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Deals with a study which evaluated the effectiveness of trimethoprim-sulfamethoxazole for the treatment of uncomplicated urinary tract infections. Patients and methods; Results; Discussion.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), still remains one of the leading causes of mortality worldwide. The elusive nature of this pathogen and its ability to develop drug resistance makes it a serious threat to global health. BCG, the only preventive vaccine for TB, has a limited efficacy and provides partial protection against the disease. A new effective recombinant vaccine capable of producing a stronger and more comprehensive immune response is required to address this global threat. In the present study, we adopted an in-silico approach to develop a multi-epitope vaccine by screening 198 "regulatory proteins" of Mtb H37Rv strain. Epitopes generated from these proteins were screened on the basis of antigenicity, cytokine profile, allergenicity, toxicity, conservancy and population coverage. Selected epitopes were docked with predominant MHC alleles that were used to develop a vaccine construct using suitable linkers and adjuvant. The construct was subjected to homology modelling, tertiary structure validation and refinement and was eventually docked with Toll-like receptor 2 receptor. Molecular dynamic simulation studies revealed stable interactions between the vaccine construct and TLR-2 receptor. The construct also displayed a high probability to elicit a protective immune response involving both humoral and cell-mediated components. In conclusion, the findings suggest that the constructed vaccine has the potential to induce a robust immune response against Mtb. However, further in-vitro and in-vivo studies are required to assess the safety, efficacy, and long-term protective effects of the vaccine construct., Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00322-8., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2025. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Distinct and seemingly independent cellular pathways affecting intracellular machinery or extracellular matrix (ECM) deposition and organization have been implicated in aneurysm formation. One of the key genes associated with this pathology in both humans and mice is lysyl oxidase (LOX), a secreted ECM-modifying enzyme, highly expressed in medial vascular smooth muscle cells. To dissect the mechanisms leading to aneurysm development, we conditionally deleted Lox in smooth muscle cells. We find that cytoskeletal organization is lost following Lox deletion. Cell culture assays and in vivo analyses demonstrate a cell-autonomous role for LOX affecting myosin light-chain phosphorylation and cytoskeletal assembly resulting in irregular smooth muscle contraction. These results not only highlight new intracellular roles for LOX, but notably, they provide a link between multiple processes leading to aneurysm formation, suggesting LOX coordinates ECM development, cytoskeletal organization, and cell contraction required for media development and function., (© 2024 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

MWCNT is being explored in various sectors like medical healthcare, electronics, aerospace, defence research, and many more leading to the continuous generation of waste discharged into water sources. Once introduced into the environment it may adversely affect flora and fauna. It is high time MWCNT should be recovered, treated, and degraded from wastewater. Bio-degradation is one of the popular sustainable techniques for the remediation of hazardous contaminants. This work evaluated indigenous microbes Bacillus nitratireducens SW_NMI_TSB1, Comamonas denitrificans SW_NMI_TSB2, and Lysinibacillus fusiformis SW_NMI_TSB3 isolated from the nanomaterial manufacturing industry from India for their competence in degrading MWCNT. The microbes in this study showed survivability in the nutrient medium devoid of carbon but containing MWCNT (100 and 400 mg/L). The bacterial strain exhibited proliferation for up to 50 days. Degradation of MWCNT can be observed through TEM images which displayed the distorted morphology, XRD, and RAMAN spectroscopy revealed that treated MWCNT exhibit a loss of structural integrity. SEM images and colony forming unit (CFU) counts show a good survival rate of the three isolates independently and in the consortium. LCMS detected intermediates generated during MWCNT degradation. The microbes isolated in this study can survive in the presence of MWCNT and exhibit degradation of MWCNT. The three isolates could biodegrade the MWCNT however their consortium showed the highest potential. The prospects of this study lie in utilizing the consortium of these strains for large-scale MWCNT degradation, improving water treatment systems, and advancing sustainable nanomaterial management practices., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest. Ethical approval: In underlying research work no experiment/ issue necessitates ethical consent/ agreement., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Fibroblasts, the most common cell type found in connective tissues, play major roles in development, homeostasis, regeneration, and disease. Although specific fibroblast subpopulations have been associated with different biological processes, the mechanisms and unique activities underlying their diversity have not been thoroughly examined. Here, we set out to dissect the variation in skeletal-muscle-resident fibroblasts (mrFibroblasts) during development. Our results demonstrate that mrFibroblasts diversify following the transition from embryonic to fetal myogenesis prior to birth. We find that mrFibroblasts segregate into two major subpopulations occupying distinct niches, with interstitial fibroblasts residing between the muscle fibers and delineating fibroblasts sheathing the muscle. We further show that these subpopulations entail distinct cellular dynamics and transcriptomes. Notably, we find that mrFibroblast subpopulations exert distinct regulatory roles on myoblast proliferation and differentiation. Finally, we demonstrate that this diversification depends on muscle contraction. Altogether, these findings establish that mrFibroblasts diversify in a spatiotemporal embryonic process into distinct cell types, entailing different characteristics and roles., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In this study, we applied the actor-partner interdependence model (APIM) to explore the associations between personality traits (Big Five) and psychological flexibility, on the one hand, and depression and anxiety, on the other hand, among patients with cancer and their spouses. Method: Forty-six patient-spouse dyads (N = 92) completed the anxiety and depression scales from the Patient-Reported Outcomes Measurement Information System (PROMIS), the ten-item personality inventory (TIPI), and the psychological flexibility scale (AAQ-2). Multilevel APIM models, adjusted for multiple testing, showed that neuroticism and psychological flexibility had actor effects on patients' depression and anxiety. Furthermore, neuroticism had actor effects on spouses' depression and anxiety, and agreeableness had actor effects on spouses' anxiety. In addition, patients' psychological flexibility and neuroticism had partner effects on spouses' depression. Conclusion: Being psychologically flexible but emotionally stable is important for one's own and one's partner's psychological outcomes in the context of dyadic coping with cancer. Implications include informing couples' therapists in the context of psycho-oncology on the importance of considering personality traits and improving psychological flexibility.

