Search

Cognitive performance manifests regional differences, correlated with education. There is less information available about regional differences in performance-based measures of functional capacity. In multi-national trials focused on cognitive enhancement, it may be impossible to validate every measure in all locations. It is unknown if regional differences in healthy controls' (HC) performance affects relative levels of impairment in participants with schizophrenia (SCZ). A multi-site study comparing SCZ and HC administered the MATRICS Consensus Cognitive Battery (MCCB) and Virtual Reality Functional Capacity Assessment Tool (VRFCAT) to 164 HC participants and 164 with SCZ across three sites (Columbia, SC, Miami, and San Diego) and a representative sample of HC (n = 390) completed the VRFCAT in Durham, NC. Performance was compared between HC and SCZ participants at the validation sites. There were statistically significant cross-site differences in HC performance on both the MCCB and VRFCAT. Differences between HC and SCZ on MCCB and VRFCAT were substantial at all three sites, indicating that regional variations in HC performance did not induce reduced differences from SCZ participants. Regional differences were smaller than diagnostic group differences, suggesting that relative impairments of participants with SCZ is consistently preserved across performance differences in HC., Competing Interests: Declaration of competing interest Dr. Harvey has also received consulting fees or travel reimbursements from Alkermes, Boehringer Ingelheim, Karuna Therapeutics, Merck Pharma, Minerva Neurosciences, and Sunovion (DSP) Pharma in the past year. He receives royalties for BAC-app and BACS (Owned by WCG Endpoint Solutions, Inc. and contained in the MCCB), but not for the VRFCAT. He is chief Scientific Officer at i-Function, Inc. Dr. Keefe was CEO at Verasci, Inc. when these data were collected and now serves as a consultant to WCG, Karuna, Novartis, Kynexis, Gedeon-Richter, Pangea, Merck, and Boehringer-Ingelheim, and receives royalties for the BAC-app, BACS and VRFCAT. Dr. Horan was Vice President at Verasci when these data were collected and is now a Full Time Employee of Karuna Therapeutics (A Division of Bristol Myers, Squibb). Dr. Klein is a full-time employee at WCG Endpoint Solutions (Formerly known as Verasci, Inc). Ms. Guzman reports no biomedical conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pickering emulsions are excellent candidates for developing soft biosensors utilized for detecting native biomolecules such as peptides and proteins through the Surface-Enhanced Raman Spectroscopy (SERS) transduction mechanism. Here, we have developed a SERS sensor based on oil-in-water Pickering emulsions stabilized by Ag nanoparticles (Ag-NPs) with the Raman active molecule (4-Aminothiphenol, 4ATP) adsorbed to their surface. The structural properties and composition of the Pickering emulsion were tuned to meet the demands of the maximal optical response. Our results show that the obtained SERS signals of the main studied Pickering emulsion (water: oil ratio 7:3, 1 wt% Ag-NPs) outperformed colloidal dispersions with the same Ag-NPs concentration by 10-fold at any studied content of 4ATP. The superior optical response of the Pickering emulsion compared to the colloidal dispersion can thus pave the way for the detection of a large variety of analytes at high sensitivity by a soft sensing device. This study innovates by comparing the SERS signals of Raman-active Ag-NPs when they are assembled at the oil/water interface of an emulsion to the case where the NPs are individually dispersed in the medium. The findings shed light on the edit value of utilizing Raman-active Pickering stabilizers for biosensing applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Decentralized clinical trials are leading to rapid changes in assessment technology, including an expansion of interest in remote delivery. As technology changes, some of the updates include migration to fully cloud-based software and data management, with attendant differences in hardware, response modalities, and modifications in the level of tester engagement. It is rare to see systematic descriptions of the process of migration and upgrading of technology-related assessments. We present comparative data on successive generations of two widely used functional capacity measures, the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) and the Functional Capacity Assessment and Training System (FUNSAT). Four samples of healthy older individuals completed either the original device-resident, computer-administered versions, or cloud-based, tablet-delivered versions of these tasks. For the VRFCAT, performance and correlations with age were similar across versions, although performance was slightly (5 %) faster with iPad delivery. For the FUNSAT, performance and correlations with age and cognitive task scores were generally similar across versions for English Speakers, though there were some differences related to the testing language for the cloud-based version. These results support the feasibility of migrating digital assessments to cloud-based delivery and substantiate fundamental similarity across delivery strategies., Competing Interests: Dr.’s Harvey and Czaja are co-Chief Scientific Officers of i-Function, Inc. Mr. Kallestrup is Chief Executive Officer of i-Function, Inc. Dr. Harvey has also received consulting fees or travel reimbursements from Alkermes, Boehringer Ingelheim, Karuna Therapeutics, Merck Pharma, Minerva Neurosciences, and Sunovion (DSP) Pharma in the past year. He receives royalties for BAC-app and BACS (Owned by WCG Endpoint Solutions, Inc. and contained in the MCCB). Dr. Keefe was CEO at Verasci when these data were collected and now serves as a consultant to WCG, Karuna, Novartis, Kynexis, Gedeon-Richter, Pangea, Merck, and Boehringer-Ingelheim, and receives royalties for the BAC, BACS and VRFCAT. Dr. Horan was Vice President at Verasci when these data were collected and is now a Full Time Employee of Karuna Therapeutics (A Division of Bristol Myers, Squibb). Dr. Klein is a full-time employee at WCG Endpoint Solutions (Formerly known as Verasci, Inc)., (© 2024 The Authors. Published by Elsevier Inc.)

Many social cognitive assessments that were developed specifically for use in clinical populations are now being widely used in undergraduate populations, either to provide a comparison for clinical groups or to explore performance across the continuum from healthy to subclinical populations. However, the appropriateness of using these assessments in the general population is unclear. The current study, therefore, seeks to determine whether the Social Cognition Psychometric Evaluation (SCOPE) battery retains its psychometric properties when used in an undergraduate sample.The initial SCOPE battery was administered to 265 undergraduate participants, and the utility of the tasks was measured by assessing floor and ceiling effects. Internal consistency, discriminant and convergent validity are reported for each task, and the relationship between task performance and neurocognition and social functioning were assessed.Several of the tasks demonstrated limited utility, with the Hinting Task specifically demonstrating a pronounced ceiling effect. Only two measures of social cognitive biases achieved satisfactory internal consistency. Select tasks demonstrated small, but significant relationships with social functioning outcomes and significantly predicted 2-3% of variance above neurocognition alone.Despite the association with social functioning, results indicate that the psychometric properties demonstrated in the initial SCOPE study with a clinical sample do not fully extend to a healthy undergraduate population and highlight the need for social cognitive tasks that validly assess ability across the continuum.

