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The liquid drop model is an empirical hypothesis established on the idea that nuclei can be thought of as incompressible liquid droplets. The AME2020 dataset was used in this work to determine binding energy using a semi-empirical mass formula and compare it with binding energies predicted by a machine learning algorithm. Random forest regressor, MLPRegressor, and XGBoost models were employed. In terms of accuracy, root mean square error, and mean absolute error, machine learning models performed better than the semi-empirical mass formula. Compared to RFR, XGBoost, and SEMF, MLPRegressor performed better in predicting binding energies for lighter nuclei. Using estimated binding energies, nuclear masses were computed, and it was shown that all three models adequately predicted nuclear masses with minimal error. This finding highlights how machine learning can be applied to nuclear physics to predict various nuclei’s properties.

We present a case report of a 55-year-old woman who had a femoral vein intravascular papillary endothelial hyperplasia that required excision of the mass and subsequent repair of the right femoral vein using her right anterior accessory saphenous vein. She first presented with findings of a non-occlusive deep vein thrombus. However, after 6 months of persistent and enlarging mass with subsequent intravascular component on a follow-up duplex scan, a decision was made to bring her to the operating room for exploration and excision.

IntroductionMyalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) presents substantial challenges in patient care due to its intricate multisystem nature, comorbidities, and global prevalence. The heterogeneity among patient populations, coupled with the absence of FDA-approved diagnostics and therapeutics, further complicates research into disease etiology and patient managment. Integrating longitudinal multi-omics data with clinical, health,textual, pharmaceutical, and nutraceutical data offers a promising avenue to address these complexities, aiding in the identification of underlying causes and providing insights into effective therapeutics and diagnostic strategies.MethodsThis study focused on an exceptionally severe ME/CFS patient with hypermobility spectrum disorder (HSD) during a period of marginal symptom improvements. Longitudinal cytokine profiling was conducted alongside the collection of extensive multi-modal health data to explore the dynamic nature of symptoms, severity, triggers, and modifying factors. Additionally, an updated severity assessment platform and two applications, ME-CFSTrackerApp and LexiTime, were introduced to facilitate real-time symptom tracking and enhance patient-physician/researcher communication, and evaluate response to medical intervention.ResultsLongitudinal cytokine profiling revealed the significance of Th2-type cytokines and highlighted synergistic activities between mast cells and eosinophils, skewing Th1 toward Th2 immune responses in ME/CFS pathogenesis, particularly in cognitive impairment and sensorial intolerance. This suggests a potentially shared underlying mechanism with major ME/CFS comorbidities such as HSD, Mast cell activation syndrome, postural orthostatic tachycardia syndrome (POTS), and small fiber neuropathy. Additionally, the data identified potential roles of BCL6 and TP53 pathways in ME/CFS etiology and emphasized the importance of investigating adverse reactions to medication and supplements and drug interactions in ME/CFS severity and progression.DiscussionOur study advocates for the integration of longitudinal multi-omics with multi-modal health data and artificial intelligence (AI) techniques to better understand ME/CFS and its major comorbidities. These findings highlight the significance of dysregulated Th2-type cytokines in patient stratification and precision medicine strategies. Additionally, our results suggest exploring the use of low-dose drugs with partial agonist activity as a potential avenue for ME/CFS treatment. This comprehensive approach emphasizes the importance of adopting a patient-centered care approach to improve ME/CFS healthcare management, disease severity assessment, and personalized medicine. Overall, these findings contribute to our understanding of ME/CFS and offer avenues for future research and clinical practice.

Summary: The brain receives constant tactile input, but only a subset guides ongoing behavior. Actions associated with tactile stimuli thus endow them with behavioral relevance. It remains unclear how the relevance of tactile stimuli affects processing in the somatosensory (S1) cortex. We developed a cross-modal selection task in which head-fixed mice switched between responding to tactile stimuli in the presence of visual distractors or to visual stimuli in the presence of tactile distractors using licking movements to the left or right side in different blocks of trials. S1 spiking encoded tactile stimuli, licking actions, and direction of licking in response to tactile but not visual stimuli. Bidirectional optogenetic manipulations showed that sensory-motor activity in S1 guided behavior when touch but not vision was relevant. Our results show that S1 activity and its impact on behavior depend on the actions associated with a tactile stimulus.

