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Ocular adnexal sebaceous carcinoma (SebCA) represents one of the most clinically problematic periocular tumors, often requiring aggressive surgical resection. The pathobiology of this tumor remains poorly understood, and few models exist that are suitable for preclinical testing. The aim of this study was to establish new cell lines to serve as models for pathobiological and drug testing. With patient consent, freshly resected tumor tissue was cultured using conditional reprogramming cell conditions. Standard techniques were used to characterize the cell lines in terms of overall growth, clonogenicity, apoptosis, and differentiation in vitro. Additional analyses including Western blotting, short tandem repeat (STR) profiling, and next-generation sequencing (NGS) were performed. Drug screening using mitomycin-C (MMC), 5-fluorouricil (5-FU), and 6-Diazo-5-oxo-L-norleucine (DON) were performed. JHH-SebCA01, JHH-SebCA02, and JHH-SebCA03 cell lines were established from two women and one man undergoing surgical resection of eyelid tumors. At passage 15, they each showed a doubling time of two to three days, and all could form colonies in anchorage-dependent conditions, but not in soft agar. The cells contained cytoplasmic vacuoles consistent with sebaceous differentiation, and adipophilin protein was present in all three lines. STR profiling confirmed that all lines were derived from their respective patients. NGS of the primary tumors and their matched cell lines identified numerous shared mutations, including alterations similar to those previously described in SebCA. Treatment with MMC or 5-FU resulted in dose-dependent growth inhibition and the induction of both apoptosis and differentiation. MYC protein was abundant in all three lines, and the glutamine metabolism inhibitor DON, previously shown to target high MYC tumors, slowed the growth of all our SebCA models. Ocular adnexal SebCA cell lines can be established using conditional reprogramming cell conditions, and our three new models are useful for testing therapies and interrogating the functional role of MYC and other possible molecular drivers. Current topical chemotherapies promote both apoptosis and differentiation in SebCA cells, and these tumors appear sensitive to inhibition or MYC-associated metabolic changes.

Abstract Optical coherence tomography angiography (OCTA) is an emerging non-invasive technique for imaging the retinal vasculature. While there are many promising clinical applications for OCTA, determination of image quality remains a challenge. We developed a deep learning-based system using a ResNet152 neural network classifier, pretrained using ImageNet, to classify images of the superficial capillary plexus in 347 scans from 134 patients. Images were also manually graded by two independent graders as a ground truth for the supervised learning models. Because requirements for image quality may vary depending on the clinical or research setting, two models were trained—one to identify high-quality images and one to identify low-quality images. Our neural network models demonstrated outstanding area under the curve (AUC) metrics for both low quality image identification (AUC = 0.99, 95%CI 0.98–1.00, $$\kappa $$ κ = 0.90) and high quality image identification (AUC = 0.97, 95%CI 0.96–0.99, $$\kappa $$ κ = 0.81), significantly outperforming machine-reported signal strength (AUC = 0.82, 95%CI 0.77–0.86, $$\kappa $$ κ = 0.52 and AUC = 0.78, 95%CI 0.73–0.83, $$\kappa $$ κ = 0.27 respectively). Our study demonstrates that techniques from machine learning may be used to develop flexible and robust methods for quality control of OCTA images.

IntroductionWhile complement is a contributor to disease severity in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, all three complement pathways might be activated by the virus. Lectin pathway activation occurs through different pattern recognition molecules, including mannan binding lectin (MBL), a protein shown to interact with SARS-CoV-2 proteins. However, the exact role of lectin pathway activation and its key pattern recognition molecule MBL in COVID-19 is still not fully understood.MethodsWe therefore investigated activation of the lectin pathway in two independent cohorts of SARS-CoV-2 infected patients, while also analysing MBL protein levels and potential effects of the six major single nucleotide polymorphisms (SNPs) found in the MBL2 gene on COVID-19 severity and outcome.ResultsWe show that the lectin pathway is activated in acute COVID-19, indicated by the correlation between complement activation product levels of the MASP-1/C1-INH complex (p=0.0011) and C4d (p

