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Yamanaka factors (YFs) can reverse some aging features in mammalian tissues, but their effects on the brain remain largely unexplored. Here, we induced YFs in the mouse brain in a controlled spatiotemporal manner in two different scenarios: brain development and adult stages in the context of neurodegeneration. Embryonic induction of YFs perturbed cell identity of both progenitors and neurons, but transient and low-level expression is tolerated by these cells. Under these conditions, YF induction led to progenitor expansion, an increased number of upper cortical neurons and glia, and enhanced motor and social behavior in adult mice. Additionally, controlled YF induction is tolerated by principal neurons in the adult dorsal hippocampus and prevented the development of several hallmarks of Alzheimer's disease, including cognitive decline and altered molecular signatures, in the 5xFAD mouse model. These results highlight the powerful impact of YFs on neural proliferation and their potential use in brain disorders., Competing Interests: Declaration of interests M.S. is a shareholder of Senolytic Therapeutics, Life Biosciences, Rejuveron Senescence Therapeutics, and Altos Labs. M.S. was a consultant of Rejuveron Senescence Therapeutics and Altos Labs until the end of 2022. M.A. is a shareholder of Altos Labs., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: The COVID-19 pandemic impacted mental health, as demonstrated by numerous studies. In recent years, especially during the pandemic, the use of social networks, including Twitter, increased. This suggests that this media could help with mental health monitoring, as attested by previous studies., Method: We conducted a multidisciplinary study on French tweets that were posted between January 1, 2019, and December 31, 2021. We selected the tweets via the Twitter API (Application Programming Interface) using five keywords relating to suicide: want to die, suicidal ideation, commit suicide, suicidal, and suicide attempt. A word frequency analysis was performed, and the data were compared with the number of emergency visits for suicidal ideation before and during the COVID-19 pandemic as recorded by the French national suicide observatory., Results: We observed that 189,005 tweets were related to suicide in 2019, 261,993 in 2020 (+38.62% of that observed in 2019), and 301,177 in 2021 (+59.35% of that observed in 2019). We also observed an increase in the number of tweets containing control words in 2020 (+30.07% of that observed in 2019), but in 2021, the number almost fell back to the level of that in 2019 (+5.96% of that observed in 2019). Furthermore, the difference between both ratios (of suicide-related tweets and of tweets containing control words) was most significant during the third lockdown. The change in the number of suicide-related tweets followed a curve that overlapped with the change in the number of emergency visits following suicidal ideations, as reported by the French national suicide observatory. In conclusion, Twitter can be an adequate and reliable tool for screening for suicidal ideation in the general population., (Copyright © 2023 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Purpose: Competency-based medical education relies on equitable assessment. This study examined the influence of faculty and trainee gender on assessments of internal medicine (IM) resident performance over time., Method: A longitudinal analysis of clinical performance assessments from 7 U.S. IM residency programs (July 2014-June 2019) was conducted. Core competency scores (patient care [PC], medical knowledge [MK], practice-based learning and improvement [PBLI], systems-based practice [SBP], professionalism [PROF], and interpersonal and communication skills [ICS]) were standardized across programs. Cross-classified mixed-effects linear regression evaluated the relationship between gender and standardized competency scores within training programs, while adjusting for multiple variables including IM In Training Examination percentile rank., Results: Data included 9,346 evaluations by 1,011 faculty (552 [55%] men, 459 [45%] women) for 664 residents (358 [54%] men, 306 [46%] women). Initially, women residents' scores were significantly lower than men's in PC (estimated difference [standard error ] -0.097 [0.033], P = .004), MK (-0.145 [0.034], P < .001), and PBLI -0.090 [0.040], P = .022). PC, MK, PBLI, and SBP scores increased more over time for women residents than men (PC: 0.050 [0.015], P = .001; MK: 0.052 [0.015], P = .001; PBLI: 0.036 [0.018], P = .048; SBP: 0.036 [0.016], P = .027). PROF and ICS scores were comparable across gender. There was a significant interaction between faculty gender and postgraduate year (PGY) across all competencies but none between resident gender, faculty gender, and PGY, indicating that men and women faculty rated residents differently over time but were consistent in how they rated men and women residents., Conclusions: Gender-based assessment differences were variable across competencies and time. Women residents had lower scores initially but greater gains in "hard skill" (MK, PC, and PBLI) than in "soft skill" (ICS and PROF) competencies, suggesting assessment inequities. Efforts to ensure equitable assessment are needed., (Copyright © 2024 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Inflammation has an essential role in healing. However, over-active inflammation disrupts normal cellular functions and can be life-threatening when not resolved. The NLRP3 inflammasome, a component of the innate immune system, is an intracellular multiprotein complex that senses stress-associated signals, and, for this reason is a promising therapeutic target for treating unresolved, pathogenic inflammation. Alternative splicing of NLRP3 RNA has been suggested as a regulatory mechanism for inflammasome activation, as some spliced isoforms encode NLRP3 proteins with compromised function. Here, we take advantage of this natural regulatory mechanism and devise a way to control pathogenic inflammation using splice-switching antisense oligonucleotides (ASOs). To identify and induce NLRP3 spliced isoforms lacking inflammatory activity, we tested a series of ASOs, each targeting a different exon, to determine the most effective strategy for down-regulating NLRP3. We identify several ASOs that modulate NLRP3 splicing, reduce NLRP3 protein, and decrease inflammasome signaling in vitro . The most effective ASO suppresses systemic inflammation in vivo in mouse models of acute inflammation and cryopyrin-associated periodic syndrome (CAPS). Our results demonstrate a systematic approach to protein engineering using splice-switching ASOs to generate isoforms with altered activity, and identify an ASO that can treat pathological inflammation in mice by reducing functional NLRP3.

