of AKI and the presence of chronic kidney disease (CKD). Results: Out of 13,326 included patients, 1,100 (8.3%) met the FA definition. FA at ICU day 3 was significantly associated with MAKE30 (adjusted odds ratio [aOR] 1.96; 95% confidence interval [CI] 1.67–2.30; p < 0.001) and all sub-components: need for renal replacement therapy (aOR 3.83; 95%CI 3.02–4.84), persistent renal dysfunction (aOR 1.72; 95%CI 1.40–2.12), and 30-day mortality (aOR 1.70; 95%CI 1.38–2.09), p all < 0.001. The sensitivity analysis showed an association of FA with MAKE30 independent from a pre-existing CKD, but exclusively in patients with AKI stage 3. Furthermore, FA was independently associated with the creatinine trajectory over the whole observation period. Conclusions: Fluid accumulation is significantly associated with MAKE30 in critically ill patients. This association is independent from pre-existing CKD and strongest in patients with AKI stage 3. [ABSTRACT FROM AUTHOR]

The scarab genus Osmoderma (Coleoptera: Scarabaeidae) includes several large species called hermit beetles that develop within dead and decaying hardwood trees. Males of at least three Palearctic species produce the aggregation-sex pheromone (R)-(+)-γ-decalactone, including the endangered O. eremita (Scopoli). However, hermit beetles have received less attention in the western hemisphere, resulting in a large gap in our knowledge of the chemical ecology of Nearctic species. Here, we identify (R)-(+)-γ-decalactone as the primary component of the aggregation-sex pheromone of the North American species Osmoderma eremicola (Knoch). Field trials at sites in Wisconsin and Illinois revealed that both sexes were attracted to lures containing (R)-(+)-γ-decalactone or the racemate, but only males of O. eremicola produced the pheromone in laboratory bioassays, alongside an occasional trace of the chain-length analog γ-dodecalactone. Females of the congener O. scabra (Palisot de Beauvois) were also significantly attracted by γ-decalactone, suggesting further conservation of the pheromone, as were females of the click beetle Elater abruptus Say (Coleoptera: Elateridae), suggesting that this compound may have widespread kairomonal activity. Further research is needed to explore the behavioral roles of both lactones in mediating behavioral and ecological interactions among these beetle species. [ABSTRACT FROM AUTHOR]

Purpose: Beneficial bacteria contribute significantly to host-plant adaptive capacities. Lilacs are common shrubs of urban areas in a northern climate. Their buds are the primary material for the Syringa aseptic micropropagation using a Murashige and Skoog medium (MS). As opposed to considering bud-associated bacteria as just contaminants, the search for plant growth-promoting bacteria (PGPB) provides a potential tool for better lilac-microbial co-cultivation. Methods: In total, six cultivars of Siringa vulgaris were studied for the bacterial diversity of their roots and buds. By scanning electron microscopy, the localization of microorganisms was studied. The composition of bacterial communities was analyzed by Illumina Miseq new generation sequencing (NGS). Culturable bacteria of rhizoplane and surface-sterilized buds were isolated and compared. Indole-3-acetic acid (IAA) production under different cultivation conditions was studied colorimetrically among bud-associated bacteria capable of growing in MS medium. Results: Pseudomonadota and Bacillota phyla dominated among cultivable bacteria; Proteobacteria, Actinobacteria, Firmicutes, Chloroflexi, Acidobacteriota, Verrucomicrobiota, Bacteroidota, and Crenarchaeota were detected by NGS. The endophytic communities differed at the genus level with dominating non-pathogenic Curtobacterium and Pseudomonas. Attached bacteria on the non-sterilized and surface-sterilized buds were observed. Bud-associated Methyllobacterium and Paenibacillus showed tryptophan-dependent biosynthesis of auxins. It strongly depended on the medium, with the lower IAA production in MS. Conclusion: Lilacs maintain a wide diversity of root-associated bacteria with a number of beneficial strains. The endophytic community is limited and varies among the cultivars. Bud-associated PGPB may survive during sterilization and reveal their growth-promoting activity by producing auxins, though optimization of plant-microbial interactions is needed. [ABSTRACT FROM AUTHOR]