The most commonly used markers to assess complement activation are split products that are produced through activation of all three pathways and are located downstream of C3. In contrast, C4d derives from the cleavage of C4 and indicates either classical (CP) or lectin pathway (LP) activation. Although C4d is perfectly able to distinguish between CP/LP and alternative pathway (AP) activation, no well-established markers are available to differentiate between early CP and LP activation. Active enzymes of both pathways (C1s/C1r for the CP, MASP-1/MASP-2 for the LP) are regulated by C1 esterase inhibitor (C1-INH) through the formation of covalent complexes. Aim of this study was to develop validated immunoassays detecting C1s/C1-INH and MASP-1/C1-INH complex levels. Measurement of the complexes reveals information about the involvement of the respective pathways in complement-mediated diseases. Two sandwich ELISAs detecting C1s/C1-INH and MASP-1/C1-INH complex were developed and tested thoroughly, and it was investigated whether C1s/C1-INH and MASP-1/C1-INH complexes could serve as markers for either early CP or LP activation. In addition, a reference range for these complexes in healthy adults was defined, and the assays were clinically validated utilizing samples of 414 COVID-19 patients and 96 healthy controls. The immunoassays can reliably measure C1s/C1-INH and MASP-1/C1-INH complex concentrations in EDTA plasma from healthy and diseased individuals. Both complex levels are increased in serum when activated with zymosan, making them suitable markers for early classical and early lectin pathway activation. Furthermore, measurements of C1-INH complexes in 96 healthy adults showed normally distributed C1s/C1-INH complex levels with a physiological concentration of 1846 ± 1060 ng/mL (mean ± 2SD) and right-skewed distribution of MASP-1/C1-INH complex levels with a median concentration of 36.9 (13.18 - 87.89) ng/mL (2.5-97.5 percentile range), while levels of both complexes were increased in COVID-19 patients (p

The SARS-CoV-2 virus continues to cause significant morbidity and mortality worldwide from COVID-19. One of the major challenges of patient management is the broad range of symptoms observed. While the majority of individuals experience relatively mild disease, a significant minority of patients require hospitalisation, with COVID-19 still proving fatal for some. As such, there remains a desperate need to better understand what drives this severe disease, both in terms of the underlying biology, but also to potentially predict at diagnosis which patients are likely to require further interventions, thus enabling better outcomes for both patients and healthcare systems. Several lines of evidence have pointed to dysregulation of the complement cascade as a major factor in severe COVID-19 outcomes. How this is underpinned mechanistically is not known. Here, we have focussed on the role of the soluble complement regulators Complement Factor H (FH), its splice variant Factor H-like 1 (FHL-1) and five Factor H-Related proteins (FHR1-5). Using a targeted mass spectrometry approach, we quantified these proteins in a cohort of 188 plasma samples from controls and SARS-CoV-2 patients taken at diagnosis. This analysis revealed significant elevations in all FHR proteins, but not FH, in patients with more severe disease, particularly FHR2 and FHR5 (FHR2: 1.97-fold, p

Abstract Purpose: To demonstrate novel treatments for patients with high juvenile xanthogranuloma (JXG) eyelid lesion burden. Case Report: A 14-year-old girl was referred to the oculoplastic surgery service for management of worsening extensive bilateral eyelid and adnexal lesions in the setting of JXG. The patient underwent intra-lesional steroid injections, serial excisions, and reconstruction with skin grafts. She was subsequently treated with CO 2 laser-assisted topical steroid application, which resulted in lesion regression. Conclusion: A novel multimodal approach to treatment of severe periocular JXG, incorporating surgical debulking, skin autograft, CO2 laser, and intra-lesional steroids, can be effective for lesion control.

