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Abstract It is unknown if cognition is impaired before clinical onset of paediatric acquired demyelinating syndromes. We conducted a matched cohort study using prospectively collected educational data in multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) patients (n = 60) and controls (pooled n = 449,553). Academic performance at ages 10–11 was impaired in MOGAD (−1.27 adjusted z‐score [95% CI: −1.81 to −0.73], P

Abstract Background Physical activity (PA) is fundamental to nursing home residents’ health. Likewise, physical capacity (PC) is essential to carry out activities of daily living. Although PC and PA are associated, misalignment has been reported in specific subgroups. Increased PC is oftentimes not linked to high PA (i.e., Can do - don’t do) and vice versa (i.e., Can’t do - do do). Therefore, identifying other contextual factors influencing PA in misaligned groups is important. This study aimed to identify contextual factors in nursing home residents with aligned or misaligned PA and PC. Methods In total, 180 nursing home residents (≥ 65 years, 79.4% females) were divided into four quadrants (Q1: Can do - do do; Q2: Can do - don’t do; Q3: Can’t do - do do; Q4: Can’t do - don’t do) based on thresholds for PA (≥ or 0.5 m/s gait speed). Kruskal-Wallis H test and effect sizes (ES) were applied to analyze quadrants’ differences regarding PA (steps per day), objective motor capacity, life-space mobility, activities of daily living (ADL), psychosocial well-being, cognition, subjective mobility-related concerns, and spatial orientation. Results Specific contextual factors differed significantly between the groups. Compared to Q1, Q2 presents a significantly lower life-space mobility (ES: 0.35) and objective motor capacity (ES: 0-36-0.49); Q3 has a lower objective motor capacity (ES: 0.55–1.10); Q4 shows lower independence in ADL (ES: 0.57), life-space mobility (ES: 0.48), subjective mobility-related concerns (ES: 0.38) and objective motor capacity (ES: 0.99–1.08). No significant group differences were found for psychosocial well-being, cognition, and spatial orientation. Conclusions This study provides new insights into PA behavior of nursing home residents. Key variables linked to PA are objective motor capacity, life-space mobility, ADL, and subjective mobility-related concerns. Surprisingly, some potentially impactful variables such as cognition, orientation, and psychosocial well-being did not differ between the groups. This may suggest that these variables may not represent key targets for interventions aiming to improve PA. This study builds the foundation for further research into the underlying mechanisms behind PA behaviors and supports future efforts to plan specific, targeted interventions for nursing home residents. Trial registration The trial was prospectively registered at DRKS.de with registration number DRKS00021423 on April 16, 2020.

Abstract Wolverine distribution contracted along the southern periphery of its range in North America during the 19th and 20th centuries due primarily to human influences. This history, along with low densities, sensitivity to climate change, and concerns about connectivity among fragmented habitats spurred the recent US federal listing of threatened status and special concern status in Canada. To help inform large scale landscape connectivity, we collected 882 genetic samples genotyped at 19 microsatellite loci. We employed multiple statistical models to assess the landscape factors (terrain complexity, human disturbance, forest configuration, and climate) associated with wolverine genetic connectivity across 2.2 million km2 of southwestern Canada and the northwestern contiguous United States. Genetic similarity (positive spatial autocorrelation) of wolverines was detected up to 555 km and a high-to-low gradient of genetic diversity occurred from north-to-south. Landscape genetics analyses confirmed that wolverine genetic connectivity has been negatively influenced by human disturbance at broad scales and positively influenced by forest cover and snow persistence at fine- and broad–scales, respectively. This information applied across large landscapes can be used to guide management actions with the goal of maintaining or restoring population connectivity.

Abstract Background Type 1 diabetes, an autoimmune disorder leading to the destruction of pancreatic β-cells, requires lifelong insulin therapy. Islet transplantation offers a promising solution but faces challenges such as limited availability and the need for immunosuppression. Induced pluripotent stem cells (iPSCs) provide a potential alternative source of functional β-cells and have the capability for large-scale production. However, current differentiation protocols, predominantly conducted in hybrid or 2D settings, lack scalability and optimal conditions for suspension culture. Methods We examined a range of bioreactor scaleup process parameters and quality target product profiles that might affect the differentiation process. This investigation was conducted using an optimized High Dimensional Design of Experiments (HD-DoE) protocol designed for scalability and implemented in 0.5L (PBS-0.5 Mini) vertical wheel bioreactors. Results A three stage suspension manufacturing process is developed, transitioning from adherent to suspension culture, with TB2 media supporting iPSC growth during scaling. Stage-wise optimization approaches and extended differentiation times are used to enhance marker expression and maturation of iPSC-derived islet-like clusters. Continuous bioreactor runs were used to study nutrient and growth limitations and impact on differentiation. The continuous bioreactors were compared to a Control media change bioreactor showing metabolic shifts and a more β-cell-like differentiation profile. Cryopreserved aggregates harvested from the runs were recovered and showed maintenance of viability and insulin secretion capacity post-recovery, indicating their potential for storage and future transplantation therapies. Conclusion This study demonstrated that stage time increase and limited media replenishing with lactate accumulation can increase the differentiation capacity of insulin producing cells cultured in a large-scale suspension environment.

Abstract Endolymphatic hydrops, increased endolymphatic fluid within the cochlea, is the key pathologic finding in patients with Meniere’s disease, a disease of episodic vertigo, fluctuating hearing loss, tinnitus, and aural fullness. Endolymphatic hydrops also can occur after noise trauma and its presence correlates with cochlear synaptopathy, a form of hearing loss caused by reduced numbers of synapses between hair cells and auditory nerve fibers. Here we tested whether there is a mechanistic link between these two phenomena by using multimodal imaging techniques to analyze the cochleae of transgenic mice exposed to blast and osmotic challenge. In vivo cochlear imaging after blast exposure revealed dynamic increases in endolymph that involved hair cell mechanoelectrical transduction channel block but not the synaptic release of glutamate at the hair cell–auditory nerve synapse. In contrast, ex vivo and in vivo auditory nerve imaging revealed that synaptopathy requires glutamate release from hair cells but not endolymphatic hydrops. Thus, although endolymphatic hydrops and cochlear synaptopathy are both observed after noise exposure, one does not cause the other. They are simply co-existent sequelae that derive from the traumatic stimulation of hair cell stereociliary bundles. Importantly, these data argue that Meniere’s disease derives from hair cell transduction channel blockade.

Abstract Post marketing safety surveillance depends in part on the ability to detect concerning clinical events at scale. Spontaneous reporting might be an effective component of safety surveillance, but it requires awareness and understanding among healthcare professionals to achieve its potential. Reliance on readily available structured data such as diagnostic codes risks under-coding and imprecision. Clinical textual data might bridge these gaps, and natural language processing (NLP) has been shown to aid in scalable phenotyping across healthcare records in multiple clinical domains. In this study, we developed and validated a novel incident phenotyping approach using unstructured clinical textual data agnostic to Electronic Health Record (EHR) and note type. It’s based on a published, validated approach (PheRe) used to ascertain social determinants of health and suicidality across entire healthcare records. To demonstrate generalizability, we validated this approach on two separate phenotypes that share common challenges with respect to accurate ascertainment: (1) suicide attempt; (2) sleep-related behaviors. With samples of 89,428 records and 35,863 records for suicide attempt and sleep-related behaviors, respectively, we conducted silver standard (diagnostic coding) and gold standard (manual chart review) validation. We showed Area Under the Precision-Recall Curve of ~ 0.77 (95% CI 0.75–0.78) for suicide attempt and AUPR ~ 0.31 (95% CI 0.28–0.34) for sleep-related behaviors. We also evaluated performance by coded race and demonstrated differences in performance by race differed across phenotypes. Scalable phenotyping models, like most healthcare AI, require algorithmovigilance and debiasing prior to implementation.