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Identifying effective, feasible, low-cost interventions that promote sustainable lifestyle changes in nonalcoholic fatty liver disease (NAFLD) is a key unmet need. The aim of this study was to assess predictors of lifestyle practice patterns of NAFLD patients and evaluate the implementation of a mobile technology-based intervention. We prospectively enrolled adults with NAFLD (diagnosed by imaging or biopsy). Individuals with additional liver diseases or decompensated cirrhosis were excluded. Patient were randomized to usual care or a FitBit based program for 6-months. We obtained anthropometrics, labs, vibration controlled transient elastography (VCTE), health-related quality of life (HRQOL), physical activity, diet and motivation to change data. 70 patients were enrolled, 33% with cirrhosis. Median age was 52.1 years, 47% males, 83% white, body mass index 32.3, liver stiffness 7.6 kPa, controlled attenuation parameter 319 db/m, and 50% had diabetes. Baseline HRQOL was 5.4/7 and independently negatively correlated with level of concern about their disease and positively with physical function. Younger age was independently associated with unhealthy diets whereas diabetes was independently associated with unhealthy diets and higher VCTE kPa. 6-month follow-up data available on 31 patients showed trends in improvement in weight. In a cohort of NAFLD patients, we identified independent correlates of lifestyle behaviors and HRQOL. Implementation of interventions that improve physical function may improve HRQOL in NAFLD. Younger patients and those with diabetes appeared to have the greatest need for dietary interventions. Structured mobile technology lifestyle interventions using Fitbit and personalized coaching showed promise but require further validation with a focus on sustainability of intervention and improvement in outcomes. [ABSTRACT FROM AUTHOR]

Abstract Loss‐of‐function mutations in APOPT1, a gene exclusively found in higher eukaryotes, cause a characteristic type of cavitating leukoencephalopathy associated with mitochondrial cytochrome c oxidase (COX) deficiency. Although the genetic association of APOPT1 pathogenic variants with isolated COX defects is now clear, the biochemical link between APOPT1 function and COX has remained elusive. We investigated the molecular role of APOPT1 using different approaches. First, we generated an Apopt1 knockout mouse model which shows impaired motor skills, e.g., decreased motor coordination and endurance, associated with reduced COX activity and levels in multiple tissues. In addition, by achieving stable expression of wild‐type APOPT1 in control and patient‐derived cultured cells we ruled out a role of this protein in apoptosis and established instead that this protein is necessary for proper COX assembly and function. On the other hand, APOPT1 steady‐state levels were shown to be controlled by the ubiquitination–proteasome system (UPS). Conversely, in conditions of increased oxidative stress, APOPT1 is stabilized, increasing its mature intramitochondrial form and thereby protecting COX from oxidatively induced degradation.

Purpose: Cancer-related fatigue is a subjective, distressing, and common sequela of cancer which is often disregarded and underdiagnosed. Fatigue is assessed by self-report requiring communication between patient and physician. In this study, we investigated the patients' perspective on the patient–physician communication about fatigue. Methods: On average five months after diagnosis 1179 cancer patients, recruited in Germany, completed a survey as part of the LIFT project. The survey included questions on sociodemographic data, fatigue, depression, fatigue management, patient–physician communication, and communication barriers. Data were analyzed descriptively and using logistic regression analyses. Results: Half of the participants reported that their physician had never asked them whether they felt exhausted. Patients undergoing chemo-, radio-, or immunotherapy were more likely to be asked about fatigue, while older age and major depression decreased the likelihood. Sixty-four percent of the patients felt impeded by communication barriers. Common barriers were not knowing who to turn to for fatigue (39%), time constraints (31%), and the fear of being perceived as weak (22%). Almost half of the participants indicated that their physicians were not appreciative and did not deal adequately with fatigue-related questions. Conclusion: This study revealed gaps in the patient–physician communication regarding cancer-related fatigue. Contrary to guideline recommendations a minority of physicians addressed fatigue. On the other hand, cancer patients felt reluctant to bring up this topic due to structural barriers and fears. Physicians should routinely address fatigue and adopt a communication style which encourages patients to likewise state their symptoms and raise their questions. Trial registration: Clinicaltrials.gov, identifier: NCT04921644. Registered in June 2021. [ABSTRACT FROM AUTHOR]