Abstract Aims While right ventricular (RV) dysfunction is associated with worse prognosis in co‐morbid pulmonary hypertension and heart failure with preserved ejection fraction (PH‐HFpEF), the mechanisms driving RV dysfunction are unclear. We evaluated the extent and clinical correlates of diffuse RV myocardial fibrosis in PH‐HFpEF, as measured by cardiovascular magnetic resonance‐derived extracellular volume (ECV). Methods and results We prospectively enrolled participants with PH‐HFpEF (n = 14), pulmonary arterial hypertension (PAH; n = 13), and controls (n = 8). All participants underwent high‐resolution cardiovascular magnetic resonance, and case subjects (PH‐HFpEF and PAH) additionally underwent right heart catheterization. T1 mapping was performed using high‐resolution modified look‐locker inversion recovery with a 1 × 1 mm2 in‐plane resolution. RV free wall T1 values were quantified, and ECV was calculated. Participants with PH‐HFpEF were older and carried higher rates of hypertension and obstructive sleep apnoea than those with PAH. While RV ECV was similar between PH‐HFpEF and PAH (33.1 ± 8.0 vs. 34.0 ± 4.5%; P = 0.57), total pulmonary resistance was lower in PH‐HFpEF compared with PAH [PH‐HFpEF: 5.68 WU (4.70, 7.66 WU) vs. PAH: 8.59 WU (8.14, 12.57 WU); P = 0.01]. RV ECV in PH‐HFpEF was associated with worse indices of RV structure (RV end‐diastolic volume: r = 0.67, P = 0.01) and RV function (RV free wall strain: r = 0.59, P = 0.03) but was not associated with RV afterload (total pulmonary resistance: r = 0.08, P = 0.79). Conversely, there was a strong correlation between RV ECV and RV afterload in PAH (r = 0.57, P = 0.04). Conclusions Diffuse RV fibrosis, as measured by ECV, is present in PH‐HFpEF and is associated with adverse RV structural and functional remodelling but not degree of pulmonary vasculopathy. In PH‐HFpEF, diffuse RV fibrosis may occur out of proportion to the degree of RV afterload.

Thyroid eye disease (TED), an autoimmune inflammatory disorder of the orbit, presents with a potential array of clinical sequelae. The pathophysiology behind TED has been partially characterized in the literature. There remain certain elusive mechanisms welcoming of research advances. Disease presentation can vary, but those that follow a characteristic course start mild and increase in severity before plateauing into an inactive phase. Diagnosis and evaluation include careful physical examination, targeted laboratory work up, appropriate imaging studies, and tailored treatment regimens. Special consideration may apply to certain populations, such as pediatric and pregnant patients.

Background: Although population-based studies have demonstrated racial heterogeneity in coronary artery calcium (CAC) burden, the degree to which such associations extend to percutaneous coronary intervention (PCI) cohorts remains poorly characterized. We sought to evaluate the associations between race/ethnicity and CAC in a PCI population. Methods: This single center retrospective study analyzed 1025 patients with prior CAC who underwent PCI between January 1, 2012 and May 15, 2020. Patients were grouped as non-Hispanic White (NHW, N = 779), non-Hispanic Black (NHB, N = 81) and Hispanic (H, N = 165). Associations between race and CAC (Agatston units) were examined using negative binomial regression while adjusting for baseline parameters. Results: Among the 1025 patients (mean age 65.8, 70% male) who underwent PCI, NHW, NHB, and H populations had median CAC scores of 760, 500, and 462 Agatston units, respectively (p

Summary: Rapid COVID-19 diagnosis in the hospital is essential, although this is complicated by 30%–50% of nose/throat swabs being negative by SARS-CoV-2 nucleic acid amplification testing (NAAT). Furthermore, the D614G spike mutant dominates the pandemic and it is unclear how serological tests designed to detect anti-spike antibodies perform against this variant. We assess the diagnostic accuracy of combined rapid antibody point of care (POC) and nucleic acid assays for suspected COVID-19 disease due to either wild-type or the D614G spike mutant SARS-CoV-2. The overall detection rate for COVID-19 is 79.2% (95% CI 57.8–92.9) by rapid NAAT alone. The combined point of care antibody test and rapid NAAT is not affected by D614G and results in very high sensitivity for COVID-19 diagnosis with very high specificity.

Abstract Background Effective control of schistosomiasis remains a challenging problem for endemic areas of the world. Given knowledge of the biology of transmission and past experience with mass drug administration (MDA) programs, it is important to critically evaluate the likelihood that MDA programs will achieve substantial reductions in Schistosoma prevalence. In implementing the World Health Organization Roadmap for Neglected Tropical Diseases it would useful for policymaking to model projections of the status of Schistosoma control in MDA-treated areas in the next 5–10 years. Methods Calibrated mathematical models were used to project the effects of different frequency and coverage of MDA for schistosomiasis haematobia control in present-day endemic communities, taking into account uncertainties of parasite biology and input data. The modeling approach in this analysis was the Stratified Worm Burden model developed in our earlier works, calibrated using data from longitudinal S. haematobium control trials in Kenya. Results Model-based simulations of MDA control in typical low-risk and higher-risk communities indicated that infection prevalence can be substantially reduced within 10 years only when there is a high degree of community participation (>70 %) with at least annual MDA. Significant risk for re-emergence of infection remains if MDA is suspended. Conclusions In a stable (stationary) ecosystem, Schistosoma reproduction and transmission are sufficiently robust that the process of human infection continues, even under pressure from aggressive MDA. MDA alone is unlikely to interrupt transmission, and once mass treatment is suspended, the prevalence of human infection is likely to rebound to pre-control levels over a period of 25–30 years. MDA success in achieving very low levels of infection prevalence is highly dependent on treatment coverage and frequency within the local human population, and requires that both adults and children be included in drug delivery coverage. Ultimately, supplemental snail control and significant improvements in sanitation will be required to achieve full control of schistosomiasis by elimination of ongoing Schistosoma transmission.

