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Abstract Human Immunodeficiency Virus Type 1 (HIV) set-point viral load is a strong predictor of disease progression and transmission risk. A recent genome-wide association study in individuals of African ancestries identified a region on chromosome 1 significantly associated with decreased HIV set-point viral load. Knockout of the closest gene, CHD1L, enhanced HIV replication in vitro in myeloid cells. However, it remains unclear if HIV spVL associated variants are associated with CHD1L gene expression changes. Here we apply a heuristic fine-mapping approach to prioritize combinations of variants that explain the majority of set-point viral load variance and identify variants likely driving the association. We assess the combined impact of these variants on CHD1L regulation using publicly available sequencing studies, and test the relationship between CHD1L expression and set-point viral load using imputed CHD1L expression from monocytes. Taken together, this work characterizes genetically regulated CHD1L expression and further expands our knowledge of CHD1L-mediated HIV restriction in monocytes.

Abstract Background Multiple sulfatase deficiency (MSD) is an exceptionally rare neurodegenerative disorder due to the absence or deficiency of 17 known cellular sulfatases. The activation of all these cellular sulfatases is dependent on the presence of the formylglycine-generating enzyme, which is encoded by the SUMF1 gene. Disease-causing homozygous or compound heterozygous variants in SUMF1 result in MSD. Other than symptomatic treatment, no curative therapy exists as of yet for MSD. Eight out of these 17 sulfatases are primarily localized in the lysosome. Methods Two siblings with attenuated MSD underwent hematopoietic cell transplantation (HCT), evaluating the possibility of lysosomal enzymatic cross-correction from the donor cells. Results There is evidence of correction of currently available biomarkers within 3 months post-HCT. Untargeted metabolomics also shows continued correction of multiple biochemical abnormalities in the post-HCT period. Furthermore, this article also presents the neuropsychological outcomes of these children as well as the results of untargeted metabolomics analysis in this condition. Conclusions These data suggest biochemical benefits post-transplant along with slowing of disease progression. Long-term follow-up is necessary to fully evaluate the therapeutic benefit of HCT in MSD.

Abstract Immune checkpoint inhibitor (ICI) treatment has proven successful for advanced melanoma, but is associated with potentially severe toxicity and high costs. Accurate biomarkers for response are lacking. The present work is the first to investigate the value of deep learning on CT imaging of metastatic lesions for predicting ICI treatment outcomes in advanced melanoma. Adult patients that were treated with ICI for advanced melanoma were retrospectively identified from ten participating centers. A deep learning model (DLM) was trained on volumes of lesions on baseline CT to predict clinical benefit. The DLM was compared to and combined with a model of known clinical predictors (presence of liver and brain metastasis, level of lactate dehydrogenase, performance status and number of affected organs). A total of 730 eligible patients with 2722 lesions were included. The DLM reached an area under the receiver operating characteristic (AUROC) of 0.607 [95%CI 0.565–0.648]. In comparison, a model of clinical predictors reached an AUROC of 0.635 [95%CI 0.59 –0.678]. The combination model reached an AUROC of 0.635 [95% CI 0.595–0.676]. Differences in AUROC were not statistically significant. The output of the DLM was significantly correlated with four of the five input variables of the clinical model. The DLM reached a statistically significant discriminative value, but was unable to improve over known clinical predictors. The present work shows that the assessment over known clinical predictors is an essential step for imaging-based prediction and brings important nuance to the almost exclusively positive findings in this field.

Abstract Chronic limb-threatening ischemia (CLTI) significantly increases the risk of major adverse limb events (MALE) and major adverse cardiac events (MACE) after lower extremity revascularization (LER). This study aims to identify novel biomarkers that help to further reduce the risk of postoperative cardiovascular complications. In this prospective, nonrandomized, observational study, baseline serum levels of sirtuin 1 (SIRT1) were assessed in 147 diabetic patients scheduled for LER due to CLTI, and participants were followed for the occurrence of MALE and MACE over 12 months. Fifty-three patients experienced MALE, and 33 experienced MACE within the follow-up period. Lower baseline SIRT1 levels were significantly associated with an increased risk of MALE and MACE, independent of other risk factors. The ROC curve analysis identified a SIRT1 cutoff of 3.79 ng/mL for predicting the risk of MALE. Moreover, incorporating SIRT1 into predictive models significantly enhanced the accuracy of predicting adverse outcomes. Results suggest serum SIRT1 is a potential independent marker for predicting MALE and MACE in diabetic patients with CLTI undergoing LER. Further research is needed to clarify the mechanistic pathways in which SIRT1 may influence cardiovascular outcomes, and the role of this novel biomarker in the management of PAD and CLTI among patients with diabetes.

Abstract Background Questions persist around whether and how to use race or geographic ancestry in biomedical research and medicine, but these forms of self-identification serve as a critical tool to inform matching algorithms for human leukocyte antigen (HLA) of varying levels of resolution for unrelated hematopoietic stem cell transplant in large donor registries. Methods Here, we examined multiple self-reported measures of race and ancestry from a survey of a cohort of over 100,000 U.S. volunteer bone marrow donors alongside their high-resolution HLA genotype data. Results We find that these self-report measures are often non-overlapping, and that no single self-reported measure alone provides a better fit to HLA genetic ancestry than a combination including both race and geographic ancestry. We also found that patterns of reporting for race and ancestry appear to be influenced by participation in direct-to-consumer genetic ancestry testing. Conclusions While these data are not used directly in matching for transplant, our results demonstrate that there is a place for the language of both race and geographic ancestry in the critical process of facilitating accurate prediction of HLA in the donor registry context.

Abstract Decidualization denotes the process of inflammatory reprogramming of endometrial stromal cells (EnSC) into specialized decidual cells (DC). During this process, EnSC are subjected to endoplasmic reticulum (ER) stress as well as acute cellular senescence. Both processes contribute to the proinflammatory mid-luteal implantation window and their dysregulation has been implicated in reproductive failure. Here, we evaluated the link between ER stress, decidual differentiation and senescence. In-silico analysis identified HSPA5 gene, codifying the ER chaperone BiP, as a potentially critical regulator of cell fate divergence of decidualizing EnSC into anti-inflammatory DC and pro-inflammatory senescent decidual cells (snDC). Knockdown of HSPA5 in primary EnSC resulted both in decreased expression of DC marker genes and attenuated induction of senescence associated β-galactosidase activity, a marker of snDC. Stalling of the decidual reaction upon HSPA5 knockdown was apparent at 8 days of differentiation and was preceded by the upregulation of ER stress associated proteins IRE1α and PERK. Further, HSPA5 knockdown impaired colony-forming unit activity of primary EnSC, indicative of loss of cellular plasticity. Together, our results point to a key role for HSPA5/BiP in decidual transformation of EnSCs and highlight the importance of constraining ER stress levels during this process.

Heritable fragile bone disorders (FBDs), ranging from multifactorial to rare monogenic conditions, are characterized by an elevated fracture risk. Validating causative genes and understanding their mechanisms remain challenging. We assessed a semi-high throughput zebrafish screening platform for rapid in vivo functional testing of candidate FBD genes. Six genes linked to severe recessive osteogenesis imperfecta (OI) and four associated with bone mineral density (BMD) from genome-wide association studies were analyzed using CRISPR/Cas9-based crispant screening in F0 mosaic founder zebrafish. Next-generation sequencing confirmed high indel efficiency (mean 88%), mimicking stable knock-out models. Skeletal phenotyping at 7, 14, and 90 days post-fertilization (dpf) using microscopy, Alizarin Red S staining, and microCT was performed. Larval crispants showed variable osteoblast and mineralization phenotypes, while adult crispants displayed consistent skeletal defects, including malformed neural and haemal arches, vertebral fractures and fusions, and altered bone volume and density. In addition, aldh7a1 and mbtps2 crispants experienced increased mortality due to severe skeletal deformities. RT-qPCR revealed differential expression of osteogenic markers bglap and col1a1a, highlighting their biomarker potential. Our results establish zebrafish crispant screening as a robust tool for FBD gene validation, combining skeletal and molecular analyses across developmental stages to uncover novel insights into gene functions in bone biology.