To identify novel genes responsible for recurrent hydatidiform moles (HMs), we performed exome sequencing on 75 unrelated patients who were negative for mutations in the known genes. We identified biallelic deleterious variants in 6 genes, FOXL2, MAJIN, KASH5, SYCP2, MEIOB, and HFM1, in patients with androgenetic HMs, including a familial case of 3 affected members. Five of these genes are essential for meiosis I, and their deficiencies lead to premature ovarian insufficiency. Advanced maternal age is the strongest risk factor for sporadic androgenetic HM, which affects 1 in every 600 pregnancies. We studied Hfm1-/- female mice and found that these mice lost all their oocytes before puberty but retained some at younger ages. Oocytes from Hfm1-/- mice initiated meiotic maturation and extruded the first polar bodies in culture; however, their meiotic spindles were often positioned parallel, instead of perpendicular, to the ooplasmic membrane at telophase I, and some oocytes extruded the entire spindle with all the chromosomes into the polar bodies at metaphase II, a mechanism we previously reported in Mei1-/- oocytes. The occurrence of a common mechanism in two mouse models argues in favor of its plausibility at the origin of androgenetic HM formation in humans.

Austropuccinia psidii is the causal agent of myrtle rust in over 480 species within the family Myrtaceae. Lineages of A. psidii are structured by their hosts in the native range, and some have success in infecting newly encountered hosts. For example, the pandemic biotype has spread beyond South America, and proliferation of other lineages is an additional risk to biodiversity and industries. Efforts to manage A. psidii incursions, including lineage differentiation, relies on variable microsatellite markers. Testing these markers is time-consuming, complex, and requires reference material that is not always readily available. We designed a novel diagnostic approach targeting eight selectively chosen loci including the fungal mating-type HD (homeodomain) transcription factor locus. The HD locus ( bW1/2-HD1 and bE1/2-HD2 ) is highly polymorphic, facilitating clear biological predictions about its inheritance from founding populations. To be considered as potentially derived from the same lineage, all four HD alleles must be identical. If all four HD alleles are identical six additional markers can further differentiate lineage identity. Our lineage diagnostics relies on PCR amplification of eight loci in different genotypes of A. psidii followed by amplicon sequencing using Oxford Nanopore Technologies (ONT) and comparative analysis. The lineage-specific assay was validated on four isolates with existing genomes, uncharacterized isolates, and directly from infected leaf material. We reconstructed alleles from amplicons and confirmed their sequence identity relative to their reference. Genealogies of alleles confirmed the variations at the loci among lineages/isolates. Our study establishes a robust diagnostic tool for differentiating known lineages of A. psidii based on biological predictions and available nucleotide sequences. This tool is suited to detecting the origin of new pathogen incursions.

Context-dependent physiological remodeling of the extracellular matrix (ECM) is essential for development and organ homeostasis. On the other hand, consumption of high-caloric diet leverages ECM remodeling to create pathological conditions that impede the functionality of different organs, including the heart. However, the mechanistic basis of high caloric diet-induced ECM remodeling has yet to be elucidated. Employing in vivo molecular genetic analyses in Drosophila, we demonstrate that high dietary sugar triggers ROS-independent activation of JNK signaling to promote fatty acid oxidation (FAO) in the pericardial cells (nephrocytes). An elevated level of FAO, in turn, induces histone acetylation-dependent transcriptional upregulation of the cytokine Unpaired 3 (Upd3). Release of pericardial Upd3 augments fat body-specific expression of the cardiac ECM protein Pericardin, leading to progressive cardiac fibrosis. Importantly, this pathway is quite distinct from the ROS-Ask1-JNK/p38 axis that regulates Upd3 expression under normal physiological conditions. Our results unravel an unknown physiological role of FAO in cytokine-dependent ECM remodeling, bearing implications in diabetic fibrosis., (© 2024 Gera et al.)