Background: Continuous retrograde flow across the aortic valve from left ventricular assist device (LVAD) therapy can result in cusp damage and progressive aortic regurgitation, potentially triggering recurrent heart and multiorgan failure. The management of aortic regurgitation after LVAD implantation has not been well defined. Methods: This study retrospectively reviewed the investigators’ experience with the management of de novo aortic regurgitation requiring intervention in patients with continuous-flow LVAD. Results: Six patients who had undergone LVAD implantation and who required intervention were identified. Two patients underwent redo sternotomy with bioprosthetic aortic valve replacement, and 4 patients underwent percutaneous management, including Amplatzer device (Abbott) placement and transcatheter aortic valve replacement. All patients had resolution of aortic regurgitation with improved hemodynamics and relief from heart failure. One early and 2 late deaths occurred. Valve function was intact, with all valves opening intermittently without greater than trivial aortic regurgitation. Conclusions: Multiple treatment modalities exist for LVAD-induced aortic valve regurgitation, including open surgical and percutaneous strategies. With a tailored risk-adjusted approach, acceptable results may be achieved.

Abstract Background Suicide-related presentations to pediatric emergency departments (PED) have increased in recent years. PED providers have the opportunity to reduce suicide risk by counseling on restricting access to lethal means. Supplementing lethal means counseling (LMC) with safety device distribution is effective in improving home safety practices. Data on PED-based LMC in high-risk patient populations is limited. The objective of this study was to determine if caregivers of children presenting to PED for mental health evaluation were more likely to secure all household firearms if given cable-style gun locks in addition to LMC. Methods In this randomized controlled trial, caregivers completed a survey regarding storage practices of firearms and medication in the home. Participants were randomized to receive LMC (control) or LMC plus 2 cable-style gun locks (intervention). Follow-up survey was distributed 1 month after encounter. Primary outcome was proportion of households reporting all household firearms secured at follow-up. Secondary outcomes included: removal of lethal means from the home, purchase of additional safety devices, use of PED-provided locks (intervention only), and acceptability of PED-based LMC. Results Two hundred participants were enrolled and randomized. Comparable portions of study groups completed follow-up surveys. Control and intervention arms had similar proportions of households reporting all firearms secured at baseline (89.9% vs. 82.2%, p = 0.209) and follow-up (97.1% vs. 98.5%, p = 0.96), respectively. Other safety behaviors such as removal of firearms (17.6% vs. 11.8%, p = 0.732), removal of medication (19.1% vs. 13.2%, p = 0.361), and purchase of additional safety devices (66.2% vs. 61.8%, p = 0.721) were also alike between the two groups. Both groups held favorable views of PED-based counseling. Within the intervention group, 70% reported use of provided locks. Preference for a different style of securement device was the most cited reason among those not using PED-provided locks. Conclusions PED-based LMC is a favorably-viewed, effective tool for improving home safety practices in families of high-risk children. Provision of cable-style gun locks did not improve rate of firearm securement compared LMC alone—likely due to high baseline rates of firearm securement and preference for different style of lock among non-utilizers. Clinical Trial Registration ID: NCT05568901 . Clinicaltrials.gov. https://clinicaltrials.gov/ . Retrospectively registered October 6, 2022. First participant enrollment: June 28, 2021.

Abstract The tropism of adenoviruses (Ads) is significantly influenced by the binding of various blood factors. To investigate differences in their binding, we conducted cryo-EM analysis on complexes of several human adenoviruses with human platelet factor-4 (PF4), coagulation factors FII (Prothrombin), and FX. While we observed EM densities for FII and FX bound to all the species-C adenoviruses examined, no densities were seen for PF4, even though PF4 can co-pellet with various Ads. Similar to FX, the γ-carboxyglutamic acid (Gla) domain of FII binds within the surface cavity of hexon trimers. While FII binds equally to species-C Ads: Ad5, Ad6, and Ad657, FX exhibits significantly better binding to Ad5 and Ad657 compared to Ad6. Although only the FX-Gla domain is observed at high-resolution (3.7 Å), the entire FX is visible at low-resolution bound to Ad5 in three equivalent binding modes consistent with the 3-fold symmetric hexon. Only the Gla and kringle-1 domains of FII are visible on all the species-C adenoviruses, where the rigid FII binds in an upright fashion, in contrast to the flexible and bent FX. These data suggest that differential binding of FII and FX may shield certain species-C adenoviruses differently against immune molecules, thereby modulating their tropism.

Abstract Objectives Serum protein abundance was assessed in adult and juvenile dermatomyositis (DM and JDM) patients to determine differentially regulated proteins, altered pathways, and candidate disease activity biomarkers. Methods Serum protein expression from 17 active adult DM and JDM patients each was compared to matched, healthy control subjects by a multiplex immunoassay. Pathway analysis and protein clustering of the differentially regulated proteins were examined to assess underlying mechanisms. Candidate disease activity biomarkers were identified by correlating protein expression with disease activity measures. Results Seventy-eight of 172 proteins were differentially expressed in the sera of DM and JDM patients compared to healthy controls. Forty-eight proteins were differentially expressed in DM, 32 proteins in JDM, and 14 proteins in both DM and JDM. Twelve additional differentially expressed proteins were identified after combining the DM and JDM cohorts. C-X-C motif chemokine ligand 10 (CXCL10) was the most strongly upregulated protein in both DM and JDM sera. Other highly upregulated proteins in DM included S100 calcium binding protein A12 (S100A12), CXCL9, and nicotinamide phosphoribosyltransferase (NAMPT), while highly upregulated proteins in JDM included matrix metallopeptidase 3 (MMP3), growth differentiation factor 15 (GDF15), and von Willebrand factor (vWF). Pathway analysis indicated that phosphoinositide 3-kinase (PI3K), p38 mitogen-activated protein kinase (MAPK), and toll-like receptor 7 (TLR7) signaling were activated in DM and JDM. Additional pathways specific to DM or JDM were identified. A protein cluster associated with neutrophils and mononuclear leukocytes and a cluster of interferon-associated proteins were observed in both DM and JDM. Twenty-two proteins in DM and 24 proteins in JDM sera correlated with global, muscle, and/or skin disease activity. Seven proteins correlated with disease activity measures in both DM and JDM sera. IL-1 receptor like 1 (IL1RL1) emerged as a candidate global disease activity biomarker in DM and JDM. Conclusion Coordinate analysis of protein expression in DM and JDM patient sera by a multiplex immunoassay validated previous gene expression studies and identified novel dysregulated proteins, altered signaling pathways, and candidate disease activity biomarkers. These findings may further inform the assessment of DM and JDM patients and aid in the identification of potential therapeutic targets.

Abstract Globally, the trend toward privatizing higher education has been accelerating, driven by economic and policy shifts. Uganda has aligned with this movement, becoming one of the African countries implementing privatization to enhance accessibility and efficiency in its universities. However, the benefits and challenges of higher education privatization in Uganda remain underexplored. This study assesses them through two private universities as case studies. An integrative literature review identified challenges in Uganda’s privatization policy. This was followed by qualitative interviews with sixteen (16) stakeholders (students, n = 10; parents, n = 3; employers, n = 3) to assess its impact on accessibility, quality, funding, and employment. Semi-structured interviews involving students, parents, and employers revealed that although the policy led to the massification of higher education, it also led to the commodification and academisation of education, whereby business principles have been imported into the country’s higher education sector, thus focusing more on profit maximisation other than quality education delivery. The study recommends that the Ugandan government and policymakers, such as the Ministry of Education and Sports and the National Council for Higher Education, do more to safeguard the education system from being too commercialised, commodified, and over-marketised.