Abstract Mid-sized mammals (i.e., mesomammals) fulfill important ecological roles, serving as essential scavengers, predators, pollinators, and seed dispersers in the ecosystems they inhabit. Consequently, declines in mesomammal populations have the potential to alter ecological processes and fundamentally change ecosystems. However, ecosystems characterized by high functional redundancy, where multiple species can fulfil similar ecological roles, may be less impacted by the loss of mesomammals and other vertebrates. The Greater Everglades Ecosystem in southern Florida is a historically biodiverse region that has recently been impacted by multiple anthropogenic threats, most notably the introduction of the Burmese python (Python molurus bivittatus). Since pythons became established, mesomammal populations have become greatly reduced. To assess whether these declines in mesomammals have affected two critical ecosystem functions—scavenging and frugivory—we conducted experiments in areas where mesomammals were present and absent. We did not observe significant differences in scavenging or frugivory efficiency in areas with and without mesomammals, but we did observe significant differences in the communities responsible for scavenging and frugivory. Despite the observed evidence of redundancy, the changes in community composition could potentially lead to indirect consequences on processes like seed dispersal and disease dynamics within this ecosystem, emphasizing the need for further study.

In March 2024, the US Department of Agriculture’s Animal and Plant Health Inspection Service reported detection of highly pathogenic avian influenza (HPAI) A(H5N1) virus in dairy cattle in the United States for the first time. One factor that determines susceptibility to HPAI H5N1 infection is the presence of specific virus receptors on host cells; however, little is known about the distribution of the sialic acid (SA) receptors in dairy cattle, particularly in mammary glands. We compared the distribution of SA receptors in the respiratory tract and mammary gland of dairy cattle naturally infected with HPAI H5N1. The respiratory and mammary glands of HPAI H5N1–infected dairy cattle are rich in SA, particularly avian influenza virus–specific SA α2,3-gal. Mammary gland tissues co-stained with sialic acids and influenza A virus nucleoprotein showed predominant co-localization with the virus and SA α2,3-gal. HPAI H5N1 exhibited epitheliotropism within the mammary gland, and we observed rare immunolabeling within macrophages.

We report highly pathogenic avian influenza A(H5N1) virus in dairy cattle and cats in Kansas and Texas, United States, which reflects the continued spread of clade 2.3.4.4b viruses that entered the country in late 2021. Infected cattle experienced nonspecific illness, reduced feed intake and rumination, and an abrupt drop in milk production, but fatal systemic influenza infection developed in domestic cats fed raw (unpasteurized) colostrum and milk from affected cows. Cow-to-cow transmission appears to have occurred because infections were observed in cattle on Michigan, Idaho, and Ohio farms where avian influenza virus–infected cows were transported. Although the US Food and Drug Administration has indicated the commercial milk supply remains safe, the detection of influenza virus in unpasteurized bovine milk is a concern because of potential cross-species transmission. Continued surveillance of highly pathogenic avian influenza viruses in domestic production animals is needed to prevent cross-species and mammal-to-mammal transmission.

Abstract The unfolded protein response (UPR) maintains proteostasis upon endoplasmic reticulum (ER) stress, and is initiated by a range of physiological and pathological processes. While there have been advances in developing fluorescent reporters for monitoring individual signaling pathways of the UPR, this approach may not capture a cell’s overall UPR activity. Here we describe a novel sensor of UPR activity, sUPRa, which is designed to report the global UPR. sUPRa displays excellent response characteristics, outperforms reporters of individual UPR pathways in terms of sensitivity and kinetics, and responds to a range of different ER stress stimuli. Furthermore, sUPRa’s dual promoter and fluorescent protein design ensures that both UPR-active and inactive cells are detected, and controls for reporter copy number. Using sUPRa, we reveal UPR activation in layer 2/3 pyramidal neurons of mouse cerebral cortex following a period of sleep deprivation. sUPRa affords new opportunities for quantifying physiological UPR activity with cellular resolution.

Abstract We report the photon (PL), electron (CL) and X-ray (XEL) induced luminescence characteristics of high aspect ratio ultra-long (~ 50 µm) ZnO nanorods (NRs) and discuss the potential for fast X-ray detection based on the consistent and efficient visible emission (~ 580 nm) from ZnO NRs. Nanostructured ZnO scintillators were rearranged to form a vertically well-aligned NR design in order to help light absorption and coupling resulting in luminescent and fast scintillation properties. The design of the nanorod array combines the key advantages of a low-cost growth technique together with environmentally friendly and widely available materials. A low temperature hydrothermal method was adopted to grow ZnO NRs in one cycle growth and their structural, optical and X-ray scintillation properties were investigated. The relatively short (~ 10 µm) ZnO NRs emitting in the near-band-edge region were found to be almost insensitive to X-rays. On the other hand, the higher XEL response of long ZnO NRs, which is a key parameter for evaluation of materials to be used as scintillators for high quality X-ray detection and imaging, along with a decay time response in the order of ns confirmed promising scintillation properties for fast and high-resolution X-ray detector applications.

Objective. To compare the adequacy, agreement, and acceptability of Papanicolaou testing (cytology) for cervical cancer screening using self-collected samples compared to physician-collected samples in Grenada in the Caribbean. Furthermore, the study identifies the human papillomavirus (HPV) genotypes present among asymptomatic women testing positive for HPV, the etiologic cause of cervical cancer. Methods. Participants were divided into two groups and two cervical samples were collected from the women in each group: a self-collected sample and a physician-collected sample. Cervical specimens were tested for cytology and HPV. HPV genotyping was performed on positive specimens. Results. Self-collected samples were adequate and in agreement with physician-collected samples, showing no difference between the two sampling methods. Oncogenic high-risk HPV genotypes were identified in cervical samples which were positive for atypical squamous cells and low-grade squamous intraepithelial lesions. The high-risk HPV genotypes found, notably HPV 45 and 53, differed from those most commonly reported. Although the commonly reported high-risk genotypes HPV 16 and 18 were found, so were 31, 33, 35, 52, 66, 68, and 82. Conclusions. Using self-collection facilitated the discovery of unexpected HPV genotypes among asymptomatic women in Grenada. These findings add new information to the literature regarding cervical cancer and neoplasia screening and HPV genotypes in the Caribbean. This genotype information may impact surveillance of women with low-grade lesions, HPV vaccine selection, and possibly further vaccine research. Research regarding HPV in Caribbean pathology samples of cervical neoplasia and cancer is needed.

OBJECTIVE: This study evaluated the impact of local treatment modalities in the management of large non-small cell lung cancer (NSCLC) tumors using a nationwide population-based dataset. MATERIAL AND METHODS: Patients with NSCLC tumors >7 cm that were cN0-1M0 in the Surveillance, Epidemiology, and End Results (SEER) registry from 2010 to 2015 were stratified by local management strategy (surgery, radiation therapy, no local treatment) and evaluated using Kaplan–Meier survival analyses, Cox proportional-hazard methods, and propensity-matched analysis. RESULTS: A total of 3156 patients were identified, of which 1580 (50.1%) underwent surgical resection, 920 (29.2%) received radiation only, 655 (20.7%) received no local treatment. Overall, the 5-year survival of patients undergoing surgical resection was 40.7%, compared to 14.7% and 5.3% for the radiation only and no local treatment groups, respectively (P < .001). Surgery with or without radiation continued to have an independent association with improved survival in multivariable analysis (HR 0.23, P < .0001). Other factors associated with improved survival included younger age, negative nodal disease, and chemotherapy use. In propensity-matched sub-analyses, 5-year survival remained significantly better after surgery alone compared to radiation alone (38.5% vs. 13.6%, P < .001), while survival after radiation alone was better than no local treatment, though both were largely poor (12.4% vs. 7.5%, P < .001). CONCLUSIONS: Survival of patients with large NSCLC managed non-surgically is very poor. Despite the significant long-term survival benefit with surgical intervention, nearly half of the study cohort did not undergo surgery. Patients and clinicians can use these results to estimate specific potential benefits when considering possible treatment strategies for large NSCLC tumors.