Competing Interests: Dr. Oud has disclosed that he does not have any potential conflicts of interest.

Epistaxis is common worldwide otorhinolaryngology emergency presenting as a life-threatening condition especially in resource-constrained hospitals with limited health-care facilities for acceptable management. The aim of this study is to find out the common causes of epistaxis. It was a cross sectional study. It was carried out on 304 patients who presented with epistaxis at tertiary care hospital of Central India (Peoples College of Medical Science & Research Centre, Bhopal). It was found that among 304 participants, maximum number of patients with epistaxis were of age group 21-30 years i.e. 66 (21.71%) with 210 (69.08%) were male and 94 (30.92%) were female. It was found that maximum patients were of nose picking i.e. 113 (37.17%) followed by trauma via accident, assault and fall i.e. 77 (25.33%), followed by hypertension i.e. 49. Epistaxis is a common emergency condition in Otorhinolaryngology. People of all ages can be affected. Hypertension and trauma were the most common etiological/risk factors among the patients in whom etiology was found although in most of the patients etiology could not be found., Competing Interests: Conflict of InterestAll author declares that they had no conflict of interest., (© The Author(s) 2024.)

Background: Lignin and xylan are important determinants of cell wall structure and lignocellulosic biomass digestibility. Genetic manipulations that individually modify either lignin or xylan structure improve polysaccharide digestibility. However, the effects of their simultaneous modifications have not been explored in a similar context. Here, both individual and combinatorial modification in xylan and lignin was studied by analysing the effect on plant cell wall properties, biotic stress responses and integrity sensing., Results: Arabidopsis plant co-harbouring mutation in FERULATE 5-HYDROXYLASE (F5H) and overexpressing Aspergillus niger acetyl xylan esterase (35S:AnAXE1) were generated and displayed normal growth attributes with intact xylem architecture. This fah1-2/35S:AnAXE1 cross was named as hyper G lignin and hypoacetylated (HrGHypAc) line. The HrGHypAc plants showed increased crystalline cellulose content with enhanced digestibility after chemical and enzymatic pre-treatment. Moreover, both parents and HrGHypAc without and after pre-treating with glucuronyl esterase and alpha glucuronidase exhibited an increase in xylose release after xylanase digestion as compared to wild type. The de-pectinated fraction in HrGHypAc displayed elevated levels of xylan and cellulose. Furthermore, the transcriptomic analysis revealed differential expression in cell wall biosynthetic, transcription factors and wall-associated kinases genes implying the role of lignin and xylan modification on cellular regulatory processes., Conclusions: Simultaneous modification in xylan and lignin enhances cellulose content with improved saccharification efficiency. These modifications loosen cell wall complexity and hence resulted in enhanced xylose and xylobiose release with or without pretreatment after xylanase digestion in both parent and HrGHypAc. This study also revealed that the disruption of xylan and lignin structure is possible without compromising either growth and development or defense responses against Pseudomonas syringae infection., (© 2024. The Author(s).)

Background: Recent reports on the national temporal trends of sepsis-related mortality in the United States (US) suggested improvement of outcomes in several race and ethnicity groups. However, it is unknown whether national data reflect state-level trajectories. Methods: We used the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research Multiple Cause of Death data set to identify all decedents with sepsis in the US during 2010-2019. Negative binomial regression models were fit to estimate national and state-level trends of age-adjusted sepsis-related mortality rates within race and ethnicity groups. Results: There were 1,852,610 sepsis-related deaths in the US during 2010-2019. Nationally, sepsis-related mortality rates decreased among Blacks and Asians, were unchanged among Hispanics and Native Americans, and rose among Whites. The percent of states with similar trends were 30.0% among Blacks, 32.1% among Asians, 74.3% among Hispanics, 75.0% among Native Americans, and 66.7%% among Whites, while trending in opposite direction from 3.6% among Asians to 15.0% among Blacks. Conclusions: National trends in sepsis-related mortality in the US did not represent state-level trajectories in race ethnicity groups. Gains in sepsis outcomes among race and ethnicity groups at the national level were not shared equitably at the state level.

Purpose: To evaluate the factors affecting corneal deformation amplitude (DA) measured using Corvis ST in eyes with open-angle glaucoma., Methods: This prospective, longitudinal study included 48 eyes with open-angle glaucoma who required additional intraocular pressure (IOP)-lowering drops. All eyes underwent a complete eye examination at baseline, including a Corvis ST, which was repeated 4-8 weeks after the change in therapy. Factors affecting the corneal biomechanics, namely the DA, were determined using mixed effect models., Results: The mean age of the cohort was 65.0 ± 7.9 years. The mean IOP reduced from 23.4 ± 5.4 mmHg to 17.9 ± 5 mmHg after the change in glaucoma treatment ( P < 0.001). The DA increased from 0.89 ± 0.16 mm to 1.00 ± 0.13 mm after IOP reduction ( P < 0.001). On mixed effect model analysis, IOP (-0.02 ± 0.001, P < 0.001) and corneal pachymetry (-0.0003 ± 0.0001, P = 0.02) affected the change in the DA., Conclusion: IOP and corneal pachymetry affect the DA and must be accounted for when using Corvis ST to evaluate corneal biomechanics in glaucoma., (Copyright © 2023 Copyright: © 2023 Indian Journal of Ophthalmology.)

