Multiple sclerosis disease activity, a multi-biomarker score of disease activity and response to treatment in multiple sclerosis.

Regular assessment of disease activity in relapsing-remitting multiple sclerosis (RRMS) is required to optimize clinical outcomes. Biomarkers can be a valuable tool for measuring disease activity in multiple sclerosis (MS) if they reflect the pathological processes underlying MS pathogenicity. In this pilot study, we combined multiple biomarkers previously analyzed in RRMS patients into an MS disease activity (MSDA) score to evaluate their ability to predict relapses and treatment response to glatiramer acetate (GA). Response Gene to Complement 32 (RGC-32), FasL, IL-21, SIRT1, phosphorylated SIRT1 (p-SIRT1), and JNK1 p54 levels were used to generate cut-off values for each biomarker. Any value below the cutoff for RGC-32, FasL SIRT1, or p-SIRT1 or above the cutoff for IL-21 or JNK1 p54 was given a +1 value, indicating relapse or lack of response to GA. Any value above the cutoff value for RGC-32, FasL, SIRT1, p-SIRT1 or below that for IL-21 or JNK1 p54 was given a -1 value, indicating clinical stability or response to GA. An MSDA score above +1 indicated a relapse or lack of response to treatment. An MSDA score below -1 indicated clinical stability or response to treatment. Our results showed that the MSDA scores generated using either four or six biomarkers had a higher sensitivity and specificity and significantly correlated with the expanded disability status scale. Although these results suggest that the MSDA test can be useful for monitoring therapeutic response to biologic agents and assessing clinically challenging situations, the present findings need to be confirmed in larger studies.

Synthesis of a 3D Flower-Like BiOCl/Bi-MOF Heterostructure for High-Performance Removal of Rhodamine B and Tetracycline Hydrochloride.

Semiconductor materials based on bismuth metal have been extensively explored for their potential in photocatalytic applications owing to their distinctive crystal structure. Herein, we present the development of a hybrid photocatalyst, CAU-17/BiOCl, featuring a flower-like nanosheet morphology tailored for the photocatalytic degradation of organic contaminants such as rhodamine B (RhB) and tetracycline hydrochloride (TCH). The composite material is obtained by growing thin CAU-17 layers directly onto the host flower-like BiOCl nanosheets under solvothermal conditions. The optimized CAU-17/BiOCl composite possesses excellent photocatalytic performance, achieving a notable 96.0% removal rate for RhB and 78.4% for TCH after 60 and 90 min of LED light irradiation, respectively. This boosted activity is attributed to the heightened absorption of visible light caused by BiOCl and the provision of additional reaction sites due to the thin CAU-17 layers. Furthermore, the establishment of an S-scheme heterojunction mechanism enables efficient charge separation between CAU-17 and BiOCl, facilitating the separation of photoinduced electrons (e-) and holes (h+). Analysis of the degradation mechanism of RhB and TCH reveals the predominant role of superoxide radicals (•O2-), e-, and h+ in the photocatalytic degradation process. Moreover, the removal efficiency of TCH can reach approximately 64.5% after four cycles of recycling of CAU-17/BiOCl. Our work provides a facile, effective solution and a theoretically explained approach for the effective degradation of pollutants using heterojunction photocatalysts.

RGC-32 mediates proinflammatory and profibrotic pathways in immune-mediated kidney disease.

Systemic lupus erythematosus is an autoimmune disease that results in immune-mediated damage to kidneys and other organs. We investigated the role of response gene to complement-32 (RGC-32), a proinflammatory and profibrotic mediator induced by TGFß and C5b-9, in nephrotoxic nephritis (NTN), an experimental model that mimics human lupus nephritis. Proteinuria, loss of renal function and kidney histopathology were attenuated in RGC-32 KO NTN mice. RGC-32 KO NTN mice displayed downregulation of the CCL20/CCR6 and CXCL9/CXCR3 ligand/receptor pairs resulting in decreased renal recruitment of IL-17+ and IFNγ+ cells and subsequent decrease in the influx of innate immune cells. RGC-32 deficiency attenuated renal fibrosis as demonstrated by decreased deposition of collagen I, III and fibronectin. Thus, RGC-32 is a unique mediator shared by the Th17 and Th1 dependent proinflammatory and profibrotic pathways and a potential novel therapeutic target in the treatment of immune complex mediated glomerulonephritis such as lupus nephritis.