Abstract Background Obstructive sleep apnea (OSA) is associated with high blood pressure that responds poorly to usual antihypertensive therapy. Methods and results Forty-one subjects with OSA had 25% higher plasma norepinephrine and 42% higher epinephrine measured every 2 h over 24 h than 20 control subjects. They also excreted more sodium during sleep. This suggested that that a sympatholytic would be a more successful antihypertensive than a diuretic. To test this hypothesis we treated a second group of 23 hypertensive apneics with placebo, 6 weeks of the sympatholytic guanfacine and 6 weeks of hydrochlorothiazide in a crossover study. Guanfacine lowered 24-hour blood pressure by 9.6/6.7 mmHg, more than the 5.4/2.9 mmHg effect of hydrochlorothiazide (P

Abstract The antibiotic fusidic acid (FA) is used to treat Staphylococcus aureus infections. It inhibits protein synthesis by binding to elongation factor G (EF-G) and preventing its release from the ribosome after translocation. While FA, due to permeability issues, is only effective against gram-positive bacteria, the available structures of FA-inhibited complexes are from gram-negative model organisms. To fill this knowledge gap, we solved cryo-EM structures of the S. aureus ribosome in complex with mRNA, tRNA, EF-G and FA to 2.5 Å resolution and the corresponding complex structures with the recently developed FA derivative FA-cyclopentane (FA-CP) to 2.0 Å resolution. With both FA variants, the majority of the ribosomal particles are observed in chimeric state and only a minor population in post-translocational state. As expected, FA binds in a pocket between domains I, II and III of EF-G and the sarcin-ricin loop of 23S rRNA. FA-CP binds in an identical position, but its cyclopentane moiety provides additional contacts to EF-G and 23S rRNA, suggesting that its improved resistance profile towards mutations in EF-G is due to higher-affinity binding. These high-resolution structures reveal new details about the S. aureus ribosome, including confirmation of many rRNA modifications, and provide an optimal starting point for future structure-based drug discovery on an important clinical drug target.

Abstract Free Fecal Liquid (FFL), also termed Fecal Water Syndrome (FWS), is an ailment in horses characterized by variable solid and liquid (water) phases at defecation. The liquid phase can be excreted before, during, or after the solid defecation phase. While the underlying causes of FFL are unknown, hindgut dysbiosis is suggested to be associated with FFL. Three European studies investigated dysbiosis in horses with FFL using 16S rRNA sequencing and reported results that conflicted between each other. In the present study, we also used 16S rRNA sequencing to study the fecal microbial composition in 14 Canadian horses with FFL, and 11 healthy stable mate controls. We found no significant difference in fecal microbial composition between FFL and healthy horses, which further supports that dysbiosis is not associated with FFL.

Summary: Decidualization denotes the differentiation of endometrial stromal cells into specialized decidual cells, essential for embryo implantation and pregnancy. The process requires coordination of progesterone and cAMP signaling, which converge on downstream transcription factors. PGE2 and relaxin, acting, respectively, through Gαs-coupled GPCRs EP2 and RXFP1, are putative candidates for generating cAMP in differentiating stromal cells. Here, we show that PGE2 is less efficacious than relaxin in elevating intracellular cAMP levels in primary stromal cells but more effective at driving the expression of decidual genes. PGE2-and relaxin-induced cAMP generation involves receptor internalization, but EP2 is endocytosed into very early endosomes (VEEs). Perturbation of VEE machinery through depletion of key trafficking proteins; APPL1 and GIPC, dysregulates PGE2-dependent cAMP profiles and disrupts key decidual signaling pathways, resulting in a disordered differentiation response. We demonstrate that regulation of EP2 via internalization is essential for coordinated activation of the downstream signaling cascades that govern decidualization.

Background Stroke represents a major source of mortality and morbidity globally. The role of a stroke Clinical Nurse Specialist (CNS) as an expert team member in early supported discharge (ESD) for stroke, is not well defined or described although it is well established in other models of after-hospital and out-reach specialist care in the community. A greater focus has been on patients receiving rehabilitation post-stroke, however there is a need for a more holistic approach to care which clinical nurse specialists can offer to patients as part of ESD. Nurses are often the cohesive point of contact for other after-hospital services, managing many aspects of secondary prevention. Objective The aim of this scoping review is to explore the evidence in relation to the role of the stroke nurse providing secondary prevention interventions to stroke patients in a community setting. Methods We will conduct a scoping review in accordance with the Arksey and O’Malley, 2005 1 scoping review framework and the PRISMA-ScR guidelines to map available literature on the role of the stroke nurse in post-stroke care of patients in the community. The Cochrane Central Register of Controlled Trials and Systematic literature searches including databases MEDLINE, EMBASE, CINAHL, google scholar and grey literature will be searched using keyword searches. Data will be charted and synthesised and a narrative synthesis will be conducted. Conclusions This scoping review will be used to identify gaps in the current literature and identify areas for future research in the role of the stroke nurse in ESD in relation to secondary prevention for stroke patients and inform the development of a pathway for stroke nursing in ESD.

UV light is known to cause damage to biomolecules in living tissue. Tissues of the eye that play highly specialised roles in forming our sense of sight are uniquely exposed to light of all wavelengths. While these tissues have evolved protective mechanisms to resist damage from UV wavelengths, prolonged exposure is thought to lead to pathological changes. In the lens, UV light exposure is a risk factor for the development of cataract, which is a condition that is characterised by opacity that impairs its function as a focusing element in the eye. Cataract can affect spatially distinct regions of the lens. Age-related nuclear cataract is the most prevalent form of cataract and is strongly associated with oxidative stress and a decrease in the antioxidant capacity of the central lens region. Since UV light can generate reactive oxygen species to induce oxidative stress, its effects on lens structure, transparency, and biochemistry have been extensively investigated in animal models in order to better understand human cataract aetiology. A review of the different light exposure models and the advances in mechanistic understanding gained from these models is presented.

Background Tumor-associated macrophages (TAMs) play a critical function in the development of tumors and are associated with protumor M2 phenotypes. Shifting TAMs towards antitumor M1 phenotypes holds promise for tumor immunotherapy. Oleamide, a primary fatty acid amide, has emerged as a potent anticancer and immunomodulatory compound. However, the regulatory effects of oleamide on TAM phenotypes remain unclear. Methods We used real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) techniques to study the influence of oleamide on primary human monocyte-derived TAM phenotypes, and we investigated the protein expression profiles based on mass spectrometry to analyze the effect of oleamide on macrophage polarization. Moreover, the advantageous binding scores between oleamide and these target candidate proteins are examined using molecular docking. Results Our study revealed that oleamide effectively suppressed the M2-like TAM phenotype by reducing interleukin (IL)-10 production and downregulating M2-like markers, including vascular endothelial growth factor A (VEGFA), MYC proto-oncogene, bHLH transcription factor (c-Myc), and mannose receptor C-type 1 (CD206). Moreover, the conditioned medium derived from oleamide-treated TAMs induces apoptosis of MDA-MB-231 breast cancer cells. Proteomic analysis identified 20 candidate up- and down-regulation proteins targeted by oleamide, showing modulation activity associated with the promotion of the M1-like phenotype. Furthermore, molecular docking demonstrated favorable binding scores between oleamide and these candidate proteins. Collectively, our findings suggest that oleamide exerts a potent antitumor effect by promoting the antitumor M1-like TAM phenotype. These novel insights provide valuable resources for further investigations into oleamide and macrophage polarization which inhibit the progression of breast cancer, which may provide insight into immunotherapeutic approaches for cancer.