Background: Severe primary graft dysfunction (PGD) after lung transplantation (LTx) is a significant risk factor for the development of bronchiolitis obliterans syndrome (BOS). Recent data from our group demonstrated that small extracellular vesicles (sEVs) isolated from the plasma of LTx recipients with BOS have reduced levels of tumor suppressor gene liver kinase B1 (LKB1) and promote epithelial-to-mesenchymal transition (EMT) and fibrosis. Here, we hypothesized that early inflammatory responses associated with severe PGD (PGD2/3) can downregulate LKB1 levels in sEVs, predisposing to the development of chronic lung allograft dysfunction (CLAD)., Methods: sEVs were isolated from the plasma of human participants by Exosome Isolation Kit followed by 0.20-µm filtration and characterized by NanoSight and immunoblotting analysis. Lung self-antigens (K alpha 1 tubulin, Collagen V), LKB1, nuclear factor kappa B, and EMT markers in sEVs were compared by densitometry analysis between PGD2/3 and no-PGD participants. Neutrophil-derived factors and hypoxia/reperfusion effects on LKB1 levels and EMT were analyzed in vitro using quantitative real-time polymerase chain reaction and Western blotting., Results: LKB1 was significantly downregulated in PGD2/3 sEVs compared with no-PGD sEVs. Within PGD2/3 participants, lower post-LTx LKB1 was associated with CLAD development. Hypoxia/reperfusion downregulates LKB1 and is associated with markers of EMT in vitro. Finally, lower LKB1 levels in PGD2/3 are associated with increased markers of EMT., Conclusions: Our results suggest that in post-LTx recipients with PGD2/3, downregulation of LKB1 protein levels in sEVs is associated with increased EMT markers and may result in the development of CLAD. Our results also suggest that ischemia/reperfusion injury during LTx may promote CLAD through the early downregulation of LKB1., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

In recent years several studies established the diagnostic value of anti-Müllerian hormone (AMH) in companion animals. However, less is known about physiological AMH concentrations in young individuals highlighting the necessity to apply the diagnostic findings to this group. The aim of this study was to determine the AMH values of healthy male and female dogs between the age of 8 and 48 weeks, tomcats under 8 weeks and up to 48 weeks of age and queens between 2 to 12 weeks of age. In total, 96 blood samples were collected. Anti-Müllerian hormone was measured in all samples and testosterone was measured in the oldest age group of the males in both species. The hormones were analyzed using a human based chemiluminescence immune assay. Overall, AMH concentrations were higher in males than in females ( p < 0.001). According to the AMH concentration there was no difference in males, but queens had significant higher AMH concentrations than bitches ( p < 0.001). AMH remained high in males up to week 24 and decreased significantly thereafter (tomcats: p = 0.015; male dogs: p = 0.013), which correlated with an increase in testosterone levels for male dogs only. In bitches, AMH remained below the detection limit until the week 16 and slightly increased subsequently. In queens, AMH was detectable from the beginning with a significant increase in the older age group ( p = 0.003). Half of the cats in the older age group even approached the chemiluminescence immune assay's upper limit. The results show that female cats secrete AMH much earlier than female dogs in which AMH secretion begins just shortly before the start of the puberty. In the male animals, the decrease in AMH concentration around puberty was similar in dogs and cats, but a correlation with the increase of testosterone was only observed in dogs. Further research is required to determine the origin of the high AMH concentrations in female kittens and the lack of correlation between testosterone and AMH concentrations in male kittens.