Background: People with HIV (PWH) with undetectable HIV viral load still have an impaired health-related quality of life (HRQoL). Cannabidiol (CBD) is a nonintoxicating cannabis-derived cannabinoid that holds promise for the treatment of many ailments. In the present study, we tested whether oral CBD-rich medication could significantly improve PWH's HRQoL., Methods: Eighty participants with undetectable HIV viral load were randomized to either a placebo or full-spectrum CBD (1 mg/kg twice a day) arm for 12 weeks plus a 4-week follow-up period. HRQoL was assessed at baseline, week 12, and week 16 using the 36-Item Short Form Health Survey questionnaire (SF-36). Primary outcomes were physical and mental component summary scores; secondary outcomes were the 8 SF-36 subscale scores. Treatment effects on outcomes were estimated using generalized estimating equations., Results: We found no effect of CBD intake on the summary score for either component. However, CBD intake was associated with a higher physical functioning score at week 12 only (regression coefficient [95% confidence interval], 7.72 [0.55-14.89]; P = .035). No significant main effect of CBD intake on the other HRQoL subscale scores was observed. Furthermore, there was no difference in self-reported adverse effects between the 2 arms., Conclusions: Twice-daily CBD full-spectrum oil at 1 mg/kg had no major effect on virologically suppressed PWH's HRQoL but had a positive effect on physical functioning. Further randomized controlled trials including PWH with lower baseline HRQoL are needed to confirm this finding., Competing Interests: Potential conflicts of interests. H.K. is a paid employee of Little Green Pharma Pty Ltd. This company provided the investigational medicinal product (ie, CBD) and placebo at no financial cost for the purposes of this research. The other authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Parameterization of dry deposition is key for modelling of atmospheric transport and deposition of radioactive particles. Still, very simple parameterizations are often encountered in radioactive preparedness models such as the SNAP model (SNAP=Severe Nuclear Accident Program) of the Norwegian Meteorological Institute. In SNAP a constant dry deposition velocity (=0.2 cm/s) neglecting aerodynamic and surface resistances, is presently used. Therefore, two new dry depositions schemes (the Emerson scheme and the EMEP (European Monitoring and Evaluation Programme) scheme) have been implemented in SNAP to evaluate the benefits of including aerodynamic and surface resistances codes with respect to model prediction skills. The three dry deposition schemes are evaluated using 137 Cs total deposition from soil sample data (n = 540) for a 60 km radial zone out from the Chernobyl Nuclear Power Plant (ChNPP) collected during the months after the accident. The present study capitalizes on high resolution meteorological data (2.5 km horizontal resolution), a detailed land-use data set with 273 sub-classes and the hitherto most comprehensive source term description for the Chernobyl accident. Based on our findings it is recommended to replace the present simple SNAP scheme with the Emerson or EMEP dry deposition scheme., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Radiation sensitive materials are among the most difficult materials to study, even more so if they exist only as nanometer-sized particles, where their size is either intentional because of enhanced properties at the nano-scale or it is unintentional because it is impossible to obtain bigger particles of the same structure. In both cases characterization methods need to be optimized to get the most information out of these particles before the radiation damages them to a point where their structure is altered. When the particles are crystallized, both characteristics, the small size and the beam sensitivity, call for electron diffraction as a privileged investigation tool. The strong interaction of electrons (as compared to X-rays) with matter allows single crystal diffraction experiments on nanometer-sized crystals and for the same amount of beam damage, electron diffraction yields more information than X-rays. These inherent advantages of electron diffraction are optimized in the recently developed low-dose electron diffraction tomography (LD-EDT) by minimizing the necessary dose for a complete data collection. In this contribution we show that in some cases even doses as low as 2 e - /Ų can induce damage in crystal structures that inhibit a correct structure refinement. However, by LD-EDT we can obtain data using extremely low doses that don't alter the structure which make it then possible not only to solve crystal structures but also to refine them using dynamical diffraction theory. Here a synthetic oxide containing volatile Na and a metal-organic framework are given as examples. A dynamical refinement of the structures is possible with data sets requiring a dose of less than 0.15 e - /Ų., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Wearable cardioverter defibrillator (WCD) is utilized in patients with assumed but not yet confirmed risk for sudden cardiac death (SCD). Many of these patients also present with atrial fibrillation (AF). However, the rate of WCD-detected ventricular or atrial arrhythmia events in this specific high-risk cohort is not well understood., Methods: In WEARIT-II, the cumulative probability of any sustained or nonsustained VT/VF (WCD-treated and nontreated), and atrial/supraventricular arrhythmias during WCD use was assessed using the Kaplan-Meier method by prior AF, with comparisons by the log-rank test. The incidence of ventricular and atrial arrhythmia events were expressed as events per 100 patient-years, and were analyzed by prior AF using negative binomial regression., Results: WEARIT-II enrolled 2000 patients, 557 (28%) of whom had AF before enrollment. Cumulative probability of any sustained or nonsustained WCD-detected VT/VF during WCD use was significantly higher among patients with a history of AF than without AF (6% vs. 3%, p = .001). Similarly, the recurrent rate of any sustained or nonsustained VT/VF was significantly higher in patients with prior AF versus no prior AF (131.5 events per 100 patient-years vs. 22.7 events per 100 patient-years, p = .001). Patients with prior AF also had a significantly higher burden of any WCD-detected atrial arrhythmias/SVT/inappropriate arrhythmias therapy (183.2 events per 100 patient-years vs. 74.8 events per 100 patient-years, p < .001)., Conclusion: Our results demonstrate that patients with a history of AF wearing the WCD for risk assessment have a higher incidence of ventricular arrhythmias that may facilitate the decision making for ICD implantation., (© 2024 Wiley Periodicals LLC.)

Hepatocellular carcinoma (HCC) and solid cancers with liver metastases are indications with high unmet medical need. Interleukin-12 (IL-12) is a proinflammatory cytokine with substantial anti-tumor properties, but its therapeutic potential has not been realized due to severe toxicity. Here, we show that orthotopic liver tumors in mice can be treated by targeting hepatocytes via systemic delivery of adeno-associated virus (AAV) vectors carrying the murine IL-12 gene. Controlled cytokine production was achieved in vivo by using the tetracycline-inducible K19 riboswitch. AAV-mediated expression of IL-12 led to STAT4 phosphorylation, interferon-γ (IFNγ) production, infiltration of T cells and, ultimately, tumor regression. By detailed analyses of efficacy and tolerability in healthy and tumor-bearing animals, we could define a safe and efficacious vector dose. As a potential clinical candidate, we characterized vectors carrying the human IL-12 (huIL-12) gene. In mice, bioactive human IL-12 was expressed in a vector dose-dependent manner and could be induced by tetracycline, suggesting tissue-specific AAV vectors with riboswitch-controlled expression of highly potent proinflammatory cytokines as an attractive approach for vector-based cancer immunotherapy., Competing Interests: All authors are employees of Boehringer Ingelheim., (Copyright © 2024 Düchs, Kratzer, Vieyra-Garcia, Strobel, Schönberger, Groß, Aljayyoussi, Gupta, Lang, Klein, Morilla, Hopf, Park, Kreuz, Klugmann and Igney.)

Objectives: Very little research has examined suicidal ideation or the factors associated with contemplating suicide among older transgender adults. This paper examines whether or not there is evidence of syndemic effects influencing suicidal ideation among transgender persons aged 50 or older., Methods: Data from the 2015 U.S. National Transgender Survey were used to examine five domains of potentially-syndemic effects (workplace issues, interactions with professionals, using public services, personal safety, and socioeconomic disadvantages) in a sample of 3,724 transgender Americans aged 50 or older. A dichotomous measure of suicidal ideation during the past year was the main outcome measure., Results: The odds of contemplating suicide increased anywhere from 96% to 121% among people experiencing any of the problems under study, and anywhere from 258% to 1,552% (depending upon the syndemic effect domain in question) when they were faced by all of the experiences included in any particular domain. When all items were combined, exposure to any of the domains' problems elevated the risk of contemplating suicide by 276% and exposure to all of the problems examined increased the risk by 861%. The syndemic effects measure remained significant in multivariate analysis controlling for the influence of other potentially-relevant factors., Conclusions: Considerable evidence for the presence of syndemic effects was found, demonstrating that the more different types of adverse conditions that older transgender person's face, the more likely they are to experience to contemplate suicide. There is evidence that these effects diminish with advancing age.

We report the presence of habitual ground nesting in a newly studied East African chimpanzee (Pan troglodytes schweinfurthii) population in the Bugoma Central Forest Reserve, Uganda. Across a 2-year period, we encountered 891 night nests, 189 of which were classified as ground nests, a rate of ~21%. We find no preliminary evidence of socio-ecological factors that would promote its use and highlight local factors, such as high incidence of forest disturbance due to poaching and logging, which appear to make its use disadvantageous. While further study is required to establish whether this behavior meets the strict criteria for nonhuman animal culture, we support the argument that the wider use of population and group-specific behavioral repertoires in flagship species, such as chimpanzees, offers a tool to promote the urgent conservation action needed to protect threatened ecosystems, including the Bugoma forest., (© 2023 The Authors. American Journal of Primatology published by Wiley Periodicals LLC.)