Anaerobic in vitro fermentation is widely used to simulate rumen kinetics and study the microbiome and metabolite profiling in a controlled lab environment. However, a better understanding of the interplay between the temporal dynamics of fermentation kinetics, metabolic profiles, and microbial composition in in vitro rumen fermentation batch systems is required. To fill that knowledge gap, we conducted three in vitro rumen fermentations with maize silage as the substrate, monitoring total gas production (TGP), dry matter degradability (dDM), and methane (CH4) concentration at 6, 12, 24, 36, and 48 h in each fermentation. At each time point, we collected rumen fluid samples for microbiome analysis and volatile fatty acid (VFA) analysis. Amplicon sequencing of 16S rRNA genes (V4 region) was used to profile the prokaryotic community structure in the rumen during the fermentation process. As the fermentation time increased, dDM, TGP, VFA concentrations, CH4 concentration, and yield (mL CH4 per g DM at standard temperature and pressure (STP)) significantly increased. For the dependent variables, CH4 concentration and yield, as well as the independent variables TGP and dDM, polynomial equations were fitted. These equations explained over 85% of the data variability (R2 > 0.85) and suggest that TGP and dDM can be used as predictors to estimate CH4 production in rumen fermentation systems. Microbiome analysis revealed a dominance of Bacteroidota, Cyanobacteria, Desulfobacterota, Euryarchaeota, Fibrobacterota, Firmicutes, Patescibacteria, Proteobacteria, Spirochaetota, and Verrucomicrobiota. Significant temporal variations in Bacteroidota, Campylobacterota, Firmicutes, Proteobacteria, and Spirochaetota were detected. Estimates of alpha diversity based on species richness and the Shannon index showed no variation between fermentation time points. This study demonstrated that the in vitro fermentation characteristics of a given feed type (e.g., maize silage) can be predicted from a few parameters (CH4 concentration and yield, tVFA, acetic acid, and propionic acid) without running the actual in vitro trial if the rumen fluid is collected from similar donor cows. Although the dynamics of the rumen prokaryotes changed remarkably over time and in accordance with the fermentation kinetics, more time points between 0 and 24 h are required to provide more details about the microbial temporal dynamics at the onset of the fermentation.

In recent times, nanoparticles have experienced a significant upsurge in popularity, primarily owing to their minute size and their remarkable ability to modify physical, chemical, and biological properties. This burgeoning interest can be attributed to the expanding array of biomedical applications where nanoparticles find utility. These nanoparticles, typically ranging in size from 10 to 100 nm, exhibit diverse shapes, such as spherical, discoidal, and cylindrical configurations. These variations are not solely influenced by the manufacturing processes but are also intricately linked to interactions with surrounding stabilizing agents and initiators. Nanoparticles can be synthesized through physical or chemical methods, yet the biological approach emerges as the most sustainable and eco-friendly alternative among the three. Among the various nanoparticle types, silver nanoparticles have emerged as the most encountered and widely utilized due to their exceptional properties. What makes the synthesis of silver nanoparticles even more appealing is the application of plant-derived sources as reducing agents. This approach not only proves to be cost-effective but also significantly reduces the synthesis time. Notably, silver nanoparticles produced through plant-mediated processes have garnered considerable attention in recent years due to their notable medicinal capabilities. This comprehensive review primarily delves into the diverse medicinal attributes of silver nanoparticles synthesized using plant-mediated techniques. Encompassing antimicrobial properties, cytotoxicity, wound healing, larvicidal effects, anti-angiogenesis activity, antioxidant potential, and antiplasmodial activity, the paper extensively covers these multifaceted roles. Additionally, an endeavor is made to provide an elucidated summary of the operational mechanisms underlying the pharmacological actions of silver nanoparticles.

Background: This study aimed to investigate the impact of in vitro rumen fermentation (IVRF) on the microbiome structure and composition of rumen fluid before and after fermentation assays. Methods and Results: Six separate fermentation batches were run for 48 h using maize silage as the basal feed. Rumen fluid samples were analyzed before (RF; only rumen fluid inoculant) and after 48 h fermentation assay (MS; maize silage as the substrate) and further processed for microbiome analysis using amplicon sequencing targeting the V4 region of the bacterial 16S rRNA gene. Bacterial alpha diversity revealed that the Shannon index and observed index were similar between MS and RF fluid. The core microbiome was detected in 88.6% of the amplicon sequence variants in MS and RF. Taxonomic analysis at the phylum level showed similar abundances of Bacteroidetes, Proteobacteria, Firmicutes, Verrucomicrobiota, Spirochaetota, Patescibacteria, and Campilobacterota in MS and RF. The Bray–Curtis distance matrix showed similar bacterial community structure among MS and RF samples. Conclusion: Our results indicated that the in vitro procedure did not affect the bacterial community structure compared to the original rumen fluid inoculum. It should be noted that assessing the microbiome at a single endpoint (i.e., 48 h) may not provide a comprehensive understanding of the microbiome profile dynamics. However, the findings of this study provide a basis for future microbiome-based in vitro fermentation tests and confirm that the technique allows a high degree of species diversity that approximates the rumen function in vivo.

Integration between public health and primary care is rising on the health policy agenda but the terms and concepts involved can be confusing. This article reviews the relevant literature and presents a new framework to help policymakers think through what they are aiming to achieve and why. We unpack different degrees and types of integration and show how they fit together. We argue that the merger of public health and primary care into a single entity with one aim, budget, and one multidisciplinary team isn't necessarily the desired end-point for most health systems, but that seamless collaboration will likely improve patient and health system outcomes, save resources, and improve population outcomes. We recommend that efforts to foster better collaboration should take an activity-based approach, promoting alignment of teams, training, budgets, values and culture around specific tasks, and in proportion to need., (Copyright © 2024, The Authors.)