Abstract Tumor immune microenvironmental alterations occur early in multiple myeloma (MM) development. In this study, we aim to systematically characterize the tumor immune microenvironment (TME) and the tumor-immune interactions from precursor stages, i.e., monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), to newly diagnosed MM, comparing these to healthy donors. Using CIBERSORT, mass cytometry (CyTOF), and single-cell RNA sequencing (scRNA-Seq), we examined innate and adaptive immune changes across these stages. We found a decrease in granulocytes in the TME predicts MM outcomes. HLA-DR is reduced in CD16+ monocytes and plasmacytoid dendritic cells, while myeloid dendritic cells show decreased expression of stress and immune-response genes. NK cells and CD8+ T cells shift from a GZMK+ to a GZMB+ cytotoxic phenotype in the TME, with increased inhibitory markers TIM3 and TIGIT. In paired samples, the proportion and gene expression pattern in patient-specific GZMB+CD8+ T cells remain largely unchanged despite MM progression. Our findings provide a comprehensive immune landscape of MM and its precursors, offering insights into therapeutic strategies. Enhancing neutrophil and NK cell cytotoxicity, tumor antigen presentation, and CD8+ T cell versatility in precursor stages may prevent MM progression.

Abstract Background The U.S. opioid crisis, resulting in nearly 500,000 deaths from 1999 to 2019, has been exacerbated by persistent stigma, which hinders treatment and recovery efforts. This stigma, whether structural, social, or self-imposed, challenges overdose prevention and recovery. Our study aimed to assess and compare levels of stigma towards opioid users among rural law enforcement officers (LEOs) and community members in Tennessee, highlighting rural community-level attitudes. Methods Methods involved surveying two groups: LEOs (N=48) and community members (N=393). Utilizing a Likert Scale based on prior research, the survey probed attitudes toward drug use across four stigma domains: dangerousness, blame, social distancing, and fatalism. Analysis employed standardized scoring and ANOVA for evaluating stigma differences by participant characteristics. Results LEOs (75%) and community members (51.7%) predominantly identify drug users as white, with varied perceptions regarding socioeconomic status and employment. Despite similar perceptions, normalized stigma scores revealed statistical differences between groups across stigma domains. ANOVA found no significant impact of participant type or gender on stigma levels, though race/ethnicity and its interaction with gender suggested potential influences on overall stigma score. Conclusions Both LEOs and community members in rural Tennessee hold measurable stigma against opioid users, spanning dangerousness, blame, social distancing, and fatalism domains. These insights highlight the need for further research into both professional and public attitudes toward individuals with opioid or other substance use disorders within shared communities. This research should aim to develop specific stigma-reducing interventions that target both providers and community members.

Abstract The identification of adjuvants to improve vaccination efficacy is a major unmet need. One approach is to augment the functionality of dendritic cells (DCs) by using Toll-like receptor-9 (TLR9) agonists such as cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs) as adjuvants. Another approach is adjuvant selection based on production of bioactive interleukin-12 (IL-12). We report a D-peptide isomer, designated D-15800, that induces monocyte differentiation to the DC phenotype in vitro and more effectively stimulates IL-12p70 production upon T cell receptor (TCR) activation than the L-isomer. In the absence of TCR activation and either IL-12p70 or interleukin-2 production, only D-15800 activates CD4+ T and natural killer cells. In the presence of CpG ODN, D-15800 synergistically enhances production of interferon-alpha (IFN-α). Taken together with its biostability in human serum and depot retention upon injection, co-delivery of D-15800 with TLR9 agonists could serve to improve vaccine efficacy.

Abstract Osteosarcoma is the most common form of primary bone cancer, which primarily afflicts children and adolescents. Chemotherapy, consisting of doxorubicin, cisplatin and methotrexate (MAP) increased the 5-year osteosarcoma survival rate from 20% to approximately 60% by the 1980s. However, osteosarcoma survival rates have remained stagnant for several decades. Patients whose disease fails to respond to MAP receive second-line treatments such as etoposide and, in more recent years, the kinase inhibitor regorafenib. BCL-2 and its close relatives enforce cellular survival and have been implicated in the development and progression of various cancer types. BH3-mimetics antagonize pro-survival members of the BCL-2 family to directly stimulate apoptosis. These drugs have been proven to be efficacious in other cancer types, but their use in osteosarcoma has been relatively unexplored to date. We investigated the potential efficacy of BH3-mimetics against osteosarcoma cells in vitro and examined their cooperation with regorafenib in vivo. We demonstrated that osteosarcoma cell lines could be killed through inhibition of MCL-1 combined with BCL-2 or BCL-xL antagonism. Inhibition of MCL-1 also sensitized osteosarcoma cells to killing by second-line osteosarcoma treatments, particularly regorafenib. Importantly, we found that inhibition of MCL-1 with the BH3-mimetic S63845 combined with regorafenib significantly prolonged the survival of mice bearing pulmonary osteosarcoma metastases. Together, our results highlight the importance of MCL-1 in osteosarcoma cell survival and present a potential therapeutic avenue that may improve metastatic osteosarcoma patient outcomes.

Background: Medical cannabis (MC) use is increasing across the US, with functional MC programs now operating in 38 states. While program policies and practices vary widely, little is known about whether and how states evaluate their programs. Better characterization of state MC program evaluation to date could inform states, program officials, and providers about best practices and provide a roadmap for future program evaluation. Summary: We conducted a narrative review of state MC program evaluations, including peer-reviewed literature and reports produced by independent state-based and non-state-based evaluators. Among 304 abstracts initially screened, seven evaluations met inclusion criteria. Within these evaluations, we report results according to three overarching themes: 1) evaluation characteristics, including comparison across evaluations; 2) program experience, including perceptions of providers and patients; and 3) assessment of cannabis use, including self-reported efficacy for qualifying medical conditions, patterns of medical and nonmedical cannabis use, and assessment of risk factors relevant to MC use. Additionally, we found that while goals and methods for state MC evaluations varied widely, evaluations that relied on independent, non-state entities tended to have more comprehensive and quantitatively rigorous results. Key Messages: Few states operating MC programs have completed a formal evaluation of their program. Among states that have completed an evaluation, approaches varied widely; however, common themes were also present, which may inform future state evaluation efforts. Evaluation through independent, non-state partners may provide an optimal strategy to ensure high-quality data and meaningful results.

Abstract This paper investigates and technically demonstrates a capacitive power transfer (CPT) system applicable to the charging of emerging very‐low‐power portable devices. The constant‐current operation of the primary LCL compensation in CPT is implemented and analysed to simplify the system design process and minimize the configuration on the receiving side. Additionally, the system design considerations for the capacitive coupler and the diode rectifier are presented based on the battery charging specifications. All the design concepts and considerations are validated through experimentation with a 13.56 MHz CPT system, which achieves load‐independent constant‐current output from full‐load to light‐load (one‐tenth of the full load) charging operations.

Abstract Audio-visual media possesses a remarkable ability to synchronise audiences’ neural, behavioural, and physiological responses. This synchronisation is considered to reflect some dimension of collective attention or engagement with the stimulus. But what is it about these stimuli that drives such strong engagement? There are several properties of media stimuli which may lead to synchronous audience response: from low-level audio-visual features, to the story itself. Here, we present a study which separates low-level features from narrative by presenting participants with the same content but in separate modalities. In this way, the presentations shared no low-level features, but participants experienced the same narrative. We show that synchrony in participants’ heart rate can be driven by the narrative information alone. We computed both visual and auditory perceptual saliency for the content and found that narrative was approximately 10 times as predictive of heart rate as low-level saliency, but that low-level audio-visual saliency has a small additive effect towards heart rate. Further, heart rate synchrony was related to a separate cohorts’ continuous ratings of immersion, and that synchrony is likely to be higher at moments of increased narrative importance. Our findings demonstrate that high-level narrative dominates in the alignment of physiology across viewers.

