Zeolite-promoted platinum catalyst for efficient reduction of nitrogen oxides with hydrogen.

Internal combustion engine fueled by carbon-free hydrogen (H2-ICE) offers a promising alternative for sustainable transportation. Herein, we report a facile and universal strategy through the physical mixing of Pt catalyst with zeolites to significantly improve the catalytic performance in the selective catalytic reduction of nitrogen oxides (NOx) with H2 (H2-SCR), a process aiming at NOx removal from H2-ICE. Via the physical mixing of Pt/TiO2 with Y zeolite (Pt/TiO2 + Y), a remarkable enhancement of NOx reduction activity and N2 selectivity was simultaneously achieved. The incorporation of Y zeolite effectively captured the in-situ generated water, fostering a water-rich environment surrounding the Pt active sites. This environment weakened the NO adsorption while concurrently promoting the H2 activation, leading to the strikingly elevated H2-SCR activity and N2 selectivity on Pt/TiO2 + Y catalyst. This study provides a unique, easy and sustainable physical mixing approach to achieve proficient heterogeneous catalysis for environmental applications.

Invention of novel 3-aminopiperidin-2-ones as calcitonin gene-related peptide receptor antagonists.

A novel series of 3-amino-piperidin-2-one-based calcitonin gene-related peptide (CGRP) receptor antagonists was invented based upon the discovery of unexpected structure-activity observations. Initial exploration of the structure-activity relationships enabled the generation of a moderately potent lead structure (4). A series of modifications, including ring contraction and inversion of stereocenters, led to surprising improvements in CGRP receptor affinity. These studies identified compound 23, a structurally novel potent, orally bioavailable CGRP receptor antagonist.

Electrochemistry Beyond Solutions: Modeling Particle Self-Crowding of Nanoparticle Suspensions.

Nanoparticle suspensions hold promise to transform functionality of next-generation electrochemical systems including batteries, capacitors, wastewater treatment, and sensors, challenging the limits of existing electrochemical models. Classical solution-based electrochemistry assumes that charge is transported and transferred by point-like carriers. Herein, we examine the electrochemistry of a model aqueous suspension of nondissolvable electroactive nanoparticles over a wide concentration range using a rotating disk electrode. Past a concentration and rotation rate threshold, the electrochemistry deviates from solution theory with a maximum attainable current due to particle "self-crowding" where reacted particles on the electrode surface reduce the area accessible for charge transfer by unreacted particles. The observed response is rationalized with an analytical model considering the physical adsorption/desorption kinetics and interfacial transport of nondissolvable finite-size charge carriers. Experimental validation shows the model to be applicable across a range of electrode sizes and thus suitable for engineering electrochemical systems employing nondissolvable nanoparticle suspensions.

Harnessing the Power of Generative Artificial Intelligence in Pathology Education.

CONTEXT.­: Generative artificial intelligence (AI) technologies are rapidly transforming numerous fields, including pathology, and hold significant potential to revolutionize educational approaches. OBJECTIVE.­: To explore the application of generative AI, particularly large language models and multimodal tools, for enhancing pathology education. We describe their potential to create personalized learning experiences, streamline content development, expand access to educational resources, and support both learners and educators throughout the training and practice continuum. DATA SOURCES.­: We draw on insights from existing literature on AI in education and the collective expertise of the coauthors within this rapidly evolving field. Case studies highlight practical applications of large language models, demonstrating both the potential benefits and unique challenges associated with implementing these technologies in pathology education. CONCLUSIONS.­: Generative AI presents a powerful tool kit for enriching pathology education, offering opportunities for greater engagement, accessibility, and personalization. Careful consideration of ethical implications, potential risks, and appropriate mitigation strategies is essential for the responsible and effective integration of these technologies. Future success lies in fostering collaborative development between AI experts and medical educators, prioritizing ongoing human oversight and transparency to ensure that generative AI augments, rather than supplants, the vital role of educators in pathology training and practice.

Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.

Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS, and previous findings indicate that case-control likelihood ratios (LRs) outperform odds ratios for variant classification. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyzed germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 303,925 unaffected controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observed 11,227 BRCA1 and BRCA2 variants, with 6,921 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control LR evidence was highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.4% specificity for BRCA1 and 92.2% sensitivity and 86.6% specificity for BRCA2. This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for clinical classification.

Use of Radiation Therapy for Ataxia-Telangiectasia Mutated (ATM)-Mutation Metastatic Renal Cell Carcinoma: A Case Report.