Therapeutic development for mental disorders has been slow despite the high worldwide prevalence of illness. Unfortunately, cellular and circuit insights into disease etiology have largely failed to generalize across individuals that carry the same diagnosis, reflecting an unmet need to identify convergent mechanisms that would facilitate optimal treatment. Here, we discuss how mesoscale networks can encode affect and other cognitive processes. These networks can be discovered through electrical functional connectome (electome) analysis, a method built upon explainable machine learning models for analyzing and interpreting mesoscale brain-wide signals in a behavioral context. We also outline best practices for identifying these generalizable, interpretable, and biologically relevant networks. Looking forward, translational electome analysis can span species and various moods, cognitive processes, or other brain states, supporting translational medicine. Thus, we argue that electome analysis provides potential translational biomarkers for developing next-generation therapeutics that exhibit high efficacy across heterogeneous disorders., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Beam sensitive nanomaterials such as zeolites or metal-organic frameworks (MOF) represent a great challenge for crystallographic structure determination and refinement. The strong electron-matter interaction and the high spatial resolution achievable make electron diffraction the technique of choice for particles of sizes below a micrometer and many different 3-dimensional electron diffraction (3D ED) techniques have been developed in recent years. Nevertheless, beam sensitivity of the samples can lead to the crystal structure being damaged during the data acquisition impeding the determination of its structure. A simple way to reduce beam damage is to lower the dose during the experiment. However, this implies weaker diffraction intensities which can become problematic for the exploitation of the data. In order to obtain complete data sets with strong intensities without damaging the crystals, we developed the dose symmetric electron diffraction tomography (DS-EDT) method, combining the low-dose electron diffraction tomography (LD-EDT) technique with the dose-symmetric tomography scheme known from cryo-EM. In order to reduce the dose on an individual crystal and still obtain enough data for a structure solution and refinement, we partition the dose over several crystals. The individual datasets are then merged in order to achieve the necessary completeness. On two test structures we first show that merging of data from small domains of the reciprocal space is indeed sufficient to obtain reliable data for structure solution and refinement. Second, we show on the beam sensitive manganese formate that high-quality data can be obtained on a few frames while the frames that have suffered from beam damage can still be used to determine the orientation matrix and the unit cell of the crystals. The results from the dynamical refinement on the obtained data show a high accuracy of the atom positions. In this way, DS-EDT can reduce the total dose on an individual crystal by an order of magnitude with respect to the already very dose-efficient LD-EDT., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Purpose: Using a minority stress paradigm, this paper examines the relationship between anti-transgender discrimination, harassment, and violence among transgender adults. Methods: Data from the 2015 U.S. National Transgender Survey were used to examine twenty types of anti-transgender experiences/problems (e.g., harassment at work, problems with police officials, verbal and physical assaults) in a sample of 27,715 transgender Americans aged 18 or older. Binge drinking during the previous month was the dependent variable, and eight control measures were examined in the multivariate analysis. Results: Experiencing any of the twenty types of anti-transgender discrimination, harassment, or violence increased the odds of binge drinking by 48%. Experiencing many such problems increased the odds of binge drinking by 104%. Multivariate analysis showed that anti-transgender discrimination, harassment, and violence remains a predictor of binge drinking even when other key measures are taken into account. Younger people, racial minority group members, and persons who were not married or "involved" were at particularly great risk. Conclusions: Consistent with the minority stress paradigm, the more different types of anti-transgender experiences people had, the more likely they were to engage in binge drinking. Targeted intervention needs to help transgender persons to avoid anti-transgender discrimination, harassment, and violence to the greatest extent possible, and to develop resiliency skills whenever they are victimized. This is particularly true for transgender persons who are younger, minority, and not "involved" in a relationship.

Purpose: This paper examines the relationships among transition milestones (i.e., transition-related events in transgender persons' lives that demarcate their life circumstances before vs. afte a milestone was reached), psychological distress, and suicidal ideation in a large sample of transgender adults., Methods: Data from the 2015 U.S. National Transgender Survey were used to examine 11 specific transition milestones in a sample of 27,715 transgender Americans aged 18 or older. The Kessler-6 scale was used to measure psychological distress and a dichotomous measure of suicidal ideation during the past year was the other main outcome measure. Covariates in the multivariate analysis included demographic measures, variables assessing support and discrimination, and 11 transition milestones., Results: Bivariate analyses revealed that, in almost all instances, reaching specific transition milestones led to reduced psychological distress and diminished odds of suicidal ideation. Multivariate analysis revealed that psychological distress was a strong predictor of suicidal ideation, but transition milestones were not retained in the final model. Structural equation analysis showed that three specific transition milestones (namely, changing one's name and/or gender on legal documents, taking gender-affirming hormones, having had any gender-conforming surgical procedures) influenced suicidal ideation indirectly, through their direct impact on psychological distress., Conclusions: Reaching specific transition milestones plays an important role in many transgender adults' lives, and may be highly beneficial in helping them to reduce psychological distress. This, in turn, is likely to have a positive impact upon their likelihood of contemplating suicide., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: A novel buprenorphine (BUP) extended-release formulation (BUP-XR) produced as a lipid-encapsulated, low viscosity BUP suspension for subcutaneous (SC) injection to control pain was evaluated for pharmacokinetics and safety in four adult male cynomolgus monkeys., Methods: Each animal was given 0.2 mg/kg reformulated BUP-XR SC. Clinical observations were made during the course of the study. Blood samples were obtained from each animal before BUP-XR administration, 6, 24, 48, 72, and 96 h post-BUP-XR injection. Plasma levels of buprenorphine were analyzed using HPLC-MS/MS. The PK values calculated included peak plasma concentration of the BUP analyte, time to peak plasma concentration, plasma half-life, area under the plasma concentration-time curve, clearance, apparent volume of distribution, and elimination rate constant (C max , T max , T ½ , AUC 0-t , CL, Vd, and Ke, respectively)., Results: Observable adverse clinical signs were not detected. BUP concentration peaked from 6 to 48 h, then declined in a linear fashion. Quantifiable plasma BUP was measured in all monkeys at all time points. Results indicate that a single BUP-XR dose at 0.2 mg/kg can reliably provide plasma levels of BUP reported in the literature to be therapeutically relevant for up to 96 h., Conclusions: Because of the lack of any clinical observations or adverse effects at the injection site or absence of observable abnormal behaviors, it may be concluded that the use of BUP-XR is safe and efficacious in this species of non-human primate at the dose regimen described in this study for up to 96 h post-administration., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Overeating disorders largely contribute to worldwide incidences of obesity. Available treatments are limited. Here, we discovered that long-term chemogenetic activation of ventrolateral periaqueductal gray (vlPAG) GABAergic cells rescue obesity of high-fat diet-induced obesity (DIO) mice. This was associated with the recovery of enhanced mIPSCs, decreased food intake, increased energy expenditure, and inguinal white adipose tissue (iWAT) browning. In vivo calcium imaging confirmed vlPAG GABAergic suppression for DIO mice, with corresponding reduction in intrinsic excitability. Single-nucleus RNA sequencing identified transcriptional expression changes in GABAergic cell subtypes in DIO mice, highlighting Cacna2d1 as of potential importance. Overexpressing CACNA2D1 in vlPAG GABAergic cells of DIO mice rescued enhanced mIPSCs and calcium response, reversed obesity, and therefore presented here as a potential target for obesity treatment.