Background: Determining the presence of bacteria in the shoulder prior to shoulder arthroplasty can be challenging especially in the case of revision arthroplasty. An open biopsy provides an opportunity to obtain tissue samples with minimal patient morbidity. The purpose of this study was to characterize the diagnostic utility of an open shoulder biopsy. Methods: A retrospective cohort study was performed at an academic medical center. All patients that underwent an open shoulder biopsy using a small proximal deltopectoral incision between 2008 and 2021 were included. Demographics, surgical history, culture results, and development of subsequent infection were recorded. Subsequent infection was defined as the development of a sinus tract, purulent drainage, or revision surgery with greater than or equal to two tissues specimens with growth of the same bacterial species. Sensitivity and negative predictive value (NPV) of an open biopsy were calculated based on the development of subsequent infection. As culture positive patients were treated for their infection, positive predictive value and specificity could not be determined. Results: We identified 55 patients that underwent 75 open biopsies. Most patients had a shoulder arthroplasty in place at the time of biopsy (69.1%), while 23.6% had an antibiotic spacer, and 7.3% had a native shoulder. Patients with a history of infection were more likely to have a spacer in place at the time of biopsy (65% vs. 0%; P

Background: The humeral head resurfacing arthroplasty (HHR) is normally used as a hemi shoulder arthroplasty and has been in use for the treatment of Gleno-Humeral osteoarthritis (OA) of the shoulder for more than 30 years. Some studies, however, shows that anatomical total shoulder arthroplasty provides better improvement in function than a HHR for patients with OA. Reasons for this may be a progressive glenoid wear (GW) or loosening of the HHR. We, therefore, wanted to investigate the migration pattern of the HHR and also GW by using radio stereometric analysis (RSA). Methods: 21 patients (21 shoulders) with OA and a mean age of 64 years were enrolled in the study. They all received the Copeland humeral resurfacing head and were followed for 2 years with RSA. We evaluated the clinical outcome at 2 years with Western Ontario Osteoarthritis of the Shoulder (WOOS), EuroQol 5 dimension 3L and Constant Shoulder Score. In addition, we assessed data on WOOS and revisions until 5 years follow-up by using the local clinic data within the Swedish Shoulder Arthroplasty Register. Results: After an initial migration at two months the implants were stable in relation to the humerus with no statistically significant difference between the 2 months and the 2 years value (P = .23). The GW continued to increase during the study period with an initial migration of mean 2.3 mm and at 2 years 3.5 mm with a statistically difference between the 6 months and 2 years value (P = .046). The WOOS, EuroQol 5 dimension 3L and Constant Shoulder Score were all improved at 2 years compared to the preoperative values. We found a weak correlation between GW at 2 years and the WOOS score at 2 and 5 years, but these did not reach statistical significance. There were 4 revisions within 5 years after the primary operation, all due to pain. Conclusion: The marker-free RSA can be used in clinical studies for assessing migration in HHR implants and was also for the first time used to measure GW. The Copeland HHR seems to obtain a secure fixation in the humerus but shows continuous GW up to two years.

Background/Aims Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge. Methods Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full model. We further validated ISS10 in an independent HCC cohort treated with nivolumab plus ipilimumab. Results The study identified a significant association between the ISS and treatment response. Among patients classified as high responders, those treated with the atezolizumab plus bevacizumab combination exhibited improved overall and progression-free survival as well as better objective response rate compared to those treated with sorafenib. We also observed a significant correlation between ISS10 and response to nivolumab plus ipilimumab treatment. Analysis of immune cell subpopulations revealed distinct characteristics associated with ISS subtypes. In particular, the ISS10 high subtype displayed a more favorable immune environment with higher proportions of antitumor macrophages and activated T-cells, potentially explaining its better response. Conclusions Our study suggests that ISS and ISS10 are promising predictive biomarkers for enhanced therapeutic outcomes in HCC patients undergoing combination immunotherapy. These markers are crucial for refining patient stratification and personalized treatment approaches to advance the effectiveness of standard-of-care regimens.

Background: Antiphospholipid syndrome (APS) is an autoimmune multisystem disorder. There has been a limited number of reported cases from Nigeria. Objectives: To determine the awareness and frequency of encounters with APS cases by medical practitioners in health institutions in South East Nigeria. Materials and Methods: It was a descriptive cross-sectional study. All medical doctors met in the clinics who were willing to participate in the study were recruited during the period of the study. Statistical Package for Social Sciences was used for data entry, validation, and analysis. Results: A total of 581 study questionnaires were distributed to medical doctors met at the clinics and clinical meetings of five hospitals in Southeast Nigeria however, 581 were approximately filled and retrieved, giving an response rate of 94.84%. Males were 383 (69.5%) and females were 168 (30.5%). A total of 445 (80.8%) were unaware of the autoimmune multisystemic nature of APS. Of the 551 respondents, 348 (63.2%) were aware that Rheumatologist is the primary care physician for APS, 290 (52.6%) reported rarity of APS, and 366 (66.4%) had up to 50% overall knowledge of APS. Respondents’ encounters with unexplained thrombotic events and unexplained stroke in the young were limited. A total of 62 (11.3%) were aware of the international classification criteria for APS. Conclusion: The authors conclude that APS awareness among medical practitioners in South East Nigeria is suboptimal.

Abstract Secondary bacterial pneumonia (2°BP) is associated with significant morbidity following respiratory viral infection, yet remains incompletely understood. In a prospective cohort of 112 critically ill adults intubated for COVID-19, we comparatively assess longitudinal airway microbiome dynamics and the pulmonary transcriptome of patients who developed 2°BP versus controls who did not. We find that 2°BP is significantly associated with both mortality and corticosteroid treatment. The pulmonary microbiome in 2°BP is characterized by increased bacterial RNA mass and dominance of culture-confirmed pathogens, detectable days prior to 2°BP clinical diagnosis, and frequently also present in nasal swabs. Assessment of the pulmonary transcriptome reveals suppressed TNFα signaling in patients with 2°BP, and sensitivity analyses suggest this finding is mediated by corticosteroid treatment. Further, we find that increased bacterial RNA mass correlates with reduced expression of innate and adaptive immunity genes in both 2°BP patients and controls. Taken together, our findings provide fresh insights into the microbial dynamics and host immune features of COVID-19-associated 2°BP, and suggest that suppressed immune signaling, potentially mediated by corticosteroid treatment, permits expansion of opportunistic bacterial pathogens.

Abstract Background Despite the well-known benefits of physical activity (PA), non-communicable disease and premature mortality rates among adults continue to rise. The relationship between adults’ goals and exercise-specific motivation on the type of PA intensity one engages remains unclear. The purpose of this study was to identify physical activity (PA) profiles based on frequency and intensity (i.e., levels of PA) in an adult sample. A secondary purpose was to examine how the PA profiles differ on the reasons people have for exercising and behavioral regulation. Methods A Cross-sectional survey was conducted with 1,169 (46.8 ± 16.7 years) participants solicited from a hospital-affiliated wellness center, social media promotions, and a research volunteer registry. The International PA Questionnaire (IPAQ) was used to determine frequency, intensity, and time spent engaging in PA. Additionally, the Reasons to Exercise (REX-2) scale, the Behavioral Regulation in Exercise Questionnaire-3 (BREQ-3), and demographics were assessed. K-cluster analyses were performed to identify profiles based on PA levels using the IPAQ guidelines. Multivariate analysis of variance (MANOVA) was used to assess profile differences. Results Five distinct PA clusters were derived, and defined as: a Low, Walking, Moderate Intensity, High Intensity, and Sitting cluster (p

Abstract Objective To obtain physicians’ “real-world” perspectives on early experiences with triamcinolone acetonide suprachoroidal injection (SCS-TA) for treatment of patients with uveitic macular edema (UME). Results Twelve retina/uveitis specialists in the United States were surveyed about SCS-TA injection procedure and patient outcomes. Survey participants administered ≥ 291 SCS-TA injections to 243 patients with UME with various disease characteristics (etiologies, chronicity, and anatomical subtypes). Commonly reported reasons for SCS-TA adoption included potential for lowering the risk of steroid-associated intraocular pressure elevations versus intravitreal injections or implants (100%), potential for longer duration of action versus intravitreal steroid injections or implants (92%), and desire to use a new delivery modality (83%). Nearly all participants (92%) found injection procedure relatively easy post-training, with most (75%) procedurally comfortable after completing 2–5 injections. 58% of participants indicated that their patients gained 2–3 lines of vision by first follow-up visit, and 92% reported having patients who experienced 100–150 μm or greater reduction in central subfield thickness. Overall, 92% of participants were satisfied with SCS-TA treatment outcomes. Findings from this survey of early adopters of SCS-TA indicate that the suprachoroidal injection technique was easy to learn and resulted in favorable patient outcomes consistent with clinical trial data.