Betulin is a biologically active triterpenoid substance, which can be isolated from birch bark. We report on a new approach to the synthesis of betulin sulfamate with sulfamic acid and ammonium sulfamate in the presence of solid catalysts, including Amberlyst 15® and Sibunit (granules) oxidized at 500 °C, Sibunit (powder) oxidized at 400 °C, Sibunit-sulfated, TiO2, and ɣ-Al2O3. It is shown that the synthesis with both sulfamic acid and ammonium sulfamate in the presence of an Amberlyst 15® catalyst yields sulfur derivatives of betulin. This catalyst has been proven to remain active at the repeated (up to four cycles) use. A reaction scheme for the catalytic production of sulfur derivatives of betulin is proposed. The obtained sulfur derivatives of betulin have been examined by Fourier transform infrared and ultraviolet visible spectroscopy, scanning electron and optical microscopy, X-ray diffractometry, thermogravimetric analysis, differential scanning calorimetry, and elemental analysis. It has been found by Fourier transform infrared spectroscopy that the use of sulfamic acid with an Amberlyst 15® catalyst ensures the formation of betulin sulfates, while when using ammonium sulfamate with the same catalyst, the sulfate and other betulin derivatives are obtained along with sulfates. It has been established from the X-ray diffractometry data that sulfation of betulin causes its stronger amorphization. [ABSTRACT FROM AUTHOR]

Large cell neuroendocrine carcinoma (LCNEC) of the lung is an aggressive malignancy, with brain metastases (BM) occurring in approximately 20% of cases. There are currently no therapy guidelines for this population as only few data on the management of LCNEC and BM have been published. For this retrospective single center study, patients with LCNEC and BM were identified from the Vienna Brain Metastasis Registry. Data on clinicopathological features, BM-specific characteristics, treatment, and outcome were extracted. In total, 52/6083 (0.09%) patients in the dataset had a diagnosis of LCNEC and radiologically verified BM. Median age at diagnosis of LCNEC and BM was 59.1 and 60.1 years, respectively. Twenty-seven (51.9%) presented with single BM, while 12 (23%) exhibited > 3 BM initially. Neurologic symptoms due to BM were present in n = 40 (76.9%), encompassing neurologic deficits (n = 24), increased intracranial pressure (n = 18), and seizures (n = 6). Initial treatment of BM was resection (n = 13), whole brain radiation therapy (n = 19), and/or stereotactic radiosurgery (n = 25). Median overall survival (mOS) from LCNEC diagnosis was 16 months, and mOS after BM diagnosis was 7 months. Patients with synchronous BM had reduced mOS from LCNEC diagnosis versus patients with metachronous BM (11 versus 27 months, p = 0.003). Median OS after BM diagnosis did not differ between LCNEC patients and a control group of small cell lung cancer patients with BM (7 versus 6 months, p = 0.17). Patients with LCNEC and BM have a poor prognosis, particularly when synchronous BM are present. Prospective trials are required to define optimal therapeutic algorithms. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic neuroinflammatory disease that involves both white and gray matter. Although gray matter damage is a major contributor to disability in MS patients, conventional clinical magnetic resonance imaging (MRI) fails to accurately detect gray matter pathology and establish a clear correlation with clinical symptoms. Using magnetic resonance elastography (MRE), we previously reported global brain softening in MS and experimental autoimmune encephalomyelitis (EAE). However, it needs to be established if changes of the spatiotemporal patterns of brain tissue mechanics constitute a marker of neuroinflammation. Here, we use advanced multifrequency MRE with tomoelastography postprocessing to investigate longitudinal and regional inflammation-induced tissue changes in EAE and in a small group of MS patients. Surprisingly, we found reversible softening in synchrony with the EAE disease course predominantly in the cortex of the mouse brain. This cortical softening was associated neither with a shift of tissue water compartments as quantified by T2-mapping and diffusion-weighted MRI, nor with leukocyte infiltration as seen by histopathology. Instead, cortical softening correlated with transient structural remodeling of perineuronal nets (PNNs), which involved abnormal chondroitin sulfate expression and microgliosis. These mechanisms also appear to be critical in humans with MS, where tomoelastography for the first time demonstrated marked cortical softening. Taken together, our study shows that neuroinflammation (i) critically affects the integrity of PNNs in cortical brain tissue, in a reversible process that correlates with disease disability in EAE, (ii) reduces the mechanical integrity of brain tissue rather than leading to water accumulation, and (iii) shows similar spatial patterns in humans and mice. These results raise the prospect of leveraging MRE and quantitative MRI for MS staging and monitoring treatment in affected patients. [ABSTRACT FROM AUTHOR]

