Origins and diversity of pan-isotype human bone marrow plasma cells.

Bone marrow plasma cells (BMPCs) produce durable, protective IgM, IgG, and IgA antibodies, and in some cases, pro-allergic IgE antibodies, but their properties and sources are unclear. We charted single BMPC transcriptional and clonal heterogeneity in food-allergic and non-allergic individuals across CD19 protein expression given its inverse correlation to BMPC longevity. Transcriptional and clonal diversity revealed distinct functional profiles. Additionally, distribution of somatic hypermutation and intraclonal antibody sequence variance suggest that CD19low and CD19high BMPCs arise from recalled memory and germinal center B cells, respectively. Most IgE BMPCs were from peanut-allergic individuals; two out of 32 from independent donors bound peanut antigens in vitro and in vivo. These findings shed light on BMPC origins and highlight the bone marrow as a source of pathogenic IgE in peanut allergy.

Harnessing Pb-S Interactions for Long-Term Water Stability in Cesium Lead Halide Perovskite Nanocrystals.

Lead halide perovskite nanocrystals (LHP NCs) have garnered attention as promising light-harvesting materials for optoelectronics and photovoltaic devices, attributed to their impressive optoelectronic properties. However, their susceptibility to moisture-induced degradation has hindered their practical applications. Despite various encapsulation strategies, challenges persist in maintaining their stability and optoelectronic performance simultaneously. Here, a ligand exchange approach is proposed using (11-mercaptoundecyl)-N,N,N-trimethylammonium bromide (MUTAB) to enhance the stability and dispersibility of CsPbBr3 (CPB) NCs in aqueous environments. MUTAB enables effective surface passivation of the CPB NCs via robust Pb-S interactions at the S-terminal while concurrently directing water molecules through the unbound cationic N-terminal or vice versa, ensuring water dispersibility and stability. Spectroscopic analysis confirms retained structural and optical integrity post-ligand exchange. Crucially, MUTAB-bound CPB NCs exhibit sustained charge transfer properties, demonstrated by aqueous colloidal oxidation reactions. This ligand exchange strategy offers a promising pathway for advancing LHP NCs toward practical optoelectronic and photocatalytic applications.

Insights into interfacial mechanisms: CsPbBr3 nanocrystals as sustainable photocatalysts for primary amine oxidation.

CsPbBr3 nanocrystals (NCs) employed as a photocatalyst resulted in efficient benzylamine oxidation under oxygen atmosphere. Improved reaction yields stem from favorable -NH2 functional group interactions on the NC surface, while additional interactions with -OMe or -SMe functional groups post-product formation result in lower yields. These insights into interfacial interactions and mechanistic aspects advance sustainable chemical transformations through cost-effective and recyclable CsPbBr3 NC-catalyzed primary amine oxidation.

Regional variation in cause of death in patients with type 2 diabetes: Insights from EXSCEL.

AIMS: Type 2 diabetes (T2D) is a risk factor for cardiovascular and non-cardiovascular mortality. However, global distribution of cause-specific deaths in T2D is poorly understood. We characterized cause-specific deaths by geographic region among individuals with T2D at risk for cardiovascular disease (CVD). METHODS AND RESULTS: The international EXSCEL trial included 14,752 participants with T2D (73% with established CVD). We identified the proportion of deaths over 5-year follow-up attributed to cardiovascular and non-cardiovascular causes, and associated risk factors. During median 3.2-year follow-up, 1,091 (7.4%) participants died. Adjudicated causes of death were 723 cardiovascular (66.3% of deaths), including 252 unknown, and 368 non-cardiovascular (33.7%). Most deaths occurred in North America (N = 356/9.6% across region) and Eastern Europe (N = 326/8.1%), with fewest in Asia/Pacific (N = 68/4.4%). The highest proportional cause-specific deaths by region were sudden cardiac in Asia/Pacific (23/34% of regional deaths) and North America (86/24%); unknown in Eastern Europe (90/28%) and Western Europe (39/21%); and non-malignant non-cardiovascular in Latin America (48/31%). Cox proportional hazards model for adjudicated causes of death showed prognostic risk factors (hazard ratio [95% CI]) for cardiovascular and non-cardiovascular deaths, respectively: heart failure 2.04 (1.72-2.42) and 1.86 (1.46-2.39); peripheral artery disease 1.83 (1.54-2.18) and 1.78 (1.40-2.26); and current smoking status 1.61 (1.29-2.01) and 1.77 (1.31-2.40). CONCLUSIONS: In a contemporary T2D trial population, with and without established CVD, leading causes of death varied by geographic region. Underlying mechanisms leading to variability in cause of death across geographic regions and its impact on clinical trial endpoints warrant future research.