Abstract Background To prospectively evaluate ultrasound backscatter coefficients (BSCs) of the supraspinatus and infraspinatus muscles and compare with Goutallier classification on magnetic resonance imaging (MRI). Methods Fifty-six participants had shoulder MRI exams and ultrasound exams of the supraspinatus and infraspinatus muscles. Goutallier MRI grades were determined and BSCs were measured. Group means were compared and the strength of relationships between the measures were determined. Using binarized Goutallier groups (0–2 versus 3–4), areas under the receiver operating characteristic curves (AUROCs) were calculated. The nearest integer cutoff value was determined using Youden’s index. Results BSC values were significantly different among most Goutallier grades for the supraspinatus and infraspinatus muscles (both p

Abstract This paper presents an open dataset of over 50 hours of near infrared spectroscopy (NIRS) recordings. Fifteen stroke patients completed a total of 237 motor imagery brain–computer interface (BCI) sessions. The BCI was controlled by imagined hand movements; visual feedback was presented based on the real–time data classification results. We provide the experimental records, patient demographic profiles, clinical scores (including ARAT and Fugl–Meyer), online BCI performance, and a simple analysis of hemodynamic response. We assume that this dataset can be useful for evaluating the effectiveness of various near–infrared spectroscopy signal processing and analysis techniques in patients with cerebrovascular accidents.

Abstract Chronic stress has been shown to induce hyperglycemia in both peripheral blood and the brain, yet the detailed mechanisms of glucose metabolism under stress remain unclear. Utilizing 13C6-labeled glucose to trace metabolic pathways, our study investigated the impact of stress by chronic social defeat (CSD) on glucose metabolites in the liver and brain one week post-stress. We observed a reduction in 13C6-enrichment of glucose metabolites in the liver, contrasting with unchanged levels in the brain. Notably, hepatic glycogen levels were reduced while lactate concentrations were elevated, suggesting lactate as an alternative energy source during stress. Long-term effects were also examined, revealing normalized blood glucose levels and restored glycogen stores in the liver three weeks post-CSD, despite sustained increases in food intake. This normalization is hypothesized to result from diminished glucagon levels leading to reduced glycogen phosphorylase activity. Our findings highlight a temporal shift in glucose metabolism, with hyperglycemia and glycogen depletion in the liver early after CSD, followed by a later phase of metabolic stabilization. These results underscore the liver’s critical role in adapting to CSD and provide insights into the metabolic adjustments that maintain glucose homeostasis under prolonged stress conditions.

Abstract The Golgi apparatus is essential for protein sorting, yet its quality control mechanisms are poorly understood. Here we show that the Dsc ubiquitin ligase complex uses its rhomboid pseudo-protease subunit, Dsc2, to assess the hydrophobic length of α-helical transmembrane domains (TMDs) at the Golgi. Thereby the Dsc complex likely interacts with orphaned ER and Golgi proteins that have shorter TMDs and ubiquitinates them for targeted degradation. Some Dsc substrates will be extracted by Cdc48 for endosome and Golgi associated proteasomal degradation (EGAD), while others will undergo ESCRT dependent vacuolar degradation. Some substrates are degraded by both, EGAD- or ESCRT pathways. The accumulation of Dsc substrates entails a specific increase in glycerophospholipids with shorter and asymmetric fatty acyl chains. Hence, the Dsc complex mediates the selective degradation of orphaned proteins at the sorting center of cells, which prevents their spreading across other organelles and thereby preserves cellular membrane protein and lipid composition.

Abstract Background Senescent immune cells exhibit altered gene expression and resistance to apoptosis. The prevalence of these cells increases with age and emerging data implicate senescence-associated maladaptive signaling as a potential contributor to sepsis and septic shock. The senolytic drug fisetin promotes clearance of senescent cells and is hypothesized to mitigate septic responses to infection. Methods We are conducting a multi-center, randomized, double-blinded, adaptive allocation phase 2 clinical trial to assess the efficacy of the senolytic drug fisetin in preventing clinical deterioration of elderly patients diagnosed with sepsis. We intend to enroll and randomize 220 elderly patients (age > 65) with the clinical diagnosis of sepsis to receive either fisetin as a single oral dose of 20 mg/kg, fisetin in two oral doses of 20 mg/kg each spaced 1 day apart, or placebo. The primary outcome will be changed in the composite of cardiovascular, respiratory, and renal sequential organ failure assessment scores at 7 days from enrollment. Secondary outcomes include quantification of senescent CD3 + cells at 7 days, and 28-day assessments of organ failure-free days, days in an intensive care unit, and all-cause mortality. Discussion This multi-center, randomized, double-blinded trial will assess the efficacy of fisetin in preventing clinical deterioration in elderly patients with sepsis and measure the effects of this drug on the prevalence of senescent immune cells. We intend that the results of this phase 2 trial will inform the design of a larger phase 3 study. Trial registration This trial is registered to ClinicalTrials.gov under identifier NCT05758246, first posted on March 7, 2023.

Abstract The abundance of Lp(a) protein holds significant implications for the risk of cardiovascular disease (CVD), which is directly impacted by the copy number (CN) of KIV-2, a 5.5 kbp sub-region. KIV-2 is highly polymorphic in the population and accurate analysis is challenging. In this study, we present the DRAGEN KIV-2 CN caller, which utilizes short reads. Data across 166 WGS show that the caller has high accuracy, compared to optical mapping and can further phase approximately 50% of the samples. We compared KIV-2 CN numbers to 24 previously postulated KIV-2 relevant SNVs, revealing that many are ineffective predictors of KIV-2 copy number. Population studies, including USA-based cohorts, showed distinct KIV-2 CN, distributions for European-, African-, and Hispanic-American populations and further underscored the limitations of SNV predictors. We demonstrate that the CN estimates correlate significantly with the available Lp(a) protein levels and that phasing is highly important.

Abstract This post hoc analysis of the randomized, placebo‐controlled N‐MOmentum study (NCT02200770) of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD) evaluated relationships between circulating B‐cell subsets and aquaporin‐4 immunoglobulin G (AQP4‐lgG) titers and attacks. Among participants receiving placebo, CD20+ and CD27+ B‐cell counts were modestly increased from the pre‐attack visit to attack; plasmablast/plasma cell gene signature was increased from baseline to the pre‐attack visit (p = 0.016) and from baseline to attack (p = 0.009). With inebilizumab treatment, B‐cell subset counts decreased and did not increase with attacks. No difference in change of AQP4‐IgG titers from baseline to time of attack was observed.