Molecular dynamics simulations are conducted to systematically investigate the insertion of spherical nanoparticles (NPs) in polymer brushes as a function of their size, strength of their interaction with the polymers, polymer grafting density, and polymer chain length. For attractive interactions between the NPs and the polymers, the depth of NPs' penetration in the brush results from a competition between the enthalpic gain due to the favorable polymer-NP interaction and the effect of osmotic pressure resulting from displaced polymers by the NP's volume. A large number of simulations show that the average depth of the NPs increases by increasing the strength of the interaction strength. However, it decreases by increasing the NPs' diameter or increasing the polymer grafting density. While the NPs' effect on the polymer density is local, their effect on their conformations is long-ranged and extends laterally over length scales larger than the NP's size. This effect is manifested by the emergence of laterally damped oscillations in the normal component of the chains' radius of gyration. Interestingly, we found that for high enough interaction strength, two NPs dimerize in the polymer brush. The dimer is parallel to the substrate if the NPs' depth in the brush is shallow. However, the dimer is perpendicular to the substrate if the NPs' are deep in the brush. These results imply that polymer brushes can be used as a tool to localize and self-assemble NPs in polymer brushes., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Purpose: Previously healthy adults with community-onset sepsis were recently reported to have, counterintuitively, higher short-term mortality than those with comorbid conditions. However, the population-level generalizability of this finding and its applicability to all hospitalized septic patients are unclear., Methods: We used a statewide dataset to identify hospitalizations aged ≥18 years with a diagnosis of sepsis in Texas during 2018-2019. Comorbidities were defined as those included in the Charlson Comorbidity Index and other prevalent conditions associated with mortality. Hierarchical models were used to estimate the association of comorbid state with short-term mortality (defined as in-hospital mortality or discharge to hospice), overall and in community-onset and hospital-onset sepsis., Results: Among 120,371 sepsis hospitalizations, 6611 (5.5%) were previously healthy and 105,455 (87.6%) had community-onset sepsis. Short-term mortality among the previously healthy and those with comorbidities was 11.7% vs 28.2% overall, 11.0% vs 25.2% in community-onset sepsis, and 22.0% vs 48.7% in hospital-onset sepsis, respectively. On adjusted analysis, being previously healthy remained associated with lower short-term mortality overall (adjusted odds ratio 0.62 [95% CI 0.57-0.69]), with findings consistent with the primary analysis in community-onset sepsis, hospital-onset sepsis., Conclusions: Previously healthy septic patients had lower short-term mortality compared to those with comorbid conditions., Competing Interests: Declaration of Competing Interest None., (Published by Elsevier Inc.)

Comorbid conditions represent a major risk for severe illness among persons with COVID-19. Previously healthy people with COVID-19 can also develop severe illness, but are expected to have better outcomes than those with comorbid conditions. Nevertheless, recent data suggest that the former may have, counterintuitively, higher risk of death among those with non-COVID sepsis. However, the epidemiology and outcomes of previously healthy people among critically ill patients with COVID-19 are unknown. We used statewide data to identify intensive care unit (ICU) admissions aged ≥18 years in Texas with COVID-19 in 2020. Multilevel logistic regression was used to estimate the association of comorbid state with short-term mortality (defined as in-hospital mortality or discharge to hospice) overall and with higher illness severity among ICU admissions. Among 52,776 ICU admissions with COVID-19, 6373 (12.1%) were previously healthy. Short-term mortality among previously healthy ICU admissions and those with comorbidities was 16.9% versus 34.6%. On adjusted analyses, the odds of short-term mortality were lower among the previously healthy compared to those with comorbidities overall (adjusted odds ratio (aOR) 0.84 (95% CI: 0.73-0.98)), but did not differ among those with ≥3 organ dysfunctions (aOR 1.11 (95% CI: 0.84-1.46)) and the mechanically ventilated (aOR 0.87 (95% CI: 0.68-1.12)), while being higher among those with do-not-resuscitate status (aOR 1.40 (95% CI: 1.04-1.89)). Over one in eight ICU admissions with COVID-19 were previously healthy. Although being previously healthy was associated with lower risk of death compared to those with comorbidities overall, it had no prognostic advantage among the more severely ill., 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.

