Result of the left bundle branch area pacing data collection registry, an international multicenter study of conduction system pacing with a Tendril STS 2088 stylet-driven lead.

INTRODUCTION: Left bundle branch area (LBBA) pacing (LBBAP) has been proposed as an alternative therapy option in patients indicated for cardiac pacing to treat bradycardia or heart failure. The aim of the study was to evaluate the safety and effectiveness of LBBAP in patients implanted with a Tendril 2088 stylet-driven lead. METHODS: The international retrospective data collection registry included 11 sites from 5 countries globally. Patients with attempted implants of the Tendril lead in the LBBA were followed for at least 6 months post the implant attempt. The primary safety and efficacy endpoints were freedom from LBBAP lead-related serious adverse events and the composite of LBBA capture threshold of ≤2.0 V and R-wave amplitudes ≥5 mV (or ≥value at implant), respectively. RESULTS: Of 221 patients with attempted implants of the Tendril 2088 lead in the LBBA, 91.4% (202/221) had successful implants for LBBAP. Regardless of the LBBAP implant success, all patients were followed for at least 6 months (8.7 ± 7.3 months). Baseline characteristics: 44% female, 84% ≥65 years old, 34% coronary artery disease, and 86% of primary indications for pacemaker implant. Both primary safety and effectiveness endpoints were met (freedom from LBBAP lead-related serious adverse device effects of 99.5% and electrical performance composite success rate of 93%). The capture thresholds in LBBAP at implant and 6 months were 0.8 ± 0.3 V@0.4 ± 0.1 ms and 0.8 ± 0.3 V@0.4 ± 0.1 ms. The rate of patients with capture threshold rise ≥1 V was 1.5% through 6 months. The R-wave amplitudes in LBBAP at implant and 6 months were 9.3 ± 3.2 mV and 10.6 ± 3.0 mV. CONCLUSIONS: This large multicenter study demonstrates that the stylet-driven Tendril™ STS 2088 lead is safe and effective for LBBAP with high success and low complication rates.

Heavy metals and trace minerals in commonly available shark species from North East Arabian Sea: A human health risk perspective.

Shark is a seafood commodity that is a good source of minerals and accumulates heavy metals and trace elements through biomagnification, which can pose health risk if taken above the permissible limit. A study was conducted on commonly landed eleven shark species (Scoliodon laticaudus, Rhizopriodon oligolinx, Sphyrna lewini (CR), Carcharhinus macloti, Carcharinus limbatus, Carcharhinus amblyrhynchoides, Carcharhinus sorrah, Carcharinus falciformes(VU), Glaucostegus granulatus, Chiloscyllium arabicum, Loxodon macrorhinus) and analyzed for their heavy metal content, Hazard Index, Total Hazard Quotient, Metal Pollution Index, and also calculated the health risk associated with the consumption. Most of the heavy metals and trace minerals were found to be within the acceptable limit. The Targeted Hazard Quotient (THQ) and the Hazard Index (HI) of all the species except two were less than 1 (HI ≤ 1.0). The Metal Pollution Index (MPI) is showing either no impact or very low contamination. An overall study on hazard identification and health risk characterization in terms of heavy metals shows contamination of some heavy metals in sharks, but there is no potential human health risk associated with consumption.

Evaluation of Efficacy of Curcumin and Caffeic Acid Phenethyl Ester in Breast Cancer by Preclinical Studies.

