Racial and Ethnic Diversity in Vitiligo Clinical Trials: A Retrospective Cross-Sectional Study Assessing Demographic Reporting of Participants.

BACKGROUND: While the prevalence of vitiligo is similar across racial and ethnic groups, the effects of vitiligo vary by demographic group, culture, and skin color, with darker-skinned individuals facing greater stigma due to increased visibility of the disease.1,2 The recruitment of diverse participants that are representative of the United States (US) population is crucial to ensuring the generalizability of findings and understanding the impacts of vitiligo across diverse patient groups.   Objectives: This study aimed to determine demographic reporting trends in US vitiligo clinical trials and to determine whether participants are representative of the US population. METHODS: A search for US vitiligo clinical trials was conducted on clinicaltrials.gov. Trials conducted between 2006 to September 5, 2023, were included if they intended to treat vitiligo, were conducted in the US, and were completed or terminated.  Results: Of the 15 trials meeting inclusion criteria, only 60% (n=9) reported participant race/ethnicity. These 9 studies included 1,510 participants, of which only 25.43% (n=384) were non-White and 20.40% were Hispanic. There was disproportionately low representation of racial minorities, particularly Black, Native American, and Native Hawaiian groups.   Limitations: Limitations of our study include small sample size, variations in demographic reporting between trials, and undercounting of minority groups by the US Census.  Conclusions: Racial and ethnic minority groups remain underrepresented in US vitiligo clinical trials. Given that the impact of vitiligo can vary by the affected individual’s demographic group and skin color, investigators must be intentional about including a more diverse and representative population in vitiligo clinical trials.  J Drugs Dermatol. 2024;23(7):e164-e166. doi:10.36849/JDD.8117e.

Advancements in Rechargeable Zn-Air Batteries with Transition-Metal Dichalcogenides as Bifunctional Electrocatalyst.

Zinc-air batteries are promising energy storage devices owing to their high energy density, low cost, and environmental friendliness. However, the development of durable and efficient bifunctional electrocatalysts is a major concern for Zn-air batteries. In this review, we summarize the recent progress on transition metal dichalcogenides (TMDs) as bifunctional electrocatalysts for Zn-air batteries. We discuss the advantages of TMDs, such as high activity, good stability, and tunable electronic structure, as well as the challenges, such as low conductivity, poor durability, and limited active sites. We also highlight the strategies for fine-tuning the properties of TMDs, such as defect engineering, doping, hybridization, and structural engineering, to enhance their catalytic performance and stability. We provide a comprehensive and in-depth analysis of the applications of TMDs in Zn-air batteries, demonstrating their potential as low-cost, abundant, and environmentally friendly alternatives to noble metal catalysts. We also suggest future directions like exploring new TMDs materials and compositions, developing novel synthesis and modification techniques, investigating the interfacial interactions and charge transfer processes, and integrating TMDs with other functional materials. This review aims to illuminate the path forward for the development of efficient and durable Zn-air batteries, aligning with the broader objectives of sustainable energy solutions.

Dose-dependent effects of Dnmt3a in an inducible murine model of KrasG12D-driven leukemia.

DNMT3A mutations are frequently found in clonal hematopoiesis and a variety of hematologic malignancies, including acute myeloid leukemia. An assortment of mouse models have been engineered to explore the tumorigenic potential and malignant lineage bias due to loss of function of DNMT3A in consort with commonly comutated genes in myeloid malignancies, such as Flt3, Nras, Kras, and c-Kit. We employed several tamoxifen-inducible Cre-ERT2 murine model systems to study the effects of constitutively active KrasG12D-driven myeloid leukemia (Kras) development together with heterozygous (3aHet) or homozygous Dnmt3a deletion (3aKO). Due to the rapid generation of diverse nonhematologic tumors appearing after tamoxifen induction, we employed a transplantation model. With pretransplant tamoxifen induction, most Kras mice died quickly of T-cell malignancies regardless of Dnmt3a status. Using posttransplant induction, we observed a dose-dependent effect of DNMT3A depletion that skewed the leukemic phenotype toward a myeloid lineage. Specifically, 64% of 3aKO/Kras mice had exclusively myeloid disease compared with 36% of 3aHet/Kras and only 13% of Kras mice. Here, 3aKO combined with Kras led to increased disease burden, multiorgan infiltration, and faster disease progression. DOT1L inhibition exerted profound antileukemic effects in malignant 3aKO/Kras cells, but not malignant cells with Kras mutation alone, consistent with the known sensitivity of DNMT3A-mutant leukemia to DOT1L inhibition. RNAseq from malignant myeloid cells revealed that biallelic Dnmt3a deletion was associated with loss of cell-cycle regulation, MYC activation, and TNF⍺ signaling. Overall, we developed a robust model system for mechanistic and preclinical investigations of acute myeloid leukemia with DNMT3A and Ras-pathway lesions.