SARS-CoV-2 infection induces the generation of virus-specific CD4 + and CD8 + effector and memory T cells. However, the contribution of T cells in controlling SARS-CoV-2 during infection is not well understood. Following infection of C57BL/6 mice, SARS-CoV-2-specific CD4 + and CD8 + T cells are recruited to the respiratory tract, and a vast proportion secrete the cytotoxic molecule granzyme B. Using depleting antibodies, we found that T cells within the lungs play a minimal role in viral control, and viral clearance occurs in the absence of both CD4 + and CD8 + T cells through 28 days postinfection. In the nasal compartment, depletion of both CD4 + and CD8 + T cells, but not individually, results in persistent, culturable virus replicating in the nasal epithelial layer through 28 days postinfection. Viral sequencing analysis revealed adapted mutations across the SARS-CoV-2 genome, including a large deletion in ORF6. Overall, our findings highlight the importance of T cells in controlling virus replication within the respiratory tract during SARS-CoV-2 infection.

Guidelines and recommendations to properly elicit and document sexual orientation and gender identity in the clinical setting are rapidly emerging; however, in the epidemiologic research setting, information about collection, analysis, presentation, and dissemination of LGBTQI data is nascent. Federal agencies have worked to optimize epidemiologic research data collection from LGBTQI people. Despite these efforts, research data collection guidelines are inconsistent, and the data remain inadequate. The consequence of neglecting to collect data accurately from LGBTQI people is epidemiologic datasets that distort health professionals' and policymakers' perception of who comprises our communities and what the disease burden truly is. Additional harm is accrued by members of the neglected groups, including medical students and trainees, who may feel invisible, disrespected, and unsafe when presented with discriminatory data. With this article, we use our perspectives as a medical educator and a medical student to describe the challenge of working with inadequate LGBTQI datasets. We recommend five actions that can be taken by individuals, departments, and institutions to mitigate harm from the existing datasets: 1) acknowledge the limitations of the data; 2) develop, disseminate, and encourage use of an inclusive lexicon; 3) include LGBTQI-related criteria on peer teaching reviews; 4) engage students and trainees as partners, and if appropriate, content experts to review curriculum; and 5) self-identify as an agent of social change. In addition, we discuss systems-level considerations for realizing the goal of having comprehensive, accurate, and inclusive national data to drive health care delivery and health policy decisions. These include expanding research guidelines to address reporting and dissemination best practices for LGBTQI data, and widespread adoption of data reporting guidelines by biomedical journals. There is an urgent need for data to support quality care of LGBTQI communities. The health of our family, friends, neighbors, and nation depends on inclusive, accurate data.

The reliability and safety of locomotives is crucial for efficient train operation. Repeated turbocharger failures in Israel Railways locomotive fleet have raised serious safety concerns. An investigation into the failures revealed that the uncontrolled acceleration and overspeed transients of the turbocharger shaft occurred before the failure. Early detection of potential turbocharger failures by predicting overspeed conditions is critical to the safety and reliability of locomotives. In this study, an enhanced novel algorithm for estimating the Instantaneous Angular Speed (IAS) of the turbocharger and diesel engines is presented to overcome the challenges of transient operating conditions of diesel engines. Using adaptive dephasing, the algorithm effectively isolates critical asynchronous vibration components that are crucial for the early detection of turbocharger failures. This algorithm is suitable for non-stationary speeds and is applicable to any range of rotational speed and rate of change. The algorithm requires the input of the basic parameters of the system, while all other parameters that control the process are determined automatically. The algorithm was developed specifically for the special operating conditions of diesel engines and improves predictive maintenance and operational reliability. The method is robust as it correlates between several characteristic frequencies of the rotating parts of the system. The algorithm was verified and validated with simulated and experimental data., (© 2024. The Author(s).)

The basolateral amygdala (BLA) contains discrete neuronal circuits that integrate positive or negative emotional information and drive the appropriate innate and learned behaviors. Whether these circuits consist of genetically-identifiable and anatomically segregated neuron types, is poorly understood. Also, our understanding of the response patterns and behavioral spectra of genetically-identifiable BLA neurons is limited. Here, we classified 11 glutamatergic cell clusters in mouse BLA and found that several of them were anatomically segregated in lateral versus basal amygdala, and anterior versus posterior regions of the BLA. Two of these BLA subpopulations innately responded to valence-specific, whereas one responded to mixed - aversive and social - cues. Positive-valence BLA neurons promoted normal feeding, while mixed selectivity neurons promoted fear learning and social interactions. These findings enhance our understanding of cell type diversity and spatial organization of the BLA and the role of distinct BLA populations in representing valence-specific and mixed stimuli., (© 2024. The Author(s).)