ims: The aim of this study was to evaluate the combined and comparative efficacy of Caffeic acid phenethyl ester (CAPE) and curcumin in breast cancer. BACKGROUND: CAPE and curcumin are a class of phenolics. While curcumin is obtained from turmeric, CAPE is found in Baccharis sarothroides and Populus deltoides. Both agents are reported to produce activities in some cancer types. The combined and comparative effects of the two agents in breast cancer have not yet reported. OBJECTIVE: We evaluated the potential of CAPE and curcumin in both in vitro and in vivo breast cancer models. METHODS: Human breast cancer cell lines, MDA-MB-231 and MCF-7, were exposed to CAPE and curcumin, followed by functional assays such as cell cytotoxicity, cell proliferation and colony formation, cell cycle, mitochondrial membrane potential, apoptosis, and monodansylcadaverine (MDC) staining for autophagy. Computational analyses and mouse models were also used. RESULTS: Employing computational analyses, both agents were found to exhibit drug-like properties. Both molecules interacted with the key molecules of the NF-κB pathway. CAPE and curcumin inhibited cell proliferation, colony formation, and invasion, triggering apoptosis in breast cancer cells. CAPE was found to be more effective than curcumin. Two agents working together were more effective than each agent working alone. Both agents suppressed the expression of survivin, Bcl-xL and GLUT-1. The level of cleaved PARP was increased by both agents. Both phenolics observed an induction in ROS generation. Further, both molecules triggered a dissipation in mitochondrial membrane potential. In mice models implanted with Ehrlich-Lettre ascites carcinoma (EAC) cells, both drugs inhibited the growth of the tumour. The phenolics also modulated the metabolic parameters in tumour-bearing mice. CONCLUSION: The observations suggest that the combination of curcumin plus CAPE may be better in comparison to individual molecules. Other: The study opens a window for analysing the efficacy of the combination of CAPE and curcumin in animal studies. This will provide a basis for examining the combined efficacy of two agents in a clinical trial.

Outcome measures in pediatric chronic inflammatory demyelinating polyradiculoneuropathy.

INTRODUCTION/AIMS: Objective outcome measures in children undergoing treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are lacking. The aim of the study was to record serial grip strength and motor nerve conduction studies to assess interval change. METHODS: This was a retrospective review of 16 children (8 females and 8 males; median age, 9.7 years; interquartile range, 6-13 years) with CIDP followed at a tertiary children's hospital from 2013 to 2021. Subjects were treated with intravenous immunoglobulin (IVIG). Right and left grip strength measurements were obtained at each clinic visit using a handheld dynamometer. Annual right median motor nerve conduction study data were recorded during the study period. RESULTS: Mean duration of follow-up was 2.9 years. Grip strength (right: 0.19 kg/month, p < 0.001; left 0.23 kg/month, p < 0.001) and median F-wave latencies (-0.23/month, p = 0.015) showed significant improvement over time. Akaike information criterion showed time + IVIG frequency <21 days as best fit for grip strength and distal compound muscle action potential amplitude. DISCUSSION: Our study results indicate serial grip strength measurements are a feasible and objective way to assess motor strength improvement in children with CIDP receiving immunotherapy.

Elucidation of Critical Catalyst Layer Phenomena toward High Production Rates for the Electrochemical Conversion of CO to Ethylene.

This work utilizes EIS to elucidate the impact of catalyst-ionomer interactions and cathode hydroxide ion transport resistance (RCL,OH-) on cell voltage and product selectivity for the electrochemical conversion of CO to ethylene. When using the same Cu catalyst and a Nafion ionomer, varying ink dispersion and electrode deposition methods results in a change of 2 orders of magnitude for RCL,OH- and ca. a 25% change in electrode porosity. Decreasing RCL,OH- results in improved ethylene Faradaic efficiency (FE), up to ∼57%, decrease in hydrogen FE, by ∼36%, and reduction in cell voltage by up to 1 V at 700 mA/cm2. Through the optimization of electrode fabrication conditions, we achieve a maximum of 48% ethylene with >90% FE for non-hydrogen products in a 25 cm2 membrane electrode assembly at 700 mA/cm2 and <3 V. Additionally, the implications of optimizing RCL,OH- is translated to other material requirements, such as anode porosity. We find that the best performing electrodes use ink dispersion and deposition techniques that project well into roll-to-roll processes, demonstrating the scalability of the optimized process.