Abstract In contrast to inherited transthyretin amyloidosis (A-ATTRv), neuropathy is not a classic leading symptom of wild type transthyretin amyloidosis (A-ATTRwt). However, neurological symptoms are increasingly relevant in A-ATTRwt as well. To better understand the role of neurological symptoms in A-ATTRwt, A-ATTRwt patients were prospectively characterized at Amyloidosis Center Charité Berlin (ACCB) between 2018 and 2023 using detailed neurological examination, quality of life questionnaires, and analysis of age- and BMI-adapted serum neurofilament light chain (NFL) levels. 16 out of 73 (21.9%) patients presented with a severe neuropathy which we defined by a Neuropathy Impairment Score (NIS) of 20 or more. In this group, quality of life was reduced, peripheral neuropathy was more severe, and spinal stenosis and joint replacements were frequent. Age- and BMI matched serum NFL levels were markedly elevated in patients with a NIS ≥ 20. We therefore conclude that highly abnormal values in neuropathy scores such as the NIS occur in A-ATTRwt, and have an important impact on quality of life. Both peripheral neuropathy and spinal canal stenosis are likely contributors. Serum NFL may serve as a biomarker for neurological affection in patients with A-ATTRwt. It will be important to consider neurological aspects of A-ATTRwt for diagnosis, clinical follow-up, and future treatment development.

Abstract Background Finding time in the medical curriculum to focus on motivational interviewing (MI) training is a challenge in many medical schools. We developed a software-based training tool, “Real-time Assessment of Dialogue in Motivational Interviewing” (ReadMI), that aims to advance the skill acquisition of medical students as they learn the MI approach. This human-artificial intelligence teaming may help reduce the cognitive load on a training facilitator. Methods During their Family Medicine clerkship, 125 third-year medical students were scheduled in pairs to participate in a 90-minute MI training session, with each student doing two role-plays as the physician. Intervention group students received both facilitator feedback and ReadMI metrics after their first role-play, while control group students received only facilitator feedback. Results While students in both conditions improved their MI approach from the first to the second role-play, those in the intervention condition used significantly more open-ended questions, fewer closed-ended questions, and had a higher ratio of open to closed questions. Conclusion MI skills practice can be gained with a relatively small investment of student time, and artificial intelligence can be utilized both for the measurement of MI skill acquisition and as an instructional aid.

Abstract Background Narrative medicine demonstrated positive impact on empathy in medicine and nursing students. However, this pedagogical approach had not been evaluated in pharmacy education. This study sought to apply and evaluate the narrative medicine approach in extending empathy in Asian undergraduate pharmacy students. Methods Narrative medicine was applied through workshops which used narratives of people with different experiences and perspectives. First-year undergraduate pharmacy students who volunteered and attended these workshops formed the intervention group (N = 31) and the remaining first-year cohort formed the control group (N = 112). A sequential explanatory mixed methods approach was adopted in which quantitative methods were first used to measure impact on pharmacy students’ empathy using the Jefferson Scale of Empathy– Health Professions Student (JSE-HPS), and qualitative methods (i.e. group interviews) were then used to assess pharmacy students’ emotional responses to narratives, and the perspectives of pharmacy students and faculty of this pedagogical approach. Results There was no difference in JSE-HPS scores between intervention and control groups across baseline (i.e. upon matriculation), pre-intervention, and post-intervention timepoints. Pharmacy students in the intervention group had lower scores in Factor 3 (“Standing in People’s Shoes”) following the intervention. Five themes, guided by internal and external factors in cognition, emerged from the Group Interviews: (1) incongruence between students’ motivation and faculty’s perception, (2) learning context, (3) academic context, (4) cognitive system, and (5) affective system. Themes 1, 4 and 5 referred to internal factors such as students’ motivation, perceived learnings, and feelings. Themes 2 and 3 referred to external factors including workshop materials, activities, content, and facilitation. Conclusion This study is the first to demonstrate that pharmacy students engaged with the narrative medicine approach as narratives elicited emotional responses, exposed them to diverse perspectives, and deepened their appreciation of the importance of empathy and complexities of understanding patients’ perspectives. Scaffolded educational interventions using narratives and real-life patient encounters, alongside longitudinal measurements of empathy, are necessary to bring about meaningful and sustained improvements in empathy.

Mental health professionals have relied primarily on clinical evaluations to identify in vivo pathology. As a result, mental health is largely reactive rather than proactive. In an effort to proactively assess mood, we collected continuous neurophysiologic data for ambulatory individuals 8–10 h a day at 1 Hz for 3 weeks (N = 24). Data were obtained using a commercial neuroscience platform (Immersion Neuroscience) that quantifies the neural value of social-emotional experiences. These data were related to self-reported mood and energy to assess their predictive accuracy. Statistical analyses quantified neurophysiologic troughs by the length and depth of social-emotional events with low values and neurophysiologic peaks as the complement. Participants in the study had an average of 2.25 (SD = 3.70, Min = 0, Max = 25) neurophysiologic troughs per day and 3.28 (SD = 3.97, Min = 0, Max = 25) peaks. The number of troughs and peaks predicted daily mood with 90% accuracy using least squares regressions and machine learning models. The analysis also showed that women were more prone to low mood compared to men. Our approach demonstrates that a simple count variable derived from a commercially-available platform is a viable way to assess low mood and low energy in populations vulnerable to mood disorders. In addition, peak Immersion events, which are mood-enhancing, may be an effective measure of thriving in adults.

IntroductionEvidence in non-ocular tissues indicate that the antioxidant glutathione (GSH) may be regulated in a circadian manner leading to the idea that GSH levels in the lens may also be controlled in a circadian manner to anticipate periods of oxidative stress.MethodsMale rat Wistar lenses (6 weeks) were collected every 4 hours over a 24-hour period at 6am, 10am, 2pm, 6pm, 10pm and 2am and quantitative-PCR, western blotting and immunohistochemistry performed to examine the expression of core clock genes and proteins (BMAL1, CLOCK, CRY1-2, PER 1-3) and their subcellular localisation over a 24-hour period. Western blotting of lenses was also performed to examine the expression of NRF2, a transcription factor involved in regulating genes involved in GSH homeostasis and GSH related enzymes (GCLC, GS and GR) over the 24-hour period. Finally, HLPC was used to measure GSH levels in the aqueous humour and lenses every 4 hours over a 24-hour period.ResultsThe rat lens contains the core molecular components of a circadian clock with the expression of core clock proteins, NRF2 and GSH related enzymes fluctuating over a 24-hour period. BMAL1 expression was highest during the day, with BMAL1 localised to the nuclei at 10am. NRF2 expression remained constant over the 24-hour period, although appeared to move in and out of the nuclei every 4 hours. GSH related enzyme expression tended to peak at the start of night which correlated with high levels of GSH in the lens and lower levels of GSH in the aqueous humour.ConclusionThe lens contains the key components of a circadian clock, and time-of-day differences exist in the expression of GSH and GSH related enzymes involved in maintaining GSH homeostasis. GSH levels in the rat lens were highest at the start of night which represents the active phase of the rat when high GSH levels may be required to counteract oxidative stress induced by cellular metabolism. Future work to directly link the clock to regulation of GSH levels in the lens will be important in determining whether the clock can be used to help restore GSH levels in the lens.