Dengue fever is a major health concern in India. There are various reports in the literature regarding the ocular manifestations of this febrile illness. We are reporting a rare case of a woman in her late 30s who developed coexisting bilateral ciliochoroidal effusion syndrome with an isolated cytotoxic corpus callosum lesion associated with dengue febrile illness. To the best of our knowledge, this is the first case of its kind. It opens the avenues for neurological and radioimaging attention for such cases with bilateral ciliochoroidal effusion syndrome., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The surge in critical illness and associated mortality brought by the coronavirus virus disease 2019 (COVID-19) pandemic, coupled with staff shortages and restrictions of family visitation, may have adversely affected delivery of palliative measures, including at the end of life of affected patients. However, the population-level patterns of palliative care (PC) utilization among septic critically ill patients with and without COVID-19 during end-of-life hospitalizations are unknown., Methods: A statewide dataset was used to identify patients aged ≥ 18 years with intensive care unit (ICU) admission and a diagnosis of sepsis in Texas, who died during hospital stay during April 1 to December 31, 2020. COVID-19 was defined by the International Classification of Diseases, 10th Revision (ICD-10) code U07.1, and PC was identified by ICD-10 code Z51.5. Multivariable logistic models were fitted to estimate the association of COVID-19 with use of PC among ICU admissions. A similar approach was used for sensitivity analyses of strata with previously reported lower and higher than reference use of PC., Results: There were 20,244 patients with sepsis admitted to ICU during terminal hospitalization, and 9,206 (45.5%) had COVID-19. The frequency of PC among patients with and without COVID-19 was 32.0% vs. 37.1%, respectively. On adjusted analysis, the odds of PC use remained lower among patients with COVID-19 (adjusted odds ratio (aOR): 0.84, 95% confidence interval (CI): 0.78 - 0.90), with similar findings on sensitivity analyses., Conclusions: PC was markedly less common among critically ill septic patients with COVID-19 during terminal hospitalization, compared to those without COVID-19. Further studies are needed to determine the factors underlying these findings in order to reduce disparities in use of PC., Competing Interests: None to declare., (Copyright 2023, Oud.)

Cadmium (Cd) exposure to the animals including humans is reported as nephrotoxic compounds i.e., disturbing redox status (increase oxidative stress), mitochondrial dysfunction, renal cell death and altered transporters in the renal system. Hsp27 (a small heat shock protein) has been shown as one of the modulators in the renal dysfunction and increased against the Cd induced toxicity. However, no studies are reported on the genetic modulation of stress protein against the Cd-induced nephrotoxicity. The current study aimed to examine the protective role of hsp27 overexpression against the Cd-induced nephrotoxicity using Drosophila melanogaster as an animal model. D. melanogaster renal system includes nephrocytes and Malpighian tubules (MTs) that show the functional similarity with mammalian kidney nephron. Overexpression of the hsp27 was found to reduce the Cd induced oxidative stress, rescue cell death in MTs of Cd exposed D. melanogaster larvae. The rescued GSH level, NADPH level and glucose 6 phosphate dehydrogenase (G6PD) activity were also observed in the MTs of the Cd exposed organism. Function (efflux activity and fluid secretion rate) of the MTs was restored in Cd exposed hsp27 overexpressed larvae. Further, results were confirmed by restored brush border microvilli density and reduced uric acid level. Tissue specific knockdown of hsp27 developed Cd like phenotypes in MTs and the phenotypes enhanced in Cd exposed condition. The present study clearly shows the role of hsp27 overexpression in restoration of the MTs function and protection against the Cd induced renal toxicity., 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. Published by Elsevier Inc.)

The increasing use of monoclonal antibodies (mAbs) in biology and medicine necessitates efficient methods for characterizing their binding epitopes. Here, we developed a high-throughput antibody footprinting method based on binding profiles. We used an antigen microarray to profile 23 human anti-influenza hemagglutinin (HA) mAbs using HA proteins of 43 human influenza strains isolated between 1918 and 2018. We showed that the mAb's binding profile can be used to characterize its influenza subtype specificity, binding region, and binding site. We present mAb-Patch-an epitope prediction method that is based on a mAb's binding profile and the 3D structure of its antigen. mAb-Patch was evaluated using four mAbs with known solved mAb-HA structures. mAb-Patch identifies over 67% of the true epitope when considering only 50-60 positions along the antigen. Our work provides proof of concept for utilizing antibody binding profiles to screen large panels of mAbs and to down-select antibodies for further functional studies., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Vaccination, especially with multiple doses, provides substantial population-level protection against COVID-19, but emerging variants of concern (VOC) and waning immunity represent significant risks at the individual level. Here we identify correlates of protection (COP) in a multicenter prospective study following 607 healthy individuals who received three doses of the Pfizer-BNT162b2 vaccine approximately six months prior to enrollment. We compared 242 individuals who received a fourth dose to 365 who did not. Within 90 days of enrollment, 239 individuals contracted COVID-19, 45% of the 3-dose group and 30% of the four-dose group. The fourth dose elicited a significant rise in antibody binding and neutralizing titers against multiple VOCs reducing the risk of symptomatic infection by 37% [95%CI, 15%-54%]. However, a group of individuals, characterized by low baseline titers of binding antibodies, remained susceptible to infection despite significantly increased neutralizing antibody titers upon boosting. A combination of reduced IgG levels to RBD mutants and reduced VOC-recognizing IgA antibodies represented the strongest COP in both the 3-dose group (HR = 6.34, p = 0.008) and four-dose group (HR = 8.14, p = 0.018). We validated our findings in an independent second cohort. In summary combination IgA and IgG baseline binding antibody levels may identify individuals most at risk from future infections., (© 2023. The Author(s).)

