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Abstract Background There is a need to develop accurate and reliable non-invasive methods to evaluate chronic kidney disease (CKD) status and assess disease progression. Given it is recognized that dysregulation in metabolic pathways occur from early CKD, there is a basis in utilizing metabolomic biomarkers to monitor CKD progression. Volatile Organic Compounds (VOCs), a form of metabolomic biomarker, are gaseous products of metabolic processes in organisms which are typically released with greater abundance in disease conditions when there is dysregulation in metabolism. How urinary VOCs reflect the abnormal metabolic profile of patients with CKD status is unknown. Our study aimed to explore this. Methods Individuals aged 18–75 years undergoing kidney biopsy were included. Pre-biopsy urine samples were collected. All biopsy samples had an interstitial fibrosis and tubular atrophy (IFTA) grade scored by standardized assessment. Urine supernatant was extracted from residue and sampled for stir bar sorptive extraction followed by Gas chromatography–mass spectrometry (GC-MS) analysis. Post-processing of GC-MS data separated complex mixtures of VOCs based on their volatility and polarity. Mass-to-charge ratios and fragment patterns were measured for individual VOCs identification and quantification. Linear discriminant analysis (LDA) was performed to assess the ability of urinary VOCs in discriminating between IFTA 0 (‘no or minimal IFTA’ i.e. 25% IFTA). Linear regression analysis adjusting for age, sex, estimated glomerular filtration rate, diabetes mellitus (DM) status, and albuminuria was conducted to determine significantly regulated urinary VOCs amongst the groups. Results 64 study participants (22 individuals IFTA 0, 15 individuals IFTA 1, 27 individuals IFTA ≥ 2) were included. There were 34 VOCs identified from GC-MS which were statistically associated with correct classification between the IFTA groups, and LDA demonstrated individuals with IFTA 0, IFTA 1 and IFTA ≥ 2 could be significantly separated by their urinary VOCs profile (p

Abstract The classical amyloid cascade hypothesis postulates that the aggregation of amyloid plaques and the accumulation of intracellular hyperphosphorylated Tau tangles, together, lead to profound neuronal death. However, emerging research has demonstrated that soluble amyloid-β oligomers (SAβOs) accumulate early, prior to amyloid plaque formation. SAβOs induce memory impairment and disrupt cognitive function independent of amyloid-β plaques, and even in the absence of plaque formation. This work describes the development and characterization of a novel anti-SAβO (E3) nanobody generated from an alpaca immunized with SAβO. In-vitro assays and in-vivo studies using 5XFAD mice indicate that the fluorescein (FAM)-labeled E3 nanobody recognizes both SAβOs and amyloid-β plaques. The E3 nanobody traverses across the blood–brain barrier and binds to amyloid species in the brain of 5XFAD mice. Imaging of mouse brains reveals that SAβO and amyloid-β plaques are not only different in size, shape, and morphology, but also have a distinct spatial distribution in the brain. SAβOs are associated with neurons, while amyloid plaques reside in the extracellular matrix. The results of this study demonstrate that the SAβO nanobody can serve as a diagnostic agent with potential theragnostic applications in Alzheimer’s disease.

The success rate of drug development today remains low, with long development cycles and high costs, especially in areas such as oncology, neurology, immunology, and infectious diseases. Single-cell omics, encompassing transcriptomics, genomics, epigenomics, proteomics, and metabolomics enable the analysis of gene expression profiles and cellular heterogeneity from the perspective of individual cells, offering a high-resolution view of their functional diversity. These technologies can help reveal disease mechanisms, drug target identification and validation, selection of preclinical models and candidate drugs, and clinical decision-making based on disease response to drugs, all at the single-cell level. The development of deep learning technology has provided a powerful tool for research in drug discovery based on single-cell techniques, which has evolved with the advent of large-scale public databases to predict drug responses and targets. In addition, traditional Chinese medicine (TCMs) research has also entered the era of single-cell technology. Single-cell omics technologies offer an alternative way in deciphering the mechanisms of TCMs in disease treatment, revealing drug targets, screening new drugs, and designing combinations of TCMs. This review aims to explore the application of single-cell omics technologies in drug screening and development comprehensively, highlighting how they accelerate the drug development process and facilitate personalized medicine by precisely identifying therapeutic targets, predicting drug responsiveness, deciphering mechanisms of action. It is also concluded that drug development process and therapeutic efficacy of drugs can be improved by combining single-cell omics and artificial intelligence techniques.

BackgroundPrior to the development of COVID-19 vaccines, policymakers instituted various non-pharmaceutical interventions (NPIs) to limit transmission. Prior studies have attempted to examine the extent to which these NPIs achieved their goals of containment, suppression, or mitigation of disease transmission. Existing evidence syntheses have found that numerous factors limit comparability across studies, and the evidence on NPI effectiveness during COVID-19 pandemic remains sparse and inconsistent. This study documents the magnitude and variation in NPI effectiveness in reducing COVID-19 transmission (i.e., reduction in effective reproduction rate [Reff] and daily contact rate) in Italy, the United States, the United Kingdom, and China.MethodsOur rapid review and narrative synthesis of existing research identified 126 studies meeting our screening criteria. We selected four contexts with >5 articles to facilitate a meaningful synthesis. This step yielded an analytic sample of 61 articles that used data from China, Italy, the United Kingdom, and the United States.ResultsWe found wide variation and substantial uncertainty around the effectiveness of NPIs at reducing disease transmission. Studies of a single intervention or NPIs that are the least stringent had estimated Reff reductions in the 10–50% range; those that examined so-called “lockdowns” were associated with greater Reff reductions that ranged from 40 to 90%, with many in the 70–80% range. While many studies reported on multiple NPIs, only six of the 61 studies explicitly used the framing of “stringency” or “mild versus strict” or “tiers” of NPIs, concepts that are highly relevant for decisionmakers.ConclusionExisting evidence suggests that NPIs reduce COVID-19 transmission by 40 to 90 percent. This paper documents the extent of the variation in NPI effectiveness estimates and highlights challenges presented by a lack of standardization in modeling approaches. Further research on NPI effectiveness at different stringency levels is needed to inform policy responses to future pandemics.

Summary: Adiponectin-based therapeutic strategies are promising for managing metabolic diseases and reducing inflammation, prompting the development of adiponectin receptor agonists. However, monitoring their pharmacodynamic actions in clinical applications is challenging. This study aimed to identify peripheral biomarkers to monitor adiponectin actions using ALY688, an adiponectin receptor agonist peptide. RNA sequencing analysis of whole blood identified a cluster of genes that were significantly increased in the ALY688-treated group compared to the control. This gene cluster was validated by qPCR and further confirmed in human peripheral blood mononuclear cells treated with ALY688 ex vivo. We also confirmed a functional outcome of ALY688 action in mice as our study also demonstrated the anti-inflammatory effect of ALY688 in a sublethal LPS mouse model. In summary, a newly identified gene cluster signature is suitable for assessing the pharmacodynamic action of adiponectin or its mimetics in blood samples.

Abstract Background Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children’s Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy. Methods SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy. Results The 62 SSADHD subjects [53% females, median (IQR) age of 9.6 (5.4–14.5) years] included in the study had a reported symptom onset at ∼ 6 months and were diagnosed at a median age of 4 years. Language developmental delays were more prominent than motor. Autism, epilepsy, movement disorders, sleep disturbances, and various psychiatric behaviors constituted the core of the disorder’s clinical phenotype. Lower clinical severity scores, indicating worst severity, coincided with older age (R= -0.302, p = 0.03), as well as age-adjusted lower values of plasma γ-aminobutyrate (GABA) (R = 0.337, p = 0.02) and γ-hydroxybutyrate (GHB) (R = 0.360, p = 0.05). While epilepsy and psychiatric behaviors increase in severity with age, communication abilities and motor function tend to improve. iPSCs, which were differentiated into GABAergic neurons, represent the first in vitro neuronal model of SSADHD and express the neuronal marker microtubule-associated protein 2 (MAP2), as well as GABA. GABA-metabolism in induced GABAergic neurons could be reversed using CRISPR correction of the pathogenic variants or mRNA transfection and SSADHD iPSCs were associated with excessive glutamatergic activity and related synaptic excitation. Conclusions Findings from the SSADHD Natural History Study converge with iPSC and animal model work focused on a common disorder within our IDDRC, deepening our knowledge of the pathophysiology and longitudinal clinical course of a complex neurodevelopmental disorder. This further enables the identification of biomarkers and changes throughout development that will be essential for upcoming targeted trials of enzyme replacement and gene therapy.