Real-World Disease Burden and Healthcare Resource Utilization Among Patients with COPD and Asthma Using Triple Therapy (FF/UMEC/VI) in the United States.

Purpose: Chronic obstructive pulmonary disease (COPD) and asthma are associated with chronic inflammation of the respiratory tract; despite some overlap of symptoms, they are considered separate disorders. Triple therapy is recommended for patients with COPD and asthma whose symptoms remain uncontrolled despite dual therapy. There are limited real-world studies evaluating outcomes among patients with COPD and asthma who are receiving inhaled triple therapy. This United States (US)-based real-world study aimed to evaluate clinical and economic outcomes among patients with COPD and asthma receiving single-inhaler triple therapy (fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI]). Patients and Methods: Retrospective pre-post study using claims data from the Optum Clinformatics® database. Patients with COPD and asthma were indexed on the first date of FF/UMEC/VI prescription (1 October 2017-31 March 2019). Each patient acted as their own control. Patients were required to have continuous health plan enrollment for 12 months prior to (pre-treatment) and following (post-treatment) index. Exacerbations, all-cause and COPD-related healthcare resource utilization, and costs were compared before and after FF/UMEC/VI initiation. Results: Overall, 2743 patients were included (mean age: 71 years; 64% female). Cardiovascular disease was the most prevalent comorbidity during both the pre- and post-treatment periods (90% for both periods). There was a lower proportion of patients with ≥1 COPD exacerbation or ≥1 asthma exacerbation post-treatment versus pre-treatment (51% vs 57%, p<0.0001, and 22% vs 32%, p<0.0001, respectively). Fewer patients had ≥1 all-cause office visit post-treatment versus pre-treatment (99.3% vs 99.7%, p=0.0329); more patients had ≥1 COPD-related office visit post-treatment versus pre-treatment (89.6% vs 87.5%, p=0.0035). Total all-cause healthcare costs were significantly higher post-treatment versus pre-treatment ($72,809 vs $63,734, p<0.0001). The driver of increased costs appeared to be primarily non-COPD-related (COPD-related costs: post-treatment $27,779 vs pre-treatment $25,081, p=0.0062). Conclusion: FF/UMEC/VI reduced exacerbations among patients with COPD and asthma in a real-world setting in the US.

Semecarpus anacardium L.f. leaf extract exhibits activities against breast cancer and prolongs the survival of tumor-bearing mice.

Semecarpus anacardium L.f. has been commonly used in various traditional medicines from ancient times. The nuts have been described in Ayurveda medication systems to treat numerous clinical ailments. However, isolating phytochemical constituents from nuts remain challenging and exhibits cytotoxic effects on other cells. In this study, we have standardized procedures for isolating phytochemicals from the leaf extract. The ethyl acetate leaf extract selectively affects cancer cells in a dose-dependent manner (IC50: 0.57 µg/ml in MCF-7 cells) in various cancer cell lines and induces apoptosis in cancer cells. However, the non-malignant cells were relatively insensitive to the extract. Next, the incubation of the leaf extract induces cell cycle arrest and suppresses cancer cell migration in the cell culture model. Moreover, oral administration of extract significantly restored tumor growth in mice. Together, these observations suggest the anti-cancer activities of S. anacardium L.f. leaf potential for both in vitro and in vivo models.

A retrospective claims analysis of fatigue in patients with multiple sclerosis on disease-modifying therapy.