Purpose: This paper examines the conjoint effects of serious psychological distress, suicidal ideation, and substance abuse among transgender adults. The principal aims are to determine the prevalence of this "triple whammy," identify the factors underlying the co-occurrence of all three problems, and to determine if there is evidence of syndemic effects underlying the "triple whammy.", Methods: Data from the 2015 U.S. National Transgender Survey were used to examine the "triple whammy" relationship in a sample of 27,715 transgender Americans aged 18 or older. Odds ratios and multivariate logistic regression were performed to examine the data., Results: 13.3 % of the study participants reported experiencing serious psychological distress, suicidal ideation, and substance abuse. The most potent predictors of the "triple whammy" were younger age, a greater number of anti-transgender experiences, and not reaching various transition milestones. Strong evidence emerged to indicate the presence of syndemic effects in operation., Conclusions: Experiencing the combination of adverse mental health and substance abuse was not uncommon in this population of transgender adults. Being young, experiencing a larger variety of types of anti-transgender discrimination, harassment, and violence, and not reaching specific transition milestones all had a significant impact on the odds that people would experience the "triple whammy." This was particularly true when these measures were examined in conjunction with one another, because of strong syndemic effects., Competing Interests: Declaration of competing interest Neither author has any conflicts of interest to report with regard to this research., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Some research suggests that schizotypal and autistic traits can produce opposing effects on the mentalizing domain of social cognition. Although such findings support a diametrical model proposing that psychotic and autistic traits represent opposite extremes of the social brain continuum, results from recent studies have been more inconsistent, and the applicability of this model to other social cognition domains remains unclear. To test the diametrical model more broadly, this study examined the interactions between schizotypal and autistic traits on emotion recognition and social functioning., Method: A total of 791 participants recruited from the general population self-reported schizotypal traits using the Schizotypal Personality Questionnaire-Brief Revised (SPQ-BR) and autistic traits using the Broad Autism Phenotype Questionnaire (BAPQ). Participants also completed the Emotion Recognition 40 task and the Specific Levels of Functioning (SLOF) scale., Results: The SPQ subscales of interpersonal relationships and disorganized symptoms interacted significantly with social BAP on overall emotion recognition performance and the accuracy of identifying neutral faces. Supporting the diametrical model, elevated levels of both schizotypal and autistic traits contributed to higher emotion recognition accuracy compared to elevations on only one trait. For social functioning, however, the diametrical model was not supported. A main effect was found such that higher interpersonal relationship difficulties on SPQ predicted lower work skills on SLOF, and higher levels of both schizotypal and autistic traits combined to produce even lower social functioning., Conclusions: These findings suggest that the diametrical model may be more relevant to social cognition than to social functioning., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Aims: De novo implanted cardiac resynchronization therapy with defibrillator (CRT-D) reduces the risk of morbidity and mortality in patients with left bundle branch block, heart failure and reduced ejection fraction (HFrEF). However, among HFrEF patients with right ventricular pacing (RVP), the efficacy of CRT-D upgrade is uncertain., Methods: In this multicentre, randomized, controlled trial, 360 symptomatic (New York Heart Association Classes II-IVa) HFrEF patients with a pacemaker or implantable cardioverter defibrillator (ICD), high RVP burden ≥ 20%, and a wide paced QRS complex duration ≥ 150 ms were randomly assigned to receive CRT-D upgrade (n = 215) or ICD (n = 145) in a 3:2 ratio. The primary outcome was the composite of all-cause mortality, heart failure hospitalization, or <15% reduction of left ventricular end-systolic volume assessed at 12 months. Secondary outcomes included all-cause mortality or heart failure hospitalization., Results: Over a median follow-up of 12.4 months, the primary outcome occurred in 58/179 (32.4%) in the CRT-D arm vs. 101/128 (78.9%) in the ICD arm (odds ratio 0.11; 95% confidence interval 0.06-0.19; P < .001). All-cause mortality or heart failure hospitalization occurred in 22/215 (10%) in the CRT-D arm vs. 46/145 (32%) in the ICD arm (hazard ratio 0.27; 95% confidence interval 0.16-0.47; P < .001). The incidence of procedure- or device-related complications was similar between the two arms [CRT-D group 25/211 (12.3%) vs. ICD group 11/142 (7.8%)]., Conclusions: In pacemaker or ICD patients with significant RVP burden and reduced ejection fraction, upgrade to CRT-D compared with ICD therapy reduced the combined risk of all-cause mortality, heart failure hospitalization, or absence of reverse remodelling., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The number of diabetic patients is rising globally and concomitantly so do the diabetes associated complications. The gut secretes a variety of proteins to control blood glucose levels and/or food intake. As the drug class of GLP-1 agonists is based on a gut secreted peptide and the positive metabolic effects of bariatric surgery are at least partially mediated by gut peptides, we were interested in other gut secreted proteins which have yet to be explored. In this respect we identified the gut secreted protein FAM3D by analyzing sequencing data from L- and epithelial cells of VSG and sham operated as well as chow and HFD fed mice. FAM3D was overexpressed in diet induced obese mice via an adeno-associated virus (AAV), which resulted in a significant improvement of fasting blood glucose levels, glucose tolerance and insulin sensitivity. The liver lipid deposition was reduced, and the steatosis morphology was improved. Hyperinsulinemic clamps indicated that FAM3D is a global insulin sensitizer and increases glucose uptake into various tissues. In conclusion, the current study demonstrated that FAM3D controls blood glucose levels by acting as an insulin sensitizing protein and improves hepatic lipid deposition., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Angiopoietin-2 (Angpt-2) is involved in the pathogenesis of the capillary leak syndrome in sepsis and has been shown to be associated with worse outcomes in diverse critical illnesses. It is however unclear whether Angpt-2 plays a similar role in severely burned patients during the early phase characterized by massive capillary leakage. Our aim was to analyze the Angiopoietin-2/Angiopoietin-1 ratio (Angpt-2/Angpt-1 ratio) over the first two days in critically ill burn patients and examine its association with survival and further clinical parameters., Methods: Adult burn patients with a total burn surface area (TBSA) ≥ 20% treated in the burn intensive care unit (ICU) of the University Hospital of Zurich, Switzerland, were included. Serum samples were collected prospectively and serum Angpt-1 and Angpt-2 were measured by enzyme-linked immunosorbent assay (ELISA) over the first two days after burn insult and stratified according to survival status, TBSA and the abbreviated burn severity index (ABSI). Due to hemodilution in the initial resuscitation phase, the Angpt-2/Angpt-1 ratio was normalized to albumin., Results: Fifty-six patients were included with a median age of 51.5 years. Overall mortality was 14.3% (8/56 patients). The total amount of infused crystalloids was 12́902 ml (IQR 9́362-16́770 ml) at 24 h and 18́461 ml (IQR 13́024-23́766 ml) at 48 h. The amount of substituted albumin was 20 g (IQR 10-50 g) at 24 h and 50 g (IQR 20-60 g) at 48 h. The albumin-corrected Angpt-2/Angpt-1 ratios increased over the first 48 h after the burn insult (d0: 0.5 pg*l/ml*g [IQR 0.24 - 0.80 pg*l/ml*g]; d1: 0.83 pg*l/ml*g [IQR 0.29 - 1.98 pg*l/ml*g]; d2: 1.76 pg*l/ml*g [IQR 0.70 - 3.23 pg*l/ml*g]; p < 0.001) and were significantly higher in eventual ICU non-survivors (p = 0.005), in patients with a higher TBSA (p = 0.001) and in patients with a higher ABSI (p = 0.001)., Conclusions: In analogy to the pathological host response in sepsis, the Angpt-2/Angpt-1 ratio steadily increases in the first two days in critically ill burn patients, suggesting a putative involvement in the pathogenesis of capillary leakage in burns. A higher Angpt-2/Angpt-1 ratio is associated with mortality, total burn surface area and burn scores., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Electrical injuries follow a specific pathophysiology and may progressively damage both skin and deeper tissues, frequently ending in amputations. Type and timing of soft tissue reconstruction after electrical burns is crucial for proper outcome. The aim of this study was to assess surgical management and outcome of patients with electrical injuries treated at the Zurich Burn Center over the last 15 years, with emphasis on risk factors for amputation and reconstructive strategy., Methods: Patient charts were reviewed retrospectively to identify cases admitted at the Zurich Burns Center (2005-2019). Patient characteristics and surgical management, with a special focus on amputations, reconstruction and outcome were analyzed and risk factors for amputation were assessed., Results: Eighty-nine patients were identified and a total of 522 operations were performed. Escharotomy and fasciotomies were performed in 40.5% and 24.7% of cases, respectively, mainly at admission. The total amputation rate was 13.5% (23 amputations, 12 patients). Development of compartment syndrome, rhabdomyolysis, high myoglobin and CK blood levels, kidney failure, sepsis and respiratory complications during the course were related to higher risk of amputation (p < 0.001). Sixty-six flap-based reconstructions were performed (25% cases): 49 loco-regional flaps, 3 distant pedicled flaps, 14 free flaps. Two flaps were lost (flap failure rate 14%). Both flap losses occurred in cases of early reconstruction (within 5-21 days)., Conclusions: Electrical injuries are still cause of elevated morbidity and mortality, with high amputation rate. Predictors for amputation can support physicians in the surgical care and decision-making. Reconstruction remains challenging in this type of injury: the surgical management with early decompression, serial necrectomies and delayed early reconstruction remains the procedure of choice at our unit., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Releases of radionuclides to the atmosphere occasionally occur with no warning and with first observation at radioactivity monitoring stations. The Chernobyl accident of 1986 was first detected at Forsmark, Sweden, long before the official announcement by the Soviet Union, and the release of Ruthenium 106 detected across Europe in 2017 still has no official release location. The current study details a method based on footprint analysis of an atmospheric dispersion model to locate the source of an atmospheric release. The method was applied to the European Tracer EXperiment of 1994 to validate the method and to the Ruthenium observations of autumn 2017 to determine likely release locations and time characteristics of this release. The method can readily utilise an ensemble of numerical weather prediction data which improves the localisation results by taking into account meteorological uncertainties compared to only using deterministic weather data. In applying the method to the ETEX scenario, the most likely release location improved from a distance of 113 km from the true release location when using deterministic meteorology, to a distance of 63 km when using ensemble meteorology data, although such improvements may be scenario dependent. The method was constructed to be robust with respect to the choices of model parameters and measurement uncertainties. The localisation method can be useful for decision makers to enact countermeasures to protect the environment against the effects of radioactivity when observations are available from environmental radioactivity monitoring networks., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Lung cancer remains a devastating disease with a poor clinical outcome. A biomarker signature which could distinguish lung cancer from metastatic disease and detect therapeutic failure would significantly improve patient management and allow for individualized, risk-adjusted therapeutic decisions. In this study, circulating Hsp70 levels were measured using ELISA, and the immunophenotype of the peripheral blood lymphocytes were measured using multiparameter flow cytometry, to identify a predictive biomarker signature for lung cancer patients pre- and post-operatively, in patients with lung metastases and in patients with COPD as an inflammatory lung disease. The lowest Hsp70 concentrations were found in the healthy controls followed by the patients with advanced COPD. Hsp70 levels sequentially increased with an advancing tumor stage and metastatic disease. In the early-recurrence patients, Hsp70 levels started to increase within the first three months after surgery, but remained unaltered in the recurrence-free patients. An early recurrence was associated with a significant drop in B cells and an increase in Tregs, whereas the recurrence-free patients had elevated T and NK cell levels. We conclude that circulating Hsp70 concentrations might have the potential to distinguish lung cancer from metastatic disease, and might be able to predict an advanced tumor stage and early recurrence in lung cancer patients. Further studies with larger patient cohorts and longer follow-up periods are needed to validate Hsp70 and immunophenotypic profiles as predictive biomarker signatures.