Papillary renal cell carcinoma (pRCC) is a rare kidney cancer with limited treatment options and poor outcomes when metastatic. We present a case of a 42-year-old male with metastatic pRCC harboring a somatic ataxia-telangiectasia mutated (ATM) mutation who was treated at our institution. After progression of disease (POD) on ipilimumab/nivolumab, followed by POD on cabozantinib, the patient was treated with radiation therapy to metastatic cervical lymphadenopathy to 60 Gy in 15 fractions as well as retroperitoneal lymphadenopathy to 36 Gy in 9 fractions, which was curtailed due to intolerance. This was followed by sequential systemic therapy with a poly (ADP-ribose) polymerase (PARP) inhibitor and pembrolizumab, which was also discontinued due to adverse effects. Despite not receiving any treatment for 10 months, his disease remains stable. We believe that the prolonged progression-free survival of this patient with ATM-mutation metastatic pRCC is likely due to the enhanced sensitivity of the tumor to radiation therapy due to ATM loss.

Rethinking the role of surgical resection in the management of primary pituitary lymphoma.

BACKGROUND: Primary pituitary lymphoma (PPL) is a rare finding in immunocompetent patients, with only 54 patients reported to date (including ours). It presents most often with headache and hypopituitarism, with MRI findings comparable to more common pituitary tumours, making the diagnosis challenging. There is no consensus on the ideal management for these lesions with the role of surgical resection not clearly established. CASE REPORT: We present here a 49-year-old female who presented with acute vision loss and was found to have PPL of diffuse large B-cell lymphoma, non-germinal centre type. The radiologic findings were distinct from prior cases with haemorrhagic components and perilesional edoema in the bilobed sellar mass. Surgical resection was halted when a diagnosis of lymphoma was suspected. This decision was based on the guidelines for the treatment of primary CNS lymphoma (PCNSL) and the lack of evidence to support surgical resection of PPL specifically. Our patient lacked mutations commonly associated with a poor prognosis in DLBCL, such as TP53 and BCL6. She remains in remission with normal vision nearly two years after treatment with minimal resection, MR-CHOP, and consolidation radiotherapy. CONCLUSION: We highlight here the clinical and diagnostic features of PPL to guide clinicians to early recognition and diagnosis. Surgical resection should be limited to what is necessary to obtain a diagnosis and critical decompression; otherwise, these lesions respond excellently to steroids and typical chemoradiation regimens.

Diffuse large B-cell lymphoma in the C8 root mimicking a schwannoma: illustrative case.

BACKGROUND: Primary lymphomas arising in peripheral nerves are extremely rare, with just a few case reports documented in the literature. OBSERVATIONS: The authors present the case of a 62-year-old female with C8 radiculopathy, initially suspected to have a schwannoma based on imaging but later diagnosed with primary C8 nerve root B-cell lymphoma. Following histopathological confirmation, the patient underwent 5 courses of chemotherapy, resulting in a decrease in the size of her lesion on magnetic resonance imaging. At her clinical follow-up 3 months later, her symptoms had improved. After performing a systematic review of the literature while adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines, the authors found only 3 similar cases, each with atypical presentations and treated with various chemotherapeutic agents and one of which experienced a central nervous system recurrence. LESSONS: These cases highlight the importance of early and accurate diagnosis for optimal management and long-term vigilance of primary lymphomas in the peripheral nerve. https://thejns.org/doi/10.3171/CASE24338.

Distribution of extracellular adhesins in environmental biofilms and flocs: Reimagining the microbial structure.

Extracellular cellular adhesins facilitate microbial aggregation; however, most of the information about extracellular adhesins is based on pure culture studies. In this study, we characterized the hydrophobic characteristics and distribution of the extracellular adhesins in environmental biofilms and flocs. The hydrophobic characteristics of the extracellular adhesins were studied by sonicating the microbial aggregates to disperse the cells and by fractionating them using the microbial adhesion to the hydrocarbon method. Furthermore, we probed environmental biofilms and flocs using immunohistochemistry coupled with confocal laser scanning microscopy for reimaging the microbial aggregates based on extracellular adhesins. Small flocs have a relatively dispersed distribution of extracellular adhesins (flagella, fimbriae, pili, and amyloid adhesins). The stratified distribution of extracellular adhesins was observed in environmental biofilms. It was observed that the pili and amyloid adhesins were predominantly present in the core of biofilms, whereas flagella and fimbriae were present in the outer layer of the microbial aggregates. The dispersion of microbial aggregates is one of the limiting factors that challenge the sustainable application of wastewater treatment processes. Greater attention to the components of extracellular protein (such as the adhesins) is required to understand the aggregation of dispersible environmental microbial aggregates.

Mean-field interacting multi-type birth-death processes with a view to applications in phylodynamics.