Abstract Cytokines operate in concert to maintain immune homeostasis and coordinate immune responses. In cases of ER+ breast cancer, peripheral immune cells exhibit altered responses to several cytokines, and these alterations are correlated strongly with patient outcomes. To develop a systems-level understanding of this dysregulation, we measured a panel of cytokine responses and receptor abundances in the peripheral blood of healthy controls and ER+ breast cancer patients across immune cell types. Using tensor factorization to model this multidimensional data, we found that breast cancer patients exhibited widespread alterations in response, including drastically reduced response to IL-10 and heightened basal levels of pSmad2/3 and pSTAT4. ER+ patients also featured upregulation of PD-L1, IL6Rα, and IL2Rα, among other receptors. Despite this, alterations in response to cytokines were not explained by changes in receptor abundances. Thus, tensor factorization helped to reveal a coordinated reprogramming of the immune system that was consistent across our cohort.

Abstract Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. For the alveolar subtype (ARMS), the presence of the PAX3::FOXO1 fusion gene and/or metastases are strong predictors of poor outcome. Metastatic PAX3::FOXO1 + ARMS often responds to chemotherapies initially, only to subsequently relapse and become resistant with most patients failing to survive beyond 8 years post-diagnosis. No curative intent phase II or phase III clinical trial has been available for patients in the past 10 years (ARST0921). Thus, metastatic ARMS represents a significantly unmet clinical need. Chemotherapy resistance in ARMS has previously been attributed to PAX3::FOXO1-mediated cell cycle checkpoint adaptation, which is mediated by an HDAC3-SMARCA4-miR-27a-PAX3::FOXO1 circuit that can be disrupted by HDAC3 inhibition. In this study, we investigated the therapeutic efficacy of combining the epigenetic regulator entinostat, a Class I Histone Deacetylase (HDAC1-3) inhibitor, with RMS-specific chemotherapies in patient derived xenograft (PDX) models of RMS. We identified single agent, additive or synergistic relationships between relapse-specific chemotherapies and clinically relevant drug exposures of entinostat in three PAX3::FOXO1 + ARMS mouse models. This preclinical data provides further rationale for clinical investigation of entinostat, already known to be well tolerated in a pediatric phase I clinical trial (ADVL1513).

Abstract Objective Describe the screening, referral, and treatment delivery associated with an opt-out tobacco treatment program (TTP) implemented in six hospitals varying in size, rurality and patient populations. Methods Between March 6, 2021 and December 17, 2021, adult patients (≥ 18 years) admitted to six hospitals affiliated with the Medical University of South Carolina were screened for smoking status. The hospitals ranged in size from 82 to 715 beds. Those currently smoking were automatically referred to one of two tobacco treatment options: 1) Enhanced care (EC) where patients could receive a bedside consult by a trained tobacco treatment specialist plus an automated post-discharge follow-up call designed to connect those smoking to the South Carolina Quitline (SCQL); or 2) Basic care (BC) consisting of the post-discharge follow-up call only. An attempt was made to survey patients at 6-weeks after hospitalization to assess smoking status. Results Smoking prevalence ranged from 14 to 49% across the six hospitals; 6,000 patients were referred to the TTP.The delivery of the bedside consult varied across the hospitals with the lowest in the Charleston hospitals which had the highest caseload of referred patients per specialist. Among patients who received a consult visit during their hospitalization, 50% accepted the consult, 8% opted out, 3% claimed not to be current smokers, and 38% were unavailable at the time of the consult visit. Most of those enrolled in the TTP were long-term daily smokers.Forty-three percent of patients eligible for the automated post-discharge follow-up call answered the call, of those, 61% reported smoking in the past seven days, and of those, 34% accepted the referral to theSCQL. Among the 986 of patients surveyed at 6-weeks after hospitalization quit rates ranged from 20%-30% based on duration of reported cessation and were similar between hospitals and for patients assigned to EC versus BC intervention groups. Conclusion Findings demonstrate the broad reach of an opt-out TTP. Elements of treatment delivery can be improved by addressing patient-to-staffing ratios, improving systems to prescribe stop smoking medications for patients at discharge and linking patients to stop smoking services after hospital discharge.