Introduction Informed decisions to enrol in the clinical investigations of Alzheimer’s disease and related dementias (ADRD) require careful consideration of complex risks and uncertain benefits. Decisions regarding whether to receive information about biomarker status are complicated by lack of scientific consensus regarding biomarkers as surrogate endpoints for Alzheimer’s disease and how information about individual risk should be evaluated and shared with research participants. This study aims to establish stakeholder consensus regarding ethically optimal approaches to sharing individual results with ADRD research participants.Methods and analysis This Delphi consensus-building study consists of multiple online surveys conducted with Alzheimer’s disease research experts, including neurologists, neuropsychologists, ethicists, research oversight specialists and clinical trialists. Panellists will be administered questionnaires developed from a synthesis of researcher- and participant-endorsed considerations and decisional needs identified in published literature and a decisional needs assessment conducted with support from an Alzheimer’s Association Research Grant. Panellists will also be asked their views on the content and implementation of processes for sharing individual research results. ≥75% agreement will be required to achieve consensus. Response rates, level of agreement, medians, interquartile ranges and group rankings will be analysed. Following each round of data collection, our research team will undertake qualitative content analysis of open-ended responses.Ethics and dissemination Ethical approval will be obtained from the Cleveland Clinic Institutional Review Board (Study Number 22–766). Delphi panellists will receive participant information sheets describing the study before agreeing to participate in the Delphi process. Results from the data we anticipate will be generated through this research and will be submitted for peer-reviewed journal publication and presentation at international conferences.

Objective Adopting a physically active lifestyle and maintaining a diet rich in antioxidants can reduce the risk of vascular diseases. Arterial stiffness is an early marker for cardiovascular diseases, indicating vascular damage. This study investigates the relationship between physical activity (PA), sedentary behaviour (SB), dietary antioxidant, trace elements intake and vascular health in men and women, with a focus on pulse wave velocity (PWV), the gold standard for assessing arterial stiffness.Design This is a nationwide population-based cross-sectional study (Observation of Cardiovascular Risk Factors in Luxembourg 2 (ORISCAV-LUX 2)).Setting The study was conducted in Luxembourg, between November 2016 and January 2018.Participants In total, 988 participants from the ORISCAV-LUX 2 study, who were Luxembourg residents, aged 25–79 years, underwent the required physical examination, agreed to wear an accelerometer for 1 week and presented no personal history of myocardial infarction or stroke, were included in the analysis.Primary outcome measure PWV was assessed with the validated Complior instrument. Elastic-net models were used to investigate the associations of dietary intake (antioxidant and trace elements) and movement behaviours (PA and SB) with PWV in men and women.Results The findings reveal diverse associations between PA, SB, dietary intake and PWV, with distinct patterns observed in men and women. In women, a longer median moderate-to-vigorous PA bout length (mean coefficient (β)=−0.039), a higher long-range temporal correlation (higher scaling exponent alpha) at larger time scales (>120 min; β=−1.247) and an increased intake of vitamin C (β=−1.987) and selenium (β=−0.008) were associated with lower PWV. In men, a shorter median SB bout length (β=0.019) and a lower proportion of SB time accumulated in bouts longer than 60 min (β=1.321) were associated with lower PWV. Moreover, a higher daily intake of polyphenols (β=−0.113) and selenium (β=−0.004) was associated with lower PWV in men.Conclusion This study underscores the multifaceted nature of the associations between movement behaviours and dietary intake with PWV, as well as sex differences. These findings highlight the significance of considering both movement behaviours and dietary antioxidant intake in cardiovascular health assessments.

BackgroundChronic kidney disease (CKD) is a major public health concern. Adequate self-management skills are vital to reduce CKD burden, optimize patient health outcomes, and control health care expenditures. Using eHealth to support CKD self-management has the potential to promote healthy behaviors and improve health outcomes of patients with CKD. However, knowledge of the implementation of such interventions in general, and in China specifically, is still limited. ObjectiveThis study aims to develop a tailored eHealth self-management intervention for patients with CKD in China based on the Dutch Medical Dashboard (MD) eHealth self-management intervention. MethodsWe used an intervention mapping approach. In phase 1, a systematic review and 2 qualitative studies were conducted to examine the needs, beliefs, and perceptions of patients with CKD and health care professionals regarding CKD self-management and eHealth interventions. Afterward, key factors gathered from the aforementioned studies were categorized following the 5 domains of the Consolidated Framework for Implementation Research (CFIR). In phase 2, we specified program outcomes, performance objectives, determinants, theory-based methods, and practical strategies. Knowledge obtained from previous results was combined to complement core components of the MD self-management intervention and adapt them for Chinese patients with CKD. Additionally, the CFIR–Expert Recommendations for Implementing Change Matching Tool was pragmatically used to generate a list of potential implementation strategies to address the key factors influencing the implementation of eHealth CKD self-management interventions, and implementation strategies were discussed and finalized with the intervention monitoring group. ResultsAn overview of the CFIR domains showed the essential factors influencing the implementation of eHealth CKD self-management interventions in Chinese settings, including “knowledge and beliefs” in the domain “individual characteristics,” “quality and advantage of eHealth intervention” in the domain “intervention characteristics,” “compatibility” in the domain “inner setting,” and “cultural context” in the domain “outer setting.” To ensure the effectiveness of the Dutch MD–based self-management intervention, we did not change the core self-management intervention components of MD that underlie its effectiveness, such as self-monitoring. We identified surface-level cultural adaptations involving customizing intervention content, messages, and approaches to the observable cultural characteristics of the local population to enhance the intervention’s appeal, receptivity, and feasibility, such as providing video or voice call options to support interactions with health care professionals. Furthermore, the adapted modules such as Knowledge Center and My Self-Monitoring were developed in a mobile health app. ConclusionsOur study resulted in the delivery of a culturally tailored, standardized eHealth self-management intervention for patients with CKD in China that has the potential to optimize patients’ self-management skills and improve health status and quality of life. Moreover, our study’s research approach and results can inform future research on the tailoring and translation of evidence-based, eHealth self-management interventions to various contexts. Trial RegistrationClinicalTrials.gov NCT04212923; https://classic.clinicaltrials.gov/ct2/show/NCT04212923

BackgroundMultidisciplinary clinics (MDCs) provide benefits to patients with amyotrophic lateral sclerosis (ALS) and their caregivers, but MDC visits are information-heavy and can last 4 hours, with patients and caregivers meeting with multiple specialists within each MDC visit. There are questions about the effectiveness of current methods of sharing information from MDCs with patients. Video recordings are a promising new method of sharing information that may allow patients and caregivers to revisit the MDC and remind them of clinical recommendations and conversations. ObjectiveThe objective of this trial is to determine the feasibility and acceptability of sharing information through video recordings of ALS MDC visits with patients and caregivers. MethodsThis study was a randomized, controlled pilot trial with 3 months of follow-up from April 2021 to March 2022 in a rural multidisciplinary neurology clinic. We recruited patients with ALS, their caregivers, and their clinicians. Patients and their caregivers were randomized to either receive their normal after-visit summary (treatment as usual) or to receive their normal after-visit summary and a video recording of their MDC visit (video). Each specialist visit had its own recording and was accessible by patients and caregivers using a secure web-based platform called HealthPAL over a 3-month follow-up period. Primary study outcomes were feasibility and acceptability of the video intervention measured by recruitment rate (target: 70%), percentage of participants watching videos (target: 75%), and the Feasibility of Intervention Measure and Acceptability of Intervention Measure (targets: 3/5). We hypothesized that video recording would be feasible and acceptable to patients and their caregivers. ResultsOf the 30 patients approached, 24 were recruited, while all caregivers (n=21) and clinicians (n=34) approached were recruited. A total of 144 specialist visits were recorded, approximately 12 specialist visits at a median of one MDC visit per patient. Of the recorded patients, 75% (9/12) viewed videos. High median intervention feasibility (4, SD 0.99) and acceptability (4, SD 1.22) of intervention measures were reported by patients and caregivers in the intervention arm. High median intervention feasibility (5, SD 0.21) and acceptability (4.88, SD 0.4) were reported by clinicians. Of the 24 patients, 50% (n=12) did not complete a 3-month follow-up, primarily due to death (n=10). ConclusionsVideo recording is highly feasible and acceptable for patients, caregivers, and clinicians at a rural ALS clinic. Our level of attrition is a useful benchmark for future studies in MDC populations. Despite high rates of patient death, 1-week assessments highlight the value of recordings for both patients and caregivers. Trial RegistrationClinicalTrials.gov NCT04719403; https://clinicaltrials.gov/study/NCT04719403