Improving Guideline-Directed Medical Therapy for Patients With Heart Failure With Reduced Ejection Fraction: A Review of Implementation Strategies.

Despite recent advances in the use of guideline-directed medical therapy (GDMT) for patients with heart failure with reduced ejection fraction (HFrEF), achievement of target GDMT use and up-titration to goal dosages continue to be modest. In recent years, a number of interventional approaches to improve the usage of GDMT have been published, but many are limited by single-center experiences with small sample sizes. However, strategies including the use of multidisciplinary teams, dedicated GDMT titration algorithms and clinician audits with feedback have shown promise. There remains a critical need for large, rigorous trials to assess the utility of differing interventions to improve the use and titration of GDMT in HFrEF. Here, we review existing literature in GDMT implementation for those with HFrEF and discuss future directions and considerations in the field.

Lymph node level ratio: Are we relying too much on numbers?

The lymph node level ratio appears to be a continuation of nodal yield and nodal density, two prognostic metrics already in use. A retrospective analysis conducted in the current study showed that a value of fewer than 4 lymph nodes/level is linked to a lower overall and disease-specific survival. This letter aims to review the reasoning behind the use of node level ratios and nodal yields as quality and prognostic indicators, and to explore possible factors that could affect these.

Enhancing Photocatalytic Attributes of Perovskite Nanocrystals in Aqueous Media via Ligand Engineering.

The remarkable catalytic potential of perovskite nanocrystals (NCs) remains underutilized due to their limited stability in polar media, resulting from the vulnerability of their structure to disruption by polar solvents. In this study, we address this challenge by employing the bolaamphiphilic NKE-12 ligand, which features multiple denticities to effectively shield the surface of CsPbBr3 NCs from polar solvent interactions without compromising their light-harvesting properties. Our research, utilizing electrochemical impedance and photocurrent response measurements, highlights efficient charge separation and charge transfer enabled by NKE-12 ligands, which feature multiple ionic groups and peptide bonds, compared to conventional oleylamine/oleic acid ligands on CsPbBr3 NCs. Through the utilization of purely ligand-derived water-dispersed CsPbBr3/NKE-12 NCs, we successfully showcased their photocatalytic activity for acrylamide polymerization. A series of control experiments unveil a radical-based reaction pathway and suggest the synergistic involvement of photogenerated electrons and holes in producing the O2·- and OH· free radicals, respectively. Our findings emphasize the crucial role of ligand engineering in stabilizing perovskites in water and harnessing their exceptional photocatalytic attributes. This study opens new avenues for applying perovskite NCs in various catalytic processes in polar media.

The Impact and Prognostic Significance of Extra-Nodal Extension in Clinically N0 Oral Cancer: A Prospective Clinical Study.