A High-Avidity, Thermostable, and Low-Cost Synthetic Capture for Ultrasensitive Detection and Quantification of Viral Antigens and Aerosols.

Lateral flow assays (LFAs) are currently the most popular point-of-care diagnostics, rapidly transforming disease diagnosis from expensive doctor checkups and laboratory-based tests to potential on-the-shelf commodities. Yet, their sensitive element, a monoclonal antibody, is expensive to formulate, and their long-term storage depends on refrigeration technology that cannot be met in resource-limited areas. In this work, LCB1 affibodies (antibody mimetic miniproteins) were conjugated to bovine serum albumin (BSA) to afford a high-avidity synthetic capture (LCB1-BSA) capable of detecting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and virus like particles (VLPs). Substituting the monoclonal antibody 2B04 for LCB1-BSA (stable up to 60 °C) significantly improved the thermal stability, shelf life, and affordability of plasmonic-fluor-based LFAs (p-LFAs). Furthermore, this substitution significantly improved the sensitivity of p-LFAs toward the spike protein and VLPs with precise quantitative ability over 2 and 3 orders of magnitude, respectively. LCB1-BSA sensors could detect VLPs at 100-fold lower concentrations, and this improvement, combined with their robust nature, enabled us to develop an aerosol sampling technology to detect aerosolized viral particles. Synthetic captures like LCB1-BSA can increase the ultrasensitivity, availability, sustainability, and long-term accuracy of LFAs while also decreasing their manufacturing costs.

Influence of Hepatitis C virus genotype and other factors on the viral load.

Anti-HCV reactive subjects were selected and relevant data was collected. Viral load and genotype were determined for all patients and were divided into low (<800,000 IU/mL) and high viral load (>800,000 IU/mL). Correlation of viral load with parameters like age, gender, risk factors and genotype etc. was determined by binomial regression. Higher viral load was noted with genotype 4, males and high risk groups like People Who Inject Drugs (PWIDs), blood transfusion before routine testing or frequent transfusion, Intravenous drug therapy and MTP by unregistered medical practitioners (P ≤ 0.5). Prevention and treatment strategies for HCV should be tailored around these areas.

Preventive hepatology at AIIMS Rishikesh: Delivering comprehensive and integrated care for liver diseases in Northern state of India.

Globally, liver diseases accounts for 4% of all deaths. Annually, over 2 million deaths occur due to preventable causes of chronic liver diseases and liver cancer like fatty liver diseases (alcoholic or non alcoholic) and viral hepatitis B and C. The burden of chronic liver diseases are increasing, and the epidemiology and demographics of people affected by these diseases are changing. Policy changes, vaccination, screening, lifestyle changes and public health awareness is the key to curb down liver disaeses. To achieve the ultimate goal of reducing mortality and linkage to care for those who need specialized care for liver disease, it is vital to have dedicated preventive hepatology clinics in sync with existing liver or gastroenterology clinics at tertary care level.

Evaluation of Hepatic Steatosis and Fibrosis Using Transient Elastography in Patients With Obstructive Sleep Apnea.