Abstract Background Pelvic organ prolapse is a debilitating condition impacting lives of millions of women worldwide. Sacrocolpopexy (SCP) is considered an effective and durable surgical technique for treatment of apical prolapse. The aim of this study was to compare short-term outcomes including postoperative complications and unanticipated healthcare encounters between patients who underwent SCP with a mini-laparotomy approach compared to patients treated with laparoscopic and robotic-assisted laparoscopic SCP. Methods This was a retrospective cohort study including patients treated for apical prolapse at a university affiliated urogynecology practice. Patients over the age of 18 who underwent abdominal SCP between 2019 and 2023 were included. The cohort was formed into two groups: (1) Patients who underwent SCP through a mini-laparotomy incision (Mini-lap group); (2) Patients who underwent laparoscopic or robotic-assisted laparoscopic SCP (Lap/Robot group). Results A total of 116 patients were included in the final analysis. Ninety patients underwent either laparoscopic or robotic-assisted SCP, whereas 26 patients underwent SCP with a mini-laparotomy approach. Study participants exhibited a mean age of 63.1 ± 10.3 years, mean body mass index (BMI) of 25.8 ± 4.9 Kg/m2, and 77.6% of them identified as Caucasian. Upon comparison of demographic and past medical history between groups there were no statistically significant differences in age, BMI, menopausal status, race, parity or comorbid conditions. Patients in the Mini-lap group were less likely to have undergone previous abdominal surgery (11.5% vs. 50.6%, p

Abstract Metabolic dysfunction‐associated steatohepatitis (MASH) is the severe form of non‐alcoholic fatty liver disease which has a high potential to progress to cirrhosis and hepatocellular carcinoma, yet adequate effective therapies are lacking. Hypoadiponectinemia is causally involved in the pathogenesis of MASH. This study investigated the pharmacological effects of adiponectin replacement therapy with the adiponectin‐derived peptide ALY688 (ALY688‐SR) in a mouse model of MASH. Human induced pluripotent stem (iPS) cell‐derived hepatocytes were used to test cytotoxicity and signaling of unmodified ALY688 in vitro. High‐fat diet with low methionine and no added choline (CDAHF) was used to induce MASH and test the effects of ALY688‐SR in vivo. Histological MASH activity score (NAS) and fibrosis score were determined to assess the effect of ALY688‐SR. Transcriptional characterization of mice through RNA sequencing was performed to indicate potential molecular mechanisms involved. In cultured hepatocytes, ALY688 efficiently induced adiponectin‐like signaling, including the AMP‐activated protein kinase and p38 mitogen‐activated protein kinase pathways, and did not elicit cytotoxicity. Administration of ALY688‐SR in mice did not influence body weight but significantly ameliorated CDAHF‐induced hepatic steatosis, inflammation, and fibrosis, therefore effectively preventing the development and progression of MASH. Mechanistically, ALY688‐SR treatment markedly induced hepatic expression of genes involved in fatty acid oxidation, whereas it significantly suppressed the expression of pro‐inflammatory and pro‐fibrotic genes as demonstrated by transcriptomic analysis. ALY688‐SR may represent an effective approach in MASH treatment. Its mode of action involves inhibition of hepatic steatosis, inflammation, and fibrosis, possibly via canonical adiponectin‐mediated signaling.

The links between chronic kidney disease (CKD) and cardiac conditions such as coronary heart disease or valvular disease are well established in the literature. However, the relationship between hypertrophic cardiomyopathy (HCM) and CKD is not as frequently described or researched. HCM is the most common form of inherited cardiac disease. It is mainly transmitted in an autosomal dominant fashion and caused by mutations in genes encoding sarcomere proteins. HCM is estimated to affect 0.2% of the general population and has an annual mortality rate of between approximately 0.5 and 1%. Our review article aims to summarize the genetics of HCM; discuss the potential clinical mimics that occur concurrently with HCM and CKD, potential interlinks that associate between these two conditions, the role of renal dysfunction as a poor prognostic indicator in HCM; and based on currently available evidence, recommend a management approach that may be suitable when clinicians are faced with this clinical scenario.

Abstract This study aims to develop an advanced mathematic model and investigate when and how will the COVID-19 in the US be evolved to endemic. We employed a nonlinear ordinary differential equations-based model to simulate COVID-19 transmission dynamics, factoring in vaccination efforts. Multi-stability analysis was performed on daily new infection data from January 12, 2021 to December 12, 2022 across 50 states in the US. Key indices such as eigenvalues and the basic reproduction number were utilized to evaluate stability and investigate how the pandemic COVD-19 will evolve to endemic in the US. The transmissional, recovery, vaccination rates, vaccination effectiveness, eigenvalues and reproduction numbers ( $${R}_{0}$$ R 0 and $${R}_{0}^{end}$$ R 0 end ) in the endemic equilibrium point were estimated. The stability attractor regions for these parameters were identified and ranked. Our multi-stability analysis revealed that while the endemic equilibrium points in the 50 states remain unstable, there is a significant trend towards stable endemicity in the US. The study's stability analysis, coupled with observed epidemiological waves in the US, suggested that the COVID-19 pandemic may not conclude with the virus's eradication. Nevertheless, the virus is gradually becoming endemic. Effectively strategizing vaccine distribution is pivotal for this transition.

Objective: To evaluate the ability of a neural network to identify severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using point-of-care electrocardiography obtained with a portable device. Patient and Methods: We enrolled 2827 patients in a prospective observational study, from December 10, 2020, through June 4, 2021, to determine the accuracy of a point-of-care, handheld, smartphone-compatible, artificial intelligence–enabled electrocardiography (ECG) (POC AI-ECG) in detecting asymptomatic SARS-CoV-2 infection using a modified version of an existing deep learning model framework trained on 12-lead ECG data. Results: Study participants were 48% (n=1067) female, 79% (n=1749) White, and 7% (n=153) endorsed previous COVID-19 infection. We found the POC AI-ECG algorithm was ineffective for detecting asymptomatic SARS-CoV-2 infection (area under curve, 0.56; 95% CI, 0.46-0.66), failing to adequately discriminate between ECGs performed among participants who tested positive compared to those who tested negative. Conclusion: Contrary to the prior 12-lead ECG study, a POC AI-ECG failed to reliably identify asymptomatic SARS-CoV-2 infection among adults. This study underscores the importance of prospective testing, assuring similar populations, and using similar signals or data when developing AI-ECG tools. Trial registration: clinicaltrials.gov Identifier: NCT04725097

The human gut microbiota constitutes a complex community of microorganisms residing within the gastrointestinal tract, encompassing a vast array of species that play crucial roles in health and disease. The disease processes involved in chronic kidney disease (CKD) and end-stage kidney disease (ESKD) are now increasingly established to result in dysregulation of gut microbiota composition and function. Gut microbiota dysbiosis has been associated with poor clinical outcomes and all-cause mortality in patients with ESKD, particularly individuals receiving dialysis. Prior studies highlighted various factors that affect gut microbiota dysbiosis in CKD and ESKD. These include, but are not limited to, uraemic toxin accumulation, chronic inflammation, immune dysfunction, medications, and dietary restrictions and nutritional status. There is a lack of studies at present that focus on the evaluation of gut microbiota dysbiosis in the context of dialysis. Knowledge on gut microbiota changes in this context is important for determining their impact on dialysis-specific and overall outcomes for this patient cohort. More importantly, evaluating gut microbiota composition can provide information into potential targets for therapeutic intervention. Identification of specific microbial signatures may result in further development of personalised treatments to improve patient outcomes and mitigate complications during dialysis. Optimising gut microbiota through various therapeutic approaches, including dietary adjustments, probiotics, prebiotics, medications, and faecal transplantation, have previously demonstrated potential in multiple medical conditions. It remains to be seen whether these therapeutic approaches are effective within the dialysis setting. Our review aims to evaluate evidence relating to alterations in the gut microbiota of patients undergoing dialysis. A growing body of evidence pointing to the complex yet significant relationship which surrounds gut microbiota and kidney health emphasises the importance of gut microbial balance to improve outcomes for individuals receiving dialysis.