Abstract Background Alpha2-adrenoceptor agonists (α2-agonists) are widely used in animals as sedatives and for pre-anaesthetic medication. Medetomidine has often been given subcutaneously (SC) to rats, although its absorption rate is slow and the individual variation in serum drug concentrations is high via this route. In addition, α2-agonists have various effects on metabolic and endocrine functions such as hypoinsulinaemia, hyperglycaemia and diuresis. Vatinoxan is a peripherally acting α2-adrenoceptor antagonist that, as a hydrophilic molecule, does not cross the blood-brain barrier in significant quantities and thus alleviates peripheral cardiovascular effects and adverse metabolic effects of α2-agonists. Aim of this study was to evaluate the effects of vatinoxan on sedation, blood glucose concentration, voiding and heart and respiratory rates and arterial oxygen saturation in rats sedated with subcutaneous medetomidine, midazolam and fentanyl. Results Onset of sedation and loss of righting reflex occurred significantly faster with vatinoxan [5.35 ± 1.08 (mean ± SD) versus 12.97 ± 6.18 min and 6.53 ± 2.18 versus 14.47 ± 7.28 min, respectively]. No significant differences were detected in heart and respiratory rates and arterial oxygen saturation between treatments. Blood glucose concentration (18.3 ± 3.6 versus 11.8 ± 1.2 mmol/L) and spontaneous urinary voiding [35.9 (15.1–41.6), range (median) versus 0.9 (0–8.0) mL /kg/min] were significantly higher without vatinoxan. Conclusions Acceleration of induction of sedation, alleviation of hyperglycaemia and prevention of profuse diuresis by vatinoxan may be beneficial when sedating rats for clinical and experimental purposes with subcutaneous medetomidine, midazolam and fentanyl.

Abstract The discovery of clandestine burials poses unique challenges for forensic specialists, requiring diverse expertise to analyze remains in various states. Bones, teeth, and hair often endure the test of time, with hair particularly exposed to the external environment. While existing studies focus on the degradation of virgin hair influenced by soil pH and decomposition fluids, the interaction between artificial dyes on hair and soil remains underexplored. This paper introduces a novel approach to forensic hair analysis that is based on high-throughput, nondestructive, and non-invasive surface-enhanced Raman spectroscopy (SERS) and machine learning. Using this approach, we investigated the reliability of the detection and identification of artificial dyes on hair buried in three distinct soil types for up to eight weeks. Our results demonstrated that SERS enabled the correct prediction of 97.9% of spectra for five out of the eight dyes used within the 8 weeks of exposure. We also investigated the extent to which SERS and machine learning can be used to predict the number of weeks since burial, as this information may provide valuable insights into post-mortem intervals. We found that SERS enabled highly accurate exposure intervals to soils for specific dyes. The study underscores the high achievability of SERS in extrapolating colorant information from dyed hairs buried in diverse soils, with the suggestion that further model refinement could enhance its reliability in forensic applications.

Introduction Asian American caregivers supporting loved ones with dementia experience greater burden and more stress than other racial/ethnic groups, warranting the need for more culturally and linguistically appropriate formal support, such as in nursing homes. Transitioning loved ones into nursing homes with dementia care units is a complex process that can be impacted by a multitude of factors. Employing several established frameworks, including the socioecological model, this qualitative study will focus on the largest Asian American subgroup (people of Chinese descent) and explore the experience of family caregivers as they support the transition of their loved ones with dementia into nursing homes in the USA. Our focus will be on the nuanced influences of the Chinese language and culture and COVID-19-related social isolation and racial discrimination.Methods and analysis Recruitment will take place starting in January 2024. Current or former Chinese caregivers for Chinese loved ones with dementia, able to communicate in Mandarin Chinese or English, and currently residing in the USA will be eligible. Key informants with intimate understanding and experience with this population will also be included. Data will be collected through 2024 using semistructured, in-depth interviews with each participant. Depending on participants’ preferences, interviews will be conducted in either Mandarin Chinese or English and either in person, via Zoom or by phone. Interviews will be transcribed verbatim. Iterative thematic analysis will be employed. A coding structure will be developed based on interview questions and themes and patterns that are revealed through data immersion. Transcripts, prepared in their original language, will be dual-coded by bilingual researchers using NVivo 14. Consensus summaries of themes will be prepared. Relevant direct quotes for each thematic area will be identified (those in Chinese will be translated into English) and cited in reports and manuscripts.Ethics and dissemination The study is approved by the UMass Chan Medical School Institutional Review Board (ID: STUDY00001376). Findings will be published in peer-review journals following the consolidated criteria for reporting qualitative research.