Travel times between different locations form the basis for most contemporary measures of spatial accessibility. Travel times allow to estimate the potential for interaction between people and places, and is therefore a vital measure for understanding the functioning, sustainability, and equity of cities. Here, we provide an open travel time matrix dataset that describes travel times between the centroids of all cells in a grid (N = 13,132) covering the metropolitan area of Helsinki, Finland. The travel times recorded in the dataset follow a door-to-door approach that provides comparable travel times for walking, cycling, public transport and car journeys, including all legs of each trip by each mode, such as the walk to a bus stop, or the search for a parking spot. We used the r5py Python package, that we developed specifically for this computation. The data are sensitive to diurnal variations and to variations between people (e.g. slow and fast walking speed). We validated the data against the Google Directions API and present use cases from a planning practice. The five key principles that guided the data set design and production - comparability, simplicity, reproducibility, transferability, and sensitivity to temporal and interpersonal variations - ensure that urban and transport planners, business and researchers alike can use the data in a wide range of applications., (© 2024. The Author(s).)

Purpose: The appropriate extrication techniques for trauma patients after car accidents remain a topic of controversy. Various techniques for immobilizing the cervical spine during prehospital extrication have been investigated., Methods: This explorative study compared the amount of spinal motion during five different extrication procedures from a racecar and a rallycar performed by two teams: a professional motorsport extrication team and a team of professional emergency medical technicians (EMTs). Two different microelectromechanical systems were used to measure spinal motion, and a motionscore was calculated to compare the amount of remaining spinal motion. A high motionscore indicates high remaining motion and a low motionscore indicates low remaining motion., Results: The use of an extricable seat results in a mean overall motion score of 1617 [95% CI 308-2926]. Emergency extrication without equipment resulted in the lowest overall motionscore 1448 [95% CI 1070-1826]. In case of urgent extrication the Extrication team attained a motionscore of 2118 [95% CI 517-3718] and the EMT team a motionscore of 2932 [95% CI 1427-4435]. When performing the procedure with the aid of a rescue boa, the EMT team achieved an overall mean motionscore in the same range 2725 [95% CI 568-4881] with boa vs. 2932 [95% CI 1427-4435] without boa. When mean scores of individual spinal segments were analyzed, we found that the EMT team did especially worse in immobilizing the cervical spine 198 vs. 758., Conclusions: Regular training of extrication procedures has paid off considerably in reducing spinal movement during extrication from a racecar. If an extricable seat is available, extrication should be performed using it. However, if emergency extrication is necessary, an additional manual cervical spine immobilization should be conducted using the Rautek maneuver to sufficiently reduce cervical spine movement., (© 2024. The Author(s).)

Background: Antiphospholipid antibody (aPL) testing is critical for the classification of antiphospholipid syndrome. The 2023 ACR/EULAR classification criteria recommend the use of enzyme-linked immunosorbent assays (ELISAs) and specific thresholds for aPL positivity. Since non-ELISA methods are increasingly used, we compared and evaluated ELISA and non-ELISA aPL assays in a real-world maximum care hospital setting. Methods: Between January 2021 and June 2024, anticardiolipin (aCL; IgG and IgM) and anti-beta2 glycoprotein I (aß2GPI; IgG and IgM) antibodies were measured using ELISA ( n = 5115) and a chemiluminescence-based automated immunoassay (CLIA) ( n = 3820). Results of parallel testing were compared, and associations with clinical and laboratory characteristics were evaluated. Results: A total of 946 samples were tested using ELISA and CLIA in parallel. A total of 136 (14%) specimens were positive for at least one aPL, and 55 (6%) specimens were from patients diagnosed with APS. Among the latter, 47 (85%) and 41 (75%) patients were positive when ELISA- or CLIA-based aPL assays were used, respectively. After applying the >40 units threshold of the new classification criteria, the number of aPL-positive specimens was significantly lower. In the entire cohort, the agreement between ELISA and CLIA aPL assays was acceptable only for aß2GPI IgG; the results from the two methods did not agree for aCL IgG/IgM and aß2GPI IgM. In APS patients, the agreement between ELISA and CLIA aPL assays was acceptable for aß2GPI IgG and IgM but poor for aCL IgG and IgM. Antibody levels in APS patients were significantly higher using CLIA compared to ELISA. Conclusions: The method-dependent discrepancies between ELISA- and CLIA-based aPL assays regarding the quantitative and qualitative results are substantial. Both methods are suitable for APS classification, but the choice of aPL assay may influence the classification, and therefore, aPL results should be interpreted carefully in the clinical context.

Background: A new indication for use of silver collagen oxidized regenerated cellulose (ORC) dressing in conjunction with negative pressure wound therapy (NPWT) and reticulated open cell foam (ROCF) dressings has recently become available., Objective: An in-person meeting with 7 health care providers (HCPs) was held to identify clinical care settings and appropriate use of silver collagen ORC dressings in conjunction with NPWT and ROCF dressings., Methods: Consensus statements were developed using a modified Delphi technique. An additional 25 HCPs completed an anonymous survey on the consensus statements. Consensus was defined as ≥80% agreement among survey respondents., Results: Use of silver collagen ORC dressings with NPWT and ROCF dressings was recommended in inpatient and outpatient health care settings. Use in traumatic wounds, surgical wounds, diabetic ulcers, venous leg ulcers, and pressure injuries/ulcers was supported. Use was not recommended in the presence of exposed unprotected organs or exposed unprotected vessels, when the potential for inadequate wound hemostasis exists, acutely ischemic wounds, third-degree burns, or surgically closed incisions, or with patient hypersensitivity to product components., Conclusions: Limited evidence exists on use of NPWT in conjunction with silver collagen ORC dressings. A panel developed 12 consensus statements detailing the recommended and contraindicated uses of NPWT in conjunction with silver collagen ORC dressings.