Abstract Background To date, the association between retained placenta and treatment success rate of misoprostol for early pregnancy failure has yet to be evaluated. The aim of this study was to evaluate this association and further investigated the connection between medical, clinical and sonographic parameters and treatment success. Methods We conducted a retrospective cohort study of women with early pregnancy failure treated with misoprostol from 2006 to 2021. The success rate of misoprostol treatment was compared between patients with history of retained placenta including women who underwent manual lysis of the placenta following delivery or patients who were found to have retained products of conception during their post-partum period (study group) and patients without such history (controls). Demographic, clinical, and sonographic characteristics as well as treatment outcomes were compared between the groups. Results A total of 271 women were included in the study (34 women in the study group compared to 237 women in the control group). Two-hundred and thirty-three women (86.0%) presented with missed abortion, and 38 (14.0%) with blighted ovum. Success rates of misoprostol treatment were 61.8% and 78.5% for the study and control groups, respectively (p = 0.032). Univariate analysis performed comparing successful vs. failed misoprostol treatment showed advanced age, gravidity, parity and gestational sac size (mm) on TVUS were associated with higher misoprostol treatment failure rate. Following a multivariate logistic regression model these variables did not reach statistical significance. Conclusion Women who have an event of retained placenta following childbirth appear to have decreased success rate of treatment with misoprostol for early pregnancy failure. Larger studies are needed to confirm this finding.

Abstract Synaptogenesis is essential for circuit development; however, it is unknown whether it is critical for the establishment and performance of goal-directed voluntary behaviors. Here, we show that operant conditioning via lever-press for food reward training in mice induces excitatory synapse formation onto a subset of anterior cingulate cortex neurons projecting to the dorsomedial striatum (ACC→DMS). Training-induced synaptogenesis is controlled by the Gabapentin/Thrombospondin receptor α2δ−1, which is an essential neuronal protein for proper intracortical excitatory synaptogenesis. Using germline and conditional knockout mice, we found that deletion of α2δ−1 in the adult ACC→DMS circuit diminishes training-induced excitatory synaptogenesis. Surprisingly, this manipulation does not impact learning but results in a significant increase in effort exertion without affecting sensitivity to reward value or changing contingencies. Bidirectional optogenetic manipulation of ACC→DMS neurons rescues or phenocopies the behaviors of the α2δ−1 cKO mice, highlighting the importance of synaptogenesis within this cortico-striatal circuit in regulating effort exertion.

If one must prioritize among the vast array of contributing factors to cancer evolution, environmental-stress-mediated chromosome instability (CIN) should easily surpass individual gene mutations. CIN leads to the emergence of genomically unstable life forms, enabling them to grow dominantly within the stable life form of the host. In contrast, stochastic gene mutations play a role in aiding the growth of the cancer population, with their importance depending on the initial emergence of the new system. Furthermore, many specific gene mutations among the many available can perform this function, decreasing the clinical value of any specific gene mutation. Since these unstable life forms can respond to treatment differently than stable ones, cancer often escapes from drug treatment by forming new systems, which leads to problems during the treatment for patients. To understand how diverse factors impact CIN-mediated macroevolution and genome integrity–ensured microevolution, the concept of two-phased cancer evolution is used to reconcile some major characteristics of cancer, such as bioenergetic, unicellular, and multicellular evolution. Specifically, the spiral of life function model is proposed, which integrates major historical evolutionary innovations and conservation with information management. Unlike normal organismal evolution in the microevolutionary phase, where a given species occupies a specific location within the spiral, cancer populations are highly heterogenous at multiple levels, including epigenetic levels. Individual cells occupy different levels and positions within the spiral, leading to supersystems of mixed cellular populations that exhibit both macro and microevolution. This analysis, utilizing karyotype to define the genetic networks of the cellular system and CIN to determine the instability of the system, as well as considering gene mutation and epigenetics as modifiers of the system for information amplification and usage, explores the high evolutionary potential of cancer. It provides a new, unified understanding of cancer as a supersystem, encouraging efforts to leverage the dynamics of CIN to develop improved treatment options. Moreover, it offers a historically contingent model for organismal evolution that reconciles the roles of both evolutionary innovation and conservation through macroevolution and microevolution, respectively.

Introduction: Kidney transplantation is the preferred modality of kidney replacement therapy for eligible patients with end-stage kidney disease (ESKD), given that it has been found to reduce mortality rates, improve quality of life, and is cost-effective compared to dialysis. Recent advancements in human leukocyte antigen (HLA) typing and donor-specific antibody (DSA) detection have helped to reduce the risk of rejection, but antibody-mediated rejection (AMR) can still occur without DSA. Previous studies suggest that rejection can be attributed to antibodies against Non-Human Leucocyte Antigens (non-HLAs). We aimed to acquire further understanding of the prevalence and distribution of non-HLA antibodies in our local population and attempt to correlate these findings with graft outcomes, as well as assess whether non-HLA antibodies can be utilized to determine graft impairment and dysfunction. Methods: We conducted a retrospective study involving kidney transplant recipients between January 2010 and December 2020. All included individuals were aged over 18 and underwent kidney-alone transplants; were ABO- and HLA-compatible; and were matched at A, B, and DR loci (mismatch 0:0:0). HLA testing was negative at the time of transplantation. The samples from both cases of early graft rejection and the control group were tested for non-HLA antibodies using One Lambda LABScreenTM, Autoantibody kit groups 1, 2, and 3, as well as the Immucor LIFECODES non-HLA autoantibody assay. Results: A total of 850 kidney transplant recipients were included, in which 12 patients experienced early graft rejection within the first month post transplant and 18 patients who did not experience graft rejection were selected as study controls. Our study reported no correlation between the total burden of non-HLA antibodies and early rejection, most likely as the result of a small sample size. Nevertheless, a sub-analysis revealed that specific high-frequency pre-transplant non-HLA antibodies such as GSTT, CXCL11, CXCL10, and HNR, detected by LIFECODES, were associated with rejection (Fisher’s exact test with Bonferroni correction, p < 0.001). Most pre-transplant non-HLA antibody levels were reduced after transplantation, which was attributed to immunosuppression. Conclusion: The ‘high frequency’ non-HLA antibodies displayed an association with graft rejection, though the overall associations between the burden of non-HLA antibodies and rejection episodes remain inconclusive. Further work is needed to establish the rebound phenomenon of non-HLA antibodies, the development of de novo non-HLA antibodies in the long run, and their implications on graft survival.

The Woven EndoBridge (WEB) (MicroVention/Terumo) device is a treatment option for wideneck bifurcation aneurysms. An uncommon adverse effect is WEB device migration. While certain bailout strategies for WEB recovery have been described, there is still a paucity of information on optimal strategies to maximize both short and long-term post-operative outcomes. We add 2 cases at our institution to the existing literature of WEBectomy in the setting of complicated intracranial aneurysm treatment. We discuss the long-term imaging outcomes with additional fluoroscopy video demonstrating our technique. Our findings reflect a clear benefit for the use of the Amplatz GooseneckTM microsnare (Medtronic) device as a means of WEB recovery, coupled with potential stent-assisted WEB embolization to remove the aneurysm from the parent circulation, while minimizing recurrence and thromboembolic complications.

ABSTRACT Sphingolipids serve as vital structural and signaling components of the cell membranes in both eukaryotes and prokaryotes. Within the gut microbiome, Bacteroides species have been identified as major producers of sphingolipids, and Bacteroides-produced sphingolipids have been shown to be modulators of host immune and metabolic functions. While Bacteroides species are a prominent feature of the gut microbiomes of populations living in industrialized countries, Prevotella copri, a member of the same phyla, albeit a different family, is the dominant feature across the remainder of the global population, although their sphingolipid-producing capabilities have not been as thoroughly investigated. To fill this gap, we examined the genomes of over 60 diverse isolates of P. copri and identified several key enzymes involved in sphingolipid synthesis in P. copri. Combining bioorthogonal labeling and liquid chromatography-mass spectrometry (LC-MS) based lipidomics, we functionally characterized the first step in P. copri de novo sphingolipid synthesis in addition to profiling the sphingolipidomes of P. copri strains, identifying key enzymes that may play roles in producing a diverse set of P. copri sphingolipids. Given the limited genetic engineering tools amenable for use in P. copri, our approach takes advantage of comparative genomics and phenotypic profiling to explore sphingolipid production in these understudied, yet highly prevalent, organisms.IMPORTANCESphingolipids are important signaling molecules for maintaining metabolic and immune homeostasis in the host. These lipids are also produced by gut commensals, most notably by Bacteroides species. Despite the global prevalence of Prevotella copri in gut microbiomes of individuals, little is known about the types of sphingolipids they produce and whether they are similar in composition and structure to those produced by Bacteroides. Given the varied associations of P. copri with diverse sphingolipid-related health outcomes, such as rheumatoid arthritis and glucose intolerance, it is important to first characterize the specific sphingolipids produced by individual strains of P. copri and to identify the genes involved in their pathways of production. This characterization of P. copri-derived sphingolipids provides further insight into how bacterial sphingolipid production can serve as a mechanism for microbial modulation of host phenotypes.