BACKGROUND: Fatigue, one of the most common symptoms in patients with multiple sclerosis (MS), severely impairs quality of life and the ability to work or perform activities of daily living. Real-world data on fatigue in MS can help inform healthcare decisions and identify care gaps. We identified fatigue in patients with MS, using existing codes for fatigue and proxies of fatigue in healthcare claims database records and characterized cohorts with and without markers of fatigue who had been prescribed disease-modifying therapies for MS (MS-DMTs). METHODS: In this cohort study, we retrospectively analyzed Optum's de-identified Clinformatics® Data Mart database from 1 January 2015 to 31 December 2019. The index date was defined as the first prescription record date for any MS-DMT during the study identification period. Included patient records were from adults (≥18 years) with ≥2 MS diagnosis claims listed within 12 months prior to the index date. Patients had ≥1 claim for any MS-DMT during the identification period (1 January 2016-31 December 2018), continuous enrollment in a health plan with medical and pharmacy benefits for 12 months before the index date (assessment one), and 12 months following the index date or to end of data availability (assessment two). After exploratory analyses, we applied the following definition to sort patient records into two cohorts according to presence or absence of markers of fatigue: ≥1 diagnosis (International Classification of Diseases, Ninth/Tenth Revisions code) claim for fatigue or ≥2 claims for stimulant drugs or ≥2 procedure claims for a sleep study or ≥2 pharmacy claims for sleep aid drugs; we used the broadest definition of fatigue so meeting any of these criteria qualified patients with MS as having fatigue. To minimize assessment one differences in selected patient characteristics between cohorts, we applied 1:1 propensity score matching with age, sex, US geographic region, and Charlson Comorbidity Index score as covariates. We analyzed demographic data, markers of fatigue, comorbidities at assessment one, and physical disabilities and neurologic impairment at assessment two. RESULTS: Of 4077 patient records that met the eligibility criteria, 1976 had markers of fatigue. The propensity score-matched cohorts included 1519 patients each with and without fatigue. Assessment one comorbidities including anxiety (25.3% vs 10.5%; P<0.0001), arthritis (17.6% vs 12.9%; P = 0.0003), depression (15.0% vs 3.5%; P<0.0001), and gastrointestinal disorders (20.3% vs 14.2%; P<0.0001) were significantly more prevalent in the cohort with markers of fatigue at assessment one compared with those without fatigue. At assessment two, the cohort with baseline fatigue upon initial assessment was more likely to have indication of physical impairments (spasticity [63.5% vs 35.8%; P<0.0001], bladder dysfunction [37.8% vs 24.0%; P<0.0001], cognitive/behavioral dysfunction [27.0% vs 18.6%; P<0.0001]), neurologic impairments (pain [59.1% vs 44.0%; P<0.0001], depression [29.2% vs 9.9%; P<0.0001], and sensory disturbances [54.2% vs 36.7%; P<0.0001]), compared with the cohort without markers of fatigue at assessment one. CONCLUSIONS: In our analysis, patients with MS and fatigue were more likely to have comorbidities at assessment one and to develop physical disabilities and neurologic impairments at assessment two. Appropriate identification of patients with MS and fatigue may facilitate targeted care interventions to a group of patients at higher risk for disease progression and disability.

Human fetal dermal fibroblast-myeloid cell diversity is characterized by dominance of pro-healing Annexin1-FPR1 signaling.

Fetal skin achieves scarless wound repair. Dermal fibroblasts play a central role in extracellular matrix deposition and scarring outcomes. Both fetal and gingival wound repair share minimal scarring outcomes. We tested the hypothesis that compared to adult skin fibroblasts, human fetal skin fibroblast diversity is unique and partly overlaps with gingival skin fibroblasts. Human fetal skin (FS, n = 3), gingiva (HGG, n = 13), and mature skin (MS, n = 13) were compared at single-cell resolution. Dermal fibroblasts, the most abundant cluster, were examined to establish a connectome with other skin cells. Annexin1-FPR1 signaling pathway was dominant in both FS as well as HGG fibroblasts and related myeloid cells while scanty in MS fibroblasts. Myeloid-specific FPR1-ORF delivered in murine wound edge using tissue nanotransfection (TNT) technology significantly enhanced the quality of healing. Pseudotime analyses identified the co-existence of an HGG fibroblast subset with FPR1high myeloid cells of fetal origin indicating common underlying biological processes.