Uncertainty is inherent in medicine and has been an enduring focus of enquiry in medical sociology. It is a particularly salient analytic concept in the context of a new emerging disease. Whilst a substantial body of work explores how clinicians manage uncertainty, scholarship that explores patients’ experiences and ways of managing uncertainty is less well developed. In this cross country research, we draw on two narrative interview studies with patients who were critically ill with Covid-19 in Brazil and in the United Kingdom (UK) in the first year of the pandemic. In Brazil, Covid-19 surveillance was introduced in hospitals, with tight restrictions on visitors in non-Covid-19 services and a visitor ban in Covid-19 services. In the UK, hospital visits were suspended entirely for several months, and later seriously restricted. Using a cross country analysis, we mobilize the concept of ‘navigation’ to highlight how a rapidly changing environment facilitates or impedes how well patients could act in, and on, their circumstances. We explore the ways in which four intersecting uncertainties affected patients, namely those relating to contagion, treatment, protocols and practice, and individual prognosis. We demonstrate how patients sought to navigate these uncertainties through relationships – with family members, clinical staff, other patients and technologies – which could provide temporary relief. We argue that it is important to attend to how patients invest in relationships in critical care, and to facilitate and support these wherever possible.

Abstract Background and Objectives Ethanol has been reported to improve tremor severity in approximately two thirds of patients with essential tremor (ET), but the accuracy of that proportion is not certain and the mechanism of action is unknown. The goal of this study was to investigate alcohol response on tremor by applying an a priori objective response definition and subsequently to describe the responder rate to a standardized ethanol dose in a cohort of 85 ET patients. A secondary analysis evaluated other tremor and nontremor features, including demographics, tremor intensity, breath alcohol concentration, nontremor effects of alcohol, self‐reported responder status to ethanol, and prior ethanol exposure. Methods This was a prospective, open‐label, single‐dose challenge of oral ethanol during which motor and nonmotor measurements were obtained starting immediately prior to ethanol administration and subsequently every 20 min for 120 min. We defined tremor reduction as a 35% decline in power in the patient's tremor frequency recorded during spiral drawing 60 min after ethanol administration. Results In total, 80% of patients were considered alcohol responsive using our objective definition. Responder status and change in the objective tremor metrics were significantly correlated with the change in breath alcohol concentration levels after ethanol administration, but no other relationships to nontremor metrics were found. Discussion A high percentage of patients actually respond to acute ethanol. However, their self‐reported response does not correlate well with their objective response. Objective response correlates with breath alcohol level but not with sedation, indicating a specific effect of ethanol on tremor.

Background Ensuring language concordant care through medical interpretation services (MIS) allows for accurate information sharing and positive healthcare experiences. The COVID-19 pandemic led to a regional halt of in-person interpreters, leaving only digital MIS options, such as phone and video. Due to longstanding institutional practices, and lack of accessibility and awareness of these options, digital MIS remained underused. A Multimodal Medical Interpretation Intervention (MMII) was developed and piloted to increase digital MIS usage by 25% over an 18-month intervention period for patients with limited English proficiency.Methods Applying quality improvement methodology, an intervention comprised digital MIS technology and education was trialled for 18 months. To assess intervention impact, the number of digital MIS minutes was measured monthly and compared before and after implementation. A questionnaire was developed and administered to determine healthcare providers’ awareness, technology accessibility and perception of MIS integration in the clinical workflow.Results Digital MIS was used consistently from the beginning of the COVID-19 pandemic (March 2020) and over the subsequent 18 months. The total number of minutes of MIS use per month increased by 44% following implementation of our intervention. Healthcare providers indicated that digital MIS was vital in facilitating transparent communication with patients, and the MMII ensured awareness of and accessibility to the various MIS modalities.Conclusion Implementation of the MMII allowed for an increase in digital MIS use in a hospital setting. Providing digital MIS access, education and training is a means to advance patient-centred and equitable care by improving accuracy of clinical assessments and communication.