Aims: Adiponectin has been shown to mediate cardioprotective effects and levels are typically reduced in patients with cardiometabolic disease. Hence, there has been intense interest in developing adiponectin-based therapeutics. The aim of this translational research study was to examine the functional significance of targeting adiponectin signaling with the adiponectin receptor agonist ALY688 in a mouse model of heart failure with reduced ejection fraction (HFrEF), and the mechanisms of cardiac remodeling leading to cardioprotection. Methods and results: Wild-type mice were subjected to transverse aortic constriction (TAC) to induce left ventricular pressure overload (PO), or sham surgery, with or without daily subcutaneous ALY688-SR administration. Temporal analysis of cardiac function was conducted via weekly echocardiography for 5 weeks and we observed that ALY688 attenuated the PO-induced dysfunction. ALY688 also reduced cardiac hypertrophic remodeling, assessed via LV mass, heart weight to body weight ratio, cardiomyocyte cross sectional area, ANP and BNP levels. ALY688 also attenuated PO-induced changes in myosin light and heavy chain expression. Collagen content and myofibroblast profile indicated that fibrosis was attenuated by ALY688 with TIMP1 and scleraxis/periostin identified as potential mechanistic contributors. ALY688 reduced PO-induced elevation in circulating cytokines including IL-5, IL-13 and IL-17, and the chemoattractants MCP-1, MIP-1β, MIP-1alpha and MIP-3α. Assessment of myocardial transcript levels indicated that ALY688 suppressed PO-induced elevations in IL-6, TLR-4 and IL-1β, collectively indicating anti-inflammatory effects. Targeted metabolomic profiling indicated that ALY688 increased fatty acid mobilization and oxidation, increased betaine and putrescine plus decreased sphingomyelin and lysophospholipids, a profile indicative of improved insulin sensitivity. Conclusion: These results indicate that the adiponectin mimetic peptide ALY688 reduced PO-induced fibrosis, hypertrophy, inflammation and metabolic dysfunction and represents a promising therapeutic approach for treating HFrEF in a clinical setting.

Objective: Hepatic steatosis is a key initiating event in the pathogenesis of alcohol-associated liver disease (ALD), the most detrimental organ damage resulting from alcohol use disorder. However, the mechanisms by which alcohol induces steatosis remain incompletely understood. We have previously found that alcohol binging impairs brain insulin action, resulting in increased adipose tissue lipolysis by unrestraining sympathetic nervous system (SNS) outflow. Here, we examined whether an impaired brain–SNS–adipose tissue axis drives hepatic steatosis through unrestrained adipose tissue lipolysis and increased lipid flux to the liver. Methods: We examined the role of lipolysis, and the brain–SNS–adipose tissue axis and stress in alcohol induced hepatic triglyceride accumulation in a series of rodent models: pharmacological inhibition of the negative regulator of insulin signaling protein-tyrosine phosphatase 1β (PTP1b) in the rat brain, tyrosine hydroxylase (TH) knockout mice as a pharmacogenetic model of sympathectomy, adipocyte specific adipose triglyceride lipase (ATGL) knockout mice, wildtype (WT) mice treated with β3 adrenergic agonist or undergoing restraint stress. Results: Intracerebral administration of a PTP1b inhibitor, inhibition of adipose tissue lipolysis and reduction of sympathetic outflow ameliorated alcohol induced steatosis. Conversely, induction of adipose tissue lipolysis through β3 adrenergic agonism or by restraint stress worsened alcohol induced steatosis. Conclusions: Brain insulin resistance through upregulation of PTP1b, increased sympathetic activity, and unrestrained adipose tissue lipolysis are key drivers of alcoholic steatosis. Targeting these drivers of steatosis may provide effective therapeutic strategies to ameliorate ALD.

Abstract Adoptive immune therapies based on the transfer of antigen-specific T cells have been used successfully to treat various cancers and viral infections, but improved techniques are needed to identify optimally protective human T cell receptors (TCRs). Here we present a high-throughput approach to the identification of natively paired human TCRα and TCRβ (TCRα:β) genes encoding heterodimeric TCRs that recognize specific peptide antigens bound to major histocompatibility complex molecules (pMHCs). We first captured and cloned TCRα:β genes from individual cells, ensuring fidelity using a suppression PCR. We then screened TCRα:β libraries expressed in an immortalized cell line using peptide-pulsed antigen-presenting cells and sequenced activated clones to identify the cognate TCRs. Our results validated an experimental pipeline that allows large-scale repertoire datasets to be annotated with functional specificity information, facilitating the discovery of therapeutically relevant TCRs.

Abstract Knowledge of factors associated with superior outcomes in women treated with urethral bulking agents for stress urinary incontinence (SUI) remains limited. The aim of this study was to examine associations between post‐treatment outcomes in women who had undergone polyacrylamide hydrogel injections for SUI, and physiological and self‐reported variables captured during pre‐treatment clinical evaluation. A cross‐sectional study was undertaken in female patients treated for SUI with polyacrylamide hydrogel injections by a single urologist between January 2012 and December 2019. Post‐treatment outcome data were gathered in July 2020 using the Patient Global Impression of Improvement (PGI‐I), Urinary Distress Inventory‐short form (UDI‐6), Incontinence Impact Questionnaire (IIQ7), and International Consultation on Incontinence Questionnaire Short Form (ICIQ SF). All other data were gathered from women's medical records including pre‐treatment patient‐reported outcomes. Associations between post‐treatment outcomes and pre‐treatment physiological and self‐reported variables were investigated using regression models. One hundred seven of the 123 eligible patients completed post‐treatment patient‐reported outcome measures. Mean age was 63.1 years (range 25–93 years), and median time between first injection and follow‐up was 51 months (inter‐quartile range 23.5–70 months). Fifty‐five (51%) women had a successful outcome based on PGI‐I scores. Women with type 3 urethral hypermobility pre‐treatment were more likely to report treatment success (PGI‐I). Poor bladder compliance pre‐treatment was associated with greater urinary distress, frequency and severity (UDI‐6 and ICIQ) post‐treatment. Older age was associated with worse urinary frequency and severity (ICIQ) post‐treatment. Associations between patient‐reported outcomes and time between first injection and follow‐up were trivial and not statistically significant. Severity of pre‐treatment incontinence impact (IIQ‐7) was associated with worse incontinence impact post‐treatment. Type 3 urethral hypermobility was associated with a successful outcome, whereas pre‐treatment incontinence impact, poor bladder compliance and older age were associated with poorer self‐reported outcomes. Long‐term efficacy appears to hold in those who responded to initial treatment.

Digital information storage capacity and biomedical technology advancements in recent decades have stimulated the maturity and popularization of “big data” in medicine. The value of utilizing big data as a diagnostic and prognostic tool has continued to rise given its potential to provide accurate and insightful predictions of future health events and probable outcomes for individuals and populations, which may aid early identification of disease and timely treatment interventions. Whilst the implementation of big data methods for this purpose is more well-established in specialties such as oncology, cardiology, ophthalmology, and dermatology, big data use in nephrology and specifically chronic kidney disease (CKD) remains relatively novel at present. Nevertheless, increased efforts in the application of big data in CKD have been observed over recent years, with aims to achieve a more personalized approach to treatment for individuals and improved CKD screening strategies for the general population. Considering recent developments, we provide a focused perspective on the current state of big data and its application in CKD and nephrology, with hope that its ongoing evolution and revolution will gradually identify more solutions to improve strategies for CKD prevention and optimize the care of patients with CKD.

After more than five decades, Moore’s Law for transistors is approaching the end of the international technology roadmap of semiconductors (ITRS). The fate of complementary metal oxide semiconductor (CMOS) architecture has become increasingly unknown. In this era, 3D transistors in the form of gate-all-around (GAA) transistors are being considered as an excellent solution to scaling down beyond the 5 nm technology node, which solves the difficulties of carrier transport in the channel region which are mainly rooted in short channel effects (SCEs). In parallel to Moore, during the last two decades, transistors with a fully depleted SOI (FDSOI) design have also been processed for low-power electronics. Among all the possible designs, there are also tunneling field-effect transistors (TFETs), which offer very low power consumption and decent electrical characteristics. This review article presents new transistor designs, along with the integration of electronics and photonics, simulation methods, and continuation of CMOS process technology to the 5 nm technology node and beyond. The content highlights the innovative methods, challenges, and difficulties in device processing and design, as well as how to apply suitable metrology techniques as a tool to find out the imperfections and lattice distortions, strain status, and composition in the device structures.