Objectives: Antinuclear antibodies (ANA) of the IgE-type have been described in several connective tissue disorders (CTD) but not yet in systemic sclerosis (SSc). Aim of the study was, therefore, to establish an ELISA for the demonstration of IgE-autoantibodies to topoisomerase-I (topo-I) and the centromeric proteins A and B (CENP-A/B), to assess their prevalence and reactivity in SSc and to analyse their clinical relevance., Methods: One hundred fifty-one patients with SSc and 88 with CREST-syndrome, 291 patients with other CTD, and 23 patients with fibromyalgia syndrome (FM) as a control collective were included into the study. Patients' sera were analysed by an in-house-ELISA for IgE autoantibodies against topo-I and CENP-A/B using recombinant antigens. Patients were assessed for median Rodnan skin score(mRSS), different organ and cutaneous manifestations., Results: Of the patients with CREST syndrome, 67% had IgE-anti-CENP-A- and 77% IgE-anti-CENP-B-antibodies. IgE-anti-topo-I antibodies were found in 56% of patients with SSc. Prevalence and reactivity were significantly higher in CREST and SSc, respectively, than in other CTD or FM. IgE-reactivity strongly correlated with IgG-antibody reactivity. In CRESTsyndrome, IgE-anti-CENP-A (but not CENP-B)-antibodies were significantly higher and more prevalent in patients with skin ulcers, high mRSS, and more than four organ manifestations. They did not correlate with blood eosinophil counts. In contrast, for IgE-anti-topo-I antibodies no correlation with clinical manifestations was observed., Conclusions: IgE-autoantibodies against CENP-A/B and topo-I occur in SSc underlining the concept that SSc may be a T helper cell type 2 mediated disease. IgE-anti-CENP-A-antibodies correlated with disease activity, but this has to be confirmed in larger studies.

Background: Clinical competence encompasses attitudes, skills, and knowledge regarding diverse client groups. Appropriate clinical competence requires an understanding of the cultural context in which healthcare is delivered. In conservative countries such as Israel, there is a noticeable scarcity of information regarding the clinical competency of physiotherapy students (PTSs) in effectively treating lesbian, gay, bisexual and transgender (LGBT) individuals. The objective of this study was to assess the level of LGBT clinical competence among PTSs in Israel., Methods: Conducted through an anonymous online self-report survey, this study gathered personal and academic background information and self-reported data on previous LGBT education during undergraduate studies of PTSs. It utilized the Hebrew version of the Lesbian, Gay, Bisexual, and Transgender Development of Clinical Skills Scale (LGBT-DOCSS) questionnaire. Descriptive statistics were computed for all outcome measures. The internal reliability of the LGBT-DOCSS was assessed. Total scores of the LGBT-DOCSS, along with scores in each of the three subscales (clinical preparedness, knowledge, and attitudes), were compared across different levels of religiosity and gender., Results: The sample comprised of 251 PTSs, with an average age of 25.57 ± 3.07 years (34.7% men, 65.3% women). All students reported a lack of LGBT community-related courses during their undergraduate studies. The translated Hebrew version demonstrated good internal consistency, with Cronbach's alpha ranging from 0.65 to 0.83. The LGBT-DOCSS total score was 4.55 ± 0.61 out of 7, indicating a low level of clinical competency. The highest mean score was in the attitudes subscale (6.55 ± 0.87), which was significantly higher than the scores for the knowledge subscale (3.14 ± 1.46) and clinical preparedness subscale (3.36 ± 0.86). Religiousness was significantly associated with clinical preparedness and attitudes. Men exhibited higher self-reported levels of knowledge and clinical preparedness, albeit with more negative attitudes compare to women. Sexual orientation was significantly associated with clinical competency, with PTSs who identified as heterosexual demonstrating a lower level of clinical competency compared to participants who identified as non-heterosexual., Conclusions: In Israel, PTSs demonstrated a low level of clinical competency in terms of self-reported knowledge and self-reported clinical preparedness but contrasting positive attitudes toward the LGBT community. Religiousness, gender and sexual orientation had a significant influence on competency levels.These preliminary findings highlight the urgent necessity to enhance the knowledge of PTSs regarding the LGBT community to improve their clinical competence., Trial Registration Nr: Not applicable., (© 2024. The Author(s).)