Regional wall motion abnormalities in transthoracic echocardiography in patients with significant coronary artery disease and coronary collateral circulation in adults.

BACKGROUND: Coronary collateral circulation is a common finding in patients with chronic total occlusions (CTOs) resulting from chronic coronary artery disease (CAD). Regional wall motion abnormalities (RWMA) on transthoracic echocardiography (TTE) can be used for the diagnosis of CAD. However, little work has been done to investigate the impact of collateral vessels on the diagnostic accuracy of resting TTE for CAD. METHODS: A retrospective chart review was conducted of adults who received a resting TTE and cardiac catheterization within 30 days over a 4-year period at the Temple Baylor Scott & White echocardiography laboratory. Exclusion criteria included catheterization without coronary angiography and prior history of CAD, percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG). We analyzed RWMA on TTE in patients with CAD and coronary collateral circulation on cardiac catheterization to assess for correlation. RESULTS: Of the 753 patients were included in this study, 453 had CAD, 272 had both CAD and RWMA, 111 had collateral circulation, and 73 had collateral circulation and RWMA. There was no significant difference in RWMA in patients with CAD with and without collateral circulation. There was no significant difference in the sensitivity (60.0 % vs 59.2 %) and specificity (78.4 % vs 73.9 %) after collateral-adjusted interpretation of RWMA and CAD (p = 0.3). DISCUSSION: Our results suggest the average coronary collateral system is of insufficient clinical significance to prevent the development of RWMA on resting TTE.

The landscape of liver transplantation for patients with alcohol-associated liver disease in the United States.

Indications for liver transplants have expanded to include patients with alcohol-associated liver disease (ALD) over the last decade. Concurrently, the liver allocation policy was updated in February 2020 replacing the Donor Service Area with Acuity Circles (ACs). The aim is to compare the transplantation rate, waitlist outcomes, and posttransplant survival of candidates with ALD to non-ALD and assess differences in that effect after the implementation of the AC policy. Scientific Registry for Transplant Recipients data for adult candidates for liver transplant were reviewed from the post-AC era (February 4, 2020-March 1, 2022) and compared with an equivalent length of time before ACs were implemented. The adjusted transplant rates were significantly higher for those with ALD before AC, and this difference increased after AC implementation (transplant rate ratio comparing ALD to non-ALD = 1.20, 1.13, 1.61, and 1.32 for the Model for End-Stage Liver Disease categories 37-40, 33-36, 29-32, and 25-28, respectively, in the post-AC era, p < 0.05 for all). The adjusted likelihood of death/removal from the waitlist was lower for patients with ALD across all lower Model for End-Stage Liver Disease categories (adjusted subdistribution hazard ratio = 0.70, 0.81, 0.84, and 0.70 for the Model for End-Stage Liver Disease categories 25-28, 20-24, 15-19, 6-14, respectively, p < 0.05). Adjusted posttransplant survival was better for those with ALD (adjusted hazard ratio = 0.81, p < 0.05). Waiting list and posttransplant mortality tended to improve more for those with ALD since the implementation of AC but not significantly. ALD is a growing indication for liver transplantation. Although patients with ALD continue to have excellent posttransplant outcomes and lower waitlist mortality, candidates with ALD have higher adjusted transplant rates, and these differences have increased after AC implementation.

Systematic decoding of cis gene regulation defines context-dependent control of the multi-gene costimulatory receptor locus in human T cells.