Abstract Objective We investigated the effects of adding regions to current dissemination in space (DIS) criteria for multiple sclerosis (MS). Methods Participants underwent brain, optic nerve, and spinal cord MRI. Baseline DIS was assessed by 2017 McDonald criteria and versions including optic nerve, temporal lobe, or corpus callosum as a fifth region (requiring 2/5), a version with all regions (requiring 3/7) and optic nerve variations requiring 3/5 and 4/5 regions. Performance was evaluated against MS diagnosis (2017 McDonald criteria) during follow‐up. Results Eighty‐four participants were recruited (53F, 32.8 ± 7.1 years). 2017 McDonald DIS criteria were 87% sensitive (95% CI: 76–94), 73% specific (50–89), and 83% accurate (74–91) in identifying MS. Modified criteria with optic nerve improved sensitivity to 98% (91–100), with specificity 33% (13–59) and accuracy 84% (74–91). Criteria including temporal lobe showed sensitivity 94% (84–98), specificity 50% (28–72), and accuracy 82% (72–90); criteria including corpus callosum showed sensitivity 90% (80–96), specificity 68% (45–86), and accuracy 85% (75–91). Criteria adding all three regions (3/7 required) had sensitivity 95% (87–99), specificity 55% (32–76), and accuracy 85% (75–91). When requiring 3/5 regions (optic nerve as the fifth), sensitivity was 82% (70–91), specificity 77% (55–92), and accuracy 81% (71–89); with 4/5 regions, sensitivity was 56% (43–69), specificity 95% (77–100), and accuracy 67% (56–77). Interpretation Optic nerve inclusion increased sensitivity while lowering specificity. Increasing required regions in optic nerve criteria increased specificity and decreased sensitivity. Results suggest considering the optic nerve for DIS. An option of 3/5 or 4/5 regions preserved specificity, and criteria adding all three regions had highest accuracy.

Abstract Background We aimed to use open source data to understand the incidence, trends, and regional differences of finger and partial hand amputations on a national level in individuals aged 15 or older in Sweden. Methods We analyzed 6,918 patients aged 15 and older who had experienced finger and partial hand amputations. Incidence rates, trends, and regional disparities were assessed using negative binomial regression models and Student’s t-tests. Future trend prediction was performed using Poisson regression. Results Finger amputations declined most, followed by partial hand and thumb amputations. Regional variations existed, with Stockholm having the lowest and Gotland highest incidence respectively. Overall, the incidence of finger, thumb and partial hand amputations in Sweden decreased slightly. Future trend analysis indicated decreasing incidence. Conclusion Although, lacking in definition, publicly available data can be used for monitoring of finger, thumb, and partial hand amputation incidence on a national level. Sex, age, and regional differences were observed, suggesting the need for targeted interventions to address disparities and mitigate the burden of finger and partial hand amputations on affected individuals.

Abstract Four distinct species of human coronaviruses (HCoVs) circulate in humans. Despite the recent attention due to SARS-CoV-2, a comprehensive understanding of the molecular epidemiology and genomic evolution of HCoVs remains unclear. Here, we employed primary differentiated human nasal epithelial cells for the successful isolation and genome sequencing of HCoVs derived from two retrospective cohorts in Singapore and Tanzania. Phylodynamic inference shows that HCoV-229E and HCoV-OC43 were subject to stronger genetic drift and reduced purifying selection from the early 2000s onwards, primarily targeting spike Domain A and B. This resulted in increased lineage diversification, coinciding with a higher effective reproductive number (Re>1.0). However, HCoV-NL63 and HCoV-HKU1 experienced weaker genetic drift and selective pressure with prolonged regional persistence. Our findings suggest that HCoV-229E and HCoV-OC43 viruses are adept at generating new variants and achieving widespread intercontinental dissemination driven by continuous genetic drift, recombination, and complex migration patterns.

Abstract Lifestyle diseases significantly contribute to the global health burden, with lifestyle factors playing a crucial role in the development of depression. The COVID-19 pandemic has intensified many determinants of depression. This study aimed to identify lifestyle and demographic factors associated with depression symptoms among Indians during the pandemic, focusing on a sample from Kolkata, India. An online public survey was conducted, gathering data from 1,834 participants (with 1,767 retained post-cleaning) over three months via social media and email. The survey consisted of 44 questions and was distributed anonymously to ensure privacy. Data were analyzed using statistical methods and machine learning, with principal component analysis (PCA) and analysis of variance (ANOVA) employed for feature selection. K-means clustering divided the pre-processed dataset into five clusters, and a support vector machine (SVM) with a linear kernel achieved 96% accuracy in a multi-class classification problem. The Local Interpretable Model-agnostic Explanations (LIME) algorithm provided local explanations for the SVM model predictions. Additionally, an OWL (web ontology language) ontology facilitated the semantic representation and reasoning of the survey data. The study highlighted a pipeline for collecting, analyzing, and representing data from online public surveys during the pandemic. The identified factors were correlated with depressive symptoms, illustrating the significant influence of lifestyle and demographic variables on mental health. The online survey method proved advantageous for data collection, visualization, and cost-effectiveness while maintaining anonymity and reducing bias. Challenges included reaching the target population, addressing language barriers, ensuring digital literacy, and mitigating dishonest responses and sampling errors. In conclusion, lifestyle and demographic factors significantly impact depression during the COVID-19 pandemic. The study’s methodology offers valuable insights into addressing mental health challenges through scalable online surveys, aiding in the understanding and mitigation of depression risk factors.

Abstract In this work, we investigated the effects of alloying elements on plastic deformation and microstructure evolution in polycrystalline copper (Cu) and Cu alloyed with 1 wt. $$\%$$ % lead (Cu-1 $$\%$$ % Pb). These materials were selected due to the size mismatch between Cu and Pb, with the latter forming precipitates at grain boundaries. Multi-modal characterization techniques, including neutron diffraction, electron backscatter diffraction (EBSD), and transmission electron microscopy (TEM), along with finite element simulations were employed to study the deformation behavior across multiple length scales. While both Cu and Cu-1 $$\%$$ % Pb exhibited similar macroscale response and final deformation textures, both dislocation line profile analysis and TEM revealed increased dislocation density in deformed Cu-1 $$\%$$ % Pb specimens. The presence of lead precipitates also significantly affected local plastic deformation during compression, with their influence diminishing with increasing strain. These results demonstrate the complex relationships between alloying elements, plastic deformation, microstructural evolution, and material behavior under load. The insights gained from this multi-scale and multi-technique approach contribute to the fundamental understanding of microstructural evolution in immiscible alloys and are valuable for tailoring the properties of structural materials for specific engineering applications.

Abstract Background Hypertrophic cardiomyopathy (HCM) can cause myocardial fibrosis, which can be a substrate for fatal ventricular arrhythmias and subsequent sudden cardiac death. Although late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) represents myocardial fibrosis and is associated with sudden cardiac death in patients with HCM, CMR is resource-intensive, can carry an economic burden, and is sometimes contraindicated. In this study for patients with HCM, we aimed to distinguish between patients with positive and negative LGE on CMR using deep learning of echocardiographic images. Methods In the cross-sectional study of patients with HCM, we enrolled patients who underwent both echocardiography and CMR. The outcome was positive LGE on CMR. Among the 323 samples, we randomly selected 273 samples (training set) and employed deep convolutional neural network (DCNN) of echocardiographic 5-chamber view to discriminate positive LGE on CMR. We also developed a reference model using clinical parameters with significant differences between patients with positive and negative LGE. In the remaining 50 samples (test set), we compared the area under the receiver-operating-characteristic curve (AUC) between a combined model using the reference model plus the DCNN-derived probability and the reference model. Results Among the 323 CMR studies, positive LGE was detected in 160 (50%). The reference model was constructed using the following 7 clinical parameters: family history of HCM, maximum left ventricular (LV) wall thickness, LV end-diastolic diameter, LV end-systolic volume, LV ejection fraction

Abstract Pluripotent stem cells have remarkable self-renewal capacity: the ability to proliferate indefinitely while maintaining the pluripotent identity essential for their ability to differentiate into almost any cell type in the body. To investigate the interplay between these two aspects of self-renewal, we perform four parallel genome-scale CRISPR-Cas9 loss-of-function screens interrogating stem cell fitness in hPSCs and the dissolution of primed pluripotent identity during early differentiation. These screens distinguish genes with distinct roles in pluripotency regulation, including mitochondrial and metabolism regulators crucial for stem cell fitness, and chromatin regulators that control pluripotent identity during early differentiation. We further identify a core set of genes controlling both stem cell fitness and pluripotent identity, including a network of chromatin factors. Here, unbiased screening and comparative analyses disentangle two interconnected aspects of pluripotency, provide a valuable resource for exploring pluripotent stem cell identity versus cell fitness, and offer a framework for categorizing gene function.