Background and Aims: Endoscopic assessment is a co-primary end point in inflammatory bowel disease registration trials, yet it is subject to inter- and intraobserver variability. We present an original machine learning approach to Endoscopic Mayo Score (eMS) prediction in ulcerative colitis and report the model's performance in differentiating key levels of endoscopic disease activity on full-length procedure videos., Methods: Seven hundred ninety-three full-length videos with centrally-read eMS were obtained from 249 patients with ulcerative colitis, who participated in a phase II trial evaluating mirikizumab (NCT02589665). A video annotation approach was established to extract mucosal features and associated eMS classification labels from each video to be used as inputs for model training. The primary objective of the model was a categorical prediction of inactive vs active endoscopic disease evaluated against 2 independent test sets: a full set with a baseline single human expert read and a consensus subset in which 2 human reads agreed., Results: On the full test set of 147 videos, the model predicted inactive vs active endoscopic disease via the eMS with an area under the curve of 89%, accuracy of 84%, positive predictive value of 80%, and negative predictive value of 85%. In the consensus test set of 94 videos, the model predicted inactive vs active endoscopic disease with an area under the curve of 92%, accuracy of 89%, positive predictive value of 87%, and negative predictive value of 90%., Conclusion: We have demonstrated that this machine learning model supervised by mucosal features and eMS video annotations accurately differentiates key levels of endoscopic disease activity., (© 2023 The Authors.)

Obesity is a risk factor for severe disease and mortality for both influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. While previous studies show that individuals with obesity generate antibody responses following influenza vaccination, infection rates within the obese group were twice as high as those in the healthy-weight group. The repertoire of antibodies raised against influenza viruses following previous vaccinations and/or natural exposures is referred to here as baseline immune history (BIH). To investigate the hypothesis that obesity impacts immune memory to infections and vaccines, we profiled the BIH of obese and healthy-weight adults vaccinated with the 2010-2011 seasonal influenza vaccine in response to conformational and linear antigens. Despite the extensive heterogeneity of the BIH profiles in both groups, there were striking differences between obese and healthy subjects, especially with regard to A/H1N1 strains and the 2009 pandemic virus (Cal09). Individuals with obesity had lower IgG and IgA magnitude and breadth for a panel of A/H1N1 whole viruses and hemagglutinin proteins from 1933 to 2009 but increased IgG magnitude and breadth for linear peptides from the Cal09 H1 and N1 proteins. Age was also associated with A/H1N1 BIH, with young individuals with obesity being more likely to have reduced A/H1N1 BIH. We found that individuals with low IgG BIH had significantly lower neutralizing antibody titers than individuals with high IgG BIH. Taken together, our findings suggest that increased susceptibility of obese participants to influenza infection may be mediated in part by obesity-associated differences in the memory B-cell repertoire, which cannot be ameliorated by current seasonal vaccination regimens. Overall, these data have vital implications for the next generation of influenza virus and SARS-CoV-2 vaccines. IMPORTANCE Obesity is associated with increased morbidity and mortality from influenza and SARS-CoV-2 infection. While vaccination is the most effective strategy for preventing influenza virus infection, our previous studies showed that influenza vaccines fail to provide optimal protection in obese individuals despite reaching canonical correlates of protection. Here, we show that obesity may impair immune history in humans and cannot be overcome by seasonal vaccination, especially in younger individuals with decreased lifetime exposure to infections and seasonal vaccines. Low baseline immune history is associated with decreased protective antibody responses. Obesity potentially handicaps overall responses to vaccination, biasing it toward responses to linear epitopes, which may reduce protective capacity. Taken together, our data suggest that young obese individuals are at an increased risk of reduced protection by vaccination, likely due to altered immune history biased toward nonprotective antibody responses. Given the worldwide obesity epidemic coupled with seasonal respiratory virus infections and the inevitable next pandemic, it is imperative that we understand and improve vaccine efficacy in this high-risk population. The design, development, and usage of vaccines for and in obese individuals may need critical evaluation, and immune history should be considered an alternate correlate of protection in future vaccine clinical trials., Competing Interests: The authors declare no conflict of interest.