Cis-regulatory elements (CREs) interact with trans regulators to orchestrate gene expression, but how transcriptional regulation is coordinated in multi-gene loci has not been experimentally defined. We sought to characterize the CREs controlling dynamic expression of the adjacent costimulatory genes CD28, CTLA4 and ICOS, encoding regulators of T cell-mediated immunity. Tiling CRISPR interference (CRISPRi) screens in primary human T cells, both conventional and regulatory subsets, uncovered gene-, cell subset- and stimulation-specific CREs. Integration with CRISPR knockout screens and assay for transposase-accessible chromatin with sequencing (ATAC-seq) profiling identified trans regulators influencing chromatin states at specific CRISPRi-responsive elements to control costimulatory gene expression. We then discovered a critical CCCTC-binding factor (CTCF) boundary that reinforces CRE interaction with CTLA4 while also preventing promiscuous activation of CD28. By systematically mapping CREs and associated trans regulators directly in primary human T cell subsets, this work overcomes longstanding experimental limitations to decode context-dependent gene regulatory programs in a complex, multi-gene locus critical to immune homeostasis.

An shRNA screen in primary human beta cells identifies the serotonin 1F receptor as a negative regulator of survival during transplant.

Islet transplantation can cure type 1 diabetes, but peri-transplant beta cell death limits this procedure to those with low insulin requirements. Improving human beta cell survival or proliferation may make islet transplantation a possibility for more type 1 patients. To identify novel regulators of beta cell survival and proliferation, we conducted a pooled small hairpin RNA (shRNA) screen in primary human beta cells transplanted into immunocompromised mice. shRNAs targeting several cyclin dependent kinase inhibitors were enriched after transplant. Here, we focused on the Gi/o-coupled GPCR, serotonin 1F receptor ( HTR1F, 5-HT 1F ) which our screen identified as a negative regulator of beta cell numbers after transplant. In vitro , 5-HT 1F knockdown induced human beta cell proliferation but only when combined with harmine and exendin-4. In vivo , knockdown of 5-HT 1F reduced beta cell death during transplant. To demonstrate the feasibility of targeting 5-HT 1F in islet transplant, we identified and validated a small molecule 5-HT 1F antagonist. This antagonist increased glucose stimulated insulin secretion from primary human islets and cAMP accumulation in primary human beta cells. Finally, the 5-HT 1F antagonist improved glycemia in marginal mass, human islet transplants into immunocompromised mice. We identify 5-HT 1F as a novel druggable target to improve human beta cell survival in the setting of islet transplantation. One Sentence Summary: Serotonin 1F receptor (5-HT 1F ) negatively regulates insulin secretion and beta cell survival during transplant.

Interfacing High-Throughput Electrosynthesis and Mass Spectrometric Analysis of Azines.

Combinatorial electrochemistry has great promise for accelerated reaction screening, organic synthesis, and catalysis. Recently, we described a new high-throughput electrochemistry platform, colloquially named "Legion". Legion fits the footprint of a 96-well microtiter plate with simultaneous individual control over all 96 electrochemical cells. Here, we demonstrate the versatility of Legion when coupled with high-throughput mass spectrometry (MS) for electrosynthetic product screening and quantitation. Electrosynthesis of benzophenone azine was selected as a model reaction and was arrayed and optimized using a combination of Legion and nanoelectrospray ionization MS. The combination of high-throughput synthesis with Legion and analysis via MS proves a compelling strategy for accelerating reaction discovery and optimization in electro-organic synthesis.

Construction of BiOCl/bismuth-based halide perovskite heterojunctions derived from the metal-organic framework CAU-17 for effective photocatalytic degradation.