BackgroundDuring the COVID-19 pandemic, many healthcare workers faced extreme working conditions and were at higher risk of infection with the coronavirus. These circumstances may have led to mental health problems, such as anxiety, among healthcare workers. Most studies that examined anxiety among healthcare workers during the COVID-19 pandemic were cross-sectional and focused on the first months of the pandemic only. Therefore, this study aimed to investigate the longitudinal association between working in healthcare and anxiety during a long-term period (i.e., 18 months) of the COVID-19 pandemic.MethodsData were used from online questionnaires of the Lifelines COVID-19 prospective cohort with 22 included time-points (March 2020–November 2021). In total, 2,750 healthcare workers and 9,335 non-healthcare workers were included. Anxiety was assessed with questions from the Mini-International Neuropsychiatric Interview, and an anxiety sum score (0–7) was calculated. Negative binomial generalized estimating equations (GEE), adjusted for demographic, work and health covariates, were used to examine the association between working in healthcare and anxiety.ResultsAnxiety sum scores over time during the COVID-19 pandemic were similar for healthcare workers and non-healthcare workers. No differences between the anxiety sum scores of healthcare workers and non-healthcare workers were found [incidence rate ratio (IRR) = 0.97, 95% CI = 0.91–1.04].ConclusionThis study did not find differences between healthcare workers and non-healthcare in perceived anxiety during the COVID-19 pandemic.

Abstract Fish physical habitat models are a tool for guiding restoration efforts in lotic ecosystems, but often they overestimate restoration outcomes because currently they do not incorporate habitat connectivity. This persistent issue can, in extreme cases, result in little or no improvement to fish populations after the restoration, wasting valuable conservation resources. We present a case study where practitioners applied a fish habitat model for multiple life stages of gravel spawning fishes to a 52‐km stretch of the Iller River but did so at a microscale implementation by setting up a model based on cross sections with a maximum of 200 m distance from each other. This approach provided an opportunity to assess the connectivity of habitats for gravel spawning fishes, that is, European Grayling (Thymallus thymallus) and Common Nase (Chondrostoma nasus), integrating probabilities to find suitable habitats for all life‐history stages and seasonal movements. We used the assessed habitat estimates (availability of distinct habitat types within reaches defined by the 200 m cross sections) to calculate the minimum distance a fish would need to overcome to change from one habitat type into the other as it hypothetically ‘grew up’ from egg to full spawning adult. This approach can be interpreted as a life cycle habitat check as it considers all habitat types that are necessary to fulfil the life cycle of gravel spawning fishes including their size, distance and flow direction‐related orientation (e.g. larvae habitats only used when downstream of spawning areas). Our results show that the assumption of complete connectivity would require long movement distances for vulnerable life stages to find suitable habitat. This puts the high priority on the creation of migration corridors and passability of migration barriers in question. Without consideration of habitat types for all life stages of a species and their spatial context, restoration will not be successful. Shortly said: A perfect migration corridor does not necessarily provide habitat connectivity. We recommend the application of the habitat connectivity approach when predicting the effect of restoration measures and particularly setting the priority of measures for mitigation of fish migration.

PurposeWhile observational studies have identified obesity as a potential risk factor for gastric cancer, the causality remains uncertain. This study aimed to evaluate the causal relationship between obesity and gastric cancer and identify the shared molecular signatures linking obesity to gastric cancer.MethodsA two-sample Mendelian randomization (MR) analysis was conducted using the GWAS data of body fat percentage (exposure, n = 331,117) and gastric cancer (outcome, n = 202,308). Bioinformatics and meta-analysis of multi-omics data were performed to identify key molecules mediating the causality. The meta-analysis of the plasma/serum proteome included 1,662 obese and 3,153 gastric cancer patients. Obesity and gastric cancer-associated genes were identified using seven common gene ontology databases. The transcriptomic data were obtained from TCGA and GEO databases. The Bioinformatic findings were clinically validated in plasma from 220 obese and 400 gastric cancer patients across two hospitals. Finally, structural-based virtual screening (SBVS) was performed to explore the potential FDA-approved drugs targeting the identified mediating molecules.ResultsThe MR analysis revealed a significant causal association between obesity and gastric cancer (IVW, OR = 1.37, 95% CI:1.12-1.69, P = 0.0028), without pleiotropy or heterogeneity. Bioinformatic and meta-analysis of multi-omics data revealed shared TNF, PI3K-AKT, and cytokine signaling dysregulation, with significant upregulation of AKT1, IL-6, and TNF. The clinical study confirmed widespread upregulation of systemic inflammatory markers in the plasma of both diseases. SBVS identified six novel potent AKT1 inhibitors, including the dietary supplement adenosine, representing a potentially preventive drug with low toxicity.ConclusionObesity causally increases gastric cancer, likely mediated by persistent AKT1/IL-6/TNF upregulation. As a potential AKT1 inhibitor, adenosine may mitigate the obesity-to-gastric cancer transition. These findings could inform preventive drug development to reduce gastric cancer risk in obesity.

Modeling fish community responses to dam removal is an emerging field of study as dam removals become more common, but uncertainties concerning recovery time and community stability remain. In Europe, an EU-wide biodiversity strategy plans to restore around 25,000 km of rivers to free-flowing status, which emphasizes the importance of being able to predict fish community responses after dam removal. We developed a multi-species size spectrum model for a fish community in the Mörrum River in Sweden to identify possible outcomes after a dam was removed in 2020. Electrofishing monitoring before the dam removal was used to calibrate the model. We projected multiple scenarios into the future to explore patterns of community stability, individual species responses, and recovery time while varying parameters related to dam removal mortality, base resource rate change, and maximum recruitment change. We created 30 hypothetical scenarios using an abrupt change perspective (parameters are step-based) and 30 scenarios using a gradual change perspective (parameters are smooth). In both perspectives, dam removal mortality and a decreasing resource rate reduced community biomass and delayed recovery time compared to pre-dam removal conditions. Our results demonstrate that recovery from a dam removal scenario is not necessarily a benefit for all species. In scenarios where dam removal practices or dam failures cause high mortality events and sustained impacts on base trophic level resources, recovery of pre-removal biomass may take decades, while community stability may be unstable for twice that time-period. Our study shows that size spectrum models can be applied to dam removal scenarios to explore potential recovery outcomes, particularly from a risk avoidance perspective. A benefit of using such an approach is the relatively low data requirements needed to perform projections (e.g., present species, fish growth rates, relative fish abundance). Implementing this model in other river systems, particularly at the reach scale, can help river restoration and management assess tradeoffs associated with different habitat restoration approaches prior to committing to a dam removal plan.

Purpose: To determine the percentage of patients who report the ability to run 1 mile at various time points after arthroscopic and open shoulder surgery. Methods: We performed a retrospective review of prospectively collected data for all active-duty military patients aged 18 to 45 years who underwent shoulder surgery at a single institution over a 2-year period. The rehabilitation protocol discouraged running before 3 months, but all patients were able to return to unrestricted running at 3 months postoperatively. Patients were excluded if they lacked 1-year follow-up data. Parameters collected included demographic information and validated patient-reported outcome measures at the preoperative and short-term postoperative visits, as well as patients’ ability to run at least 1 mile postoperatively. Results: A total of 126 patients were identified who underwent shoulder surgery with return-to-running data. Compared with baseline, significant improvements in patient-reported outcomes were shown at 1 and 2 years postoperatively (P = .001). The percentage of patients reporting the ability to run 1 mile postoperatively was 59% at 3 months, 74% at 4.5 months, 79% at 6 months, 83% at 12 months, and 91% at 24 months. There was no significant difference in patients undergoing shoulder surgery for instability versus non-instability diagnoses or in patients undergoing open versus arthroscopic anterior stabilization. All 11 patients unable to return to running at final follow-up had chronic lower-extremity diagnoses limiting their running ability. Conclusions: Young military athletes undergoing arthroscopic and open shoulder surgery have a high rate of early return to running. Approximately 60% of patients report the ability to run 1 mile at 3 months postoperatively, and three-quarters of patients do so at 4.5 months. Age, sex, military occupation, underlying diagnosis or type of surgery did not influence the rate of return to running after shoulder surgery. Level of Evidence: Level IV, therapeutic case series.