A real-world evidence analysis of the impact of switching from factor VIII to emicizumab prophylaxis in patients with hemophilia A without inhibitors.

BACKGROUND: This study retrospectively compared annualized billed bleed rates (ABRb) in people with hemophilia A (PwHA) without inhibitors who switched from factor VIII (FVIII) prophylaxis to emicizumab. RESEARCH DESIGN AND METHODS: A real-world comparison study was performed on the effect of switching from FVIII to emicizumab prophylaxis in male, non-inhibitor patients on ABRb using an all-payer claims database (APCD) dataset from 1 January 2014, to 31 March 2021. The identification period was from 1 November 2017, to 30 September 2020. RESULTS: One hundred and thirty-one patients were included with a total of 82 and 45 bleeds in the pre- and post-switch periods, respectively. The average follow-up period pre-switch was 978.37 days (SD 555.03), whereas the average follow-up period post-switch was 522.26 days (SD 191.36). No significant differences in mean ABRb were observed pre-/post-switch (0.25 and 0.20, respectively; P = 0.4456). CONCLUSIONS: The results of this study demonstrate no significant reduction in ABRb, suggesting that switching from FVIII to emicizumab may not deliver incremental benefits to PwHA receiving prophylactic care.

Effects of different cooking methods on the proximate composition and physical properties of Brown shrimp (Metapenaeus dobsonii) during cooking and freezing cycle.

Present study aimed to evaluate the changes in proximate composition and physical attributes in brown shrimp (Metapenaeus dobsonii) exposed to different methods of cooking followed by freezing. For this, three different grades (100/200, 200/300, and 300/500 numbers per kg) of brown shrimp were cooked at 90°C till the core temperature of the product reaches 85°C using hot water, steam, and microwave (400W) techniques. The changes in yield, cooking loss, proximate composition, textural, and colour profile were assessed for cooked shrimps. The cooking loss was higher for larger grades of shrimp, whereas shrimp cooked using hot water exhibited the highest cooking loss. Lowest cooking loss was observed for microwave-cooked shrimp. Moisture content decreased after cooking whereas protein, fat, ash, and calorie content increased. After cooking, different grades of shrimp showed an increase in their lightness (L*), redness (a*), and yellowness (b*) values. The smaller grade shrimp exhibited lower value for cohesiveness, hardness, chewiness, and gumminess. Different cooking techniques yielded cooked shrimp of varying hardness values.

Hospitalization Among Pulmonary Arterial Hypertension Patients With and Without Connective Tissue Disease Comorbidities Prescribed Oral Selexipag.

INTRODUCTION: Patients with connective tissue disorders (CTD) and pulmonary arterial hypertension (PAH) have a poorer prognosis than those with other PAH etiologies. This study assessed the impact of CTD on healthcare outcomes among PAH patients with and without CTD comorbidities that were treated with oral selexipag. METHODS: The study utilized Optum's de-identified Clinformatics® Data Mart Database (2007-2021) from January 1, 2014 to June 30, 2019, and identified patients with PAH without CTD and PAH with CTD treated with oral selexipag. Patients had ≥ 12-month baseline period with no requirement for a minimum follow-up period. Patients were followed until any of the following events: discontinuation of oral selexipag, or health plan disenrollment, or death, or presence of a diagnosis claim for CTEPH, or study end date, whichever occurred first. PAH-related hospitalizations, PAH disease progression, and healthcare utilizations and costs were assessed in the follow-up period. The Cox proportional hazards model was used to evaluate the time to hospitalization and generalized linear models were used to examine healthcare costs and utilization between the two cohorts. RESULTS: In the analysis, 237 PAH without CTD, and 80 PAH patients with CTD comorbidities prescribed oral selexipag were included. The PAH without CTD comorbidities cohort was older (65 vs. 63 years old), had proportionately less females (72 vs. 83%), and higher comorbidity burden than PAH with CTD comorbidities (mean CCI index 3 vs. 2). After adjusting for potential confounders, the risk for PAH-related hospitalization (hazard ratio (HR) 1.13, p value 0.641), all-cause hospitalization (HR 1.09, p value: 0.765), and PAH disease progression (HR 1.14, p value 0.522) between the two cohorts were similar. After adjusting for baseline demographic and clinical characteristics, PAH with CTD comorbidities incurred higher total mean all-cause PAH-related medical care costs compared to PAH without CTD comorbidities. CONCLUSIONS: In this real-world study, the risk of hospitalization and PAH disease progression were similar between the two cohorts who received oral selexipag. The results from this study corroborate findings of the GRIPHON post hoc analysis of PAH-associated CTD patients and support oral selexipag use in PAH-CTD patients.