Background: To assess the frequency, clinical features, and outcome of peri-ictal delirium in adult patients experiencing seizures during intensive care. Methods: This observational study was conducted at a Swiss intensive care unit from 2015 to 2020. Patients aged ≥ 18 years with seizures were categorized as peri-ictal delirious (Intensive Care Delirium Screening Checklist [i.e., ICDSC] ≥ 4) or not (i.e., ICDSC < 4) within 24 h of seizures. The frequency of peri-ictal delirium and in-hospital death were defined as the primary endpoints. Illness severity and treatment characteristics between delirious and non-delirious patients were secondary endpoints. Logistic regression was used to compare in-hospital death and differences regarding clinical characteristics between delirious and non-delirious patients. Results: 48% of 200 patients had peri-ictal delirium for a median of 3 days. Delirious patients were older (median age 69 vs. 62 years, p = 0.002), had lower Simplified Acute Physiology Scores II (SAPS II; median 43 vs. 54, p = 0.013), received neuroleptics more frequently (31 vs. 5%, p < 0.001), were mechanically ventilated less often (56% vs. 73%, p = 0.013) and shorter (median 3 vs. 5 days, p = 0.011), and had decreased odds for in-hospital death with delirium (OR = 0.41, 95% CI 0.20–0.84) in multivariable analyses. Conclusions: Delirium emerged in every second patient experiencing seizures and was associated with lower SAPS II, shorter mechanical ventilation, and better outcomes, contradicting assumptions that altered cerebral function, from seizures and delirium, are linked to unfavorable outcomes. [ABSTRACT FROM AUTHOR]

Hydrothermal methods are commonly applied in pretreatment of lignocellulose for conversion to biofuels and chemicals. This pretreatment partially disassembles and solubilizes hemicelluloses and lignin, releasing sugars and phenolic compounds, which are potential inhibitors for the subsequent enzymatic saccharification step. In this work, the inhibitory effect of soluble phenolics in hydrothermal pretreatment liquor on canonical Trichoderma reesei enzymes was investigated, using purified cellobiohydrolases, endoglucanases, a xylanase, and a lytic polysaccharide monooxygenase, as well as commercial enzyme cocktails Cellic Ctec2 and Celluclast. The pretreatment liquor was fractionated to enrich the phenolics, and thoroughly analyzed. The most sensitive to phenolics inhibition were cellobiohydrolases, the major enzymes in crystalline cellulose degradation and the primary component in cellulolytic mixtures. These were inhibited by the oligophenolics and phenol-carbohydrate complexes (lignin-carbohydrate complex type of compounds), the latter of which could be mitigated by other enzymes, i.e., xylanases and endoglucanases. Addition of lytic polysaccharide monooxygenase to the hydrolysis reactions was found to relieve the negative effect of phenolics. Similarly, hydrolytic activity of a commercial enzyme cocktail Cellic Ctec2 was enhanced in the presence of low concentrations of phenolics. [ABSTRACT FROM AUTHOR]

Arabinogalactan is a biologically active water-soluble polysaccharide contained in great amounts in larch wood. A sulfate group introduced into the arabinogalactan molecule increases its biological activity and imparts new anticoagulant and hypolipedemic properties. A new method for the catalytic sulfation of arabinogalactan with ammonium sulfamate is proposed. The catalytic activity in the reaction of arabinogalactan sulfation with ammonium sulfamate has been investigated for both the base activators (urea and thiourea) and oxidants (KMnO4 and K2Cr2O7). It has been shown that, in this process, the most effective activator is KMnO4, which ensures the highest (11.3 wt %) sulfur content in sulfated arabinogalactan. The effect of temperature and time of the arabinogalactan sulfation with ammonium sulfamate and the nature of solvents used on the sulfur content in sulfated arabinogalactan has been examined. It has been found that the highest (11.3%) sulfur content in the product is obtained by sulfation of arabinogalactan in 1,4-dioxane at a temperature of 90 °C for 4 h with the KMnO4 activator. The introduction of a sulfate group into the arabinogalactan molecule has been confirmed by the FTIR and NMR spectroscopy data. The FTIR spectrum of sulfated arabinogalactan, in contrast to that of the initial arabinogalactan, includes an absorption band at 1249 cm−1. According to the 13C NMR spectroscopy data, the sulfate groups are located at carbon atoms C2 and C4 of the main galactan chain and at carbon atom C6 of the end galactose units of the main and side arabinogalactan chains. It has been established by gel permeation chromatography that, during the sulfation, the molecular mass of arabinogalactan molecules increases proportionally to the introduced sulfate groups. The absence of low molecular weight fractions is indicative of the absence of depolymerization under the conditions of sulfation and evolution of sulfated arabinogalactan. [ABSTRACT FROM AUTHOR]