Abstract Bacteriophages are influential within the human gut microbiota, yet they remain understudied relative to bacteria. This is a limitation of studies on fecal microbiota transplantation (FMT) where bacteriophages likely influence outcome. Here, using metagenomics, we profile phage populations - the phageome - in individuals recruited into two double-blind randomized trials of FMT in ulcerative colitis. We leverage the trial designs to observe that phage populations behave similarly to bacterial populations, showing temporal stability in health, dysbiosis in active disease, modulation by antibiotic treatment and by FMT. We identify a donor bacteriophage putatively associated with disease remission, which on genomic analysis was found integrated in a bacterium classified to Oscillospiraceae, previously isolated from a centenarian and predicted to produce vitamin B complex except B12. Our study provides an in-depth assessment of phage populations during different states and suggests that bacteriophage tracking has utility in identifying determinants of disease activity and resolution.

Abstract Background Breast cancer patients have an increased risk of cardiometabolic disease and for many patients, adjuvant therapy causes an altered lipid profile, insulin resistance and inflammation. Previous follow-up studies are inconclusive regarding the duration of therapy-induced inflammation. We examined the acute and persistent changes of adjuvant chemotherapy on inflammatory and metabolic health markers in breast cancer patients. Methods Plasma levels of IL-6, IL-8, IL-10, IFN-γ, TNF-α, high-sensitivity C-reactive protein (hsCRP) and metabolic health parameters were analyzed before, shortly after and every six months up to two years after adjuvant chemotherapy treatment in 51 postmenopausal early breast cancer (EBC) patients, as well as in 41 healthy age- and BMI-matched controls. A target-specific multiplex assay was applied for cytokine measurements. Results Before initiation of adjuvant therapy, plasma IL-8 levels were higher in EBC patients (31%, p = 0.0001). Also, a larger proportion of the patients had a hsCRP level above 2 mg/L (41%) compared to the controls (17%, Χ2 = 5.15, p = 0.023). Plasma levels of all five cytokines, but not hsCRP, were significantly increased after compared to before adjuvant chemotherapy (15–48% increase; all p ≤ 0.05). Already six months after ending chemotherapy treatment, all plasma cytokine levels were significantly reduced and close to pre-chemotherapy levels. Adjuvant chemotherapy caused a worsened lipid profile (increased triglycerides, lower HDL levels), insulin resistance and increased plasma insulin levels that remained high during the first year after chemotherapy. Conclusion Postmenopausal women with EBC have temporarily increased plasma levels of pro-inflammatory cytokines after adjuvant chemotherapy. Although transient, the therapy-induced increase in plasma cytokine levels, together with dyslipidemia and insulin resistance, may contribute to cardiometabolic risk in breast cancer patients treated with adjuvant chemotherapy. Trial registration The clinical trial (registration number NCT03784651) was registered on www.clinicaltrials.gov on 24 December 2018.

Introduction: Cannabidiol (CBD) has sparked considerable interest because of its wide range of pharmacological uses and the fact that it does not induce psychoactive effects. CBD formulation development presents significant challenges due to its limited water solubility and susceptibility to first-pass metabolism, both of which restrict its overall bioavailability. The current research aimed to use hot-melt extrusion (HME) technology to develop mucoadhesive buccal films to improve CBD solubility and reduce first-pass metabolism. Methods: Five formulations containing 10% w/w CBD were extruded using a counter-rotating twin-screw extruder (Haake Minilab II, Thermo Fisher Scientific). Different characterization studies were conducted on the developed formulations. Results: Differential scanning calorimetry (DSC) revealed that the CBD endothermic peak disappeared in some of the developed films, indicating that CBD was converted from crystalline to amorphous form. A bio-adhesion study showed that the formulations containing Carbopol® (BF2, BF3, BF4, and BF5) had higher adhesiveness properties. In vitro release and solubility studies showed an increase in CBD release and water solubility in the developed formulations when compared to pure CBD. Stability studies revealed that CBD content and release in the lead formulation (BF2) was stable over 15 months. Conclusion: The current study demonstrates that HME was successfully used as an approach to develop CBD mucoadhesive buccal films and CBD solubility was enhanced.

Abstract As the global prevalence of chronic liver disease continues to rise, the need to determine which patients will develop end-stage liver disease and require liver transplantation is increasingly important. However, current prognostic models perform sub-optimally. We aim to determine microRNA profiles associated with clinical decompensation and mortality/transplantation within 1 year. We examined microRNA expression profiles in plasma samples from patients across the spectrum of cirrhosis (n = 154), acute liver failure (ALF) (n = 22), sepsis (n = 20) and healthy controls (HC) (n = 20). We demonstrated that a microRNA-based model (miR-24 and -27a) associated with systemic inflammation differentiated decompensated cirrhosis states from compensated cirrhosis and HC (AUC 0.77 (95% CI 0.69–0.85)). 6 patients within the compensated cirrhosis group decompensated the subsequent year and their exclusion improved model performance (AUC 0.81 (95% CI 0.71–0.89)). miR-191 (associated with liver injury) predicted risk of mortality across the cohort when acutely decompensated and acute-on-chronic-liver failure patients were included. When they were excluded miR-24 (associated with systemic inflammation) predicted risk of mortality. Our findings demonstrate that microRNA associated with systemic inflammation and liver injury predict adverse outcomes in cirrhosis. miR-24 and -191 require further investigation as prognostic biomarkers and therapeutic targets for patients with liver disease.

Abstract Background Lung cancer ranks as one of the most rapidly growing malignancies. Which is characterized by its poor prognosis and a low survival rate due to late diagnosis and limited efficacy of conventional treatments. In recent years nanotechnology has emerged as a promising frontier in the management of lung cancer, presenting novel strategies to enhance drug administration, improve therapeutic efficiency, and mitigate side effects. This research comprehensively evaluates the current state and research trends concerning the application of nanomaterials in lung cancer through bibliometric analysis. Materials and methods We employed a systematic approach by retrieving studies from the Scopus database that focused on nanomaterials and lung cancer between 2003 and 2023. Subsequently, we carefully selected relevant articles based on predetermined inclusion criteria. The selected publications were then subjected to bibliometric and visual analysis using softwares such as VOSviewer and Biblioshiny. Results A total of 3523 studies that meet inclusion criteria were selected for bibliometric analysis. We observed a progressive increase in the number of annual publications from 2003 to 2023, indicating the growing interest in this field. According to our analysis, China is the primary contributor to publication output among the countries. The “Ministry of Education of the People's Republic of China” was the most influential institution. Among the authors, "Dr. Jack A. Roth” and “Dr. Huang Leaf” had the highest number of publications and cited publications, respectively. The “International Journal of Nanomedicine” was found to be the most prolific journal in this field. Additionally, “Biomaterials” emerged as the most cited journal. Through keyword analysis, we identified five main research themes and future research directions; nono-immunotherapy and green synthesis are the hot topics in this research field. Conclusion Our study summarized the key characteristics of publications in this field and identified the most influential countries, institutions, authors, journals, hot topics, and trends related to the application of nanomaterials in lung cancer. These findings contribute to the existing body of knowledge and serve as a foundation for future research endeavors in this area. More effective efforts are needed in this field to reduce the burden of lung cancer and help achieve the United Nation’s Sustainable Development Goals.