Background: Coronavirus disease 2019 (COVID-19)-related organ dysfunction is increasingly considered as sepsis of viral origin. In recent clinical and autopsy studies, sepsis has been present in the majority of decedents with COVID-19. Given the high mortality toll of COVID-19, sepsis epidemiology would be expected to be substantially transformed. However, the impact of COVID-19 on sepsis-related mortality at the national level has not been quantified. We aimed to estimate the contribution of COVID-19 to sepsis-related mortality in the USA during the first year of the pandemic., Methods: We used the Centers for Disease Control Wide-Ranging Online Data for Epidemiological Research (CDC WONDER) Multiple Cause of Death dataset to identify decedents with sepsis during 2015 - 2019, and those with a diagnosis of sepsis, COVID-19, or both in 2020. Negative binomial regression was used on the 2015 - 2019 data to forecast the number of sepsis-related deaths in 2020. We then compared the observed vs. predicted number of sepsis-related deaths in 2020. In addition, we examined the frequency of a diagnosis of COVID-19 among decedents with sepsis and the proportion of a diagnosis of sepsis among decedents with COVID-19. The latter analysis was repeated within each of the Department of Health and Human Services (HHS) regions., Results: In 2020, there were 242,630 sepsis-related deaths, 384,536 COVID-19-related deaths, and 35,807 deaths with both in the USA. The predicted number of sepsis-related deaths for 2020 was 206,549 (95% confidence interval (CI): 201,550 - 211,671). COVID-19 was reported in 14.7% of decedents with sepsis, while a diagnosis of sepsis was reported in 9.3% of all COVID-19-related deaths, ranging from 6.7% to 12.8% across HHS regions., Conclusions: A diagnosis of COVID-19 was reported in less than one in six of decedents with sepsis in 2020, with corresponding less than one in 10 diagnoses of sepsis among decedents with COVID-19. These findings suggest that death certificate-based data may have substantially underestimated the toll of sepsis-related deaths in the USA during the first year of the pandemic., Competing Interests: None to declare., (Copyright 2023, Oud et al.)

Competing Interests: None to declare.

Since late 2020, SARS-CoV-2 variants have regularly emerged with competitive and phenotypic differences from previously circulating strains, sometimes with the potential to escape from immunity produced by prior exposure and infection. The Early Detection group is one of the constituent groups of the US National Institutes of Health National Institute of Allergy and Infectious Diseases SARS-CoV-2 Assessment of Viral Evolution program. The group uses bioinformatic methods to monitor the emergence, spread, and potential phenotypic properties of emerging and circulating strains to identify the most relevant variants for experimental groups within the program to phenotypically characterize. Since April 2021, the group has prioritized variants monthly. Prioritization successes include rapidly identifying most major variants of SARS-CoV-2 and providing experimental groups within the National Institutes of Health program easy access to regularly updated information on the recent evolution and epidemiology of SARS-CoV-2 that can be used to guide phenotypic investigations.

Systemic lupus erythematosus (SLE) is associated with higher risks of sepsis and sepsis-related mortality compared to the general population. However, the prognostic impact of SLE in sepsis is uncertain. We used statewide data to identify hospitalizations aged ≥18 years in Texas with sepsis, with and without SLE during 2014-2017. Multilevel logistic regression with propensity adjustment (primary model), propensity score matching, and multivariable logistic regression without propensity adjustment were used to estimate the association of SLE with short-term mortality (defined as in-hospital mortality or discharge to hospice) among sepsis hospitalizations. Among 283,025 sepsis hospitalizations, 2933 (1.0%) had SLE. Compared to sepsis hospitalizations without SLE, those with SLE were younger (aged ≥65 years, 25.0% vs 57.0%) and had higher burden of comorbidities (mean Deyo comorbidity index 3.0 vs 2.6). Short-term mortality of sepsis hospitalizations with and without SLE was 22.9% vs 31.3%. SLE remained associated with lower short-term mortality on the secondary models, but not on the primary one (adjusted odds ratio: 0.905; 95% confidence interval: 0.817-1.001). When in-hospital mortality was used as secondary outcome, SLE was associated with mortality only on propensity score matching. The increased sepsis-related mortality in SLE is driven by higher risk of sepsis, but not by higher case fatality among septic patients. SLE may be associated with lower risk of mortality among septic patients, but further studies are needed due to heterogeneity of the prognostic associations across models.

Linking scalp electroencephalography (EEG) signals and spontaneous firing activity from deep nuclei in humans is not trivial. To examine this, we analyzed simultaneous recordings of scalp EEG and unit activity in deeply located sites recorded overnight from patients undergoing pre-surgical invasive monitoring. We focused on modeling the within-subject average unit activity of two medial temporal lobe areas: amygdala and hippocampus. Linear regression model correlates the units' average firing activity to spectral features extracted from the EEG during wakefulness or non-REM sleep. We show that changes in mean firing activity in both areas and states can be estimated from EEG (Pearson r > 0.2, p≪0.001). Region specificity was shown with respect to other areas. Both short- and long-term fluctuations in firing rates contributed to the model accuracy. This demonstrates that scalp EEG frequency modulations can predict changes in neuronal firing rates, opening a new horizon for non-invasive neurological and psychiatric interventions., Competing Interests: T.H. is an employee and shareholder of GrayMatters Health Ltd., (© 2023 The Authors.)