The policy-making process for health financing in most places lacks equity, failing to adequately consider the voices of ordinary citizens, residents, and especially those facing significant disadvantage. Procedural fairness is about addressing this imbalance, which requires a recalibration of power dynamics, ensuring that decision-making incorporates a more diverse range of perspectives. In this comment, we highlight the important contributions made by the report 'Open and inclusive: Fair processes for financing universal health coverage' in furthering the understanding and importance of procedural fairness in health financing decision-making especially as it relates to the three sub-functions of financing - revenue raising, pooling, and purchasing. We also argue for the importance of conceptual clarity - especially as to the added value of procedural fairness vis-à-vis accountability - and critically review the proposed framework for procedural fairness, emphasising the role of voice as the linchpin to advancing equity in influence.

A more accurate descriptive and clinically useful diagnosis based upon pathophysiology for what is commonly referred to as venous outflow stenosis is inflow-outflow imbalance. In these cases, the total outflow capacity of the AV access is inadequate to handle the inflow volume (Qa) without an increase in pressure. The relative inadequacy of the access outflow capacity in comparison to Qa results in increased outflow resistance and a proportional increase in intraluminal pressure. The clinical indicators associated with venous stenosis are the resulting manifestations of this imbalance. The point at which this occurs is dependent upon variations in these two parameters-Qa and outflow resistance. The variations in these two parameters are considerable and reciprocal. Excessive Qa results in or can lead to an entire list of serious problems that adversely affect patient morbidity and mortality. Most studies dealing with AV access Qa reduction have been for the treatment of an existing condition rather than its prevention; however, prevention of disease rather than waiting for its development is an important tenet of medical practice. The resulting clinical picture of inflow-outflow imbalance is taken as an indication for corrective treatment. In the past, in most cases this has meant angioplasty to open the outflow if it is reduced; however, this clinical picture may be associated with an excessive Qa and angioplasty in these cases creates the risk for a further increase in Qa. It is the authors' opinion that access flow measurements should be a part of the evaluation of these cases prior to planning treatment. Using this information, a bimodal approach to primary treatment should be adopted involving either angioplasty for cases with a low or normal Qa or flow reduction in cases with an elevated Qa., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: Obliteration of the round window (RW) in cases of otosclerosis presents a significant clinical challenge due to its association with more severe hearing loss and a poorer prognosis for functional recovery after stapes surgery. The objective is to assess and characterize the occurrence of RW involvement in otosclerosis cases and to identify patterns of disease progression that may indicate a potential for RW obliteration., Methods: We selected archival temporal bones from donors with otosclerosis. We evaluated the degree of RW obliteration using a semi-quantitative scale and the location of the foci within the temporal bone, and whether the foci were continuous or isolated., Results: Most of the foci were located anteriorly to the oval window (89.2%), while RW area involvement was seen in 26.9% of the ears. In cases with fenestral foci, 68.1% directly involved and/or fixed the footplate. Among donors with bilateral otosclerosis, foci affected both ears in a similar pattern in 64.2%. Among donors with RW involvement, ones with continuous, large lesions that extended from the oval window associated with complete RW obliteration, while ones with smaller degrees of obliteration had solitary foci scattered within the otic capsule., Conclusion: Our results demonstrate a high rate of RW involvement in cases of otosclerosis. Ears with continuous lesions extending from the oval window region to the RW area were more likely to present with complete RW obliteration. These results provide insights that could lead to better prognostic assessment of patients with otosclerosis in the future., Level of Evidence: N/A Laryngoscope, 2024., (© 2024 The Author(s). The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

The study of evolution at the cellular level traditionally has focused on the evolution of metabolic pathways, endomembrane systems, and genomes, but there has been increasing interest in evolution of more complex cellular structures and behaviors, particularly in the eukaryotes. Ciliates have major advantages for such studies due to their easily visible surface patterning and their dramatic and complex behaviors that can be easily analyzed. Among the ciliates, the genus Stentor epitomizes the features that are useful for studying evolution: they are widespread in freshwater environments, easy to visualize because of their large size, and capable of complex behaviors such as learning, decision-making, and phototaxis. Here, we introduce the discovery of a new species within this genus: Stentor stipatus , so named for their distinctive dark brown aggregates. We present morphological, phylogenetic, ecological, and behavioral characterizations of these cells. The S. stipatus clade has a bootstrap value of 93 and is phylogenetically distinct from S. amethystinus , the closest related species which shares a sequence similarity of 98.9%. S. stipatus is capable of phototaxis and can also habituate more quickly than S. coeruleus , the Stentor species in which most habituation studies have previously been conducted. These findings expand our understanding of Stentor species diversity, natural history, and demonstrate common principles of complex behavior that are present in single-celled organisms.