The designed synthesis of an S-scheme heterojunction has possessed a great potential for improving photocatalytic wastewater treatment by demonstrating increased the photoredox capacity and improved the charge separation efficiency. Here, we introduce the fabrication of a heterojunction-based photocatalyst comprising bismuth oxychloride (BiOCl) and bismuth-based halide perovskite (BHP) nanosheets, derived from metal-organic frameworks (MOFs). Our composite photocatalyst is synthesized through a one-pot solvothermal strategy, where a halogenation process is applied to a bismuth-based metal-organic framework (CAU-17) as the precursor for bismuth sourcing. As a result, the rod-like structure of CAU-17 transforms into well-defined plate and nanosheet architectures after 4 and 8 h of solvothermal treatment, respectively. The modulation of the solvothermal reaction time facilitates the establishment of an S-scheme heterojunction, resulting in an increase in the photocatalytic degradation efficiency of rhodamine B (RhB) and sulfamethoxazole (SMX). The optimized BiOCl/BHP composite exhibits superior RhB and SMX degradation rates, achieving 99.8% degradation of RhB in 60 min and 75.1% degradation of SMX in 300 min. Also, the optimized BiOCl/BHP composite (CAU-17-st-8h sample) exhibited the highest rate constant (k = 3.48 × 10-3 min-1), nearly 6 times higher than that of the bare BHP in the photocatalytic degradation process of SMX. The enhanced photocatalytic efficiency can be endorsed to various factors: (i) the in-situ formation of two-components BiOCl/BHP photocatalyst, derived from CAU-17, effectively suppresses the aggregation of pristine BHP and BiOCl particles; (ii) the S-scheme heterostructure establishes a closely-knit interfacial connection, thereby facilitating efficient pathways for charge separation/transfer; and (iii) the BiOCl/BHP heterostructure enhances its capacity to absorb visible light. Our investigation establishes an effective strategy for constructing heterostructured photocatalysts, offering significant potential for application in photocatalytic wastewater treatment.

The effect of age on alpha rhythms in the human brain derived from source localized resting-state electroencephalography.

With increasing age, peak alpha frequency (PAF) is slowed, and alpha power is reduced during resting-states with eyes closed. These age-related changes are evident across the whole scalp but remained unclear at the source level. The purpose of this study was to determine whether age impacts the power and frequency of the dominant alpha rhythm equally across source generators or whether the impact of age varies across sources. A total of 28 young adults and 26 elderly adults were recruited. High-density EEG was recorded for 10 mins with eyes closed. Single dipoles for each independent component were localized and clustered based on their anatomical label, resulting in 36 clusters. Meta-analyses were then conducted to assess effect sizes for PAF and power at PAF for all 36 clusters. Subgroup analyses were then implemented for frontal, sensorimotor, parietal, temporal, and occipital regions. The results of the meta-analyses showed that the elderly group exhibited slower PAF and less power at PAF compared to the young group. Subgroup analyses revealed age effects on PAF in parietal (g = 0.38), temporal (g = 0.65), and occipital regions (g = 1.04), with the largest effects observed in occipital regions. For power at PAF, age effects were observed in sensorimotor (g = 0.84) and parietal regions (g = 0.80), with the sensorimotor region showing the largest effect. Our findings show that age-related slowing and attenuation of the alpha rhythm manifests differentially across cortical regions, with sensorimotor and occipital regions most susceptible to age effects.

Causes and consequences of tipping points in river delta social-ecological systems.

The sustainability of social-ecological systems within river deltas globally is in question as rapid development and environmental change trigger "negative" or "positive" tipping points depending on actors' perspectives, e.g. regime shift from abundant sediment deposition to sediment shortage, agricultural sustainability to agricultural collapse or shift from rural to urban land use. Using a systematic review of the literature, we show how cascading effects across anthropogenic, ecological, and geophysical processes have triggered numerous tipping points in the governance, hydrological, and land-use management of the world's river deltas. Crossing tipping points had both positive and negative effects that generally enhanced economic development to the detriment of the environment. Assessment of deltas that featured prominently in the review revealed how outcomes of tipping points can inform the long-term trajectory of deltas towards sustainability or collapse. Management of key drivers at the delta scale can trigger positive tipping points to place social-ecological systems on a pathway towards sustainable development.

Case Illustration of the Natural History of Left Dominant Arrhythmogenic Cardiomyopathy.