Enhanced Carbon Monoxide Electroreduction to >1†A cm-2 C2+ Products Using Copper Catalysts Dispersed on MgAl Layered Double Hydroxide Nanosheet House-of-Cards Scaffolds.

Cu catalysts are most apt for reducing CO(2) to multi-carbon products in aqueous electrolytes. To enhance the product yield, we can increase the overpotential and the catalyst mass loading. However, these approaches can cause inadequate mass transport of CO(2) to the catalytic sites, which will then lead to H2 evolution dominating the product selectivity. Herein, we use a MgAl LDH nanosheet 'house-of-cards' scaffold to disperse CuO-derived Cu (OD-Cu). With this support-catalyst design, at -0.7 VRHE , CO could be reduced to C2+ products with a current density (jC2+ ) of -1251 mA cm-2 . This is 14× that of the jC2+ shown by unsupported OD-Cu. The current densities of C2+ alcohols and C2 H4 were also high at -369 and -816 mA cm-2 respectively. We propose that the porosity of the LDH nanosheet scaffold enhances CO diffusion through the Cu sites. The CO reduction rate can thus be increased, while minimizing H2 evolution, even when high catalyst loadings and large overpotentials are used.

Identification of a physiologic vasculogenic fibroblast state to achieve tissue repair.

Tissue injury to skin diminishes miR-200b in dermal fibroblasts. Fibroblasts are widely reported to directly reprogram into endothelial-like cells and we hypothesized that miR-200b inhibition may cause such changes. We transfected human dermal fibroblasts with anti-miR-200b oligonucleotide, then using single cell RNA sequencing, identified emergence of a vasculogenic subset with a distinct fibroblast transcriptome and demonstrated blood vessel forming function in vivo. Anti-miR-200b delivery to murine injury sites likewise enhanced tissue perfusion, wound closure, and vasculogenic fibroblast contribution to perfused vessels in a FLI1 dependent manner. Vasculogenic fibroblast subset emergence was blunted in delayed healing wounds of diabetic animals but, topical tissue nanotransfection of a single anti-miR-200b oligonucleotide was sufficient to restore FLI1 expression, vasculogenic fibroblast emergence, tissue perfusion, and wound healing. Augmenting a physiologic tissue injury adaptive response mechanism that produces a vasculogenic fibroblast state change opens new avenues for therapeutic tissue vascularization of ischemic wounds.

CSF IL-8 Associated with Response to Gene Therapy in a Case Series of Spinal Muscular Atrophy.