Oral cavity squamous cell carcinoma (OCSCC) demonstrates a high propensity to metastasize to regional lymph nodes. Despite technological and scientific advances, identification of pathological adverse features preoperatively remains elusive. This study intended to identify the true occurrence of extra-nodal extension (ENE) in clinically and radiologically N0 OCSCC patients and to investigate its impact and prognostic significance. A prospective, single-centre, non-randomized study was conducted at a tertiary cancer centre in South India to include all untreated operable patients of OCSCC without clinical, radiological, or cytological evidence of nodal metastasis (cN0). All the patients underwent tumor resection surgery with neck dissection and received adjuvant therapy when indicated. Patients were followed up and neck dissection specimens were histopathologically analyzed. The primary outcome was to assess the presence of ENE in cN0 OCSCC patients and its extent. The secondary outcomes were 2-year disease-free survival (DFS) and tumor characteristics. A total of 237 patients with operable OCSCC were evaluated. Out of these, 80 patients who were clinically and radiologically N0 were included in the study and they underwent tumor resection surgery and neck dissection. The final histopathological evaluation revealed that 21.25% of patients (n = 17) had metastatic neck disease and 7.5% of patients (n = 6) had ENE, and all were reported as microscopic ENE. Within the node-positive group, the 2-year DFS for patients with and without ENE were 50% and 90.9%, respectively (p = 0.0362). The results suggest that ENE remains a strong predictor of adverse outcomes, recurrence, and survival in oral cancer patients.

CsPbBr3 Nanocrystals as Efficient Photocatalysts for Dehydrohalogenation: Toward Environmentally Friendly Trichloroethylene Synthesis.

The demand for a benign alternative to energy-intensive industrial chemical transformations is critical. Lead halide perovskites have emerged as promising candidates due to their unique optoelectronic properties, including high absorption coefficients in the visible region, tunable band gaps, and long charge carrier-diffusion lengths. In this study, we present a model reaction to showcase the photocatalytic utility of perovskite nanocrystals (NCs). Specifically, we demonstrate the synthesis of trichloroethylene (TCEt) from 1,1,2,2-tetrachloroethane (TCE) using CsPbBr3 NCs under white light illumination. The band-edge positions of the NCs and the redox potential of TCE enable efficient electron transfer for C-Cl bond activation. Furthermore, while ensuring operational stability, CsPbBr3 NCs undergo light-controlled modification, leading to the formation of mixed-halide perovskite (CsPbBrxCl3-x) NCs during the reaction. This procedure yields a mixed-halide perovskite that maintains stability while containing the desired halide content. Additionally, the reaction produces HBr as a byproduct, serving as a self-cleaning technique to eliminate excess Br- ions from the solution. Ultimately, we achieve nearly 100% conversion of CsPbBr3 to pure CsPbCl3 NCs, with a full width at half-maximum of approximately 11.2 nm. Our clean and efficient approach to synthesizing TCEt using perovskite NCs provides interesting insights into violet light-emitting diode (LED) fabrication and color patterning. This study highlights the promising potential of perovskite materials for sustainable chemical transformations and optoelectronic applications.

Role of Sentinel Lymph Node Biopsy in Clinically Node Negative Carcinoma Penis - a Prospective Study.

Nodal metastasis is a strong prognostic indicator in carcinoma penis, with 25% difference in 5-year cancer-specific survival among node negative and node positive patients. This study aims to assess efficacy of SLNB in identifying occult nodal metastasis (seen in 20-25% of cases), thus avoiding morbidity of prophylactic groin dissection in rest. Study was conducted between June 2016 and December 2019 on 42 patients (84 groins). Primary outcomes assessed were sensitivity, specificity, false negative rates, positive predictive value, and negative predictive value of sentinel lymph node biopsy (SLNB) compared to superficial inguinal node dissection (SIND). Secondary outcomes were to know prevalence of nodal metastasis, sensitivity, specificity, false negative rates, positive predictive value (PPV), negative predictive value (NPV) of frozen section study, and ultrasonography (USG) compared to histopathological examination (HPE) and to evaluate false negative results of fine needle aspiration cytology (FNAC). Patients with impalpable inguinal nodes were subjected to USG and FNAC of suspicious nodes. Only those with non-suspicious USG/negative FNAC were included. Patients who were node positive, had prior chemotherapy/radiotherapy/prior groin surgery, or medically unfit for surgery were excluded. Dual-dye technique was used to identify sentinel node. Superficial inguinal dissection was done in all cases and both specimens were subject to frozen section. If ≥ 2 nodes were involved on frozen section, ilioinguinal dissection was done. SLNB had sensitivity, specificity, PPV, NPV, and accuracy of 100%, respectively. There were no false negative results of frozen section study among 168 specimens. Ultrasonography had sensitivity of 50%, specificity of 48.75%, PPV of 4.65%, NPV of 95.12%, and accuracy of 48.81%. We had 2 false negative results of FNAC. Sentinel node biopsy with frozen section study when done in properly selected cases using dual-dye technique in high volume centers by experienced professionals is a very reliable tool in establishing the nodal status, thereby facilitating need directed treatment, thus prevent either over/under treatment.