Multi-type birth-death processes underlie approaches for inferring evolutionary dynamics from phylogenetic trees across biological scales, ranging from deep-time species macroevolution to rapid viral evolution and somatic cellular proliferation. A limitation of current phylogenetic birth-death models is that they require restrictive linearity assumptions that yield tractable message-passing likelihoods, but that also preclude interactions between individuals. Many fundamental evolutionary processes - such as environmental carrying capacity or frequency-dependent selection - entail interactions, and may strongly influence the dynamics in some systems. Here, we introduce a multi-type birth-death process in mean-field interaction with an ensemble of replicas of the focal process. We prove that, under quite general conditions, the ensemble's stochastically evolving interaction field converges to a deterministic trajectory in the limit of an infinite ensemble. In this limit, the replicas effectively decouple, and self-consistent interactions appear as nonlinearities in the infinitesimal generator of the focal process. We investigate a special case that is rich enough to model both carrying capacity and frequency-dependent selection while yielding tractable message-passing likelihoods in the context of a phylogenetic birth-death model.

Efficacy and safety of implantable cardioverter-defibrillator implantation in the elderly-The I-70 Study: A randomized clinical trial.

Background: There is conflicting evidence on the efficacy of primary prevention implantable cardioverter-defibrillator (ICD) implantation in the elderly. Objective: The purpose of this study was to determine the efficacy and safety of ICD implantation in patients 70 years and older. Methods: Patients (n = 167) aged 70 years or older and eligible for ICD implantation were randomly assigned (1:1) to receive either optimal medical therapy (OMT) (n = 85) or OMT plus ICD (n = 82). Results: Of the 167 participants (mean age 76.4 years; 165 men), 144 completed the study protocol according to their assigned treatment. Average participant follow-up was 31.5 months. Mortality was similar between the 2 groups: 27 deaths in OMT vs 26 death in ICD (unadjusted hazard ratio 0.92; 95% confidence interval 0.53-1.57), but there was a trend favoring the ICD over the first 36 months of follow-up. Rates of sudden death (7 vs 5; P = .81) and all-cause hospitalization (2.65 events per participant in OMT vs 3.09 in ICD; P = .31) were not statistically significantly different. Eleven participants randomized to ICD received appropriate therapy. Five participants received an inappropriate therapy that included at least 1 ICD shock. Conclusion: The study did not recruit to target sample size, and accumulated data did not show benefit of ICD therapy in patients 70 years or older. Future studies similar in design might be feasible but will need to contend with patient treatment preference given the large number of patients who do not want an ICD implanted. Further research is needed to determine whether the ICD is effective in prolonging life among elderly device candidates.

Loss to follow-up among people living with HIV on tuberculosis preventive treatment at four regional referral hospitals, Uganda, 2019-2021.

Introduction: Tuberculosis (TB) remains the leading cause of death among people living with HIV (PLHIV). TB preventive treatment (TPT) can prevent active TB infection in PLHIV for several years after it is completed. During 2019-2021, the six-month course of TPT (using isoniazid) was the most readily available in Uganda; however, program data indicated a TPT program loss to follow-up (LTFU) rate of 12 % during this period. We evaluated factors associated with TPT LTFU among PLHIV in four regional referral hospitals (RRHs) in Uganda from 2019 to 2021. Methods: We abstracted program data from TPT registers on patient LTFU at Masaka, Mbale, Mubende, and Jinja RRHs. Additional data collected included client demographics, duration on HIV antiretroviral therapy (ART), year of TPT initiation, adherence, and point of entry. LTFU was defined as the failure to finish six consecutive months of isoniazid without stopping for more than two months at a time. We conducted bivariate analysis using the chi-square test for independence. Variables with p < 0.05 in bivariate analysis were included in a logistic regression model to establish independent factors associated with LTFU. Results: Overall, 24,206 clients were started on TPT in the four RRHs. Their median age was 40 years (range, 1-90 years), and 15,962 (66 %) were female. A total of 22,260 (92 %) had TPT adherence >95 %. Independent factors associated with LTFU included being on ART for <3 months (AOR: 3.1, 95 % CI: 2.1-4.5) and 20-24 years (AOR: 4.7, 95 % CI: 1.9-12) or 25-29 years (AOR: 3.3, 95 % CI: 1.3-8.2) compared to 15-19 years. Conclusions: PLHIV just starting ART and young adults had higher odds of being LTFU from TPT during 2019-2021 in the four RRHs. Close follow-up of PLHIV aged 20-29 years and those newly initiated on ART could improve TPT completion.

The Impact of Vitamin D and L-Cysteine Co-Supplementation on Upregulating Glutathione and Vitamin D-Metabolizing Genes and in the Treatment of Circulating 25-Hydroxy Vitamin D Deficiency.