The increasing prevalence of stimulant use disorder (StUD) involving methamphetamine and cocaine has been a growing healthcare concern in the United States. Cocaine usage is associated with atherosclerosis, systolic and diastolic dysfunction, and arrhythmias. Furthermore, approximately one of every four MIs is cocaine-induced among patients aged 18 to 45. Methamphetamine use has been associated with nerve terminal damage in the dopaminergic system resulting in impaired motor function, cognitive decline, and co-morbid psychiatric disorders. Current treatment options for StUD are extremely limited, and there are currently no FDA-approved pharmacotherapies. Behavioral interventions are considered first-line treatment; however, in a recent meta-analysis comparing behavioral treatment options for cocaine, contingency management programs provided the only significant reduction in use. Current evidence points to the potential of various neuromodulation techniques as the next best modality in treating StUD. The most promising evidence thus far has been transcranial magnetic stimulation which several studies have shown to reduce risk factors associated with relapse. Another more invasive neuromodulation technique being studied is deep-brain stimulation, which has shown promising results in its ability to modulate reward circuits to treat addiction. Results showing the impact of transcranial magnetic stimulation (TMS) in the treatment of StUD are limited by the lack of studies conducted and the limited understanding of the neurological involvement driving addiction-based diseases such as StUD. Future studies should seek to provide data on consumption-reducing effects rather than craving evaluations.

Objective: To develop a simple, interpretable value metric (VM) to assess the value of care of hospitals for specific procedures or conditions by operationalizing the value equation: Value = Quality/Cost. Patients and Methods: The present study was conducted on a retrospective cohort from 2015 to 2018 drawn from the 100% US sample of Medicare inpatient claims. The final cohort comprised 637,341 consecutive inpatient encounters with a cancer-related Medicare Severity-Diagnosis Related Grouping and 13,307 consecutive inpatient encounters with the International Classification of Diseases, Ninth Revision or International Classification of Diseases, Tenth Revision procedure code for partial or total gastrectomy. Claims-based demographic and clinical variables were used for risk adjustment, including age, sex, year, dual eligibility, reason for Medicare entitlement, and binary indicators for each of the Elixhauser comorbidities used in the Elixhauser mortality index. Risk-adjusted 30-day mortality and risk-adjusted encounter-specific costs were combined to form the VM, which was calculated as follows: number needed to treat = 1/(Mortalitynational − Mortalityhospital), and VM = number needed to treat × risk-adjusted cost per encounter. Results: Among hospitals with better-than-average 30-day cancer mortality rates, the cost to prevent 1 excess 30-day mortality for an inpatient cancer encounter ranged from $71,000 (best value) to $1.4 billion (worst value), with a median value of $543,000. Among hospitals with better-than-average 30-day gastrectomy mortality rates, the cost to prevent 1 excess 30-day mortality for an inpatient gastrectomy encounter ranged from $710,000 (best value) to $95 million (worst value), with a median value of $1.8 million. Conclusion: This simple VM may have utility for interpretable reporting of hospitals’ value of care for specific conditions or procedures. We found substantial inter- and intrahospital variation in value when defined as the costs of preventing 1 excess cancer or gastrectomy mortality compared with the national average, implying that hospitals with similar quality of care may differ widely in the value of that care.

Peritonitis is a common and potentially serious complication of peritoneal dialysis (PD). Common organisms include Staphylococcus Aureus, enterococci, and coagulase-negative staphylococcus. However, Stenotrophomonas maltophilia (S. maltophilia) is an uncommon cause of PD-related infection. We describe a series of three cases of S. maltophilia PD infection (two cases of PD peritonitis and one case of PD exit-site infection) that were identified over a seven-week period in a single centre. The cases were treated with antibiotics (the primary antibiotic being co-trimoxazole) for a mean duration of 30 ± 7.9 days. All of the patients required PD catheter removal due to treatment failure with antibiotics. Hospital admission was required in two of the cases and one case resulted in mortality, with the cause of death directly associated with complications from S. maltophilia infection. A multi-disciplinary team using root-cause analysis did not identify a common link between our cases but highlighted possible risk factors contributing to these presentations. Given the relative rarity of S. maltophilia, evidence on its management options remains limited. In this article, we draw upon our own experiences and examine the literature available from previously published case reports and series. These reports highlight S. maltophilia as a complex and challenging organism to treat. Our experience demonstrated the importance of early PD catheter removal in S. maltophilia PD infection, as this is likely more effective than prolonged antibiotic therapy and hence a safer management option, considering the resistant nature of S. maltophilia.

Merkel cell carcinoma (MCC) is an uncommon form of skin neoplasm with poor histological differentiation and an aggressive disease process, leading to high recurrence and mortality. There are multiple risk factors in which being in an immunocompromised state is a significant factor, and the discovery of Merkel cell polyomavirus (MCPyV) since 2008 has strengthened causal associations between MCC and immunosuppression. Individuals who have undergone kidney transplantation are therefore more susceptible to having MCC, secondary to post-transplant immunosuppression which plays a vital role in reducing the risk of transplant kidney rejection. Over recent years a rise in the incidence of MCC following kidney transplantation is noted, with increased reporting of such cases. Whilst localized MCC is observed, MCC metastasis to the lymphatic system, brain, bone, liver, lung, and heart has been previously observed in patients with transplanted kidneys. Kidney metastasis is less common and has been only reported in recent years with greater frequency. The management of aggressive, metastatic MCC has historically been palliative, and prognosis is poor. Recently, the use of immune checkpoint inhibitors for metastatic MCC in multi-center phase II clinical trials have shown promising survival outcomes and have been approved for use in countries such as the United States as a first-line treatment. In this review we will explore the potential pathophysiological processes of MCC manifesting post-kidney transplantation. We will then evaluate the epidemiology of MCC within the context of kidney transplantation, before discussing the various clinical presentations, diagnostic measures, surveillance strategies, and current treatment options as well as future directions to best manage MCC in kidney transplant recipients.

Background: Prostate-specific membrane antigen (PSMA) positron emission tomography/computerised tomography (PET/CT) is increasingly being utilised in the diagnostic pathway for prostate cancer (PCa). Recent publications have suggested that this might help identify those who can avoid biopsy. Objective: The primary objective of this study was to determine whether PET magnetic resonance imaging (MRI) fusion could negate the need to biopsy prior to prostatectomy in a selected population of men. Design, setting, and participant: Multiparametric MRI (mpMRI) for PCa is our standard of care prior to prostate biopsy. Biopsy-naïve men with one or more Prostate Imaging Reporting and Data System (PI-RADS) 4 or 5 lesions ≥10 mm on mpMRI were invited to undergo PSMA PET/CT prior to biopsy. Following ethics approval, 60 men were recruited between September 2020 and March 2021. The key exclusion criteria included a previous history of PCa and previous prostate surgery or biopsy. Outcome measurements and statistical analysis: A positive PET MRI fusion scan was defined as “consistent with” as per the Memorial Sloan Kettering Cancer Center lexicon of certainty, and concordance with biopsy results was analysed. Clinically significant PCa (csPCa) was defined as grade group (GG) ≥2 on pathology. A chi-square analysis was performed with statistical significance defined at p

Objective: To estimate rates and identify factors associated with asymptomatic COVID-19 in the population of Olmsted County during the prevaccination era. Patients and Methods: We screened first responders (n=191) and Olmsted County employees (n=564) for antibodies to SARS-CoV-2 from November 1, 2020 to February 28, 2021 to estimate seroprevalence and asymptomatic infection. Second, we retrieved all polymerase chain reaction (PCR)-confirmed COVID-19 diagnoses in Olmsted County from March 2020 through January 2021, abstracted symptom information, estimated rates of asymptomatic infection and examined related factors. Results: Twenty (10.5%; 95% CI, 6.9%-15.6%) first responders and 38 (6.7%; 95% CI, 5.0%-9.1%) county employees had positive antibodies; an additional 5 (2.6%) and 10 (1.8%) had prior positive PCR tests per self-report or medical record, but no antibodies detected. Of persons with symptom information, 4 of 20 (20%; 95% CI, 3.0%-37.0%) first responders and 10 of 39 (26%; 95% CI, 12.6%-40.0%) county employees were asymptomatic. Of 6020 positive PCR tests in Olmsted County with symptom information between March 1, 2020, and January 31, 2021, 6% (n=385; 95% CI, 5.8%-7.1%) were asymptomatic. Factors associated with asymptomatic disease included age (0-18 years [odds ratio {OR}, 2.3; 95% CI, 1.7-3.1] and >65 years [OR, 1.40; 95% CI, 1.0-2.0] compared with ages 19-44 years), body mass index (overweight [OR, 0.58; 95% CI, 0.44-0.77] or obese [OR, 0.48; 95% CI, 0.57-0.62] compared with normal or underweight) and tests after November 20, 2020 ([OR, 1.35; 95% CI, 1.13-1.71] compared with prior dates). Conclusion: Asymptomatic rates in Olmsted County before COVID-19 vaccine rollout ranged from 6% to 25%, and younger age, normal weight, and later tests dates were associated with asymptomatic infection.