The US Food and Drug Agency (FDA) requires clinical trials targeting cognitive impairment associated with schizophrenia (CIAS) to demonstrate the functional relevance of cognitive improvements by employing a functional co-primary measure. Although quantitative evidence supports the suitability of the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) for this purpose, FDA guidelines for qualification of clinical outcome assessments require evidence of content validity, defined as qualitative evidence that key stakeholders view the measure as relevant and important. To collect this important qualitative data, semi-structured interviews were conducted with outpatients with schizophrenia ( n = 24), caregivers ( n = 12), and professional peer support specialists ( n = 12) to elicit their views about the definition and importance of functional independence, the importance of the functional domains assessed by the VRFCAT (meal planning, using transportation, handling money, shopping), and the relevance of the VRFCAT tasks to these domains. Qualitative thematic analyses revealed consistent themes across groups in defining functional independence, including performing instrumental self-care, financial, and social tasks; making decisions autonomously; and not depending on others to carry out daily activities. There were, however, notable differences in their views regarding the importance of and barriers to functional independence. All groups viewed the VRFCAT as assessing skill domains that are central to independent functioning and, with some minor differences, the VRFCAT tasks were viewed as relevant and meaningful examples of the domains. These qualitative results provide converging evidence that key stakeholders view the VRFCAT as a content-valid measure., (© The Author(s) 2023. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.)

Measuring 25-hydroxyvitamin D (25D) can be a challenge in veterinary medicine because of laboratory accessibility and required sample volume. We compared 2 dried-blood-spot (DBS) tests and a lateral flow assay (LFA) to the gold standard, liquid chromatography-tandem mass spectrometry (LC-MS/MS). We hypothesized that there would be good agreement among the tests, within a clinically significant limit of agreement of ± 25 nmol/L. We collected blood from 6 healthy purpose-bred 2-y-old cats at 6 times over 6 wk, and measured 25D concentrations with all 4 tests. Agreement of the 3 candidate tests and LC-MS/MS was evaluated via Bland-Altman analysis, Passing-Bablok regression, and Lin correlation coefficients. Bland-Altman analysis demonstrated that the mean bias was >± 25 nmol/L for all 3 candidate tests in comparison to serum LC-MS/MS concentrations. The 95% CIs for the mean bias did not include zero, further supporting the presence of significant bias among methods. Additionally, all 3 tests had poor agreement with serum LC-MS/MS concentrations when analyzed by Lin correlation coefficient analysis, and bias between methods was further characterized by Passing-Bablok analysis. Based on these results, none of these 3 tests is recommended as an alternative to LC-MS/MS testing for 25D measurement in cats.

Background: Radiological high-resolution computed tomography-based evaluation of cochlear implant candidates' cochlear duct length (CDL) has become the method of choice for electrode array selection. The aim of the present study was to evaluate if MRI-based data match CT-based data and if this impacts on electrode array choice., Methods: Participants were 39 children. CDL, length at two turns, diameters, and height of the cochlea were determined via CT and MRI by three raters using tablet-based otosurgical planning software. Personalized electrode array length, angular insertion depth (AID), intra- and interrater differences, and reliability were calculated., Results: Mean intrarater difference of CT- versus MRI-based CDL was 0.528 ± 0.483 mm without significant differences. Individual length at two turns differed between 28.0 mm and 36.6 mm. Intrarater reliability between CT versus MRI measurements was high (intra-class correlation coefficient (ICC): 0.929-0.938). Selection of the optimal electrode array based on CT and MRI matched in 90.1% of cases. Mean AID was 629.5° based on the CT and 634.6° based on the MRI; this is not a significant difference. ICC of the mean interrater reliability was 0.887 for the CT-based evaluation and 0.82 for the MRI-based evaluation., Conclusion: MRI-based CDL measurement shows a low intrarater difference and a high interrater reliability and is therefore suitable for personalized electrode array selection.

Insomnia is a significant difficulty and is reported by large proportion of people with tinnitus. Although cognitive behavioural therapy for insomnia (CBTi) might be an effective treatment, no controlled studies had been conducted to date. This randomised controlled trial evaluated the benefits of CBTi on a sample of 102 people with tinnitus-related insomnia. Participants were randomised to 1) CBTi, 2) Audiology-Based Care (ABC) or 3) Sleep Support Group (SSG). Primary outcomes included insomnia, sleep efficiency and total sleep time. Secondary outcomes measured sleep onset latency, sleep quality, tinnitus distress, psychological distress, functioning and quality of life. CBTi was superior at reducing insomnia and increasing sleep efficiency compared to ABC post-intervention and at 6-month follow-up. ABC was superior at reducing insomnia and increasing sleep efficiency compared to SSG. Both CBTi and ABC reported increased total sleep time compared to SSG at 6-month follow. More than 80% of participants in the CBTi group reported clinically meaningful improvements compared to 47% in ABC and 20% for those receiving social support. CBTi was more effective in reducing tinnitus distress and improving sleep quality, functioning and some aspects of mental health. CBTi and ABC offer effective treatments for tinnitus-related sleep disorder but CBTi offers a sizeable benefit.

Fecal diagnostics are a mainstay of feline medicine, and fecal identification markers help to distinguish individuals in a multi-cat environment. However, the impact of identification markers on the fecal microbiota are unknown. Given the increased interest in using microbiota endpoints to inform diagnosis and treatment, the objective of this study was to examine the effects of orally supplemented glitter and crayon shavings on the feline fecal microbiota (amplicon sequencing of 16S rRNA gene V4 region). Fecal samples were collected daily from six adult cats that were randomized to receive oral supplementation with either glitter or crayon for two weeks, with a two-week washout before receiving the second marker. No adverse effects in response to marker supplementation were seen for any cat, and both markers were readily identifiable in the feces. Microbiota analysis revealed idiosyncratic responses to fecal markers, where changes in community structure in response to glitter or crayon could not be readily discerned. Given these findings, it is not recommended to administered glitter or crayon shavings as a fecal marker when microbiome endpoints are used, however their clinical use with other diagnostics should still be considered., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nealon, Wood, Rudinsky, Klein, Salerno, Parker, Quimby, Howard and Winston.)

Objective: Obesity and its associated comorbidities represent a global health challenge with a need for well-tolerated, effective, and mechanistically diverse pharmaceutical interventions. Oxyntomodulin is a gut peptide that activates the glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) and reduces bodyweight by increasing energy expenditure and reducing energy intake in humans. Here we describe the pharmacological profile of the novel glucagon receptor (GCGR)/GLP-1 receptor (GLP-1R) dual agonist BI 456906., Methods: BI 456906 was characterized using cell-based in vitro assays to determine functional agonism. In vivo pharmacological studies were performed using acute and subchronic dosing regimens to demonstrate target engagement for the GCGR and GLP-1R, and weight lowering efficacy., Results: BI 456906 is a potent, acylated peptide containing a C18 fatty acid as a half-life extending principle to support once-weekly dosing in humans. Pharmacological doses of BI 456906 provided greater bodyweight reductions in mice compared with maximally effective doses of the GLP-1R agonist semaglutide. BI 456906's superior efficacy is the consequence of increased energy expenditure and reduced food intake. Engagement of both receptors in vivo was demonstrated via glucose tolerance, food intake, and gastric emptying tests for the GLP-1R, and liver nicotinamide N-methyltransferase mRNA expression and circulating biomarkers (amino acids, fibroblast growth factor-21) for the GCGR. The dual activity of BI 456906 at the GLP-1R and GCGR was supported using GLP-1R knockout and transgenic reporter mice, and an ex vivo bioactivity assay., Conclusions: BI 456906 is a potent GCGR/GLP-1R dual agonist with robust anti-obesity efficacy achieved by increasing energy expenditure and decreasing food intake., (Copyright © 2022 Boehringer Ingelheim Pharma GmbH & CoKG. Published by Elsevier GmbH.. All rights reserved.)