Vitamin D receptors are expressed in many organs and tissues, which suggests that vitamin D (VD) affects physiological functions beyond its role in maintaining bone health. Deficiency or inadequacy of 25(OH)VD is widespread globally. Population studies demonstrate that a positive association exists between a high incidence of VD deficiency and a high incidence of chronic diseases, including dementia, diabetes, and heart disease. However, many subjects have difficulty achieving the required circulating levels of 25(OH)VD even after high-dose VD supplementation, and randomized controlled clinical trials have reported limited therapeutic success post-VD supplementation. Thus, there is a discordance between the benefits of VD supplementation and the prevention of chronic diseases in those with VD deficiency. Why this dissociation exists is currently under debate and is of significant public interest. This review discusses the downregulation of VD-metabolizing genes needed to convert consumed VD into 25(OH)VD to enable its metabolic action exhibited by subjects with metabolic syndrome, obesity, and other chronic diseases. Research findings indicate a positive correlation between the levels of 25(OH)VD and glutathione (GSH) in both healthy and diabetic individuals. Cell culture and animal experiments reveal a novel mechanism through which the status of GSH can positively impact the expression of VD metabolism genes. This review highlights that for better success, VD deficiency needs to be corrected at multiple levels: (i) VD supplements and/or VD-rich foods need to be consumed to provide adequate VD, and (ii) the body needs to be able to upregulate VD-metabolizing genes to convert VD into 25(OH)VD and then to 1,25(OH)2VD to enhance its metabolic action. This review outlines the association between 25(OH)VD deficiency/inadequacy and decreased GSH levels, highlighting the positive impact of combined VD+LC supplementation on upregulating GSH, VD-metabolizing genes, and VDR. These effects have the potential to enhance 25(OH)VD levels and its therapeutic efficacy.

The Impact of Local Control on Overall Survival after Y-90 Selective Internal Radiotherapy of Liver Metastases in Oligometastatic Cancer: A Retrospective Analysis.

Y-90 Selective Internal Radiotherapy (SIRT) is an ablative therapy used for inoperable liver metastasis. The purpose of this investigation was to examine the impact of local control after SIRT on overall survival (OS) in oligometastatic patients. A retrospective, single-institution study identified oligometastatic patients with ≤5 non-intracranial metastases receiving unilateral or bilateral lobar Y-90 SIRT from 2009 to 2021. The primary endpoint was OS defined from Y-90 SIRT completion to the date of death or last follow-up. Local failure was classified as a progressive disease at the target lesion(s) by RECIST v1.1 criteria starting at 3 months after SIRT. With a median follow-up of 15.7 months, 33 patients were identified who had a total of 79 oligometastatic lesions treated with SIRT, with the majority histology of colorectal adenocarcinoma (n = 22). In total, 94% of patients completed the Y-90 lobectomy. Of the 79 individual lesions treated, 22 (27.8%) failed. Thirteen patients received salvage liver-directed therapy following intrahepatic failure; ten received repeat SIRT. Median OS (mOS) was 20.1 months, and 12-month OS was 68.2%. Intralesional failure was associated with worse 1 y OS (52.3% vs. 86.2%, p = 0.004). These results suggest that intralesional failure following Y-90 may be associated with inferior OS, emphasizing the importance of disease control in low-metastatic-burden patients.

Leveraging community health workers for COVID-19 response in Democratic Republic of Congo, Nigeria, Senegal, and Uganda: roles, barriers, and facilitators.

BACKGROUND: The Corona Virus Disease 2019 (COVID-19) pandemic overwhelmed health systems and disrupted the delivery of health services globally. Community Health Workers (CHWs) play a critical role in linking communities to health systems, supporting the prevention and control of diseases in many low- and middle-income countries. However, their roles, barriers, and facilitators in the response and control of the COVID-19 pandemic have not been well documented. We described the roles of CHWs in the COVID-19 response, including the barriers and facilitators. METHODS: A cross-sectional study design was used to assess the COVID-19 response in the Democratic Republic of Congo (DRC), Nigeria, Senegal, and Uganda. This involved 110 key informant interviews with policymakers, health facility managers, district health managers, and CHWs to understand the role of CHWs in the COVID 19 response, selected purposively. The total sample size was based on information saturation in each of the countries. A document review on the COVID-19 response was also conducted. We searched Google, Google Scholar, and PubMed for published and grey literature. Data from the selected documents were extracted into a Google master matrix in MS Excel and analyzed thematically. RESULTS: In COVID-19 Control, CHWs supported community-based surveillance, contact tracing, risk communication, community mobilization, and home-based care. To support the continuity of other non-COVID-19 services, the CHWs conducted community mobilization, sensitizations, outreaches, referrals, and patient follow-ups. CHWs were challenged by movement restrictions, especially in the initial stages of the lockdown, inadequate PPE, increased workload, low allowances, and motivation. CHW were facilitated by trainings, the development of guidelines, development partners' support/funding, and the provision of personal protective equipment (PPE) and tools. CONCLUSION: CHWs supported both the COVID-19 control and continuity of non-COVID-19 health care during the COVID-19 pandemic. CHWs are a critical resource that must be adequately supported to build resilient health systems.