Background: There is limited information on return to shooting following shoulder surgery. The purpose of this study is to determine the rate and timing for resuming shooting a rifle following shoulder surgery. Methods: We performed a retrospective review of prospectively collected data. The study included patients undergoing arthroscopic and open shoulder stabilization for unidirectional shoulder instability, and arthroscopic surgery for rotator cuff tears, SLAP lesions, biceps tendinopathy, and acromioclavicular pathology. Data collected included the laterality of surgery, shooting dominance, and patient-reported outcome measures at the preoperative and postoperative visits. Starting at the 4.5-month clinic visit, patients were asked if they could shoot a military rifle. Results: One hundred patients were identified with arthroscopic and open shoulder surgery with a mean age of 30 years (range, 18-45) and a mean follow-up of 24 months (range, 12-32). The cohort consisted of patients undergoing arthroscopic Bankart repair (n = 23), arthroscopic posterior labral repair (n = 18), open Latarjet (n = 16), mini-open subpectoral biceps tenodesis (OBT) (n = 25), OBT with open distal clavicle resection (DCR) (n = 10), open DCR (n = 4), and arthroscopic rotator cuff repair with concomitant OBT (n = 4). Significant improvement in SSV, VAS, ASES, and WOSI was shown at 1-year postoperative, SSV 85, VAS 2, ASES 85, WOSI 239, P = .001. The percentage of patients reporting the ability to shoot a military rifle postoperatively were 47%, 63%, 85%, and 94% at 4.5 months, 6 months, 1 year, and 2 years, respectively. At 4.5 months postoperatively, patients who underwent surgery ipsilateral to their shooting dominance (n = 59) had a rate of return to shooting (33%) versus shoulder surgery on the contralateral side of shooting dominance (n = 41) (60%), P = .04. However, there was no significant difference in the groups at 6 months and 1 year. Additionally, there was a significant difference in the rate of return to shooting at 6 months in patients undergoing arthroscopic posterior labral repair versus the remainder of the cohort (posterior instability (33%) vs. (69%), P = .016), and a significant difference between posterior shoulder stabilization and anterior shoulder stabilization (70%), P = .03. Conclusion: Patients undergoing arthroscopic and open shoulder surgery have a high rate of return to shooting. Approximately 60% of patients resume shooting at 6 months postoperatively and 85% return at 1 year. Patients undergoing shoulder surgery on the contralateral side of their shooting dominance return to shooting significantly faster than those with shoulder surgery ipsilateral to their shooting dominance. Additionally, those undergoing arthroscopic posterior shoulder stabilization return to shooting at a slower rate than anterior stabilization surgery.

Symptoms of fatigue, social withdrawal and mood disturbances are commonly encountered in patients with chronic liver disease and have a detrimental effect on patient quality of life. Treatment options for these symptoms are limited and a current area of unmet medical need. In this review, we will evaluate the potential mechanistic avenues within the gut-liver-brain axis that may be altered in the setting of chronic liver disease that drive the development of these symptoms. Both clinical and pre-clinical studies will be highlighted as we discuss how perturbations in host immune response, microbiome, neural responses, and metabolites composition can affect the central nervous system.

Summary: Neurogenesis and differentiation of neural stem cells (NSCs) are controlled by cell-intrinsic molecular pathways that interact with extrinsic signaling cues. In this study, we identify a circuit that regulates neurogenesis and cell proliferation in the lateral ventricle-subventricular zone (LV-SVZ). Our results demonstrate that direct glutamatergic projections from the anterior cingulate cortex (ACC), as well as inhibitory projections from calretinin+ local interneurons, modulate the activity of cholinergic neurons in the subependymal zone (subep-ChAT+). Furthermore, in vivo optogenetic stimulation and inhibition of the ACC-subep-ChAT+ circuit are sufficient to control neurogenesis in the ventral SVZ. Both subep-ChAT+ and local calretinin+ neurons play critical roles in regulating ventral SVZ neurogenesis and LV-SVZ cell proliferation.

Clostridioides difficile (C. difficile) is a bacterial organism that typically infects the colon, which has had its homeostasis of healthy gut microbiota disrupted by antibiotics or other interventions. Patients with kidney transplantation are a group that are susceptible to C. difficile infection (CDI) and have poorer outcomes with CDI given that they conventionally require long-term immunosuppression to minimize their risk of graft rejection, weakening their responses to infection. Recognizing the risk factors and complex pathophysiological processes that exist between immunosuppression, dysbiosis, and CDI is important when making crucial clinical decisions surrounding the management of this vulnerable patient cohort. Despite the clinical importance of this topic, there are few studies that have evaluated CDI in the context of kidney transplant recipients and other solid organ transplant populations. The current recommendations on CDI management in kidney transplant and solid organ transplant recipients are mostly extrapolated from data relating to CDI management in the general population. We provide a narrative review that discusses the available evidence examining CDI in solid organ transplant recipients, with a particular focus on the kidney transplant recipient, from the epidemiology of CDI, clinical features and implications of CDI, potential risk factors of CDI, and, ultimately, prevention and management strategies for CDI, with the aim of providing areas for future research development in this topic area.

We present the Citizen Science program Active Asteroids and describe discoveries stemming from our ongoing project. Our NASA Partner program is hosted on the Zooniverse online platform and launched on 2021 August 31, with the goal of engaging the community in the search for active asteroids—asteroids with comet-like tails or comae. We also set out to identify other unusual active solar system objects, such as active Centaurs, active quasi-Hilda asteroids (QHAs), and Jupiter-family comets (JFCs). Active objects are rare in large part because they are difficult to identify, so we ask volunteers to assist us in searching for active bodies in our collection of millions of images of known minor planets. We produced these cutout images with our project pipeline that makes use of publicly available Dark Energy Camera data. Since the project launch, roughly 8300 volunteers have scrutinized some 430,000 images to great effect, which we describe in this work. In total, we have identified previously unknown activity on 15 asteroids, plus one Centaur, that were thought to be asteroidal (i.e., inactive). Of the asteroids, we classify four as active QHAs, seven as JFCs, and four as active asteroids, consisting of one main-belt comet (MBC) and three MBC candidates. We also include our findings concerning known active objects that our program facilitated, an unanticipated avenue of scientific discovery. These include discovering activity occurring during an orbital epoch for which objects were not known to be active, and the reclassification of objects based on our dynamical analyses.

Anemia in chronic kidney disease (CKD) has become an important clinical issue with the increased prevalence of elderly patients living with CKD progressing to kidney failure. The causes of anemia in elderly individuals tend to be multifactorial, exacerbated by the physiological effects of aging, frailty and declining kidney function. Erythropoiesis-stimulating agents (ESAs) are the conventional therapeutic option for anemia in CKD. However, ESA hyporesponsiveness is a commonly observed issue in clinical practice and an issue that is more challenging to resolve in elderly patients living with frailty, kidney disease, and multi-morbidities. Following the emergence of oral hypoxia-induced factor prolyl-hydroxylase inhibitors (HIF-PHI) in recent years, there is discussion on whether it is a solution to the conundrum of ESA hyporesponsiveness, as HIF-PHI treats anemia via an alternative physiological pathway. There remains uncertainty on the suitability of HIF-PHI use in elderly patients, given a lack of data on its safety over long-term follow-up for the elderly population. Further study is needed to provide answers, considering the clinical significance of this issue within a public-health scale.

Abstract The purpose of this study was to compare swing time and golf club angle parameters during golf swings using three, two dimensional (2D) low cost, Augmented-Video-based-Portable-Systems (AVPS) (Kinovea, SiliconCoach Pro, SiliconCoach Live). Twelve right-handed golfers performed three golf swings whilst being recorded by a high-speed 2D video camera. Footage was then analysed using AVPS-software and the results compared using both descriptive and inferential statistics. There were no significant differences for swing time and the golf phase measurements between the 2D and 3D software comparisons. In general, the results showed a high Intra class Correlation Coefficient (ICC > 0.929) and Cronbach’s Coefficient Alpha (CCA > 0.924) reliability for both the kinematic and temporal parameters. The inter-rater reliability test for the swing time and kinematic golf phase measurements on average were strong. Irrespective of the AVPS software investigated, the cost effective AVPS can produce reliable output measures that benefit golf analyses.