Gene therapies have greatly changed the outlook in spinal muscular atrophy (SMA), and this disorder provides a rare opportunity to study longitudinal biomarker changes correlated with reduced disease burden and improved clinical outcomes. Recent work suggests clinical response to correlate with declining cerebrospinal fluid (CSF) levels of the neurodegenerative marker neurofilament light chain (NfL) in children receiving serial anti-sense oligonucleotide therapy. However, change in CSF NfL levels is no longer a practical biomarker as more children undergo single-dose gene replacement therapy. Here we leverage serial CSF samples (median of 4 per child) collected in 13 children with SMA undergoing anti-sense oligonucleotide therapy to characterize the longitudinal profiles of NfL as well as inflammatory and neuronal proteins. In contrast to neurodegeneration in adults, we found NfL levels to first decrease following initiation of treatment but then increase upon further treatment and improved motor functions. We then examined additional CSF inflammatory and neuronal markers for linear association with motor function during SMA treatment. We identified longitudinal IL-8 levels to inversely correlate with motor functions determined by clinical examination (F(1, 47) = 12.903, p = 0.001) or electromyography in the abductor pollicis brevis muscle (p = 0.064). In keeping with this, lower baseline IL-8 levels were associated with better longitudinal outcomes, even though this difference diminished over 2 years in the younger group. We thus propose CSF IL-8 as a biomarker for baseline function and short-term treatment response in SMA, and a candidate biomarker for future treatment trials in other neurodegenerative disorders.

Seroprevalence of Adeno-Associated Virus Neutralizing Antibodies in Males with Duchenne Muscular Dystrophy.

Adeno-associated virus (AAV)-based gene therapies are emerging strategies in Duchenne muscular dystrophy (DMD) treatment. Exposure to wild-type AAV can lead to development of neutralizing antibodies (NAbs) and blocking of AAV transduction, thereby limiting the delivery of AAV vector-based gene therapy. Therefore, it is imperative to check for the presence of AAV NAbs in a patient who is a candidate for gene therapy. We prospectively enrolled 101 genetically confirmed males with DMD (median age 11 years, 48% ambulatory and 59% on steroids) and performed AAV neutralization assays against AAV2, AAV8, AAV9, and AAVrh74 serotypes. The serotype analysis showed that AAV9 (36%) and AAVrh74 (32%) seroprevalence was lower compared with AAV2 (56%) and AAV8 (47%). Interestingly, age was not correlated with NAb titer for any of the capsids. NAb responses were observed at a higher frequency in African American participants and at a lower frequency in Caucasian participants for all four serotypes. Further analysis showed no significant differences in NAb titers regardless of serotype and whether participants were taking steroids or not. Finally, we observed higher AAV8, AAV9, and AAVrh74 seroprevalence and significantly higher AAV2 and AAV8 NAb titers in participants who were ambulatory compared with nonambulatory participants. Overall, these data identify AAV9 and AAVrh74 as the two serotypes with lower pre-existing NAb titers in this study's cohort of 101 males with DMD, possibly showing their utility in future gene therapy applications in treatment of this cohort of patients with DMD.

PEBAT, an Intriguing Neurodegenerative Tubulinopathy Caused by a Novel Homozygous Variant in TBCD: A Case Series and Literature Review.

Progressive encephalopathy with brain atrophy and thin corpus callosum (PEBAT) is a severe and rare progressive neurodegenerative disease (OMIM 617913). This condition has been described in individuals with pathogenic variants affecting tubulin-specific chaperone protein D (TBCD), which is responsible for proper folding and assembly of tubulin subunits. Here we describe two unrelated infants from Central America presenting with worsening neuromuscular weakness, respiratory failure, polyneuropathy, and neuroimaging findings of severe cerebral volume loss with thin corpus callosum. These individuals harbored the same homozygous variant of uncertain significance in the TBCD gene on whole exome sequencing (WES). Predicted protein modeling of this variant confirmed disruption of the protein helix at the surface of TBCD. The goal of this report is to emphasize the importance of rapid WES, careful interpretation of uncertain variants, prognostication, and family counseling especially when faced with a neurodegenerative clinical course.

Current trends in solid tannery waste management.