A new method for obtaining ultrafine particles of cobalt ferrites is proposed. This synthesis is a two-step process: the first step is the synthesis of ultrafine particles from aqueous solutions of nitrates under the action of non-equilibrium low-temperature plasma. The second stage is high-temperature treatment of the resulting powders. The action of plasma on solutions of iron and cobalt nitrates leads to the formation of a colloidal suspension at the plasma-solution interface in the liquid anode. The kinetics of co-precipitation from solutions under the action of plasma has been studied. It is shown that the process of formation is complex, includes several stages. The rate of formation of particles directly depends on the concentration of iron nitrate in the initial mixture. An increase in the discharge current leads to an increase in the rate of particle formation. The obtained substances were studied immediately after the plasma-solution interaction, after centrifugation, and after high-temperature treatment. X-ray diffraction analysis showed that the resulting ultrafine particles are a mixture of hydroxonitrites and hydroxides of cobalt and iron. The data of thermogravimetric analysis confirm the data of X-ray diffraction analysis. The surface morphology was studied using a scanning electron microscope; the resulting powders have a well-developed surface. The resulting particles are characterized by two sizes, 92 nm and 1.46 μm. The magnetic characteristics of the particles were studied using a vibrating magnetometer at room temperature with a maximum applied field of up to 30 kOe. The coercive force of the obtained particles was 210 Oe. The saturation magnetization (MS) obtained at room temperature was found to be 65 emu/g and remanent magnetization (Mr) was 22 emu/g. [ABSTRACT FROM AUTHOR]

Purpose: Gastroesophageal adenocarcinoma is associated with poor prognosis, even in resectable stages. Systemic inflammation plays a key role in cancer progression. Yet, information on prognostic values of systemic inflammatory parameters in European cohorts is scarce. Methods: We analysed systemic inflammatory biomarkers (neutrophil-to-lymphocyte ratio (NLR), leucocyte-to-lymphocyte ratio (LLR), platelet-to-lymphocyte ratio (PLR), systemic inflammation response index (SIRI) and modified Glasgow Prognostic Score (mGPS)) at the time of cancer diagnosis and their association with overall survival (OS) in patients with gastroesophageal adenocarcinoma treated at the Medical University of Vienna between 1990 and 2020. Results: In this analysis of 769 patients with gastroesophageal adenocarcinoma, higher mGPS (0–2) scores were associated with shorter OS in the overall cohort (24.9 versus 11.9 versus 7.6 months; HR 1.74, 95% CI 1.549–1.056; p < 0.001), in locally advanced (31.1 versus 19.8 versus 13.9 months, HR 1.561, 95% CI 1.274–1.912; p < 0.001) and in advanced/metastatic settings (12.3 versus 7.3 versus 5.8 months; HR 1.377, 95% CI 1.777–1.611; p < 0.001). In multivariate analyses, the association of mGPS with the OS stayed statistically significant in the locally advanced cohort (HR 1.397, 95% CI 1.068–1.828; p = 0.015), whereas NLR, LLR, PLR and SIRI did not. mGPS was associated with more advanced stages (p < 0.001) and weight loss (p = 0.002). Conclusion: mGPS poses a feasible prognostic tool in patients with locally advanced gastroesophageal cancer. [ABSTRACT FROM AUTHOR]

The Structured Inventory of Malingered Symptomology (SIMS) is a measure of symptom validity that is widely utilized in a variety of settings and populations. Both legitimate and valid symptoms may artificially conflate SIMS scores. The purpose of this analysis was to evaluate the SIMS potential to reflect psychological symptoms of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) as opposed to negative response bias in veterans. Participants were 483 veterans who completed diagnostic clinical interviews and the SIMS. Descriptive statistics evaluated item-level frequencies. Nonparametric analyses assessed differences between those with and without current diagnoses of MDD, PTSD, a mixed mental health group, and healthy controls. Veterans with PTSD and MDD scored significantly higher than those without these diagnoses on the SIMS Total score and SIMS Affective Functioning (AF) subscale score (p <.001). Thirty-six percent (n = 27) of items were frequently endorsed (≥25%) in the valid MDD subsample, and 40% (n = 30) in the PTSD subsample. Regression analyses showed that MDD was significantly associated with the SIMS Total score (B = 4.34, p <.001) and the SIMS AF subscale score (B = 1.64, p <.001). PTSD was also significantly associated with the SIIMS Total score (B = 6.11, p <.001) and SIMS AF (B = 5.83, p <.001) subscale score. Results suggest that the SIMS may not be an appropriate validity measure for veterans with MDD and/or PTSD. [ABSTRACT FROM AUTHOR]