Pressured cytotoxic T cell epitope strength among SARS-CoV-2 variants correlates with COVID-19 severity.

Heterogeneity in susceptibility among individuals to COVID-19 has been evident through the pandemic worldwide. Cytotoxic T lymphocyte (CTL) responses generated against pathogens in certain individuals are known to impose selection pressure on the pathogen, thus driving emergence of new variants. In this study, we probe the role played by host genetic heterogeneity in terms of HLA-genotypes in determining differential COVID-19 severity in patients. We use bioinformatic tools for CTL epitope prediction to identify epitopes under immune pressure. Using HLA-genotype data of COVID-19 patients from a local cohort, we observe that the recognition of pressured epitopes from the parent strain Wuhan-Hu-1 correlates with COVID-19 severity. We also identify and rank list HLA-alleles and epitopes that offer protectivity against severe disease in infected individuals. Finally, we shortlist a set of 6 pressured and protective epitopes that represent regions in the viral proteome that are under high immune pressure across SARS-CoV-2 variants. Identification of such epitopes, defined by the distribution of HLA-genotypes among members of a population, could potentially aid in prediction of indigenous variants of SARS-CoV-2 and other pathogens.

Electronic health record characterization and outcomes of heart failure with preserved ejection fraction.

BACKGROUND: Electronic health record (EHR)-based identification of heart failure with preserved ejection fraction (HFpEF) in the clinical setting may facilitate screening for clinical trials by improving the understanding of its epidemiology and outcomes; yet, previous data have yielded variable results. We sought to characterize groups identified with HFpEF by different EHR screening strategies and their associated long-term outcomes across a large and diverse population. METHODS: We retrospectively analyzed 116,499 consecutive patients from an academic referral center who underwent echocardiography, and 9,263 patients who underwent echocardiography within 6 months of right heart catheterization (RHC), between 2008 and 2018. EHR-based screening strategies identified patients with HFpEF using 1) International Classification of Diseases (ICD)-9/10 codes, 2) H2FpEF score ≥6 and ejection fraction (EF) ≥50%, or 3) RHC wedge pressure ≥15 mmHg and EF ≥50%, when available. Primary outcomes were 1) cumulative incident heart failure hospitalization (HFH), and 2) death, over 10 years. RESULTS: There were 33,461 (29%) patients who met either ICD or H2FpEF-HFpEF definition, of whom 5,310 (16%) met both criteria. Compared to ICD-HFpEF, patients with H2FpEF-HFpEF were more likely older (median age 72 vs 67), White (78% vs 64%), and had atrial fibrillation (97% vs 41%). Among those also with RHC, 6,353 (69%) patients met any HFpEF criteria, of whom only 783 (12%) satisfied all three criteria. Female sex was more common among RHC-HFpEF (55%) compared to other methods (H2FpEF-HFpEF, 47%; ICD-HFpEF, 43%). Atrial fibrillation was substantially higher among HFpEF identified by the H2FpEF score (97%) compared to other methods (49% for ICD and 47% for RHC). Across HFpEF screening methods, 10-year cumulative incidence rates for HFH was 32% to 45% for echocardiography only and 43% to 52% for echocardiography and RHC populations; 10-year risk of death was 54% to 56% for echocardiography only and 52% to 57% for echocardiography and RHC populations. CONCLUSIONS: Different EHR-based HFpEF definitions identified cohorts with modest overlap and varying baseline characteristics. Yet, long-term risk for HFH and death were similarly high for cohorts identified among both populations undergoing echocardiography only or echocardiography and RHC. These data aid in identifying relevant subgroups in clinical trials of HFpEF.