Background: Gel-based autologous chondrocyte implantation (GACI) enables a simpler and more effective delivery of chondrocytes with reproducible three-dimensional structural restoration of the articular cartilage surface. There is limited documentation of medium-term outcomes. This study assessed safety and effectiveness of GACI for treatment of cartilage defects of the knee., Methods: This multicentric retrospective study was conducted across eight hospitals in India. Patients who had undergone GACI (CARTIGROW®) between 2008 and 2014 for the treatment of focal articular cartilage defects of the knee (mean defect size 4.5 ± 5.8 cm 2 ) in limbs with normal alignment were analyzed. Primary outcomes were changes in Lysholm Knee Scoring Scale score, and Knee Outcome Sports Activity Scale (SAS)., Results: A total of 107 patients (110 knee joints) with mean age 31.0 ± 10.5 years were included. The mean follow-up was 9.8 ± 1.5 years (range 7.85-13.43). Majority had osteochondritis dissecans (n = 51; 46.4%). The mean Lysholm Knee Scoring Scale score (81.23 ± 13.21 vs. 51.32 ± 17.89; p < 0.0001) and SAS score (80.93 ± 8.26 vs. 28.11 ± 12.28; p < 0.0001) improved significantly at follow-up as compared to pre-operative. Magnetic Resonance Observation of Cartilage Repair Tissue score in 39 patients at minimum 2 years follow-up was 84.5 ± 4.3. Among 30 patients who were playing sports before treatment, 17 patients (56.7%) could return to the same or higher level of sports post-transplantation. No major intra-operative or post-operative complications were noted. Four patients warranted revision surgery., Conclusion: GACI is an effective treatment option for large focal articular cartilage defects of the knee with a low complication rate and revision rate and significant improvement in functional scores., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Mesenchymal stromal cells (MSCs) are investigated as cellular therapeutics for inflammatory bowel diseases and associated perianal fistula, although consistent efficacy remains a concern. Determining host factors that modulate MSCs' potency including their secretion of angiogenic and wound-healing factors, immunosuppression, and anti-inflammatory properties are important determinants of their functionality. We investigated the mechanisms that regulate the secretion of angiogenic and wound-healing factors and immune suppression of human bone marrow MSCs. Secretory analysis of MSCs focusing on 18 angiogenic and wound-healing secretory molecules identified the most abundancy of vascular endothelial growth factor A (VEGF-A). MSC viability and secretion of other angiogenic factors are not dependent on VEGF-A secretion which exclude the autocrine role of VEGF-A on MSC's fitness. However, the combination of inflammatory cytokines IFNγ and TNFα reduces MSC's VEGF-A secretion. To identify the effect of intestinal microvasculature on MSCs' potency, coculture analysis was performed between human large intestine microvascular endothelial cells (HLMVECs) and human bone marrow-derived MSCs. HLMVECs do not attenuate MSCs' viability despite blocking their VEGF-A secretion. In addition, HLMVECs neither attenuate MSC's IFNγ mediated upregulation of immunosuppressive enzyme indoleamine 2,3-dioxygenase nor abrogate suppression of T-cell proliferation despite the attenuation of VEGF-A secretion. We found that HLMVECs express copious amounts of endothelial nitric oxide synthase and mechanistic analysis showed that pharmacological blocking reverses HLMVEC-mediated attenuation of MSC's VEGF-A secretion. Together these results suggest that secretion of VEGF-A and immunosuppression are separable functions of MSCs which are regulated by distinct mechanisms in the host., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Pontocerebellar hypoplasia (PCH) may present with supratentorial phenotypes and is often accompanied by microcephaly. Damaging mutations in the X-linked gene CASK produce self-limiting microcephaly with PCH in females but are often lethal in males. CASK deficiency leads to early degeneration of cerebellar granule cells but its role in other regions of the brain remains uncertain., Method: We generated a conditional Cask knockout mice and deleted Cask ubiquitously after birth at different times. We examined the clinical features in several subjects with damaging mutations clustered in the central part of the CASK protein. We have performed phylogenetic analysis and RT-PCR to assess the splicing pattern within the same protein region and performed in silico structural analysis to examine the effect of splicing on the CASK's structure., Result: We demonstrate that deletion of murine Cask after adulthood does not affect survival but leads to cerebellar degeneration and ataxia over time. Intriguingly, damaging hemizygous CASK mutations in boys who display microcephaly and cerebral dysfunction but without PCH are known. These mutations are present in two vertebrate-specific CASK exons. These exons are subject to alternative splicing both in forebrain and hindbrain. Inclusion of these exons differentially affects the molecular structure and hence possibly the function/s of the CASK C-terminus., Conclusion: Loss of CASK function disproportionately affects the cerebellum. Clinical data, however, suggest that CASK may have additional vertebrate-specific function/s that play a role in the mammalian forebrain. Thus, CASK has an ancient function shared between invertebrates and vertebrates as well as novel vertebrate-specific function/s., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To conduct a systematic review on the effects of multisectoral interventions for health on health system performance., Methods: We conducted a systematic review according to the preferred reporting items for systematic review and meta-analysis protocols. We searched for peer-reviewed journal articles in PubMed®, Scopus, Web of Science, Cumulated Index to Nursing and Allied Health Literature, and the Cochrane Database of Systematic Reviews on 31 August 2023 (updating on 28 February 2024). We removed duplicates, screened titles and abstracts, and then conducted a full-text eligibility and quality assessment., Findings: We identified an initial 1118 non-duplicate publications, 62 of which met our inclusion and exclusion criteria. The largest proportions of reviewed studies focused on multisectoral interventions directly related to specific health outcomes (66.1%; 41 studies) and/or social determinants of health (48.4%; 30 studies), but without explicit reference to overall health system performance. Most reviewed publications did not address process indicators (83.9%; 52/62) or discuss sustainability for multisectoral interventions in health (72.6%; 45/62). However, we observed that the greatest proportion (66.1%; 41/62) considered health system goals: health equity (68.3%; 28/41) and health outcomes (63.4%; 26/41). Although the greatest proportion (64.5%; 40/62) proposed mechanisms explaining how multisectoral interventions for health could lead to the intended outcomes, none used realistic evaluations to assess these., Conclusion: Our review has established that multisectoral interventions influence health system performance through immediate improvements in service delivery efficiency, readiness, acceptability and affordability. The interconnectedness of these effects demonstrates their role in addressing the complexities of modern health care., ((c) 2024 The authors; licensee World Health Organization.)