Introduction Bronchiectasis is a worldwide chronic lung disorder where exacerbations are common. It affects people of all ages, but especially Indigenous populations in high-income nations. Despite being a major contributor to chronic lung disease, there are no licensed therapies for bronchiectasis and there remain relatively few randomised controlled trials (RCTs) conducted in children and adults. Our RCT will address some of these unmet needs by evaluating whether the novel mucoactive agent, erdosteine, has a therapeutic role in children and adults with bronchiectasis.Our primary aim is to determine in children and adults aged 2–49 years with bronchiectasis whether regular erdosteine over a 12-month period reduces acute respiratory exacerbations compared with placebo. Our primary hypothesis is that people with bronchiectasis who regularly use erdosteine will have fewer exacerbations than those receiving placebo.Our secondary aims are to determine the effect of the trial medications on quality of life (QoL) and other clinical outcomes (exacerbation duration, time-to-next exacerbation, hospitalisations, lung function, adverse events). We will also assess the cost-effectiveness of the intervention.Methods and analysis We are undertaking an international multicentre, double-blind, placebo-RCT to evaluate whether 12 months of erdosteine is beneficial for children and adults with bronchiectasis. We will recruit 194 children and adults with bronchiectasis to a parallel, superiority RCT at eight sites across Australia, Malaysia and Philippines. Our primary endpoint is the rate of exacerbations over 12 months. Our main secondary outcomes are QoL, exacerbation duration, time-to-next exacerbation, hospitalisations and lung function.Ethics and dissemination The Human Research Ethics Committees (HREC) of Children’s Health Queensland (for all Australian sites), University of Malaya Medical Centre (Malaysia) and St. Luke’s Medical Centre (Philippines) approved the study. We will publish the results and share the outcomes with the academic and medical community, funding and relevant patient organisations.Trial registration number ACTRN12621000315819.

Introduction: This in-vitro study aimed to evaluate the retentive force and dislodgment time of three stud attachment systems used for mandibular two-implant overdentures by simulating insertion/removal cycles. Materials and methods: From a simulation of a completely edentulous mandible with two parallel implants (Ø4.5 mm internal hex connection) (Zimmer Biomet, Warsaw, IN), 15 resin bases were fabricated and divided into three groups (n = 5 each): OT Equator (Rhein83, Bologna, IT), Locator (Zest Dental Solutions, Escondido, CA) and Locator R-Tx (Zest Dental Solutions, Escondido, CA). Pink inserts underwent 2000 cycles of thermocycling (SD MECHATRONIK GmbH, Feldkirchen-Westerham, Germany) and were soaked in citric acid for 24 days in an incubator. Each base underwent 2000 insertion/removal cycles on the Versa Test testing machine (Mecmesin Ltd., W. Sussex, UK) which was used to measure the retentive force and dislodgment time. The results were analyzed using ANOVA followed by the post-hoc Tukey test, Kruskal–Wallis test, and Pearson correlation coefficient test. A p-value of 0.05). The OT Equator had the most stable retention over the cycles (p > 0.05; cycle 1500). Conclusion: The three systems showed satisfactory retentive force ​​during the 2000 cycles. The Locator R-Tx demonstrated the best retention, while the OT Equator exhibited the most stable retention over time.

Abstract Organisms must regulate their behavior flexibly in the face of environmental challenges. Failure can lead to a host of maladaptive behavioral traits associated with a range of neuropsychiatric disorders, including attention deficit hyperactivity disorder, autism, and substance use disorders. This maladaptive dysregulation of behavior is influenced by genetic and environmental factors. For example, environmental enrichment produces beneficial neurobehavioral effects in animal models of such disorders. The present study determined the effects of environmental enrichment on a range of measures related to behavioral regulation using a large cohort of male, outbred heterogeneous stock (HS) rats as subjects. Subjects were reared from late adolescence onwards either in pairs in standard housing with minimal enrichment (n = 200) or in groups of 16 in a highly enriched environment consisting of a large multi-level cage filled with toys, running wheels, and shelters (n = 64). Rats were subjected to a battery of tests, including: (i) locomotor response to novelty, (ii) light reinforcement, (iii) social reinforcement, (iv) reaction time, (v) a patch-depletion foraging test, (vi) Pavlovian conditioned approach, (vii) conditioned reinforcement, and (viii) cocaine conditioned cue preference. Results indicated that rats housed in the enriched environment were able to filter out irrelevant stimuli more effectively and thereby regulate their behavior more efficiently than standard-housing rats. The dramatic impact of environmental enrichment suggests that behavioral studies using standard housing conditions may not generalize to more complex environments that may be more ethologically relevant.

Abstract Background Due to the abundant usage of chemotherapy in young triple-negative breast cancer (TNBC) patients, the unbiased prognostic value of BRCA1-related biomarkers in this population remains unclear. In addition, whether BRCA1-related biomarkers modify the well-established prognostic value of stromal tumor-infiltrating lymphocytes (sTILs) is unknown. This study aimed to compare the outcomes of young, node-negative, chemotherapy-naïve TNBC patients according to BRCA1 status, taking sTILs into account. Methods We included 485 Dutch women diagnosed with node-negative TNBC under age 40 between 1989 and 2000. During this period, these women were considered low-risk and did not receive chemotherapy. BRCA1 status, including pathogenic germline BRCA1 mutation (gBRCA1m), somatic BRCA1 mutation (sBRCA1m), and tumor BRCA1 promoter methylation (BRCA1-PM), was assessed using DNA from formalin-fixed paraffin-embedded tissue. sTILs were assessed according to the international guideline. Patients’ outcomes were compared using Cox regression and competing risk models. Results Among the 399 patients with BRCA1 status, 26.3% had a gBRCA1m, 5.3% had a sBRCA1m, 36.6% had tumor BRCA1-PM, and 31.8% had BRCA1-non-altered tumors. Compared to BRCA1-non-alteration, gBRCA1m was associated with worse overall survival (OS) from the fourth year after diagnosis (adjusted HR, 2.11; 95% CI, 1.18–3.75), and this association attenuated after adjustment for second primary tumors. Every 10% sTIL increment was associated with 16% higher OS (adjusted HR, 0.84; 95% CI, 0.78–0.90) in gBRCA1m, sBRCA1m, or BRCA1-non-altered patients and 31% higher OS in tumor BRCA1-PM patients. Among the 66 patients with tumor BRCA1-PM and ≥ 50% sTILs, we observed excellent 15-year OS (97.0%; 95% CI, 92.9–100%). Conversely, among the 61 patients with gBRCA1m and

Cavernous angiomas (CAs) are benign vascular malformations predominantly seen in the brain parenchyma and therefore referred to as intra-axial. Extra-axial dural-based cavernous angiomas, on the other hand, are rare vascular lesions found outside of the brain parenchyma. They occur in the middle fossa and may be easily misdiagnosed as meningiomas due to their extra-axial location. In addition, CAs that are located outside the middle fossa, such as in the convexity, have a better prognosis since they are more surgically accessible. Surgical resection is the main treatment of choice in CAs. However, other options, such as embolization and radiotherapy, may also be considered therapeutic choices or additive treatment options. The pathogenesis of CA and the involvement of other factors (genetics or environmental factors) are still unknown and require further investigation. We are presenting a young man who presented for evaluation of seizure-like events without any family history of neurologic conditions. The physical examination was unremarkable except for a slightly antalgic gait. Imaging studies showed an extra-axial left tentorial mass suggestive of a meningioma, hemangiopericytoma, or other extra-axial lesions. The lesion was resected where its vascular nature was mentioned initially, and the histology proved the diagnosis of cavernous angioma. Here we give an overview of the known pathogenesis, causes, clinical features, and diagnostic and therapeutic options in CA. Better knowledge about CA, its causes, clinical features, and treatment options would help clinicians in early diagnosis and patient management.