Background: Arrhythmogenic left ventricular cardiomyopathy is an increasingly recognized cause of recurrent myocarditis, a mimicker of acute coronary syndrome, and an important cause of malignant ventricular arrythmias and heart failure. Desmoplakin is a protein that is critical to maintaining the structural integrity of the myocardium. Disruption of desmoplakin leads to fibrofatty infiltration of the myocardium which leads to congestive heart failure, cardiac arrhythmias, and sudden cardiac death. However, desmoplakin cardiomyopathy is often misdiagnosed, resulting in significant morbidity and mortality. We report 2 contrasting cases illustrating the natural history-hot and cold phases-of arrhythmogenic left ventricular cardiomyopathy. Case Series: The first case demonstrates a common phenotypic presentation of desmoplakin cardiomyopathy manifested as recurrent myocarditis and myocardial injury representing the hot phase. The second case is an undulating course of chronic systolic heart failure and ventricular arrhythmias representing the cold phase. Conclusion: Arrhythmogenic cardiomyopathy manifests as a spectrum of disease processes that involve the right, left, or both ventricles. Mutations in the desmoplakin gene are often associated with a left dominant ventricular cardiomyopathy. Diagnosis remains difficult as the condition has no signature clinical presentation, and imaging findings are variable.

Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains.

A key aspect of nutrient absorption is the exquisite division of labour across the length of the small intestine, with individual nutrients taken up at different proximal:distal positions. For millennia, the small intestine was thought to comprise three segments with indefinite borders: the duodenum, jejunum and ileum. By examining the fine-scale longitudinal transcriptional patterns that span the mouse and human small intestine, we instead identified five domains of nutrient absorption that mount distinct responses to dietary changes, and three regional stem cell populations. Molecular domain identity can be detected with machine learning, which provides a systematic method to computationally identify intestinal domains in mice. We generated a predictive model of transcriptional control of domain identity and validated the roles of Ppar-δ and Cdx1 in patterning lipid metabolism-associated genes. These findings represent a foundational framework for the zonation of absorption across the mammalian small intestine.

TREATMENT OF IRRECOVERABLE RADIAL NERVE PALSY USING THE MODIFIED MERLE D'AUBIGNÉ TENDON TRANSFER METHOD.

Background: Irrecoverable radial nerve palsy (RNP) leads to the inability to extend the wrist and fingers and significant reduction in grip strength. The aim was to assess the outcomes of treating non-recovering motor RNP using the modified Merle d'Aubigné tendon transfer method. Materials and Methods: A descriptive prospective study involved 33 patients between January 2017 and March 2019. Results: Males constituted the majority (32/33 cases, 97%). The ratio of radial nerve and posterior interosseous nerve injuries was nearly equivalent (16/17). The mean extension range of the wrist was 48.6° ± 14.9° during finger extension and 30.9° ± 14.4° during finger flexion. The mean flexion range of the wrist was 34.8° ± 15.8° during finger extension and 42.6° ± 14.8° during finger flexion. 93.9% of patients achieved full finger extension when the wrist joint was extended beyond 10°. The mean angulation range of the index finger was 55.3° ± 7.4°. The Kapanji score achieved was 8.4 ± 1.2. The achieved grip strength was 65.4% compared to the unaffected side. The surgery did not induce radial deviation deformities of the wrist joint. 32/33 patients were satisfied with the surgical outcomes. 31/33 patients returned to their previous professions. 93.9% of patients achieved very good and good results, while 6.1% achieved fair results. Conclusion: Treating irrecoverable radial nerve palsy using the modified Merle d'Aubigné tendon transfer method yields very good results. The utilization of the pronator teres for wrist extensor transfer and the flexor carpi radialis for finger extensor transfer is appropriate and contributes to limiting wrist joint radial deviation deformities. This modified technique has been researched and recommended by various authors worldwide.

ARID1A loss is associated with increased NRF2 signaling in human head and neck squamous cell carcinomas.

Prior to the next generation sequencing and characterization of the tumor genome landscape, mutations in the SWI/SNF chromatin remodeling complex and the KEAP1-NRF2 signaling pathway were underappreciated. While these two classes of mutations appeared to independently contribute to tumor development, recent reports have demonstrated a mechanistic link between these two regulatory mechanisms in specific cancer types and cell models. In this work, we expand upon these data by exploring the relationship between mutations in BAF and PBAF subunits of the SWI/SNF complex and activation of NRF2 signal transduction across many cancer types. ARID1A/B mutations were strongly associated with NRF2 transcriptional activity in head and neck squamous carcinomas (HNSC). Many additional tumor types showed significant association between NRF2 signaling and mutation of specific components of the SWI/SNF complex. Different effects of BAF and PBAF mutations on the polarity of NRF2 signaling were observed. Overall, our results support a context-dependent functional link between SWI/SNF and NRF2 mutations across human cancers and implicate ARID1A inactivation in HPV-negative HNSC in promoting tumor progression and survival through activation of the KEAP1-NRF2 signaling pathway. The tumor-specific effects of these mutations open a new area of study for how mutations in the KEAP1-NRF2 pathway and the SWI/SNF complex contribute to cancer.