Metachromatic leukodystrophy (MLD) is a fatal, progressive neurodegenerative disorder caused by biallelic pathogenic mutations in the ARSA (Arylsulfatase A) gene. With the advent of presymptomatic diagnosis and the availability of therapies with a narrow window for intervention, it is critical to define a standardized approach to diagnosis, presymptomatic monitoring, and clinical care. To meet the needs of the MLD community, a panel of MLD experts was established to develop disease-specific guidelines based on healthcare resources in the United States. This group developed a consensus opinion for best-practice recommendations, as follows: (i) Diagnosis should include both genetic and biochemical testing; (ii) Early diagnosis and treatment for MLD is associated with improved clinical outcomes; (iii) The panel supported the development of newborn screening to accelerate the time to diagnosis and treatment; (iv) Clinical management of MLD should include specialists familiar with the disease who are able to follow patients longitudinally; (v) In early onset MLD, including late infantile and early juvenile subtypes, ex vivo gene therapy should be considered for presymptomatic patients where available; (vi) In late-onset MLD, including late juvenile and adult subtypes, hematopoietic cell transplant (HCT) should be considered for patients with no or minimal disease involvement. This document summarizes current guidance on the presymptomatic monitoring of children affected by MLD as well as the clinical management of symptomatic patients. Future data-driven evidence and evolution of these recommendations will be important to stratify clinical treatment options and improve clinical care., Competing Interests: Declaration of Competing Interest No honorarium, grant, or other form of payment was received to produce the manuscript. LAA is a consultant to Biogen, Takeda Pharmaceuticals, Orchard Therapeutics, is a site subinvestigator for the Takeda trial, and serves on the scientific advisory board of Cure MLD and MLD Foundation; JLB is a site principal investigator for the Takeda SHP611 trial; JJB has received consulting fees from Sobi, Omeros, Bluebird Bio, Sanofi, SmartImmune, Merck and Bluerock; EM has no conflicts of interest to disclose; RAN has no conflicts of interest to disclose; JAB is a site principal investigator for the Takeda SHP611 trial; AB is site subinvestigator for the Takeda SHP611 trial and received travelling support by Orchard-Tx; BB is a site principal investigator for the Takeda SHP611 trial and is a consultant to Aro, AlltRNA, Orchard Therapeutics, Astella, Passage Bio, Biomarin, PTC Therapeutics, JCR Pharma, Takeda; received honoraria from Astra Zeneca, Biomarin, Chiesi, Horizon, JCR Pharma; grant funding from Biomarin Pharmaceutical, Takeda, Homology Medicines, Denali Therapeutics, Sangamo, JCR Pharma, and Ultragenyx; AD has participated in an advisory board organized by Orchard Therapeutics; FE has <1% equity in Swan Bio, and royalties from AAV9 license for AMN; receives consulting fees from Leal Therapeutics, Swan Bio, Ionis, Minoryx, UptoDate, Origen, Takeda Therapeutics and Third Rock Ventures; founder and consultant of Swan Bio and serves on the chair on the advisory board of European Leukodystrophy Association, and as a board member at United Leukodystrophy Foundation; EE has participated in several advisory boards arranged by Orchard Therapeutics; LE serves on the advisory board for Ionis pharmaceuticals; ME is Chief Medical Officer at Forge Biologics; AF receives research support from SwanBio, Autobahn Therapeutics, Poxel Therapeutics, Vertex Pharmaceuticals, and Maryland Stem Cell Research Fund, was a Data and Safety Monitoring Board (DSMB) member for BlueBird Bio, and coinvented a patent currently licensed to Ashvattha; JF is a consultant for GeneDx, Educational Consultant on the Impact of Exome and Genome Sequencing in Well-Phenoptyped Populations and is Chair of the Maryland Secretary's Advisory Council on Hereditary and Congenital Disorders; AG has received payment or honoraria from Spark Therapeutics and Orchard Therapeutics, consulting fees from Takeda; chair of the MN Rare Disease Advisory Council and the Clinical and Laboratory Standards Institute; SK is a clinical trial site principal investigator for Ionis and was a consultant for Veristat; MCP is the site principal investigator for clinical trials funded by Azafaros, Glycomine, Idorsia, Maggie's Pearl, Takeda, and Zevra, and has consulted for Azafaros, Takeda, and Zevra; serves as editor in chief of the Journal of Child Neurology and an editor for JIMD, and royalties as section editor for up to date; PO is a consultant to Orchard Therapeutics, serves on a DSMB for Ionis, and has clinical trial support from Immusoft and Allovir; JOM is a consultant to Novoglia and site principal investigator for Vigil Neuroscience; JDS is a consultant to Biogen and Cycle Pharma; LS is a consultant to Vico Therapeutics and a site principal investigator for trials of Vigil Neuroscience, Stealth Biotherapeutics and PTC Therapeutics; CS is PI of the Takeda clinical trial and consultant for Orchard Therapeutics; INS has no conflicts of interest to disclose; DR is site PI for the Takeda trial; JPR has no conflicts of interest to disclose; KVH is a consultant for Bluebird bio and Poxel, a site PI for trials funded by Minoryx, Bluebird bio, IONIS and a trial advisor for Calico; MW has received research support from Abeona Therapeutics, Alexion Pharmaceuticals, the Ara Parseghian Medical Research Foundation, BioMarin Pharmaceutical, Cure Sanfilippo Foundation, Dana's Angels Research Trust, Firefly Fund, Mirum Pharma, Noah's Hope, Orchard Therapeutic, Passage Bio, Sanofi Genzyme, Sio Gene Therapies, Takeda Pharmaceutical, Travere Therapeutics, and Ultragenyx Pharmaceutical; has received consulting fees from Sanofi Genzyme; AZ is a site subinvestigator for the Takeda trial; FF is License holder of OTL-200, I Orchard Therapeutics trial, advisor Orchard, Takeda, funding Telethon Foundation, GSK, Orchard; LL has no conflicts of interest to disclose; AV is an advisor to Takeda, Passagebio, Orchard; and is site PI Takeda trial., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