Abstract Acoustic sequences have been described in a range of species and in varying complexity. Cetaceans are known to produce complex song displays but these are generally limited to mysticetes; little is known about call combinations in odontocetes. Here we investigate call combinations produced by killer whales (Orcinus orca), a highly social and vocal species. Using acoustic recordings from 22 multisensor tags, we use a first order Markov model to show that transitions between call types or subtypes were significantly different from random, with repetitions and specific call combinations occurring more often than expected by chance. The mixed call combinations were composed of two or three calls and were part of three call combination clusters. Call combinations were recorded over several years, from different individuals, and several social clusters. The most common call combination cluster consisted of six call (sub-)types. Although different combinations were generated, there were clear rules regarding which were the first and last call types produced, and combinations were highly stereotyped. Two of the three call combination clusters were produced outside of feeding contexts, but their function remains unclear and further research is required to determine possible functions and whether these combinations could be behaviour- or group-specific.

Abstract The study aims to determine Rotavirus genotypes between 2013 and 2018 during implementation of ROTARIX vaccine in Tanzania. The analysis of surveillance data obtained between 2013 and 2018 was done to determine circulating genotypes after introduction of Rotarix vaccine. From 2013 to 2018, a total of 10,557 samples were collected and screened for Rotavirus using an enzyme immunoassay. A significant decrease in Rotavirus positivity (29.3% to 17.8%) from 2013 to 2018 (OR 0.830, 95% CI 0.803–0.857, P

Abstract The distribution of tick-borne encephalitis virus (TBEV) is expanding to Western European countries, including the Netherlands, but the contribution of different rodent species to the transmission of TBEV is poorly understood. We investigated whether two species of wild rodents native to the Netherlands, the wood mouse Apodemus sylvaticus and the yellow-necked mouse Apodemus flavicollis, differ in their relative susceptibility to experimental infection with TBEV. Wild-caught individuals were inoculated subcutaneously with the classical European subtype of TBEV (Neudoerfl) or with TBEV-NL, a genetically divergent TBEV strain from the Netherlands. Mice were euthanised and necropsied between 3 and 21 days post-inoculation. None of the mice showed clinical signs or died during the experimental period. Nevertheless, TBEV RNA was detected up to 21 days in the blood of both mouse species and TBEV was also isolated from the brain of some mice. Moreover, no differences in infection rates between virus strains and mouse species were found in blood, spleen, or liver samples. Our results suggest that the wood mouse and the yellow-necked mouse may equally contribute to the transmission cycle of TBEV in the Netherlands. Future experimental infection studies that include feeding ticks will help elucidate the relative importance of viraemic transmission in the epidemiology of TBEV.

The COVID-19 pandemic has triggered the adoption of new technologies to reduce the need for in-person physical therapy (PT). This study evaluated the impact of the COVID-19 pandemic on PT utilization and outcomes of patients prescribed a smartphone-based care management platform (sbCMP) for self-directed rehabilitation (SDR). A secondary analysis of data collected in a multicenter, prospective cohort trial investigating a mobile platform to deliver SDR after arthroplasty was performed. Patients who used the sbCMP for 2 weeks prior to undergoing partial knee arthroplasty (PKA), total knee arthroplasty (TKA), or total hip arthroplasty (THA) and provided 3 months of post-operative data were included. Use of adjunct PT at 3 months, step counts, and KOOS JR and HOOS JR scores were compared during the early versus late pandemic period. The cohort data was available for 1665 patients. Use of SDR without adjunct PT was higher in the early period of the COVID-19 pandemic in TKA (35.3% vs. 27.6%, p = 0.03) and THA (72.5% vs. 59.3%, p < 0.001), but not in the PKA cohort (58.9% vs. 53.3%, p = 0.53). Post-operative step counts improved at 3 months compared to pre-operative levels in all procedure types. Change in HOOS JR and KOOS JR scores from pre-operative to post-operative levels were similar by pandemic period in all cohorts. Use of SDR increased early during the COVID-19 pandemic, corresponding to pandemic restrictions, without negatively impacting patient outcomes. SDR facilitated via a sbCMP may be beneficial for patients unable or unwilling to participate in traditional PT visits.

The gabapentenoids such as gabapentin (GP) and pregabalin are approved for the treatment of chronic pain, but their utility is limited by persistent side effects. These adverse effects result from GPs affecting many types of neurons and muscle cells, not just the pain-sensing neurons that are the intended targets. We have recently discovered a type of peripheral neuron, rat sympathetic neurons from the superior cervical ganglion (SCG), that is uniquely insensitive to GP effects. Currents were measured using whole-cell patch-clamp electrophysiology from cells in primary culture from either the SCG or the Nodose Ganglion (NDG) as a positive control for the effects of GP. We find that the calcium current density was dramatically reduced by GP pretreatment in NDG neurons, but that neurons from the SCG were resistant. Further, when GP was cytoplasmically injected into these neurons, the resistance of SCG neurons to GP treatment persisted. These data demonstrate that rat sympathetic neurons appear to be uniquely resistant to GP treatment. These results may help us to better understand the mechanism of action of, and resistance to, GP in altering calcium channel current density, which may help to develop future treatments with fewer side effects.

Since May 2022, mpox has been identified in 108 countries without endemic disease; most cases have been in gay, bisexual, or other men who have sex with men. To determine number of missed cases, we conducted 2 studies during June–September 2022: a prospective serologic survey detecting orthopoxvirus antibodies among men who have sex with men in San Francisco, California, and a retrospective monkeypox virus PCR testing of swab specimens submitted for other infectious disease testing among all patients across the United States. The serosurvey of 225 participants (median age 34 years) detected 18 (8.0%) who were orthopoxvirus IgG positive and 3 (1.3%) who were also orthopoxvirus IgM positive. The retrospective PCR study of 1,196 patients (median age 30 years; 54.8% male) detected 67 (5.6%) specimens positive for monkeypox virus. There are likely few undiagnosed cases of mpox in regions where sexual healthcare is accessible and patient and clinician awareness about mpox is increased.

Abstract An interesting feature of the brain is its ability to respond to disparate sensory signals from the environment in unique ways depending on the environmental context or current brain state. In dynamical systems, this is an example of multi-stability, the ability to switch between multiple stable states corresponding to specific patterns of brain activity/connectivity. In this article, we describe chimera states, which are patterns consisting of mixed synchrony and incoherence, in a brain-inspired dynamical systems model composed of a network with weak individual interactions and chaotic/periodic local dynamics. We illustrate the mechanism using synthetic time series interacting on a realistic anatomical brain network derived from human diffusion tensor imaging. We introduce the so-called vector pattern state (VPS) as an efficient way of identifying chimera states and mapping basin structures. Clustering similar VPSs for different initial conditions, we show that coexisting attractors of such states reveal intricately “mingled” fractal basin boundaries that are immediately reachable. This could explain the nimble brain’s ability to rapidly switch patterns between coexisting attractors.

Stress-induced islet graft loss during the peri-transplantation period reduces the efficacy of islet transplantation. In this prospective, randomized, double-blind clinical trial, we evaluated the safety and efficacy of 60 mg/kg human alpha-1 antitrypsin (AAT) or placebo infusion weekly for four doses beginning before surgery in chronic pancreatitis (CP) patients undergoing total pancreatectomy and islet autotransplantation (TP-IAT). Subjects were followed for 12 months post-TP-IAT. The dose of AAT was safe, as there was no difference in the types and severity of adverse events in participants from both groups. There were some biochemical signals of treatment effect with a higher oxygen consumption rate in AAT islets before transplantation and a lower serum C-peptide (an indicator of islet death) in the AAT group at 15 min after islet infusion. Findings per the statistical analysis plan using a modified intention to treat analysis showed no difference in the C-peptide area under the curve (AUC) following a mixed meal tolerance test at 12 months post-TP-IAT. There was no difference in the secondary and exploratory outcomes. Although AAT therapy did not show improvement in C-peptide AUC in this study, AAT therapy is safe in CP patients and there are experiences gained on optimal clinical trial design in this challenging disease.