Background and aim: Brain-derived neurotrophic factor (BDNF) functions not only in the brain but also in peripheral tissues such as the liver. Genetic factors determine the development of alcohol dependence and somatic consequences of chronic intoxication, especially liver cirrhosis. The BDNF gene polymorphisms are associated with alcohol dependence; however, their relationship with the development of alcohol-related liver cirrhosis (ALC) has not yet been established. This study evaluated the association between single-nucleotide polymorphisms (SNPs) within the BDNF gene and liver cirrhosis in heavy drinkers. Methods: BDNF-related SNPs rs925946, rs6265, rs10835210, rs7103411, and rs75945125 were determined using real-time PCR in heavy drinkers with and without liver cirrhosis. Single SNPs and defined haplotypes within the BDNF gene were tested for association with ALC. Results: According to both codominant and recessive genetic models, carriers of the rs925946 TT genotype have an elevated risk of liver cirrhosis development with odds ratios (confidence intervals) 6.287 (1.286–30.738) and 6.321 (1.317–30.348), respectively. BDNF SNPs rs6265, rs10835210, rs7103411, and rs75945125 do not associate with risk of ALC. One block of haplotypes consisting of rs10835210 and rs7103411 demonstrated linkage disequilibrium (D′ = 1 and r2 = 0.228). The revealed haplotypes do not associate with the development of liver cirrhosis in alcohol heavy drinkers. Conclusion: Thus, the BDNF rs925946 SNP is associated with the risk of ALC in heavy drinkers. Future investigations of the BDNF gene-related genetic markers of ALC will help to objectively assess the risk and severity of liver damage and correct the corresponding therapy. [ABSTRACT FROM AUTHOR]

The vast majority of Parkinson's disease cases are idiopathic. Unclear etiology and multifactorial nature complicate the comprehension of disease pathogenesis. Identification of early transcriptomic and metabolic alterations consistent across different idiopathic Parkinson's disease (IPD) patients might reveal the potential basis of increased dopaminergic neuron vulnerability and primary disease mechanisms. In this study, we combine systems biology and data integration approaches to identify differences in transcriptomic and metabolic signatures between IPD patient and healthy individual-derived midbrain neural precursor cells. Characterization of gene expression and metabolic modeling reveal pyruvate, several amino acid and lipid metabolism as the most dysregulated metabolic pathways in IPD neural precursors. Furthermore, we show that IPD neural precursors endure mitochondrial metabolism impairment and a reduced total NAD pool. Accordingly, we show that treatment with NAD precursors increases ATP yield hence demonstrating a potential to rescue early IPD-associated metabolic changes. Transcriptomics and metabolomics data integration coupled with systems biology reveal signature differences in idiopathic Parkinson's disease vs healthy controls, with pyruvate, amino acid, lipid and NAD metabolism as most dysregulated pathways. [ABSTRACT FROM AUTHOR]

Objectives: While self-compassion is increasingly being researched, a clear understanding of what self-compassion is, how it works, and for which outcomes remains elusive. This article summarizes and critically evaluates current theoretical and empirical trends in the self-compassion literature. We provide directions for future research to support a more comprehensive understanding of self-compassion. Method: This paper systematically evaluates issues in three interrelated areas: (1) over-reliance on a particular conceptualization of self-compassion, (2) a narrow focus on the affective mechanisms as per the general resource model of self-regulation, and (3) the prioritization of intrapersonal outcomes over inter-personal outcomes. Results: Our analysis suggests that current understandings of what self-compassion is and how it impacts outcomes are limited in several ways. Firstly, self-compassion is almost exclusively operationalized using the Self Compassion Scale, inadvertently constraining how we think about this complex construct. Secondly, a heavy emphasis remains on unmeasured changes in "general resources" as explanatory, while more specific pathways beyond affectivity or resource management are rarely considered. Lastly, intrapersonal outcomes are prioritized over interpersonal or social outcomes, which restricts our understanding of the broader benefits of self-compassion. Conclusions: To address the limitations, we suggest embracing and assessing multiple conceptualizations of self-compassion, empirically testing a wider range of plausible mediators, and investigating a broader range of outcomes, including those in both interpersonal and social spheres. Ongoing consideration of such issues will facilitate our empirical and theoretical understanding of self-compassion, enabling us to adapt more efficient interventions to benefit a wider group of individuals and our society at large. [ABSTRACT FROM AUTHOR]