While alterations in nucleus size, shape, and color are ubiquitous in cancer, comprehensive quantification of nuclear morphology across a whole-slide histologic image remains a challenge. Here, we describe the development of a pan-tissue, deep learning-based digital pathology pipeline for exhaustive nucleus detection, segmentation, and classification and the utility of this pipeline for nuclear morphologic biomarker discovery. Manually-collected nucleus annotations were used to train an object detection and segmentation model for identifying nuclei, which was deployed to segment nuclei in H&E-stained slides from the BRCA, LUAD, and PRAD TCGA cohorts. Interpretable features describing the shape, size, color, and texture of each nucleus were extracted from segmented nuclei and compared to measurements of genomic instability, gene expression, and prognosis. The nuclear segmentation and classification model trained herein performed comparably to previously reported models. Features extracted from the model revealed differences sufficient to distinguish between BRCA, LUAD, and PRAD. Furthermore, cancer cell nuclear area was associated with increased aneuploidy score and homologous recombination deficiency. In BRCA, increased fibroblast nuclear area was indicative of poor progression-free and overall survival and was associated with gene expression signatures related to extracellular matrix remodeling and anti-tumor immunity. Thus, we developed a powerful pan-tissue approach for nucleus segmentation and featurization, enabling the construction of predictive models and the identification of features linking nuclear morphology with clinically-relevant prognostic biomarkers across multiple cancer types., (© 2024. The Author(s).)

Objectives: Although previous research has indicated inner ear changes in diabetes mellitus (DM) patients, no prior study has explored the middle ear, particularly the ossicles and their joints, in DM patients. This study aimed to investigate whether type 2 DM is associated with middle ear changes, specifically affecting the ossicular chain and joints., Methods: This study included 47 ears from 25 patients with DM (male = 13, female = 12, age: 51.0 ± 20.5) and age- and sex-matched controls (male = 10, female = 10, age: 54.8 ± 15.9) (sex; p = 1.000, Age; p = 0.991). Otopathological evaluations of the auditory ossicles and incudomalleolar joint (IMJ) were performed using light microscopy., Results: In the IMJ of DM cases, malleus hyalinized cartilage (Malleus hC) and incus hyalinized cartilage (Incus hC) were significantly increased compared with control cases (Malleus hC; DM, 34.17 ± 9.71 μm vs. control 21.96 ± 4.16 μm, p < 0.001) (Incus hC; DM 35.11 ± 10.12 μm vs. control 22.42 ± 4.368 μm, p < 0.001). In addition, bone-line distance was significantly longer than in DM cases than control cases (DM 266.72 ± 59.11 μm vs. control 239.81 ± 35.56 μm p = 0.040). On the other hand, joint discus distance was longer in the control group than in DM cases (DM 96.84 ± 36.80 μm vs. Control 113.63 ± 23.81 μm, p = 0.001)., Conclusions: This study reveals a notable increase in the hyalinized cartilage layer and bone-line distance accompanied by reducing joint discus distance within the IMJ in DM cases. These findings suggest that DM may influence microjoints, such as the IMJ, and potentially impact auditory function., Evidence Level: N/A Laryngoscope, 134:2871-2878, 2024., (© 2024 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Competing Interests: No declaration of competing interests.