Human papillomavirus (HPV) is the most common sexually transmitted pathogen that causes anogenital disease. Cervical screening by cytology and HPV testing (co-testing) are important in prevention of cervical cancer. The Bethesda System category of atypical squamous cells (ASC) is used when a neoplastic process cannot be confidently identified. In such cases, the differential diagnosis is broad and includes benign conditions. Monitoring of ASC/SIL ratio is a commonly used laboratory quality assurance measure to prevent over- or under-use of this category. High risk human papillomavirus (hr-HPV) has been used in conjunction with the ASC/SIL ratio in determining whether a particular pathologist is over/under-using the indefinite category. However, the laboratory overall sample population prevalence rate of hr-HPV subtypes has not been previously examined for association with the ASC rate. In this study, the relationships between ASC/SIL ratio and hr-HPV prevalence rate and hr-HPV subtypes (16/18 and non-16/18) to the laboratory ASC prevalence were studied. The results demonstrate that HPV non-16/18 is the main subtype which is associated with ASC-US category. A large proportion of non-16/18 HPV-related cases are seen in young patients, which largely abates by the by fourth decade. In addition, there are differences in the ASC/SIL ratio for HPV 16/18 and non-16/18 types. The overall ASC/SIL ratio is an average of the ASC/SIL rate for the non-16/18 population and the HPV 16/18 population. Instead of basing the laboratory and practitioners' quality indicator solely on ASC/SIL ratio, the overall prevalence of HPV and its subtype ratio should also be reported as they are more reflective of laboratory performance., (© 2024 Wiley Periodicals LLC.)

Objective: To characterize urology resident on-call activities overnight at a multi-site academic medical center and model the expected volume of clinical activity using inpatient beds, emergency room visits, and attendings covered., Materials and Methods: On-call activities for 70 13-hour overnight shifts spanning 5 nonconsecutive months between May 2022 and February 2023 were recorded. Clinical coverage included 5 academic hospitals encompassing 1761 staffed inpatient beds and an expected nightly volume of 255 Emergency Department (ED) visits. The time, source, and clinical features of every call were documented., Results: An average of 15 unique calls were received during each shift. Of these, 35% required an in-person evaluation and 12% required a bedside or operative procedure. Approximately a third of calls (36%) were received after midnight. An in-person evaluation occurred within the first hour of 53% of shifts and every shift required at least 1 evaluation. When normalized for inpatient bed volume, an average of 7 unique patient communications occurred per 1000 beds, leading to 2 in-person evaluations. When normalized for an expected number of overnight ED visits, an average of 1 new ED consultation occurred per 100 ED visits., Conclusion: After-hours clinical coverage models vary significantly by specialty and institution, and coverage decisions must balance quality clinical care with safe provider workload. Patient needs were appropriately addressed by a single overnight on-call resident, providing a robust clinical experience. The volume of patient care activities in this experience supports the practice of a "night-float" resident with the clear expectation on-site care is required., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

During infection, adenoviruses inhibit the cellular RNA interference (RNAi) machinery by saturating the RNA-induced silencing complex (RISC) of the host cells with large amounts of virus-derived microRNAs (mivaRNAs) that bind to the key component of the complex, Argonaute 2 (AGO2). In the present study, we investigated AGO2 as a prominent player at the intersection between human adenovirus 5 (HAdV-5) and host cells because of its ability to interfere with the HAdV-5 life cycle. First, the ectopic expression of AGO2 had a detrimental effect on the ability of the virus to replicate. In addition, in silico and in vitro analyses suggested that endogenous microRNAs (miRNAs), particularly hsa-miR-7-5p, have similar effects. This miRNA was found to be able to target the HAdV-5 DNA polymerase mRNA. The inhibitory effect became more pronounced upon overexpression of AGO2, likely due to elevated AGO2 levels, which abolished the competition between cellular miRNAs and mivaRNAs for RISC incorporation. Collectively, our data suggest that endogenous miRNAs would be capable of significantly inhibiting viral replication if adenoviruses had not developed a mechanism to counteract this function. Eventually, AGO2 overexpression-mediated relief of the RISC-saturating action of mivaRNAs strongly enhanced the effectiveness of artificial miRNAs (amiRNAs) directed against the HAdV-5 preterminal protein (pTP) mRNA, suggesting a substantial benefit of co-expressing amiRNAs and AGO2 in RNAi-based strategies for the therapeutic inhibition of adenoviruses.