The tannery is one of the leading revenue-generating sectors in developing countries. The ever-increasing demand for leather products in the global market requires converting large amounts of rawhide/skins into resilient non-putrescible finished leather. Only 20% of the raw material is converted into a finished product; the rest 80% is discarded as solid and liquid wastes during leather processing. A heavy discharge of improperly treated solid tannery waste (STW) causes a severe impact on the surrounding environment by polluting soil, surface water, and groundwater resources, posing severe hazards to human and animal health. STW comprises proteinaceous untanned and tanned waste, which requires proper treatment for eco-friendly disposal. Several strategies have been developed over the years for the reduction and recycling of STW for producing renewable energy (biogas and biohydrogen), biofuels (biodiesel and briquettes), construction material, fertilizers, commercial products (adsorbents, animal feeds, proteins, fats, and enzymes), and biodegradable packaging and non-packaging materials. In this review, we discuss various strategies adopted for recycling, reutilization, and reduction of STW in an environment-friendly manner. Furthermore, an overview of the current perspectives toward achieving a zero-waste policy is also presented to reduce the environmental burden using green-clean technology to aid the survival of present-day tanneries.

RGS7-ATF3-Tip60 Complex Promotes Hepatic Steatosis and Fibrosis by Directly Inducing TNFα.

Aims: The pathophysiological mechanism(s) underlying non-alcoholic fatty liver disease (NAFLD) have yet to be fully delineated and only a single drug, peroxisome proliferator-activated receptor (PPAR) α/γ agonist saroglitazar, has been approved. Here, we sought to investigate the role of Regulator of G Protein Signaling 7 (RGS7) in hyperlipidemia-dependent hepatic dysfunction. Results: RGS7 is elevated in the livers of NAFLD patients, particularly those with severe hepatic damage, pronounced insulin resistance, and high inflammation. In the liver, RGS7 forms a unique complex with transcription factor ATF3 and histone acetyltransferase Tip60, which is implicated in NAFLD. The removal of domains is necessary for ATF3/Tip60 binding compromises RGS7-dependent reactive oxygen species generation and cell death. Hepatic RGS7 knockdown (KD) prevented ATF3/Tip60 induction, and it provided protection against fibrotic remodeling and inflammation in high-fat diet-fed mice translating to improvements in liver function. Hyperlipidemia-dependent oxidative stress and metabolic dysfunction were largely reversed in RGS7 KD mice. Interestingly, saroglitazar failed to prevent RGS7/ATF3 upregulation but it did partially restore Tip60 levels. RGS7 drives the release of particularly tumor necrosis factor α (TNFα) from isolated hepatocytes, stellate cells and its depletion reverses steatosis, oxidative stress by direct TNFα exposure. Conversely, RGS7 overexpression in the liver is sufficient to trigger oxidative stress in hepatocytes that can be mitigated via TNFα inhibition. Innovation: We discovered a novel non-canonical function for an R7RGS protein, which usually functions to regulate G protein coupled receptor (GPCR) signaling. This is the first demonstration for a functional role of RGS7 outside the retina and central nervous system. Conclusion: RGS7 represents a potential novel target for the amelioration of NAFLD. Antioxid. Redox Signal. 38, 137-159.

Loss of Function of the Cytoplasmic Fe-S Assembly Protein CIAO1 Causes a Neuromuscular Disorder with Compromise of Nucleocytoplasmic Fe-S Enzymes.

Cytoplasmic and nuclear iron-sulfur enzymes that are essential for genome maintenance and replication depend on the cytoplasmic iron-sulfur assembly (CIA) machinery for cluster acquisition. Here we report that patients with biallelic loss of function in CIAO1 , a key CIA component, develop proximal and axial muscle weakness, fluctuating creatine kinase elevation and respiratory insufficiency. In addition, they present with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, macrocytic anemia and gastrointestinal symptoms. Mutational analysis and functional assays revealed reduced stability of the variants compared to wild-type CIAO1. Loss of CIAO1 impaired DNA helicases, polymerases and repair enzymes which rely on the CIA complex to acquire their Fe-S cofactors, with lentiviral restoration reversing all patient-derived cellular abnormalities. Our study identifies CIAO1 as a novel human disease gene and provides insights into the broader implications of the iron-sulfur assembly pathway in human health and disease.