Background and objectives Direct pulp capping (dPC) is a therapeutic process that involves the application of a protective chemical to an exposed pulp with the intent to facilitate the restoration and preservation of its vitality and function. Despite numerous proposed solutions, researchers have yet to find a dependable, non-absorbable bioactive pulp capping substance that constantly activates cellular healing processes, consequently preserving pulpal vitality over an extended period of time. The objective of this study was to assess and contrast the efficacy of a novel tricalcium silicate cement and calcium hydroxide in preserving the long-term health of the dental pulp following dPC using clinical and radiographic observations. Materials and methods A total of 60 individuals with symptoms of reversible pulpitis associated with deep carious lesions were chosen for dPC in the study. Two groups comprising 30 patients each underwent dPC using the novel tricalcium silicate cement (experimental group) and calcium hydroxide (control group) out of the total number of patients. A thin protective covering of self-curing glass ionomer base was applied on top of the capping material. The dentist provided instant permanent restoration employing direct posterior composite resin. Follow-up examinations were conducted three, six, nine, and 12 months after the procedure, during which assessments were performed using clinical and radiographic parameters. Results The minimum age of the study group was 16, and its maximum age was 34 (22.35 ± 2.3 years). The control group consisted of 12 males and 18 females, while the Biodentine group consisted of 13 males and 17 females. The age and gender distribution were determined to have insignificant statistical differences across the groups. The pain score exhibited statistical significance at both the three-month and six-month follow-up visits (p < 0.05). The pain score at the 12-month follow-up was 0.38 ± 0.52 in the case group and 0.42 ± 0.61 in the control group (p = 0.79). The average Periapical Index (PAI) score for the Dycal and Biodentin groups after the 12-month follow-up was 1.38 ± 0.97 and 1 ± 0.3, respectively. This difference was found to be statistically significant (p = 0.044). In addition, there was a statistically significant difference in the PAI score at the three-month, six-month, and nine-month follow-ups (p < 0.01). During the entirety of the follow-up duration, one individual in the Biodentine group had tenderness upon percussion, a negative reaction for pulp vitality, pulpal changes, and a widening of the periodontal space. Statistically significant differences were observed in pulpal changes and tenderness on percussion during the nine-month and 12-month follow-up periods (p < 0.05). After 12 months, the rate of success in the group treated with Dycal was 91.3%, while the success percentage in the group treated with Biodentine was 98.55%. This difference in outcomes was determined to be statistically significant (λ 2 = 5.46; p = 0.019). Conclusion The study findings indicate that Biodentine, a novel tricalcium silicate cement, outperforms calcium hydroxide in preserving pulp vitality over the long term following dPC. The Biodentine group attained an overall success rate of 98.55%, whereas the Dycal group had a success rate of 91.3% following 12 months of subsequent follow-up visits., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Shaji et al.)

Introduction: The increased use of soft drinks leads to a high prevalence of dental erosion (DE), and the use of polymers can decrease tooth demineralization by a carbonated drink. Assessment of the effect of food-approved polymers such as highly esterified pectin (HP), propylene glycol alginate (PGA), and gum arabic (GA) on their efficiency to reduce enamel demineralization on addition with a commercially available carbonated drink was the main objective of this study., Materials and Methods: For this study, 300 premolar teeth were studied for enamel erosion and were divided into five groups consisting of 60 samples in each group. The teeth treated with distilled water had negative control, a commercially available carbonated drink with pH 2.7 had positive control, and food polymers were added individually to the carbonated drink in a specified quantity with minimal pH change and were taken as groups A, B, and C, respectively. The enamel erosion that occurred in study groups was measured using a laser fluorescence spectroscopic system with laser excitation at 404 nm at different treatment times (30, 60, and 120 seconds).  Results: Demineralization was less in samples treated with polymer added to carbonated drink solutions compared to samples exposed to plain carbonated drink. As the time of exposure increased up to 120 seconds, a significant decrease in demineralization occurred in polymer-treated groups of samples as against plain carbonated drink with HP showing more decreased demineralization with extended exposure periods compared to other polymers. The surface morphology of tooth samples exhibited the anti-erosive effect of polymers, and the scanning electron microscopic pictures revealed a smoother surface for the polymer-added group., Conclusion: This study shows the efficacy of HP, PGA, and GA on reducing the effect of carbonated drink-induced enamel demineralization, and these polymers' addition to drinks can be an innovative way to reduce the demineralization potential of carbonated acidic drinks., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, George et al.)