We present incomplete gamma kernels, a generalization of Locally Optimal Projection (LOP) operators. In particular, we reveal the relation of the classical localized L 1 estimator, used in the LOP operator for point cloud denoising, to the common Mean Shift framework via a novel kernel. Furthermore, we generalize this result to a whole family of kernels that are built upon the incomplete gamma function and each represents a localized L p estimator. By deriving various properties of the kernel family concerning distributional, Mean Shift induced, and other aspects such as strict positive definiteness, we obtain a deeper understanding of the operator's projection behavior. From these theoretical insights, we illustrate several applications ranging from an improved Weighted LOP (WLOP) density weighting scheme and a more accurate Continuous LOP (CLOP) kernel approximation to the definition of a novel set of robust loss functions. These incomplete gamma losses include the Gaussian and LOP loss as special cases and can be applied to various tasks including normal filtering. Furthermore, we show that the novel kernels can be included as priors into neural networks. We demonstrate the effects of each application in a range of quantitative and qualitative experiments that highlight the benefits induced by our modifications.

Objectives: Due to insufficient empirical data on the occupational participation of people affected by severe mental illness receiving integration assistance, routine data from a community psychiatry service were evaluated., Methods: Reference workers filled out a short questionnaire on different occupational and employment aspects of their clients from supported housing/floating outreach. In addition to descriptive and exploratory analyses, overall results from previous survey rounds were also evaluated., Results: N=1418 individuals (M=47.6 years) could be included, of whom approximately 45% had no job, sheltered employment, or daytime service. This percentage has remained almost unchanged over the last decades., Conclusion: Overall, there is an urgent need for action to improve occupational participation opportunities for people with mental illness and substance addiction., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht, (Thieme. All rights reserved.)

Background: CareNet is the IT-based tool for Case and Care Management (CCM) in Tyrol, which facilitates standardised documentation of CCM activities., Objectives: Analysing the pilot usage of CareNet Tyrol., Methods: Evaluation of the success and user experience of CareNet, expert interviews and a questionnaire-based assessment., Results: Feedback from users in both phases indicated that the CareNet platform provides general benefits, but falls short of fully supporting the daily work of CCM experts and avoiding the need for parallel use of different documentation tools., Conclusion: This paper provides an insight into the ongoing transition to digital documentation for CCM at LIV Tyrol. While user feedback highlights areas for improvement, digital documentation is proved to be beneficial for the CCM team.

There was evidence that perinuclear antineutrophil cytoplasmic antibodies (pANCA) in autoimmune liver diseases react with human beta-tubulin-5 (TBB5). Here, we reevaluate the specificity and clinical relevance of anti-TBB5 antibodies. Patients with untreated autoimmune hepatitis (AIH; n = 53), AIH under immunosuppressive therapy (AIH-IS; n = 125), primary sclerosing cholangitis (PSC; n = 40), primary biliary cholangitis (PBC; n = 250), nonautoimmune liver diseases (n = 158), inflammatory bowel diseases (IBD; n = 30), and healthy individuals (n = 62) were tested by enzyme-linked immunosorbent assay for IgG- and IgA-antibodies against recombinant human TBB5. pANCA were detected by immunofluorescence test. Sera were absorbed with TBB5 coupled to cyanogen bromide-activated sepharose. Prevalence and reactivity of IgG anti-TBB5 were significantly higher in patients with untreated AIH (68%; arbitrary units [AU] median: 369) than in PSC (28%; AU median: 84, P < 0.001), other liver diseases (14%; AU median: 185, P < 0.0001), IBD (3%; AU median: 111, P < 0.0001), and healthy controls (3%; AU median: 135; P < 0.0001). Anti-TBB5 did not correlate with pANCA, and immunoprecipitation with TBB5 did not abolish pANCA reactivity. In untreated AIH, anti-TBB5-reactivity was significantly higher than in AIH-IS. Transaminases decreased under IS preferentially in anti-TBB5-negative patients. There was no correlation between anti-TBB5-reactivity and histological stages. IgA-anti-TBB5 was mainly found in alcohol-associated liver disease (ALD; 39%). Our data do not support TBB5 as an autoantigenic target of pANCA. However, IgG-anti-TBB5 showed high specificity for (untreated) AIH. While they did not correlate with histological and laboratory parameters, their presence may indicate a poor response to IS., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The motivation to eat is suppressed by satiety and aversive stimuli such as nausea. The neural circuit mechanisms of appetite suppression by nausea are not well understood. Pkcδ neurons in the lateral subdivision of the central amygdala (CeA) suppress feeding in response to satiety signals and nausea. Here, we characterized neurons enriched in the medial subdivision (CeM) of the CeA marked by expression of Dlk1. CeA Dlk1 neurons are activated by nausea, but not satiety, and specifically suppress feeding induced by nausea. Artificial activation of CeA Dlk1 neurons suppresses drinking and social interactions, suggesting a broader function in attenuating motivational behavior. CeA Dlk1 neurons form projections to many brain regions and exert their anorexigenic activity by inhibition of neurons of the parabrachial nucleus. CeA Dlk1 neurons are inhibited by appetitive CeA neurons, but also receive long-range monosynaptic inputs from multiple brain regions. Our results illustrate a CeA circuit that regulates nausea-induced feeding suppression., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Treatment with high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (aHSCT) is an intensive treatment option for patients with severe forms of systemic sclerosis (SSc). Even though associated with a high treatment related mortality, the results in this high-risk population are generally favourable. The knowledge on the potential mechanism of action of this therapy and how it can improve patients with SSc is crucial to better select the right patients for aHSCT., Methods: This is a monocentric retrospective study from Tübingen, Germany, including 32 patients who underwent aHSCT. Peripheral blood samples were analysed for different lymphocyte subsets at various timepoints before and after aHSCT. Patients were divided into responders and non-responders according to the modified Rodnan skin score and lung function test in the three years following aHSCT., Results: Responders showed significantly lower levels of cluster of differentiation (CD)4 positive T cells in the first months after aHSCT (month 1 and 3), B cells (month 3 and 6 after aHSCT) and natural killer cells (month 1). Mantel-cox test showed a significant deviation of the probability curves, i.e. patients with lower CD4 + T cells and natural killer cells one month and B cells after 3 months after stem cell transplantation had a higher probability to belong to the responder group., Conclusions: Taken together, this study supports the theory that a profound CD4 + T cell and B cell lymphopenia is important for patients with SSc to achieve a sustained response after aHSCT., (© 2024. The Author(s).)