Non-small cell lung cancer (NSCLC) is the second most frequently diagnosed tumor worldwide. Despite the clinical progress which has been achieved by multimodal therapies, including radiochemotherapy, and immune checkpoint inhibitor blockade, the overall survival of patients with advanced-stage NSCLC remains poor, with less than 16 months. It is well established that many aggressive tumor entities, including NSCLC, overexpress the major stress-inducible heat shock protein 70 (Hsp70) in the cytosol, present it on the plasma membrane in a tumor-specific manner, and release Hsp70 into circulation. Although high Hsp70 levels are associated with tumor aggressiveness and therapy resistance, membrane-bound Hsp70 can serve as a tumor-specific antigen for Hsp70-primed natural killer (NK) cells, expressing the C-type lectin receptor CD94, which is part of the activator receptor complex CD94/NKG2C. Therefore, we investigated circulating Hsp70 levels and changes in the composition of peripheral blood lymphocyte subsets as potential biomarkers for the advanced Union for International Cancer Control (UICC) stages in NSCLC. As expected, circulating Hsp70 levels were significantly higher in NSCLC patients compared to the healthy controls, as well as in patients with advanced UICC stages compared to those in UICC stage I. Smoking status did not influence the circulating Hsp70 levels significantly. Concomitantly, the proportions of CD4+ T helper cells were lower compared to the healthy controls and stage I tumor patients, whereas that of CD8+ cytotoxic T cells was progressively higher. The prevalence of CD3-/CD56+, CD3-/NKp30, CD3-/NKp46+, and CD3-/NKG2D+ NK cells was higher in stage IV/IIIB of the disease than in stage IIIA but were not statistically different from that in healthy individuals. However, the proportion of NK cells expressing CD94 and the activation/exhaustion marker CD69 significantly increased in higher tumor stages compared with stage I and the healthy controls. We speculate that although elevated circulating Hsp70 levels might promote the prevalence of CD94+ NK cells in patients with advanced-stage NSCLC, the cytolytic activity of these NK cells also failed to control tumor growth due to insufficient support by pro-inflammatory cytokines from CD4+ T helper cells. This hypothesis is supported by a comparative multiplex cytokine analysis of the blood in lung cancer patients with a low proportion of CD4+ T cells, a high proportion of NK cells, and high Hsp70 levels versus patients with a high proportion of CD4+ T cells exhibiting lower IL-2, IL-4, IL-6, IFN-γ, granzyme B levels.

Retinopathies are multifactorial diseases with complex pathologies that eventually lead to vision loss. Animal models facilitate the understanding of the pathophysiology and identification of novel treatment options. However, each animal model reflects only specific disease aspects and understanding of the specific molecular changes in most disease models is limited. Here, we conducted transcriptome analysis of murine ocular tissue transduced with recombinant Adeno-associated viruses (AAVs) expressing either human VEGF-A, TNF-α, or IL-6. VEGF expression led to a distinct regulation of extracellular matrix (ECM)-associated genes. In contrast, both TNF-α and IL-6 led to more comparable gene expression changes in interleukin signaling, and the complement cascade, with TNF-α-induced changes being more pronounced. Furthermore, integration of single cell RNA-Sequencing data suggested an increase of endothelial cell-specific marker genes by VEGF, while TNF-α expression increased the expression T-cell markers. Both TNF-α and IL-6 expression led to an increase in macrophage markers. Finally, transcriptomic changes in AAV-VEGF treated mice largely overlapped with gene expression changes observed in the oxygen-induced retinopathy model, especially regarding ECM components and endothelial cell-specific gene expression. Altogether, our study represents a valuable investigation of gene expression changes induced by VEGF, TNF-α, and IL-6 and will aid researchers in selecting appropriate animal models for retinopathies based on their agreement with the human pathophysiology., (© 2022. The Author(s).)

Widespread, comprehensive sequencing of patient tumors has facilitated the usage of precision medicine (PM) drugs to target specific genomic alterations. Therapeutic clinical trials are necessary to test new PM drugs to advance precision medicine, however, the abundance of patient sequencing data coupled with complex clinical trial eligibility has made it challenging to match patients to PM trials. To facilitate enrollment onto PM trials, we developed MatchMiner, an open-source platform to computationally match genomically profiled cancer patients to PM trials. Here, we describe MatchMiner's capabilities, outline its deployment at Dana-Farber Cancer Institute (DFCI), and characterize its impact on PM trial enrollment. MatchMiner's primary goals are to facilitate PM trial options for all patients and accelerate trial enrollment onto PM trials. MatchMiner can help clinicians find trial options for an individual patient or provide trial teams with candidate patients matching their trial's eligibility criteria. From March 2016 through March 2021, we curated 354 PM trials containing a broad range of genomic and clinical eligibility criteria and MatchMiner facilitated 166 trial consents (MatchMiner consents, MMC) for 159 patients. To quantify MatchMiner's impact on trial consent, we measured time from genomic sequencing report date to trial consent date for the 166 MMC compared to trial consents not facilitated by MatchMiner (non-MMC). We found MMC consented to trials 55 days (22%) earlier than non-MMC. MatchMiner has enabled our clinicians to match patients to PM trials and accelerated the trial enrollment process., (© 2022. The Author(s).)

Competing Interests: The authors declare that they have no conflict of interest.

The therapeutic potential of pluripotent stem cells is great as they promise to usher in a new era of medicine where cells or organs may be prescribed to replace dysfunctional tissue. At the forefront are efforts in the eye to develop this technology as it lends itself to in vivo monitoring and sophisticated non-invasive imaging modalities. In the retina, retinal pigment epithelium (RPE) is the most promising replacement cell as it has a single layer, is relatively simple to transplant, and is associated with several eye diseases. However, after transplantation, the cells may transform and cause complications. This transformation may be partially due to incomplete maturation. With the goal of learning how to mature RPE, we compared induced pluripotent stem cell-derived RPE (iPSC-RPE) cells with adult human primary RPE (ahRPE) cells and the immortalized human ARPE-19 line. We cultured ARPE-19, iPSC-RPE, and ahRPE cells for one month, and evaluated morphology, RPE marker staining, and transepithelial electrical resistance (TEER) as quality control indicators. We then isolated RNA for bulk RNA-sequencing and DNA for genotyping. We genotyped ahRPE lines for the top age-related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR) risk allele polymorphisms. Transcriptome data verified that both adult and iPSC-RPE exhibit similar RPE gene expression signatures, significantly higher than ARPE-19. In addition, in iPSC-RPE, genes relating to stem cell maintenance, retina development, and muscle contraction were significantly upregulated compared to ahRPE. We compared ahRPE to iPSC-RPE in a model of epithelial-mesenchymal transition (EMT) and observed an increased sensitivity of iPSC-RPE to producing contractile aggregates in vitro which resembles incident reports upon transplantation. P38 inhibition was capable of inhibiting iPSC-RPE-derived aggregates. In summary, we find that the transcriptomic signature of iPSC-RPE conveys an immature RPE state which may be ameliorated by targeting "immature" gene regulatory networks., Competing Interests: EM, HK, CV, WR, BS, SK, HN, and RB as employees of Boehringer Ingelheim Pharma GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Markert, Klein, Viollet, Rust, Strobel, Kauschke, Makovoz, Neubauer, Bakker and Blenkinsop.)