The control of some physiological parameters, such as the heart rate, is known to have a role in cognitive and emotional processes. Cardiac changes are also linked to mental health issues and neurodegeneration. Thus, it is not surprising that many of the brain structures typically associated with cognition and emotion also comprise a circuit—the central automatic network—responsible for the modulation of cardiovascular output. The mediodorsal thalamus (MD) is involved in higher cognitive processes and is also known to be connected to some of the key neural structures that regulate cardiovascular function. However, it is unclear whether the MD has any role in this circuitry. Here, we show that discrete manipulations (microstimulation during anaesthetized functional neuroimaging or localized cytotoxin infusions) to either the magnocellular or the parvocellular MD subdivisions led to observable and variable changes in the heart rate of female and male rhesus macaque monkeys. Considering the central positions that these two MD subdivisions have in frontal cortico-thalamocortical circuits, our findings suggest that MD contributions to autonomic regulation may interact with its identified role in higher cognitive processes, representing an important physiological link between cognition and emotion. [ABSTRACT FROM AUTHOR]

Evidence-based practices (EBPs) are often adapted during community implementation to improve EBP fit for clients and the service context. Augmenting EBPs with additional dosing and content may improve fit. However, reducing EBP content can reduce EBP effectiveness. Using multilevel regression models, this study examined whether supportive program climate and program-furnished EBP-specific implementation strategies (e.g., materials, ongoing training, in-house experts) are associated with augmenting and reducing adaptations, and whether therapist emotional exhaustion moderated these associations. Data were collected from surveys completed by 439 therapists from 102 programs 9 years after a system-driven EBP implementation initiative. Supportive program climate was associated with more augmenting adaptations. Emotional exhaustion was a significant moderator. When organizations used more EBP-specific implementation strategies, more emotionally exhausted therapists reduced EBPs less and less emotionally exhausted therapists augmented EBPs more. Findings provide guidance on how organizations can support appropriate EBP adaptations in spite of therapist emotional exhaustion. [ABSTRACT FROM AUTHOR]

In 2020, almost half a million individuals developed rifampicin-resistant tuberculosis (RR-TB). We estimated the global burden of RR-TB over the lifetime of affected individuals. We synthesized data on incidence, case detection, and treatment outcomes in 192 countries (99.99% of global tuberculosis). Using a mathematical model, we projected disability-adjusted life years (DALYs) over the lifetime for individuals developing tuberculosis in 2020 stratified by country, age, sex, HIV, and rifampicin resistance. Here we show that incident RR-TB in 2020 was responsible for an estimated 6.9 (95% uncertainty interval: 5.5, 8.5) million DALYs, 44% (31, 54) of which accrued among TB survivors. We estimated an average of 17 (14, 21) DALYs per person developing RR-TB, 34% (12, 56) greater than for rifampicin-susceptible tuberculosis. RR-TB burden per 100,000 was highest in former Soviet Union countries and southern African countries. While RR-TB causes substantial short-term morbidity and mortality, nearly half of the overall disease burden of RR-TB accrues among tuberculosis survivors. The substantial long-term health impacts among those surviving RR-TB disease suggest the need for improved post-treatment care and further justify increased health expenditures to prevent RR-TB transmission. Rifampicin-resistant tuberculosis (RR-TB) requires longer, more toxic therapy than rifampicin-sensitive disease and is associated with a higher occurrence of long-term sequelae. In this mathematical modeling study, the authors estimate that incident RR-TB in 2020 will be responsible for ~6.9 million disability-adjusted life years; 44% due to post-tuberculosis sequelae. [ABSTRACT FROM AUTHOR]