Chronic kidney disease-associated pruritus (CKDaP) is an often under-diagnosed and under-recognized condition, despite its considerable prevalence within the chronic kidney disease (CKD) population. Universally accepted guidelines are also lacking. The true prevalence of CKDaP worldwide therefore remains unknown, although its negative impact on mortality and health-related quality of life outcomes is very clear. The pathophysiological mechanisms leading to the onset of CKDaP are only partly understood. CKDaP is currently believed to be caused by a multifactorial process, from local skin changes, metabolic alterations, the development of neuropathy and dysregulation of opioid pathways, and psychological factors. Much work has been carried out towards a more systematic and structured approach to clinical diagnosis. Various tools are now available to assess the severity of CKDaP. Many of these tools require greater validation before they can be incorporated into the guidelines and into routine clinical practice. Further efforts are also needed in order to increase the awareness of clinicians and patients so that they can identify the CKDaP signs and symptoms in a timely manner. Currently established treatment options for CKDaP focus on the prevention of xerosis via topical emollients, the optimization of dialysis management, early referral to kidney transplantation if appropriate, oral antihistamine, and a variety of neuropathic agents. Other novel treatment options include the following: topical analgesics, topical tacrolimus, cannabinoid-containing compounds, antidepressants, oral leukotrienes, opioids, and non-pharmacological alternative therapies (i.e., phototherapy, dietary supplements, acupuncture/acupressure). We provide an updated review on the evidence relating to the epidemiology, the pathophysiology, the clinical assessment and diagnosis, and the management of CKDaP.

Abstract This study aimed to evaluate the efficacy of 18-month 0.01% atropine in 61 myopic children (aged 7–10) and the relationship with central retinal response (by multifocal electroretinogram [mfERG]) in a double-masked randomized placebo-controlled clinical trial. Global-flash mfERG was measured at baseline, while cycloplegic spherical equivalent refraction (SER) and axial length (AL) were measured at baseline and at 6-month intervals. Annualized change in SER and AL were compared between atropine and control groups, and the relationships with baseline mfERG were evaluated. Changes in SER (−0.70 ± 0.39D vs. −0.66 ± 0.41D, p = 0.63) and AL (0.32 ± 0.16 mm vs. 0.30 ± 0.22 mm, p = 0.52) were similar in atropine and control groups. Interestingly, in the placebo group, mfERG amplitude was negatively correlated with axial elongation (Rp = −0.44, p = 0.03) as in our previous study. However, in the atropine group, an opposite trend was observed that axial elongation was positively correlated with mfERG amplitude (Ra = 0.37, p = 0.04). Annualized myopia progression demonstrated similar opposite effect between atropine and placebo groups but did not reach statistical significance. An ERG screening protocol may be warranted to identify suitable candidates to reduce the likelihood of an unfavorable treatment response by 0.01% atropine.

Animals can learn to repeat behaviors to earn desired rewards, a process commonly known as reinforcement learning. While previous work has implicated the ascending dopaminergic projections to the basal ganglia in reinforcement learning, little is known about the role of the hippocampus. Here, we report that a specific population of hippocampal neurons and their dopaminergic innervation contribute to operant self-stimulation. These neurons are located in the dentate gyrus, receive dopaminergic projections from the locus coeruleus, and express D1 dopamine receptors. Activation of D1 + dentate neurons is sufficient for self-stimulation: mice will press a lever to earn optogenetic activation of these neurons. A similar effect is also observed with selective activation of the locus coeruleus projections to the dentate gyrus, and blocked by D1 receptor antagonism. Calcium imaging of D1 + dentate neurons revealed significant activity at the time of action selection, but not during passive reward delivery. These results reveal the role of dopaminergic innervation of the dentate gyrus in supporting operant reinforcement.

Commercial airline cockpit crew (CCC) are potentially exposed to occupational risk factors that may have detrimental health effects. However, available literature on prostate cancer (PCa) as a health outcome is conflicted. Therefore, this review of cohort studies aims to evaluate the incidence of and mortality from PCa in CCC based on studies published to date. PubMed, Medline, EMBASE and SCOPUS were searched from 1946 to April 2021. Cohort studies reporting standardized incidence ratios (SIR) and/or standardized mortality ratios (SMR) of PCa in CCC were included. Military, cabin crew and service personnel data were excluded. Independent data extraction was conducted, and study quality assessed. Standardized ratios were pooled using a fixed effects model and expressed with 95% confidence intervals. 75 studies were assessed for eligibility from which 6 involving 129 374 licensed CCC were included in the final analysis: Two reported incidence only, 1 incidence and mortality and 3 reported mortalities only. The pooled SIR for PCa in CCC was 1.41 (95% CI 1.17 to 1.71) with moderate heterogeneity (I2 = 53%) however, the pooled SMR was not statistically significant (1.08; 95% CI 0.94 to 1.24) also with moderate heterogeneity (I2 = 70%). The available evidence shows that CCC are at a higher risk of developing PCa but there is no evidence to suggest a similarly higher risk of death from the disease. The effect of early detection through PSA testing in this cohort is unclear. Occupational exposure to radiation and sleep disturbance may play a role, but clear evidence of additional risk is lacking. Our review indicates that most evidence is dated and to confidently assess contemporary health outcomes of CCC, further research is required.

Abstract The worldwide COVID-19 pandemic caused by the SARS-CoV-2 betacoronavirus has highlighted the need for a synthetic biology approach to create reliable and scalable sources of viral antigen for uses in diagnostics, therapeutics and basic biomedical research. Here, we adapt plasmid-based systems in the eukaryotic microalgae Phaeodactylum tricornutum to develop an inducible overexpression system for SARS-CoV-2 proteins. Limiting phosphate and iron in growth media induced expression of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein from the P. tricornutum HASP1 promoter in the wild-type strain and in a histidine auxotrophic strain that alleviates the requirement for antibiotic selection of expression plasmids. The RBD was purified from whole cell extracts (algae-RBD) with yield compromised by the finding that 90–95% of expressed RBD lacked the genetically encoded C-terminal 6X-histidine tag. Constructs that lacked the TEV protease site between the RBD and C-terminal 6X-histidine tag retained the tag, increasing yield. Purified algae-RBD was found to be N-linked glycosylated by treatment with endoglycosidases, was cross-reactive with anti-RBD polyclonal antibodies, and inhibited binding of recombinant RBD purified from mammalian cell lines to the human ACE2 receptor. We also show that the algae-RBD can be used in a lateral flow assay device to detect SARS-CoV-2 specific IgG antibodies from donor serum at sensitivity equivalent to assays performed with RBD made in mammalian cell lines. Our study shows that P. tricornutum is a scalable system with minimal biocontainment requirements for the inducible production of SARS-CoV-2 or other coronavirus antigens for pandemic diagnostics.

Abstract Background West Virginia has one of the highest rates of opioid overdose related deaths and is known as the epicenter of the opioid crisis in the United States. In an effort to reduce opioid-related harms, SB 273 was signed in 2018, and aimed to restrict opioid prescribing in West Virginia. SB 273 was enacted during a time when physician arrests and convictions had been increasing for years and were becoming more prevalent and more publicized. This study aims to better understand the impact of the legislation on patients and providers. Methods Twenty semi-structured interviews were conducted with opioid-prescribing primary care physicians and specialists practicing throughout West Virginia. Results Four themes emerged, 1. Fear of disciplinary action, 2. Exacerbation of opioid prescribing fear due to restrictive legislation, 3. Care shifts and treatment gaps, and 4. Conversion to illicit substances. The clinicians recognized the harms of inappropriate prescribing and how this could affect their patients. Decreases in opioid prescribing were already occurring prior to the law implementation. Disciplinary actions against opioid prescribers resulted in prescriber fear, which was then exacerbated by SB 273 and contributed to shifts in care that led to forced tapering and opioid under-prescribing. Providers felt that taking on patients who legitimately required opioids could jeopardize their career. Conclusion A holistic and patient-centered approach should be taken by legislative and disciplinary bodies to ensure patients are not abandoned when disciplinary actions are taken against prescribers or new legislation is passed.