Endometriosis, a chronic condition characterized by the growth of endometrial-like tissue outside of the uterus, poses substantial challenges in terms of diagnosis and treatment. Artificial intelligence (AI) has emerged as a promising tool in the field of medicine, offering opportunities to address the complexities of endometriosis. This review explores the current landscape of endometriosis diagnosis and treatment, highlighting the potential of AI to alleviate some of the associated burdens and underscoring common pitfalls and challenges when employing AI algorithms in this context. Women’s health research in endometriosis has suffered from underfunding, leading to limitations in diagnosis, classification, and treatment approaches. The heterogeneity of symptoms in patients with endometriosis has further complicated efforts to address this condition. New, powerful methods of analysis have the potential to uncover previously unidentified patterns in data relating to endometriosis. AI, a collection of algorithms replicating human decision-making in data analysis, has been increasingly adopted in medical research, including endometriosis studies. While AI offers the ability to identify novel patterns in data and analyze large datasets, its effectiveness hinges on data quality and quantity and the expertise of those implementing the algorithms. Current applications of AI in endometriosis range from diagnostic tools for ultrasound imaging to predicting treatment success. These applications show promise in reducing diagnostic delays, healthcare costs, and providing patients with more treatment options, improving their quality of life. AI holds significant potential in advancing the diagnosis and treatment of endometriosis, but it must be applied carefully and transparently to avoid pitfalls and ensure reproducibility. This review calls for increased scrutiny and accountability in AI research. Addressing these challenges can lead to more effective AI-driven solutions for endometriosis and other complex medical conditions.

BackgroundSexual pain is a common but neglected disorder that affects approximately 3% to 18% of women and an unmeasured number of gender-diverse people worldwide. Despite its wide prevalence, many people feel reluctant to visit conventional health care services or disclose their symptoms due to the fear of stigmatization. To alleviate this stigma, various web-based interventions have been developed to complement and, in some cases, replace conventional sexual health interventions. However, the way these web-based interventions are developed could inadvertently reproduce, perpetuate, or exacerbate stigma among end user patients. ObjectiveThe purpose of this study was to understand patients’ perspectives on how sexual pain–related web platforms can be designed to alleviate stigma or prevent the unintended effects of stigma among patients who use web-based interventions. MethodsIndividual semistructured interviews were conducted among 16 participants with lived experiences of painful sex in a large urban city in Western Canada. Participants were recruited via social media platforms, newsletters, and a provincial health volunteer website. Using a sample sexual pain website to provide context, participants were interviewed about their experiences of stigma and how they think web platforms could be designed to address stigma. The interviews were conducted via Zoom (Zoom Technologies Inc) and analyzed using thematic analysis. ResultsThe findings revealed 4 overarching themes that represented participants’ perspectives on designing web platforms that may alleviate or prevent the unintended effects of stigma. These findings suggested the design of inclusive web platforms, having a nonprovocative and calming user interface, having features that facilitate connections among users and between users and providers, and displaying personal testimonials and experiences of sexual pain. ConclusionsThis study highlighted patient-centered design approaches that could serve as a reference guide in developing web platforms that alleviate or prevent the unintended effects of stigma, particularly among nonheterosexual and gender-diverse people. While this study was conducted in the context of sexual pain, the results might also apply to web platforms on other potentially stigmatizing health-related disorders or conditions.

Abstract Background Molecular profiling of the tumour immune microenvironment (TIME) has enabled the rational choice of immunotherapies in some adult cancers. In contrast, the TIME of paediatric cancers is relatively unexplored. We speculated that a more refined appreciation of the TIME in childhood cancers, rather than a reliance on commonly used biomarkers such as tumour mutation burden (TMB), neoantigen load and PD-L1 expression, is an essential prerequisite for improved immunotherapies in childhood solid cancers. Methods We combined immunohistochemistry (IHC) with RNA sequencing and whole-genome sequencing across a diverse spectrum of high-risk paediatric cancers to develop an alternative, expression-based signature associated with CD8+ T-cell infiltration of the TIME. Furthermore, we explored transcriptional features of immune archetypes and T-cell receptor sequencing diversity, assessed the relationship between CD8+ and CD4+ abundance by IHC and deconvolution predictions and assessed the common adult biomarkers such as neoantigen load and TMB. Results A novel 15-gene immune signature, Immune Paediatric Signature Score (IPASS), was identified. Using this signature, we estimate up to 31% of high-risk cancers harbour infiltrating T-cells. In addition, we showed that PD-L1 protein expression is poorly correlated with PD-L1 RNA expression and TMB and neoantigen load are not predictive of T-cell infiltration in paediatrics. Furthermore, deconvolution algorithms are only weakly correlated with IHC measurements of T-cells. Conclusions Our data provides new insights into the variable immune-suppressive mechanisms dampening responses in paediatric solid cancers. Effective immune-based interventions in high-risk paediatric cancer will require individualised analysis of the TIME.

Abstract Objective Shoulder pain is a common presentation in the primary care setting, and shoulder pain after vaccination has a growing body of literature. The present study sought to understand how a standardized treatment protocol would aid patients experiencing shoulder injury related to vaccine administration (SIRVA). Methods Patients experiencing SIRVA were retrospectively recruited between February 2017 and February 2021. All patients were treated with physical therapy and offered a cortisone injection. Post-treatment range of motion (i.e., forward elevation, external rotation, internal rotation) and patients’ reported outcomes were collected with the visual analogue scale (VAS), American Shoulder and Elbow Surgeons (ASES), simple shoulder test (SST), and single assessment numeric evaluation (SANE) scores. Results A total of 9 patients were retrospectively examined. Among them, 6 patients presented within one month of a recent vaccination event, while 3 patients presented 67, 87, and 120 days after vaccination. Furthermore, 8 of the patients completed physical therapy, and 6 of them underwent a cortisone injection. The follow-up time averaged 8 months. At final follow-up, the mean external rotation was 61º (standard deviation, SD±3º) and the mean forward elevation was 179º (SD±45º). Internal rotation ranged between L3 and T10. The VAS pain scores were 3.5/10.0 (SD±2.4), the mean ASES score was 63.5/100.0 (SD±26.3), and the SST scores were 8.5/12.0 (SD±3.9). Finally, the SANE scores were 75.7/100.0 (SD±24.7) and 95.7/100.0 (SD±6.1) in the injured and contralateral shoulders respectively. Conclusion Shoulder pain after a vaccination treated with physical therapy and cortisone injection ultimately resulted in favorable shoulder range of motion and functional score outcomes. Level of Evidence IV

Abstract Functional lung imaging modalities such as hyperpolarized gas MRI ventilation enable visualization and quantification of regional lung ventilation; however, these techniques require specialized equipment and exogenous contrast, limiting clinical adoption. Physiologically-informed techniques to map proton (1H)-MRI ventilation have been proposed. These approaches have demonstrated moderate correlation with hyperpolarized gas MRI. Recently, deep learning (DL) has been used for image synthesis applications, including functional lung image synthesis. Here, we propose a 3D multi-channel convolutional neural network that employs physiologically-informed ventilation mapping and multi-inflation structural 1H-MRI to synthesize 3D ventilation surrogates (PhysVENeT). The dataset comprised paired inspiratory and expiratory 1H-MRI scans and corresponding hyperpolarized gas MRI scans from 170 participants with various pulmonary pathologies. We performed fivefold cross-validation on 150 of these participants and used 20 participants with a previously unseen pathology (post COVID-19) for external validation. Synthetic ventilation surrogates were evaluated using voxel-wise correlation and structural similarity metrics; the proposed PhysVENeT framework significantly outperformed conventional 1H-MRI ventilation mapping and other DL approaches which did not utilize structural imaging and ventilation mapping. PhysVENeT can accurately reflect ventilation defects and exhibits minimal overfitting on external validation data compared to DL approaches that do not integrate physiologically-informed mapping.