Abstract The mechanisms underlying male infertility are poorly understood. Most mammalian spermatozoa have two centrioles: the typical barrel-shaped proximal centriole (PC) and the atypical fan-like distal centriole (DC) connected to the axoneme (Ax). These structures are essential for fertility. However, the relationship between centriole quality and subfertility (reduced fertility) is not well established. Here, we tested the hypothesis that assessing sperm centriole quality can identify cattle subfertility. By comparing sperm from 25 fertile and 6 subfertile bulls, all with normal semen analyses, we found that unexplained subfertility and lower sire conception rates (pregnancy rate from artificial insemination in cattle) correlate with abnormal centriolar biomarker distribution. Fluorescence-based Ratiometric Analysis of Sperm Centrioles (FRAC) found only four fertile bulls (4/25, 16%) had positive FRAC tests (having one or more mean FRAC ratios outside of the distribution range in a group’s high-quality sperm population), whereas all of the subfertile bulls (6/6, 100%) had positive FRAC tests (P = 0.00008). The most sensitive biomarker was acetylated tubulin, which had a novel labeling pattern between the DC and Ax. These data suggest that FRAC and acetylated tubulin labeling can identify bull subfertility that remains undetected by current methods and may provide insight into a novel mechanism of subfertility.

Molten chloride salts hold significant promise as both thermal transfer and storage media for next-generation concentrated solar power (CSP) systems. However, molten chlorides pose a considerable corrosion risk to structural materials, particularly Ni-based alloys. One approach to enhancing corrosion resistance is through the optimization of grain structure; however, it remains uncertain whether increasing or decreasing grain size enhances corrosion resistance. A cellular automata (CA) program was developed to evaluate the interplay between grain size and corrosion in Ni-based alloy. Our CA program tracks alloy composition, surface roughness, and thickness loss via a graphical user interface, displaying corrosion and diffusion status, and multiple user input cards for tuning the simulation. CA simulations of Inconel 625 indicate enhanced corrosion resistance with increased grain size, with passivating oxides offering limited protection. Additionally, the temporal evolution of alloy surface roughness demonstrates notable fluctuations, with abrupt increases attributed to corrosion along vertical grain boundaries and sudden decreases to grain detachment from the protective film.

Secondary lymphedema is caused by damage to the lymphatic system from surgery, cancer treatment, infection, trauma, or obesity. This damage induces stresses such as oxidative stress and hypoxia in lymphatic tissue, impairing the lymphatic system. In response to damage, vascular endothelial growth factor C (VEGF-C) levels increase to induce lymphangiogenesis. Unfortunately, VEGF-C often fails to repair the lymphatic damage in lymphedema. The underlying mechanism contributing to lymphedema is not well understood. In this study, we found that surgery-induced tail lymphedema in a mouse model increased oxidative damage and cell death over 16 days. This corresponded with increased VEGF-C levels in mouse tail lymphedema tissue associated with macrophage infiltration. Similarly, in the plasma of patients with secondary lymphedema, we found a positive correlation between VEGF-C levels and redox imbalance. To determine the effect of oxidative stress in the presence or absence of VEGF-C, we found that hydrogen peroxide (H2O2) induced cell death in human dermal lymphatic endothelial cells (HDLECs), which was potentiated by VEGF-C. The cell death induced by VEGF-C and H2O2 in HDLECs was accompanied by increased reactive oxygen species (ROS) levels and a loss of mitochondrial membrane potential. Antioxidant pre-treatment rescued HDLECs from VEGF-C-induced cell death and decreased ROS under oxidative stress. As expected, VEGF-C increased the number of viable and proliferating HDLECs. However, upon H2O2 treatment, VEGF-C failed to increase either viable or proliferating cells. Since oxidative stress leads to DNA damage, we also determined whether VEGF-C treatment induces DNA damage in HDLECs undergoing oxidative stress. Indeed, DNA damage, detected in the form of gamma H2AX (γH2AX), was increased by VEGF-C under oxidative stress. The potentiation of oxidative stress damage induced by VEFG-C in HDLECs was associated with p53 activation. Finally, the inhibition of vascular endothelial growth factor receptor-3 (VEGFR-3) activation blocked VEGF-C-induced cell death following H2O2 treatment. These results indicate that VEGF-C further sensitizes lymphatic endothelial cells to oxidative stress by increasing ROS and DNA damage, potentially compromising lymphangiogenesis.