Objectives: Obstructive sleep apnea (OSA) is an independent risk factor for non-alcoholic fatty liver disease. This study was planned to assess proportion of patients with OSA that have hepatic steatosis and fibrosis, as measured by transient elastography, to explore variables influencing their development and to find out the polysomnography parameters that predict the need for transient elastography screening in OSA. Methods: Consecutive participants having polysomnography proven OSA were included in the study after screening for eligibility criteria. Data of the polysomnography were scored manually following standard criteria. Participants were subjected to transient elastography (Fibroscan®) and serum investigations after diagnostic polysomnography. The polysomnography, fibroscan®, and laboratory data were tabulated and analyzed. Results: A total of 71 participants were enrolled. 16.9% participants had mild OSA, 28.2% had moderate OSA, and remaining participants had severe OSA. Liver steatosis was found in 63.4% participants while hepatic fibrosis was noted in 9.9%. Oxygen desaturation index (ODI), apnea-hypopnea index (AHI), and percentage of sleep spent below 90% oxygen saturation (T90) were significantly associated with the presence of hepatic steatosis and fibrosis. Receiver operating curve (ROC) showed that at the cut-offs of 73 events/hr, 13% and 72.2 events/hr, AHI, T90 and ODI, predicted hepatic fibrosis with area under ROC of 0.960, 0.944, and 0.933, respectively (P < 0.001). Conclusions: Patients with OSA are at increased risk for development of hepatic steatosis and fibrosis. ODI, AHI, and T90 during polysomnography predict the presence of underlying hepatic fibrosis.

Transcriptomic profiling reveals a pronociceptive role for angiotensin II in inflammatory bowel disease.

ABSTRACT: Visceral pain is a leading cause of morbidity in inflammatory bowel disease (IBD), contributing significantly to reduced quality of life. Currently available analgesics often lack efficacy or have intolerable side effects, driving the need for a more complete understanding of the mechanisms causing pain. Whole transcriptome gene expression analysis was performed by bulk RNA sequencing of colonic biopsies from patients with ulcerative colitis (UC) and Crohn's disease (CD) reporting abdominal pain and compared with noninflamed control biopsies. Potential pronociceptive mediators were identified based on gene upregulation in IBD biopsy tissue and cognate receptor expression in murine colonic sensory neurons. Pronociceptive activity of identified mediators was assessed in assays of sensory neuron and colonic afferent activity. RNA sequencing analysis highlighted a 7.6-fold increase in the expression of angiotensinogen transcripts, Agt , which encode the precursor to angiotensin II (Ang II), in samples from UC patients ( P = 3.2 × 10 -8 ). Consistent with the marked expression of the angiotensin AT 1 receptor in colonic sensory neurons, Ang II elicited an increase in intracellular Ca 2+ in capsaicin-sensitive, voltage-gated sodium channel subtype Na V 1.8-positive sensory neurons. Ang II also evoked action potential discharge in high-threshold colonic nociceptors. These effects were inhibited by the AT 1 receptor antagonist valsartan. Findings from our study identify AT 1 receptor-mediated colonic nociceptor activation as a novel pathway of visceral nociception in patients with UC. This work highlights the potential utility of angiotensin receptor blockers, such as valsartan, as treatments for pain in IBD.

Microneedle patch-based enzyme-linked immunosorbent assay to quantify protein biomarkers of tuberculosis.

There is a clinical need for differential diagnosis of the latent versus active stages of tuberculosis (TB) disease by a simple-to-administer test. Alpha-crystallin (Acr) and early secretory antigenic target-6 (ESAT-6) are protein biomarkers associated with the latent and active stages of TB, respectively, and could be used for differential diagnosis. We therefore developed a microneedle patch (MNP) designed for application to the skin to quantify Acr and ESAT-6 in dermal interstitial fluid by enzyme-linked immunosorbent assay (ELISA). We fabricated mechanically strong microneedles made of polystyrene and coated them with capture antibodies against Acr and ESAT-6. We then optimized assay sensitivity to achieve a limit of detection of 750 pg/ml and 3,020 pg/ml for Acr and ESAT-6, respectively. This study demonstrates the feasibility of an MNP-based ELISA for differential diagnosis of latent TB disease.

Surface acoustic wave actuated plasmonic signal amplification in a plasmonic waveguide.

Enhancement of nanoscale confinement in the subwavelength waveguide is a concern for advancing future photonic interconnects. Rigorous innovation of plasmonic waveguide-based structure is crucial in designing a reliable on-chip optical waveguide beyond the diffraction limit. Despite several structural modifications and architectural improvements, the plasmonic waveguide technology is far from reaching its maximum potential for mass-scale applications due to persistence issues such as insufficient confined energy and short propagation length. This work proposes a new method to amplify the propagating plasmons through an external on-chip surface acoustic signal. The gold-silicon dioxide (Au-SiO2) interface, over Lithium Niobate (LN) substrate, is used to excite propagating surface plasmons. The voltage-varying surface acoustic wave (SAW) can tune the plasmonic confinement to a desired signal energy level, enhancing and modulating the plasmonic intensity. From our experimental results, we can increase the plasmonic intensity gain of 1.08 dB by providing an external excitation in the form of SAW at a peak-to-peak potential swing of 3 V, utilizing a single chip.