Anterior approach for a stab wound with penetrating rebar injury causing incomplete cauda equina syndrome in lumbosacral spine lesion: a case report and literature review.

PURPOSE: To report a unique case of incomplete CES following a rebar penetrating injury in perineal region with retro-pulsed fragment, which was treated with anterior approach and discuss suitable surgical approach. METHODS: Incomplete cauda equina syndrome caused by non-missile penetrating injury is extremely rare. A 26-year-old male patient presented incomplete cauda equina syndrome due to a penetrating rebar wound from his perineal region to the lumbosacral spine. Computed tomography demonstrated a bony fragment broken from S1 body compressing into the spinal canal. RESULTS: By anterior approach, we performed partial corpectomy of L5, decompression by retrieving the bony fragment and L5-S1 interbody fusion. The patient had a significant recovery, and no clinical complication was found after over 2-year follow-up. CONCLUSION: It is challenging to determine the optimal strategy of surgical treatment for penetrating spinal injuries with retained foreign bodies, here we suggest an anterior approach situation that has the advantage of being able to effectively perform decompression and prevent iatrogenic damages of thecal sac and nerve rootlets.

Matching Patients to Accelerate Clinical Trials (MPACT): Enabling Technology for Oncology Clinical Trial Workflow.

Clinical trial enrollment is impeded by the significant time burden placed on research coordinators screening eligible patients. With 50,000 new cancer cases every year, the Veterans Health Administration (VHA) has made increased access for Veterans to high-quality clinical trials a priority. To aid in this effort, we worked with research coordinators to build the MPACT (Matching Patients to Accelerate Clinical Trials) platform with a goal of improving efficiency in the screening process. MPACT supports both a trial prescreening workflow and a screening workflow, employing Natural Language Processing and Data Science methods to produce reliable phenotypes of trial eligibility criteria. MPACT also has a functionality to track a patient's eligibility status over time. Qualitative feedback has been promising with users reporting a reduction in time spent on identifying eligible patients.

Antimicrobial Resistance Patterns of Common Gram-Negative Microorganisms Isolated from Patients with Lower Respiratory Tract Infections in a Teaching Hospital in Vietnam.

This cross-sectional study investigated the antimicrobial resistance (AMR) patterns of gram-negative pathogens isolated from 4,789 hospitalized patients with lower respiratory tract infections (LRTIs). Of the collected specimens, 1,325 (27.7%) tested positive for gram-negative bacteria. Acinetobacter baumannii (38.6%), Pseudomonas aeruginosa (33.5%), Klebsiella pneumoniae (18.7%), Escherichia coli (5.6%), and Klebsiella aerogenes (3.5%) were the most prevalent isolates. AMR analysis revealed high resistance rates (79.9%-100%) of A. baumannii isolates to multiple classes of antibiotics except amikacin, trimethoprim/sulfamethoxazole, and colistin. P. aeruginosa displayed low resistance to colistin (< 10%) but high resistance to other antibiotics. K. pneumoniae displayed high resistance rates of 90.0%-100.0% to most penicillins, whereas resistance rates were notably lower for colistin (7.1%) and amikacin (16.7%). K. aerogenes exhibited high resistance to various antibiotics and sensitivity to amikacin (95.1%), ampicillin (100.0%), and colistin (100.0%). E. coli isolates exhibited resistance to ampicillin (96.9%) and maximum sensitivity to several antibiotics. Our study identified significant AMR trends and highlighted the prevalence of multidrug-resistant strains (93.6% for K. aerogenes and 69.1%-92.4% for other isolates). These findings emphasize the urgent need for appropriate antibiotic management practices to combat AMR in gram-negative pathogens associated with LRTIs.