Sickle cell nephropathy (SCN) is a leading cause of morbidity and mortality in sickle cell disease (SCD). Early intervention is crucial for mitigating its effects. However, current diagnostic methods rely on generic tests and may not detect SCN until irreversible renal damage occurs. Therefore, specific biomarkers for early diagnosis of SCN are needed. Urinary exosomes, membrane-bound vesicles secreted by renal podocytes and epithelial cells, contain both common and cell type-specific membrane and cytosolic proteins, reflecting the physiologic and pathophysiologic states of the kidney. Using proteomics, we analyzed the proteomes of urinary exosomes from humanized SCD mice at 2 months (without albuminuria) and 4 months (with albuminuria) of age. Excretion of 164 proteins were significantly increased and 176 proteins was significantly decreased in the exosomes when mice developed albuminuria. Based on the relevance to SCD, chronic kidney disease and Western blot confirmation in mice, we analyzed protein abundance of heparanase, cathepsin C, α2-macroglobulin and sarcoplasmic endoplasmic Ca2+ ATPase-3 (SERCA3) in the urinary exosomes and urine of 18 SCD subjects without albuminuria and 12 subjects with albuminuria using Western blot analyses. Both male and female subjects increased or tended to increase the excretion of these proteins in their urinary exosomes upon developing albuminuria, but female subjects demonstrated stronger correlations between the excretion of these proteins and urine albumin creatinine ratio (UACR) compared to male subjects. In contrast, exosomal excretion of Tamm-Horsfall protein, β-actin and SHP-1 was independent of albuminuria. These findings provide a foundation for a time-course study to determine whether increases in the levels of these proteins precede the onset of albuminuria in patients, which will help determine the potential of these proteins as biomarkers for early detection of SCN.

Introduction: Genetic factors impact alcohol consumption and use disorder (AUD), with large-scale genome-wide association studies (GWAS) identifying numerous associated variants. Aggregate genetic methods in combination with important environmental factors (e.g., interpersonal trauma [IPT]) can be applied to expand our understanding of the ways by which genetic and environmental variables work together to influence alcohol consumption and disordered use. The present study aimed to detail the relationships between genome-wide polygenic scores (PGS) for alcohol phenotypes (i.e., alcohol consumption and AUD status) and IPT exposure as well as the interaction between them across ancestry.Methods: Data were drawn from the Spit for Science (S4S) study, a US college student population, where participants reported on IPT exposure prior to college and alcohol consumption and problems during college (N = 9,006; ancestry: 21.3% African [AFR], 12.5% Admixed Americas [AMR], 9.6% East Asian [EAS], 48.1% European [EUR], 8.6% South Asian [SAS]). Two trans-ancestry PGS were constructed, one for alcohol consumption and another for AUD, using large-scale GWAS summary statistics from multiple ancestries weighted using PRS-CSx. Regression models were applied to test for the presence of associations between alcohol-PGS and IPT main and interaction effects.Results: In the meta-analysis across ancestry groups, IPT exposure and PGS were significantly associated with alcohol consumption (βIPT = 0.31, PIPT = 0.0002; βPGS = 0.09, PPGS = 0.004) and AUD (ORIPT = 1.12, PIPT = 3.5 × 10−8; ORPGS = 1.02, PPGS = 0.002). No statistically significant interactions were detected between IPT and sex nor between IPT and PGS. When inspecting ancestry specific results, the alcohol consumption-PGS and AUD-PGS were only statistically significant in the EUR ancestry group (βPGS = 0.09, PPGS = 0.04; ORPGS = 1.02, PPGS = 0.022, respectively).Discussion: IPT exposure prior to college was strongly associated with alcohol outcomes in this college-age sample, which could be used as a preventative measure to identify students at high risk for problematic alcohol use. Additionally, results add to developing evidence of polygenic score association in meta-analyzed samples, highlighting the importance of continued efforts to increase ancestral representation in genetic studies and inclusive analytic approaches to increase the generalizability of results from genetic association studies.