Checkpoint inhibitor hepatotoxicity: pathogenesis and management.

Immunotherapy, including immune checkpoint inhibitor (ICI) therapy, has been a paradigm shift in cancer therapeutics, producing durable cancer responses across a range of primary malignancies. ICI drugs increase immune activity against tumor cells, but may also reduce immune tolerance to self-antigens, resulting in immune-mediated tissue damage. ICI-associated hepatotoxicity usually manifests as hepatocellular enzyme elevation and may occur in 2%-25% of ICI-treated patients. Although ICI-associated hepatotoxicity is clinically and pathologically distinct from idiopathic autoimmune hepatitis, our understanding of its pathogenesis continues to evolve. Pending greater understanding of the pathophysiology, mainstay of management remains through treatment with high-dose corticosteroids. This approach works for many patients, but up to 30% of patients with high-grade hepatotoxicity may not respond to corticosteroids alone. Furthermore, atypical cholestatic presentations are increasingly recognized, and rare cases of fulminant hepatitis due to ICI hepatotoxicity have been reported. Optimal management for these challenging patients remains uncertain. Herein, we review the current understanding of pathogenesis of ICI-associated toxicities, with a focus on hepatotoxicity. Based on the existing literature, we propose evolving management approaches to incorporate strategies to limit excess corticosteroid exposure, and address rare but important presentations of cholestatic hepatitis and fulminant liver failure. Finally, as ICI hepatotoxicity frequently occurs in the context of treatment for advanced malignancy, we review the impact of hepatotoxicity and its treatment on cancer outcomes, and the overall safety of re-challenge with ICI, for patients who may have limited treatment options.

Plasmon-Enhanced Digital Fluoroimmunoassay for Subfemtomolar Detection of Protein Biomarkers.

Rapid and accurate quantification of low-abundance protein biomarkers in biofluids can transform the diagnosis of a range of pathologies, including infectious diseases. Here, we harness ultrabright plasmonic fluors as "digital nanolabels" and demonstrate the detection and quantification of subfemtomolar concentrations of human IL-6 and SARS-CoV-2 alpha and variant proteins in clinical nasopharyngeal swab and saliva samples from COVID-19 patients. The resulting digital plasmonic fluor-linked immunosorbent assay (digital p-FLISA) enables detection of SARS-CoV-2 nucleocapsid protein, both in solution and in live virions. Digital p-FLISA outperforms the "gold standard" enzyme-linked immunosorbent assay (ELISA), having a nearly 7000-fold lower limit-of-detection, and outperforms a commercial antigen test, having over 5000-fold improvement in analytical sensitivity. Detection and quantification of very low concentrations of target proteins holds potential for early detection of pathological conditions, treatment monitoring, and personalized medicine.

Neutrophil Gelatinase-associated Lipocalin Predicts Short-term Outcomes in Decompensated Cirrhosis With Acute Kidney Injury.