The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPADM) in acute myeloid leukemia (AML) with a combination of hypermorphic N-terminal mutations (CEBPANT), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. The most frequently co-mutated genes in CEBPADM AML are GATA2 and TET2, however the molecular mechanisms underlying this co-mutational spectrum are incomplete. By combining transcriptomic and epigenomic analyses of CEBPA-TET2 co-mutated patients with models thereof, we identify GATA2 as a conserved target of the CEBPA-TET2 mutational axis, providing a rationale for the mutational spectra in CEBPADM AML. Elevated CEBPA levels, driven by CEBPANT, mediate recruitment of TET2 to the Gata2 distal hematopoietic enhancer thereby increasing Gata2 expression. Concurrent loss of TET2 in CEBPADM AML induces a competitive advantage by increasing Gata2 promoter methylation, thereby rebalancing GATA2 levels. Of clinical relevance, demethylating treatment of Cebpa-Tet2 co-mutated AML restores Gata2 levels and prolongs disease latency. TET2 and GATA2 are two frequently co-mutated genes in CEBPA double mutated acute myeloid leukemia (AML). Here the authors show that the underlying mechanism for this cooccurrence is for TET2 loss-of-function mutation to counteract the increase in GATA2 expression, which is disadvantageous to these type of AML cells. [ABSTRACT FROM AUTHOR]

Background: In regions where there is only itraconazole capsule as a therapeutic option for treatment of chronic pulmonary aspergillosis (CPA), measuring the serum concentrations becomes even more important for therapeutic success. Objective: Evaluate the initial itraconazole serum trough concentrations after the administration of oral capsule of itraconazole for the treatment of CPA. Methods: The measurement was performed at least 7-days after initiation of therapy. The standard treatment at our institution was a 200 mg capsule every 12 h. We defined that an adequate serum trough concentration of itraconazole during treatment was 1–4 mg/L. Results: This study recruited 28 patients. The median value was 0.30 mg/L (IQR 0.01–0.70). Only 11% (n = 3) had adequate serum concentrations based on guideline recommendation. All patients with clinical deterioration had itraconazole serum levels ≤ 0.8 mg/L. Conclusion: The initial serum concentrations of itraconazole after capsule formulation administration were low. Increasing the dose should be considered when the itraconazole concentration is low, especially if it is ≤ 0.8 mg/L, and the patient presents with clinical deterioration. Larger studies are needed to evaluate the adequate concentrations recommended for CPA. [ABSTRACT FROM AUTHOR]

Objectives: Self-compassion has been associated with numerous benefits at a personal level. However, despite suggestions that self-compassion might also lead to benefits for others, findings are inconsistent, and evidence regarding putative mechanisms is lacking. This pre-registered study examined whether personal values (self-transcendence, self-enhancement, conservation) mediated the link between self-compassion and compassion for others (within one's social network) in a general population sample. Method: A community sample (n = 707) anonymously completed measures indexing demographics, self- and other-focused compassion, and personal values in an online survey. Results: As predicted, self-compassion was associated with higher compassion for others. A parallel multiple mediation model showed that differences in self-transcendence values (but not conservation or self-enhancement) were significant mediators (a3b3 = 0.94, 95% CI [0.40, 1.55]). Conclusions: Self-compassion may be a way to enhance compassion for others, and differences in personal values (i.e., self-transcendence) may help explain this important link. Findings suggest the importance of evaluating motivation-related mediators in self-compassion research. Moreover, the research emphasizes the importance of identifying specific pathways through which self-compassion can potentially yield benefits. Further work in this area can enhance our understanding of the construct as well as inform future self-compassion interventions. Pre-registration: This study was pre-registered in AsPredicted.org (#86706). [ABSTRACT FROM AUTHOR]

Taurine-respiring gut bacteria produce H2S with ambivalent impact on host health. We report the isolation and ecophysiological characterization of a taurine-respiring mouse gut bacterium. Taurinivorans muris strain LT0009 represents a new widespread species that differs from the human gut sulfidogen Bilophila wadsworthia in its sulfur metabolism pathways and host distribution. T. muris specializes in taurine respiration in vivo, seemingly unaffected by mouse diet and genotype, but is dependent on other bacteria for release of taurine from bile acids. Colonization of T. muris in gnotobiotic mice increased deconjugation of taurine-conjugated bile acids and transcriptional activity of a sulfur metabolism gene-encoding prophage in other commensals, and slightly decreased the abundance of Salmonella enterica, which showed reduced expression of galactonate catabolism genes. Re-analysis of metagenome data from a previous study further suggested that T. muris can contribute to protection against pathogens by the commensal mouse gut microbiota. Together, we show the realized physiological niche of a key murine gut sulfidogen and its interactions with selected gut microbiota members. Authors utilise a multi-omics approach for the ecophysiological characterization of a taurine-respiring mouse gut bacterium. [ABSTRACT FROM AUTHOR]