Current guidelines do not account for possible sex differences in the risk of ventricular tachyarrhythmia (VTA). We sought to identify specific factors associated with increased risk for VTA in women implanted with a primary prevention implantable cardioverter-defibrillator (ICD). Our study cohort consisted of 4,506 patients with an ICD or cardiac resynchronization therapy-defibrillator who were enrolled in the 4 landmark MADIT studies - MADIT-II, MADIT-RISK, MADIT-CRT and MADIT-RIT (1,075 women [24%]). Fine and Gray regression models were used to identify female-specific risk factors for the primary end point of VTA, defined as ICD-recorded, treated, or monitored, sustained ventricular tachycardia ≥170 beats per minute or ventricular fibrillation. At 3.5 years of follow-up, the cumulative incidence of VTA was significantly lower in women than men (17% vs 26%, respectively; p <0.001 for the entire follow-up). Use of amiodarone at enrollment, Black race, and history of previous myocardial infarction without previous revascularization was found to be independent risk factors of VTA in women. Of these factors, only Black race was associated with a statistically significant risk increase in men. At 3.5 years, the cumulative incidence of VTA in women with one or more of these risk factors was 27% compared with 14% in women with none of the risk factors (hazard ratio [confidence interval] = 2.08 [1.49 to 2.91]). In conclusion, our study, comprising 4 landmark ICD clinical trials, shows that sex and race have the potential to be used for improved risk stratification of patients who are candidates for primary prevention ICD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We have previously established a novel mouse model of lung fibrosis based on Adeno-associated virus (AAV)-mediated pulmonary overexpression of TGFβ1. Here, we provide an in-depth characterization of phenotypic and transcriptomic changes (mRNA and miRNA) in a head-to-head comparison with Bleomycin-induced lung injury over a 4-week disease course. The analyses delineate the temporal state of model-specific and commonly altered pathways, thereby providing detailed insights into the processes underlying disease development. They further guide appropriate model selection as well as interventional study design. Overall, Bleomycin-induced fibrosis resembles a biphasic process of acute inflammation and subsequent transition into fibrosis (with partial resolution), whereas the TGFβ1-driven model is characterized by pronounced and persistent fibrosis with concomitant inflammation and an equally complex disease phenotype as observed upon Bleomycin instillation. Finally, based on an integrative approach combining lung function data, mRNA/miRNA profiles, their correlation and miRNA target predictions, we identify putative drug targets and miRNAs to be explored as therapeutic candidates for fibrotic diseases. Taken together, we provide a comprehensive analysis and rich data resource based on RNA-sequencing, along with a strategy for transcriptome-phenotype coupling. The results will be of value for TGFβ research, drug discovery and biomarker identification in progressive fibrosing interstitial lung diseases., (© 2022. The Author(s).)

Introduction: Physical activity (PA) promotes resilience with respect to cognitive decline, although the underlying mechanisms are not well understood. We examined the associations between objectively measured PA and resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) across seven anatomically distributed neural networks., Methods: rs-fcMRI, amyloid beta (Aβ) positron emission tomography (PET), PA (steps/day × 1 week), and longitudinal cognitive (Preclinical Alzheimer's Cognitive Composite) data from 167 cognitively unimpaired adults (ages 63 to 90) were used. We used linear and linear mixed-effects regression models to examine the associations between baseline PA and baseline network connectivity and between PA, network connectivity, and longitudinal cognitive performance., Results: Higher PA was associated selectively with greater connectivity in three networks previously associated with cognitive decline (default, salience, left control). This association with network connectivity accounted for a modest portion of PA's effects on Aβ-related cognitive decline., Discussion: Although other mechanisms are likely present, PA may promote resilience with respect to Aß-related cognitive decline, partly by increasing connectivity in a subset of cognitive networks., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Label-free characterization of single biomolecules aims to complement fluorescence microscopy in situations where labeling compromises data interpretation, is technically challenging or even impossible. However, existing methods require the investigated species to bind to a surface to be visible, thereby leaving a large fraction of analytes undetected. Here, we present nanofluidic scattering microscopy (NSM), which overcomes these limitations by enabling label-free, real-time imaging of single biomolecules diffusing inside a nanofluidic channel. NSM facilitates accurate determination of molecular weight from the measured optical contrast and of the hydrodynamic radius from the measured diffusivity, from which information about the conformational state can be inferred. Furthermore, we demonstrate its applicability to the analysis of a complex biofluid, using conditioned cell culture medium containing extracellular vesicles as an example. We foresee the application of NSM to monitor conformational changes, aggregation and interactions of single biomolecules, and to analyze single-cell secretomes., (© 2022. The Author(s).)

Importance: Current guidelines for primary implantable cardioverter-defibrillator (ICD) therapy do not account for sex differences in arrhythmic risk in ICD candidates., Objective: To evaluate the association between sex and risk of ventricular tachyarrhythmia (VTA) and mortality., Design, Setting, and Participants: This cohort study compared differences in the risk of VTA and mortality between 4506 men and women enrolled in the 4 Multicenter Automatic Defibrillator Implantation Trials (MADIT) between July 1, 1997, and December 31, 2011. Data from prospective randomized controlled multicenter studies were analyzed retrospectively. Men and women with an ICD or cardiac resynchronization therapy defibrillator who were enrolled in all MADIT studies were included. Data were analyzed between January 10 and June 10, 2021., Exposures: ICD implant., Main Outcomes and Measures: The primary end point was sustained VTA, defined as ICD-recorded, treated or monitored VTA at least 170/min or ventricular fibrillation. Secondary VTA end points included VTA at least 200/min, appropriate ICD shocks, and appropriate antitachycardia pacing. All end points were included in a first and recurrent event analysis., Results: Of the 4506 study participants, 3431 were men (76%). Mean (SD) age of the cohort was 64 (12) years. For women vs men, the mean (SD) age (64 [12] years vs 64 [11] years) and left ventricular ejection fraction (24% vs 25%) were similar, but women exhibited a higher frequency of nonischemic cardiomyopathy (454 of 1075 women [42%] vs 2535 of 3431 men [74%]). Women had significantly lower 3-year cumulative probability of sustained VTA (16% vs 26%), fast VTA (9% vs 17%), and appropriate ICD shocks (7% vs 15%) compared with men (P < .001 for all). Multivariable analysis showed that female sex was independently associated with at least 40% lower risk of all first and recurrent VTA end points (P < .001 for all), including the primary end point (first event, HR = 60 [95% CI, 50-73], P < .001; recurrent event, HR = 49 [95% CI, 43-55], P < .001), after accounting for the competing risk of all-cause mortality and nonarrhythmic mortality. The lower VTA risk associated with female sex was consistent in risk subsets but was significantly more pronounced in patients with nonischemic cardiomyopathy (female vs male in the ischemic group: hazard ratio, 0.73 [95% CI, 0.56-0.95], P = .02; nonischemic group: hazard ratio, 0.50 [95% CI, 0.38-0.66], P < .001; P = .03 for interaction between female sex and cardiomyopathy)., Conclusions and Relevance: Findings suggest that women display a significantly lower risk of first and recurrent life-threatening VTA events than men, and that it is more pronounced in patients with nonischemic cardiomyopathy, suggesting a need for sex-specific risk assessment for primary prevention ICD therapy.

Background: Paranoid ideation is a core feature of psychosis and is associated with impaired social functioning. Severity of paranoia can fluctuate across time as symptoms wax and wane; however, no study has systematically investigated how this intra-individual variability in paranoia may relate to social impairments and social functioning., Methods: Fifty-five patients with DSM-5 diagnoses and recent paranoia were followed for up to one year and completed the suspiciousness/persecution section (P6) of the Positive and Negative Symptom Scale (PANSS) on a monthly basis to monitor fluctuations in paranoia. Categorical changes between paranoid and non-paranoid status were monitored and tallied. Participants self-reported current paranoia and anxiety levels as well as social functioning when demonstrating paranoia changes., Results: Most patients showed changes between paranoid categories (60%). Individuals with no paranoia change showed higher current paranoia and lower independence-competence subscores of the Birchwood Social Functioning Scale (SFS) compared with those with one change. Current paranoia and state anxiety explained significant variance in the prosocial activities subscore of SFS, and importantly, paranoia changes accounted for variance above and beyond these effects. Individuals with higher current paranoia participated less in prosocial activities, however those with higher paranoia variability were more involved in social activities. Similarly, individuals with more paranoia variability demonstrated better overall social functioning as measured by the averaged SFS total score., Conclusion: Paranoia fluctuation is prevalent across time, and both paranoia severity and variability impact social functioning, in that lower levels of paranoia severity and higher levels of paranoia variability are associated with better interpersonal functioning., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)

Background: Due to the COVID-19 pandemic, digitalization in healthcare grew rapidly. Auditory training after cochlear implantation usually takes place face-to-face but social distancing interferes with this therapeutic approach., Materials and Methods: In follow-up treatment, 42 adult cochlear implant (CI) users aged 53.8 (±15.6) years received video therapy 1 x/week for 5 weeks on a certified platform. After each therapy session, the technical process and therapeutic content were assessed. At the end of the study, usability and the relationship between therapist and patient were evaluated by patients and therapists using the System Usability Scale (SUS), a final questionnaire and by the Skala Therapeutische Allianz - Revised (STA-R). Furthermore, a cost-benefit analysis was done., Results: Usability for both users was high (87.97 versus 93.0). Despite the lack of personal contact, therapeutic alliance was highly appreciated by patients and therapists (87.8% versus 84.8%). The main advantages for the patients were reductions in time and costs. In contrast, the rehabilitation center faced higher costs initially due to the longer time therapists needed to prepare the lessons. Technical problems had to be solved in > 75% of the first sessions but did not bother training thereafter. In total, 47.6% of the patients believe that teletherapy can completely fulfill their therapeutic needs., Conclusion: Video therapy has been judged as a useful tool by all users and the majority wants to continue. However, it remains questionable whether the therapist-patient relationship can be sufficiently maintained over a longer period and whether online therapy is as effective as face-to-face therapy., (© 2021. The Author(s).)