Enhancing the Carbon Monoxide Oxidation Performance through Surface Defect Enrichment of Ceria-Based Supports for Platinum Catalyst.

Effective synthesis and application of single-atom catalysts on supports lacking enough defects remain a significant challenge in environmental catalysis. Herein, we present a universal defect-enrichment strategy to increase the surface defects of CeO2-based supports through H2 reduction pretreatment. The Pt catalysts supported by defective CeO2-based supports, including CeO2, CeZrOx, and CeO2/Al2O3 (CA), exhibit much higher Pt dispersion and CO oxidation activity upon reduction activation compared to their counterpart catalysts without defect enrichment. Specifically, Pt is present as embedded single atoms on the CA support with enriched surface defects (CA-HD) based on which the highly active catalyst showing embedded Pt clusters (PtC) with the bottom layer of Pt atoms substituting the Ce cations in the CeO2 surface lattice can be obtained through reduction activation. Embedded PtC can better facilitate CO adsorption and promote O2 activation at PtC-CeO2 interfaces, thereby contributing to the superior low-temperature CO oxidation activity of the Pt/CA-HD catalyst after activation.

Defect-Driven Configurational Entropy in the High-Entropy Oxide Li1.5MO3-δ.

Layered lithiated oxides are promising materials for next generation Li-ion battery cathode materials; however, instability during cycling results in poor performance over time compared to the high capacities theoretically possible with these materials. Here we report the characterizations of a Li1.47Mn0.57Al0.13Fe0.095Co0.105Ni0.095O2.49 high-entropy layered oxide (HELO) with the Li2MO3 structure where M = Mn, Al, Fe, Co, and Ni. Using electron microscopy and X-ray spectroscopy, we identify a homogeneous Li2MO3 structure stabilized by the entropic contribution of oxygen vacancies. This defect-driven entropy would not be attainable in the LiMO2 structure sometimes observed in similar materials as a secondary phase owing to the presence of fewer O sites and a 3+ oxidation state for the metal site; instead, a Li2-γMO3-δ is produced. Beyond Li2MO3, this defect-driven entropy approach to stabilizing novel compositions and phases can be applied to a wide array of future cathode materials including spinel and rock salt structures.

Susceptibility gene mutations in germline and tumors of patients with HER2-negative advanced breast cancer.

Germline mutations in BRCA1 and BRCA2 (gBRCA1/2) are required for a PARP inhibitor therapy in patients with HER2-negative (HER2-) advanced breast cancer (aBC). However, little is known about the prognostic impact of gBRCA1/2 mutations in aBC patients treated with chemotherapy. This study aimed to investigate the frequencies and prognosis of germline and somatic BRCA1/2 mutations in HER2- aBC patients receiving the first chemotherapy in the advanced setting. Patients receiving their first chemotherapy for HER2- aBC were retrospectively selected from the prospective PRAEGNANT registry (NCT02338167). Genotyping of 26 cancer predisposition genes was performed with germline DNA of 471 patients and somatic tumor DNA of 94 patients. Mutation frequencies, progression-free and overall survival (PFS, OS) according to germline mutation status were assessed. gBRCA1/2 mutations were present in 23 patients (4.9%), and 33 patients (7.0%) had mutations in other cancer risk genes. Patients with a gBRCA1/2 mutation had a better OS compared to non-mutation carriers (HR: 0.38; 95%CI: 0.17-0.86). PFS comparison was not statistically significant. Mutations in other risk genes did not affect prognosis. Two somatic BRCA2 mutations were found in 94 patients without gBRCA1/2 mutations. Most frequently somatic mutated genes were TP53 (44.7%), CDH1 (10.6%) and PTEN (6.4%). In conclusion, aBC patients with gBRCA1/2 mutations had a more favorable prognosis under chemotherapy compared to non-mutation carriers. The mutation frequency of ~5% with gBRCA1/2 mutations together with improved outcome indicates that germline genotyping of all metastatic patients for whom a PARP inhibitor therapy is indicated should be considered.