Abstract Differential accessibility (DA) analysis of single-cell epigenomics data enables the discovery of regulatory programs that establish cell type identity and steer responses to physiological and pathophysiological perturbations. While many statistical methods to identify DA regions have been developed, the principles that determine the performance of these methods remain unclear. As a result, there is no consensus on the most appropriate statistical methods for DA analysis of single-cell epigenomics data. Here, we present a systematic evaluation of statistical methods that have been applied to identify DA regions in single-cell ATAC-seq (scATAC-seq) data. We leverage a compendium of scATAC-seq experiments with matching bulk ATAC-seq or scRNA-seq in order to assess the accuracy, bias, robustness, and scalability of each statistical method. The structure of our experiments also provides the opportunity to define best practices for the analysis of scATAC-seq data beyond DA itself. We leverage this understanding to develop an R package implementing these best practices.

Abstract Background Dyslipidemia is a known risk factor for cardiovascular disease. While statins are the primary treatment, some individuals require additional lipid-lowering therapies, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Alirocumab and evolocumab have shown efficacy in reducing low-density lipoprotein cholesterol (LDL-C) levels and reduce the risk of major cardiovascular events (MACE) but have not been directly compared in clinical trials. This study aims to assess the effects of PCSK9 inhibitors on LDL-C levels and evaluate the impact of a mandated switch from alirocumab to evolocumab. Methods Taking advantage of the mandated switch in PCSK9 treatment in Denmark, we conducted a register-based cohort study of 907 individuals with dyslipidemia treated with PCSK9 inhibitors in the Capital Region of Denmark from 2016 to 2022. We analyzed LDL-C levels, treatment retention, and MACE, adjusting for variables such as age, sex, dose, and concurrent lipid-lowering medications. Results We show that PCSK9 inhibitors treatment resulted in a 49% reduction in LDL-C levels. Following a mandated switch from alirocumab to evolocumab, no significant difference was observed in LDL-C levels or adverse clinical outcomes, including MACE. Treatment discontinuation was most likely within the first 100 days, and no significant difference in discontinuation rates was found between the two drugs. Conclusions Our study demonstrates that both alirocumab and evolocumab are effective in significantly reducing LDL-C levels in individuals with dyslipidemia. The mandated switch from alirocumab to evolocumab did not result in significant changes in LDL-C or clinical outcomes, suggesting that these treatments can be used interchangeably. These findings support the clinical equivalence of the two PCSK9 inhibitors and may guide therapeutic decisions in lipid management.

Abstract We have recently made the strikingly discovery that upon a muscle injury, Wnt7a is upregulated and secreted from new regenerating myofibers on the surface of exosomes to elicit its myogenerative response distally. Despite recent advances in extracellular vesicle (EVs) isolation from diverse tissues, there is still a lack of specific methodology to purify EVs from muscle tissue. To eliminate contamination with non-EV secreted proteins and cytoplasmic fragments, which are typically found when using classical methodology, such as ultracentrifugation, we adapted a protocol combining Tangential Flow Filtration (TFF) and Size Exclusion Chromatography (SEC). We found that this approach allows simultaneous purification of Wnt7a, bound to EVs (retentate fraction) and free non-EV Wnt7a (permeate fraction). Here we described this optimized protocol designed to specifically isolate EVs from hind limb muscle explants, without cross-contamination with other sources of non-EV bounded proteins. The first step of the protocol is to remove large EVs with sequential centrifugation. Extracellular vesicles are then concentrated and washed in exchange buffer by TFF. Lastly, SEC is performed to remove any soluble protein traces remaining after TFF. Overall, this procedure can be used to isolate EVs from conditioned media or biofluid that contains EVs derived from any cell type or tissue, improving reproducibility, efficiency, and purity of EVs preparations. Our purification protocol results in high purity EVs that maintain structural integrity and thus fully compatible with in vitro and in vivo bioactivity and analytic assays.

Abstract Background Diviner’s sage (Salvia divinorum; Lamiaceae) is the source of the powerful hallucinogen salvinorin A (SalA). This neoclerodane diterpenoid is an agonist of the human Κ-opioid receptor with potential medical applications in the treatment of chronic pain, addiction, and post-traumatic stress disorder. Only two steps of the approximately twelve step biosynthetic sequence leading to SalA have been resolved to date. Results To facilitate pathway elucidation in this ethnomedicinal plant species, here we report a chromosome level genome assembly. A high-quality genome sequence was assembled with an N50 value of 41.4 Mb and a BUSCO completeness score of 98.4%. The diploid (2n = 22) genome of ~ 541 Mb is comparable in size and ploidy to most other members of this genus. Two diterpene biosynthetic gene clusters were identified and are highly enriched in previously unidentified cytochrome P450s as well as crotonolide G synthase, which forms the dihydrofuran ring early in the SalA pathway. Coding sequences for other enzyme classes with likely involvement in downstream steps of the SalA pathway (BAHD acyl transferases, alcohol dehydrogenases, and O-methyl transferases) were scattered throughout the genome with no clear indication of clustering. Differential gene expression analysis suggests that most of these genes are not inducible by methyl jasmonate treatment. Conclusions This genome sequence and associated gene annotation are among the highest resolution in Salvia, a genus well known for the medicinal properties of its members. Here we have identified the cohort of genes responsible for the remaining steps in the SalA pathway. This genome sequence and associated candidate genes will facilitate the elucidation of SalA biosynthesis and enable an exploration of its full clinical potential.

Abstract Resource allocation for invasive species management requires information about the size of the invasive population, which may be expensive and time‐consuming to obtain. The trade‐off between investment in monitoring and control efforts is a challenging decision problem, and existing mathematical tools are often difficult to interpret, and/or limited to a specific case study. We propose a partially observable Markov decision process (POMDP) framework to help decision‐makers understand effective monitoring and control policymaking. POMDPs can deal with uncertainty in both the model and state of the system but are more challenging to solve due to the continuous and high‐dimensional state space. Rather than limiting the possible states of the system, as do most previously proposed methods, we work through the development of a density projection approach, which reduces the dimensionality of the space of beliefs by restricting them to a parametrised family of probability distributions. This serves to align the mathematical representation of the problem with the real‐world quantities relevant to human decision‐making. The result of our model is a sequence of actions, which minimises the expected cost incurred in managing the invasive species, where the recommendation depends on an estimate of the species' abundance, and the uncertainty in this estimate. We demonstrate the effectiveness of our proposed framework with a case study on tropical fire ant (Solenopsis geminata) control and two generic case studies of varying complexity. Furthermore, we investigate sensitivity of the results to the choices of control cost and efficacy, and monitoring cost and error. The framework proposed by this paper makes the powerful machinery of POMDPs available to environmental managers. It computes the optimal course of action to manage a growing population of an invasive species, incorporating a varying time horizon and multiple control interventions. We sidestep the computational difficulties of general POMDPs to provide a clear, visual overview of decision‐making recommendations, and how these decisions change in new situations. Initial results and scenario‐based analysis show promising results, and the framework could be extended to the related field of disease management.

This study examined the impact of transformational leadership on innovative work behaviour (IWB) among employees in Ghana's hospitality sector. It also explored how organizational and employee absorptive capacity (AC) moderates the relationship between transformational leadership and innovative work behaviour. Data were randomly collected from 795 employees across star-rated hotels in the Volta Region of Ghana through structured questionnaires. The findings reveal that transformational leadership significantly impacts employees' innovative work behaviour. In addition, organizational and employee absorptive capacity significantly moderate the transformational leadership and innovative work behaviour relationship (albeit negatively for organizational absorptive capacity). Therefore, hospitality managers can exhibit higher levels of inspiration and support to their employees to generate innovative activities and outcomes. Also, firms can implement appropriate structures that foster knowledge exploration, acquisition and application at the employee level. This is because it enhances employee innovative work behaviour, especially in the presence of a transformational leadership style.