Objectives: First, establishment and validation of a novel questionnaire documenting the burden of xerostomia and sialadenitis symptoms, including quality of life. Second, to compare two versions regarding the answering scale (proposed developed answers Q3 vs. 0-10 visual analogue scale Q10) of our newly developed questionnaire, in order to evaluate their comprehension by patients and their reproducibility in time., Study Design: The study is a systematic review regarding the evaluation of the existing questionnaire and a cohort study regarding the validation of our new MSGS questionnaire., Materials and Methods: A Multidisciplinary Salivary Gland Society (MSGS) questionnaire consisting of 20 questions and two scoring systems was developed to quantify symptoms of dry mouth and sialadenitis. Validation of the questionnaire was carried out on 199 patients with salivary pathologies (digestive, nasal, or age-related xerostomia, post radiation therapy, post radioiodine therapy, Sjögren's syndrome, IgG4 disease, recurrent juvenile parotitis, stones, and strictures) and a control group of 66 healthy volunteers. The coherence of the questionnaire's items, its reliability to distinguish patients from healthy volunteers, its comparison with unstimulated sialometry, and the time to fill both versions were assessed., Results: The novel MSGS questionnaire showed good internal coherence of the items, indicating its pertinence: the scale reliability coefficients amounted to a Cronbach's alpha of 0.92 for Q10 and 0.90 for Q3. The time to complete Q3 and Q10 amounted, respectively, to 5.23 min (±2.3 min) and 5.65 min (±2.64 min) for patients and to 3.94 min (±3.94 min) and 3.75 min (±2.11 min) for healthy volunteers. The difference between Q3 and Q10 was not significant., Conclusion: We present a novel self-administered questionnaire quantifying xerostomia and non-tumoral salivary gland pathologies. We recommend the use of the Q10 version, as its scale type is well known in the literature and it translation for international use will be more accurate. Laryngoscope, 132:322-331, 2022., (© 2021 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Atmospheric dispersion models are crucial for nuclear risk assessment and emergency response systems since they rapidly predict air concentrations and deposition of released radionuclides, providing a basis for dose estimations and countermeasure strategies. Atmospheric dispersion models are associated with relatively large and often unknown uncertainties that are mostly attributed to meteorology, source terms and parametrisation of the dispersion model. By developing methods that can provide reliable uncertainty ranges for model outputs, decision makers have an improved basis for handling nuclear emergency situations. In the present work, model skill of the Severe Nuclear Accident Programme (SNAP) model was quantified by employing an ensemble method in which 51 meteorological realisations from a numerical weather prediction model were combined with 9 source term descriptions for the accidental 137 Cs releases from Fukushima Daiichi Nuclear Power Plant during 14th-17th March 2011. The meteorological forecast was compared to observations of wind speed from 30 meteorological stations. The 459 dispersion realisations were compared with hourly observations of activity concentrations from 100 air filter stations. Exclusive use of deterministic meteorology resulted in most members of the dispersion ensemble showing too low concentration values, however this was mitigated by applying ensemble meteorology. Ensemble predictions, including both the meteorological and source term ensemble, show an overall higher prediction skill compared to individual meteorology and source term runs, with true predictive rate accuracy increasing from 30%-50% to 70%-90%, with a decrease in positive predictive rate accuracy from 75%-80% to 65%-75%. Skill scores and other ensemble indicators also showed improvements in using ensembles of source terms and meteorology. From the present study on the Fukushima accident there are strong indications that ensemble predictions improve the basis for decision making in the early phase after a nuclear accident, which emphasises the importance of including ensemble prediction in nuclear preparedness tools of the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Carpels in maize undergo programmed cell death in half of the flowers initiated in ears and in all flowers in tassels. The HD-ZIP I transcription factor gene GRASSY TILLERS1 ( GT1 ) is one of only a few genes known to regulate this process. To identify additional regulators of carpel suppression, we performed a gt1 enhancer screen and found a genetic interaction between gt1 and ramosa3 ( ra3 ). RA3 is a classic inflorescence meristem determinacy gene that encodes a trehalose-6-phosphate (T6P) phosphatase (TPP). Dissection of floral development revealed that ra3 single mutants have partially derepressed carpels, whereas gt1 ; ra3 double mutants have completely derepressed carpels. Surprisingly, gt1 suppresses ra3 inflorescence branching, revealing a role for gt1 in meristem determinacy. Supporting these genetic interactions, GT1 and RA3 proteins colocalize to carpel nuclei in developing flowers. Global expression profiling revealed common genes misregulated in single and double mutant flowers, as well as in derepressed gt1 axillary meristems. Indeed, we found that ra3 enhances gt1 vegetative branching, similar to the roles for the trehalose pathway and GT1 homologs in the eudicots. This functional conservation over ∼160 million years of evolution reveals ancient roles for GT1 -like genes and the trehalose pathway in regulating axillary meristem suppression, later recruited to mediate carpel suppression. Our findings expose hidden pleiotropy of classic maize genes and show how an ancient developmental program was redeployed to sculpt floral form., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

Background: With the increasing focus on prevention of Alzheimer's disease, there is need for characterization of preclinical populations. Local participant registries offer an opportunity to facilitate research engagement via remote data collection, inform recruitment, and characterize preclinical samples, including individuals with subjective cognitive decline., Objectives: We sought to characterize subjective cognitive decline in a registry sample, as related to psychiatric history and related variables, including personality and loneliness, quality of life, and factors related to dementia risk (e.g., family history of dementia)., Design, Setting, Participants: Participants were 366 individuals (mean age=67.2 (range 50-88), 65% female, 94% white, 97% non-Hispanic or Latino, 82% with at least a bachelor's degree) with no reported history of mild cognitive impairment or dementia. All participants had expressed interest in research, primarily via community outreach events and prior research involvement. Data was collected via electronic surveys, distributed using REDCap. Electronic questionnaires included questions on demographic variables, subjective cognitive decline, quality of life, loneliness, and personality., Results: There was a high prevalence of risk factors for dementia in the registry sample (68% with family history of dementia, 31% with subjective cognitive decline). Subjective cognitive decline was more common in women and associated with history of depression, but not with family history of dementia. Subjective cognitive decline was also associated with lower conscientiousness and lower emotional stability, as well as higher loneliness and lower quality of life. Among participants who endorsed a psychiatric history, most reported onset more than 10 years prior, rather than within the last 10 years., Conclusions: Subjective cognitive decline in a registry sample may be more strongly associated with longstanding psychiatric and personality variables, rather than family history of dementia, adding to the literature on characterization of subjective cognitive decline across different settings. These findings highlight the acceptability of remote data collection and the potential of registries to inform recruitment by characterizing registrants, which may help to stratify dementia risk and match participants to eligible trials., Competing Interests: G. Reynolds has nothing to disclose.

Healthy adipose tissue remodeling depends on the balance between de novo adipogenesis from adipogenic progenitor cells and the hypertrophy of adipocytes. De novo adipogenesis has been shown to promote healthy adipose tissue expansion, which confers protection from obesity-associated insulin resistance. Here, we define the role and trajectory of different adipogenic precursor subpopulations and further delineate the mechanism and cellular trajectory of adipogenesis, using single-cell RNA-sequencing datasets of murine adipogenic precursors. We identify Rspo2 as a functional regulator of adipogenesis, which is secreted by a subset of CD142 +  cells to inhibit maturation of early progenitors through the receptor Lgr4. Increased circulating RSPO2 in mice leads to adipose tissue hypertrophy and insulin resistance and increased RSPO2 levels in male obese individuals correlate with impaired glucose homeostasis. Taken together, these findings identify a complex cellular crosstalk that inhibits adipogenesis and impairs adipose tissue homeostasis., (© 2022. The Author(s).)