Background and aims: Acute kidney injury (AKI) increases mortality in cirrhosis. Early identification of the cause of AKI helps in planning appropriate management. We aimed to find whether neutrophil gelatinase-associated lipocalin (NGAL) can be used to differentiate between different types of AKI in cirrhosis and predict short-term outcomes in patients with decompensated cirrhosis and AKI. Method: This was a time-bound study in which consecutive hospitalized patients with cirrhosis and AKI were prospectively recruited and managed as per standard care. Acute on chronic liver failure (ACLF) was diagnosed as per the EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) criteria. Urine NGAL was measured by enzyme-linked immunosorbent assay (ELISA) by Epitope Diagnostics Inc. kit (San Diego, USA.) in all patients on admission, and patients were followed up until hospital discharge or death. Results: A total of 110 consecutive patients (median [range] age: 44 [28-81] years;87.3%were male; ACLF: 71.8%; acute decompensation 28.2%; Model for end-stage liver disease (MELD) 27 [13-46]; Child-Turcotte-Pugh (CTP) 11 [7-15]) with cirrhosis and AKI were recruited. Alcohol was the most common etiology of cirrhosis(64.5%)). Pre-renal azotemia (PRA) was the most common cause of AKI (n = 56). Urine NGAL was significantly elevated in acute tubular necrosis (ATN) (1747 [6-6141] ng/ml than in hepatorenal syndrome (HRS) (379 [33.5-2320] ng/ml; P < 0.0001) and PRA (167 ng/ml [3.34-660]; P < 0.0001). Sixty-four percent patients with ATN, 27.6% patients with HRS, and none with PRA required dialysis. A total of 79.31% patients with HRS and 76% with ATN died. Urine NGAL was significantly higher in patients who required hemodialysis than in those who did not (1733 [243-6141] ng/ml vs 235 [3.34-2320] ng/ml; P < 0.0001). Both urine NGAL (n = 110) and plasma NGAL (n = 90) were significantly higher in patients who died (urine NGAL: -475 [6-6141] ng/ml vs 247 [3.34-2320] ng/ml; P = 0.002;plasma NGAL-950 [94-4859] ng/ml vs 608 [18-3300)]g/ml; P < 0.001). On multivariate analysis, urine NGAL and INR could predict mortality. Conclusion: NGAL can differentiate between different types of AKI in cirrhosis and predict the need for hemodialysis and mortality in decompensated cirrhosis with AKI.

"De novo replication repair deficient glioblastoma, IDH-wildtype" is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade.

Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant "ultrahypermutation". The median age at diagnosis was 50 years (range 27-78), compared with 63 years for the other 450 patients with conventional glioblastoma (p < 0.01). All tumors had histologic features of the giant cell variant of glioblastoma. They lacked EGFR amplification, lacked combined trisomy of chromosome 7 plus monosomy of chromosome 10, and only rarely had TERT promoter mutation or CDKN2A homozygous deletion, which are hallmarks of conventional IDH-wildtype glioblastoma. Instead, they harbored frequent inactivating mutations in TP53, NF1, PTEN, ATRX, and SETD2 and recurrent activating mutations in PDGFRA. DNA methylation profiling revealed they did not align with known reference adult glioblastoma methylation classes, but instead had unique globally hypomethylated epigenomes and mostly classified as "Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A". Five patients were treated with immune checkpoint blockade, four of whom survived greater than 3 years. The median overall survival was 36.8 months, compared to 15.5 months for the other 450 patients (p < 0.001). We conclude that "De novo replication repair deficient glioblastoma, IDH-wildtype" represents a biologically distinct subtype in the adult population that may benefit from prospective identification and treatment with immune checkpoint blockade.

A Portable Low-Cost Respiration Rate Measurement System for Sleep Apnea Detection.

Continuous monitoring of breathing activity is vital in detecting respiratory-based diseases such as obstructive sleep apnea (OSA) and hypopnea. Sleep apnea (SA) is a potentially dangerous sleep problem that occurs when a person's breathing stops and begins periodically while they sleep. In addition, SA interrupts sleep, causing significant daytime sleepiness, weirdness, and irritability. This study aims to design a single inertial measurement unit (IMU) sensor-based system to analyze the respiratory rate of humans. The results of the developed system is validated with the Equivital Wireless Physiological Systems for different activities. Further, the experiment has been designed to identify the optimal sensor placement location for efficient respiration rate estimation during different activities. The performance of the developed model has been quantified using breathing rate estimation accuracy (% BREA) and mean absolute error (MAE). Among all sensor placement locations and activities combinations, a window size of 30sec resulted in the worst performance, whereas a window size ≥ 60sec resulted in a better performance (p-value<0.05). In addition, the performance of the model has been found consistent for window size ≥ 60sec (p-value>0.05). For activity 3 (lying straight), comparably similar performance, 0.52±0.24 and 0.52±0.12 (p-value>0.05) have been depicted by the sensor placement position 3 (Abdomen) and position 1 (chest), respectively. Further, for the other two activities, activity 1 (sitting and working) and activity 2 (sitting straight), the best performance has been depicted as 0.32±0.18, 0.49±0.21 respectively (p-value<0.05), by the sensor placement position 2 (left ribs). This research presents a reliable, cost-effective, portable respiration monitoring system that could detect SA during sleep.