In recent times, usage of pesticide, herbicides and synthetic fertilizers in farming lands has made the environment worse. The pesticide residues and toxic byproducts from agricultural lands were found to contaminate the aquatic ecosystem. The misuse of synthetic pesticide not only affects the environment, but also affects the health status of aquatic organisms. The organophosphate pesticide pollutants are emerging contaminants, which threatens the terrestrial and aquatic ecosystem. Monocrotophos (MCP) is an organophosphate insecticide, utilized on crops including rice, maize, sugarcane, cotton, soybeans, groundnuts and vegetables. MCP is hydrophilic in nature and their solubilizing properties reduce the soil sorption which leads to groundwater contamination. The half-life period of MCP is 17-96 and the half-life period of technical grade MCP is 2500 days if held stable at 38 °C in a container. MCP causes mild to severe confusion, anxiety, hyper-salivation, convulsion and respiratory distress in mammals as well as aquatic animals. The MCP induced toxicity including survival rate, behavioural changes, reproductive toxicity and genotoxicity in different aquatic species have been discussed in this review. Furthermore, the ultimate aim of this review is to highlight the international regulations, future perspectives and challenges involved in using the MCP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Abstract: This article discusses a case of cochlear otosclerosis leading to secondary hydrops and near-complete hearing loss. Histopathological examination revealed advanced multifocal otosclerosis in both temporal bones, with specific focus on cochlear invasion and significant bone resorption. The severity of the case ruled out surgical intervention due to the risk of further hearing loss. The article emphasizes the challenges in managing otosclerosis-related hydrops and highlights the potential use of advanced imaging techniques for diagnosis. The study underscores the complexity of otosclerosis-induced hearing loss, contributing to the understanding of this pathology and its impact on auditory function., Competing Interests: Conflicts of interest: The authors disclose no conflicts of interest., (Copyright © 2024, Otology & Neurotology, Inc.)

Indium phosphide (InP) quantum dots (QDs) have recently garnered considerable interest in the design of bioprobes due to their non-toxic nature and excellent optical properties. Several attempts for the conjunction of InP QDs with various entities such as organic dyes and dye-labeled proteins have been reported, while that with fluorescent proteins remains largely uncharted. This study reports the development of a Förster resonance energy transfer pair comprising glutathione-capped InP/GaP/ZnS QDs [InP(G)] and the fluorescent protein mCherry. Glutathione on InP(G) undergoes effective bioconjugation with mCherry consisting of a hexahistidine tag, and the nonradiative energy transfer is investigated using steady-state and time-resolved measurements. Selective one-photon excitation of InP(G) in the presence of mCherry shows a decay of the emission of the QDs and a concomitant growth of acceptor emission. Time-resolved investigations prove the nonradiative transfer of energy between InP(G) and mCherry. Furthermore, the scope of two-photon-induced energy transfer between InP(G) and mCherry is investigated by exciting the donor in the optical transparency range. The two-photon absorption is confirmed by the quadratic relationship between the emission intensity and the excitation power. In general, near-infrared excitation provides a path for effective light penetration into the tissues and reduces the photodamage of the sample. The two-photon-induced energy transfer in such assemblies could set the stage for a wide range of biological and optoelectronic applications in the foreseeable future., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

The outer membrane lipase (oml) gene, encoding a novel autotransporter-dependent lipase from Pseudomonas guariconensis, was cloned and sequenced. The oml gene has an open reading frame of 1866 bp. It encodes the 621 amino acid autotransporter-dependent GDSL lipase (OML), which has the highest sequence similarity (64.08 %) with the EstA of Pseudomonas aeruginosa (PDB:3kvn.1. A). OML was expressed and purified, which showed a purified band of approximately 70 kDa. The purified enzyme showed maximum activity at pH 9 and 40 °C. Substrate specificity studies and kinetic study by Lineweaver-Burk plot of purified OML showed K m of 1.27 mM and Vmax of 333.33 U/mL with p-nitrophenyl palmitate. The purified enzyme showed good stability in the presence of hexane, methanol, and ethanol, while the presence of the metal ion Mg 2+ showed maximum lipase activity. Bioinformatics analysis supported the in vitro findings by predicting enzyme substrate specificity towards long-chain fatty acids and fatty acids with shorter chain lengths. The stability of the interaction of the protein-ligand complex (OML-ricinoleic acid) was confirmed using MDS and castor oil bioconversion using purified OML was confirmed using High-Performance Liquid Chromatography (HPLC)., Competing Interests: Declaration of competing interest The authors declare no conflict of interest in publishing this article in this journal., (Copyright © 2023 Elsevier B.V. All rights reserved.)