Introduction: Postoperative opioid prescriptions are associated with an increased risk of opioid dependance. While studies on no-opioid discharge strategies have been assessed following many urologic procedures, the effect of no-opioid discharges on health care utilization following artificial urinary sphincter placement is unknown. We performed a single-surgeon retrospective comparison of health care system interactions following artificial urinary sphincter implantation between patients who received an opioid prescription on discharge to those who did not., Methods: We identified 101 male patients who underwent 3-piece artificial urinary sphincter placement or revision by 1 provider between 2015 and 2022. All patients were discharged with acetaminophen and ibuprofen; none received intraoperative local anesthetic. Demographic information, preprocedural opioid use, opioid prescriptions following the procedure, postoperative office communications, unplanned office visits, and emergency department (ED) visits were recorded for each patient for 90 days., Results: Forty-five patients (45%) were discharged without an opioid prescription and 56 patients (55%) were discharged with an opioid prescription. No differences in age, race, BMI, operative time, or presence of a preoperative opioid prescription were observed. Discharge without an opioid did not significantly increase the number of office communications (55% vs 40%, P = .11), unplanned office visits (36% vs 23%, P = .19), or ED visits (20 vs 12, P = .41) within 90 days of implantation/revision., Conclusions: Opioids can be omitted from the discharge analgesic regimen following artificial urinary sphincter placement without increasing burden to surgical office staff or local EDs. Providers should consider no-opioid discharges for patients undergoing uncomplicated sphincter placement to limit risk of opioid-related morbidity.

Background: Equitable assessment is critical in competency-based medical education. This study explores differences in key characteristics of qualitative assessments (i.e., narrative comments or assessment feedback) of internal medicine postgraduate resident performance associated with gender and race and ethnicity., Methods: Analysis of narrative comments included in faculty assessments of resident performance from six internal medicine residency programs was conducted. Content analysis was used to assess two key characteristics of comments- valence (overall positive or negative orientation) and specificity (detailed nature and actionability of comment) - via a blinded, multi-analyst approach. Differences in comment valence and specificity with gender and race and ethnicity were assessed using multilevel regression, controlling for multiple covariates including quantitative competency ratings., Results: Data included 3,383 evaluations with narrative comments by 597 faculty of 698 residents, including 45% of comments about women residents and 13.2% about residents who identified with race and ethnicities underrepresented in medicine. Most comments were moderately specific and positive. Comments about women residents were more positive (estimate 0.06, p 0.045) but less specific (estimate - 0.07, p 0.002) compared to men. Women residents were more likely to receive non-specific, weakly specific or no comments (adjusted OR 1.29, p 0.012) and less likely to receive highly specific comments (adjusted OR 0.71, p 0.003) or comments with specific examples of things done well or areas for growth (adjusted OR 0.74, p 0.003) than men. Gendered differences in comment specificity and valence were most notable early in training. Comment specificity and valence did not differ with resident race and ethnicity (specificity: estimate 0.03, p 0.32; valence: estimate - 0.05, p 0.26) or faculty gender (specificity: estimate 0.06, p 0.15; valence: estimate 0.02 p 0.54)., Conclusion: There were significant differences in the specificity and valence of qualitative assessments associated with resident gender with women receiving more praising but less specific and actionable comments. This suggests a lost opportunity for well-rounded assessment feedback to the disadvantage of women., (© 2024. The Author(s).)