The displacement and trapping of the colon between the liver and the right hemidiaphragm are known as the Chilaiditi sign or syndrome. The Chilaiditi sign presents in an asymptomatic patient, while Chilaiditi syndrome presents with symptoms such as abdominal pain, distension, and constipation, in addition to complications such as perforation, volvulus, and bowel obstruction. It is often misdiagnosed as pneumoperitoneum or free air under the diaphragm and liver, often seen on the abdomen and chest radiography. It more commonly presents in males than in females. Here, we present the case of a 37-year-old female who reported abdominal pain and persistent constipation. An abdominal CT scan showed entrapment of a bowel segment, which is referred to as the Chilaiditi sign. The patient's presentation with hepatobowel entrapment and persistent gastrointestinal symptoms was diagnosed as Chilaiditi syndrome. This presentation entails a conservative management approach. The aim of this report is to educate about the rare occurrence of Chilaiditi sign and Chilaiditi syndrome as a differential diagnosis to often misdiagnosed critical conditions such as pneumoperitoneum and intestinal perforation. Correctly identifying these patients will reduce overtreatment and help improve outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Akram et al.)

The Vitamin D Receptor (VDR) ligand-binding domain undergoes conformation change upon the binding of VDR agonists/antagonists. Helix 12 ((H)12) is one of the important helices at VDR ligand binding and its conformational changes are controlled by the binding of agonists and antagonists molecules. Various molecular modeling studies are available to explain the agonistic and antagonistic activity of vitamin D analogs. In this work, for the first time, we attempted to generate a machine learning model with fingerprints, 2D, 3D and MD descriptors that are specific to Vitamin D analogs and VDR. Initially, 2D and 3D descriptors and fingerprints of 1003 vitamin D analogs were calculated using CDK and RDKit. The machine learning model was generated using descriptors and fingerprints. Further, 80 Vitamin D analogs (40 VDR agonists + 40 VDR antagonists) were docked in the VDR active site. 50ns MD simulation was performed for each protein-ligand complex. Different MD descriptors such as Solvent Accessible Surface Area (SASA), radius of gyration, PC1 and PC2 were calculated and considered along with CDK and RDKit descriptors as features for machine learning calculations. A few other descriptors that are related to VDR conformational changes such as conformation of the (H)12, the angle at kink were considered for machine learning model generation. It was observed that the descriptors calculated from VDR conformational changes i) were able to distinguish between agonists and antagonists ii) provide key and comprehensive information about the unique binding characteristics of agonists and antagonists iii) provide a strong basis for the machine learning model generation. Overall, this study attempts the utilization of descriptors that are specific to a protein conformation will be helpful for the generation of an efficient machine learning model., 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 © 2022 Elsevier Inc. All rights reserved.)

Purpose: The use of digital symptom monitoring with patient-reported outcomes (PROs) has been shown to improve patient outcomes. The evidence of benefit has been largely derived from research studies. The feasibility of adopting this technology in the real-world setting is unknown., Methods: We report on the clinical implementation of a proprietary electronic patient-reported outcome (ePRO)-based digital symptom monitoring platform at the Highlands Oncology Group practice, a large community oncology practice. We present here our experience with patient enrollment, engagement, and retention; reasons for discontinued use; proportion of reports generating alerts and containing severe symptoms; and the responses to alerts including nursing telephone consultations and urgent office visits., Results: Over an approximately 17-month period, 923 patients were successfully enrolled. Patients enrolled from June 20, 2020, through November 30, 2021, with follow-up through February 28, 2022. Retention rates at 3, 6, 9, and 12 months were 94%, 88%, 73%, and 67%, respectively, with greater retention at 12 months in patients age 65 years or older. Few patients discontinued use for reasons related to the platform (n = 47; 5%). Of the 25,311 ePRO reports submitted, 49% (n = 12,334) exceeded the predefined alert thresholds and 8% (n = 1,920) included severe symptoms. The nursing team responded within 24 hours by telephone to 31.2% (n = 3,910) of all reports with alerts. Of reports with severe symptoms, 72.7% (n = 1,395) received a call. Only 6.4% (n = 249) of phone calls required an office evaluation within 72 hours of the report., Conclusion: This single-center experience indicates that an ePRO-based digital symptom monitoring platform can be effectively implemented at a large scale with a high level of long-term patient engagement. Most reports could be effectively resolved by nurses, and physician intervention was infrequently required.

"Myiasis" is considered in Hindu mythology as "God's punishment for sinners". Literature abounds with reports of myiasis affecting the nasal cavity, ear, non healing ulcers, exophytic malignant growth and cutaneous tissue. But case report of myiasis of the tracheostomy wound is relatively rare and that also peristomally is seen first time. We are reporting two cases whose tracheostomy was done, one for laryngeal cancer and other for laryngocoele. We are discussing the need for the proper care of tracheostomy wound myiasis because the site of such an infestation is close to vital organs in the neck and avoiding complications., Competing Interests: Conflict of interestDr. Lavi Ukawat declares that there is no conflict of interest. Dr. S. K. Pippal declares that there is no conflict of interest. Dr. Ankur Gupta declares that there is no conflict of interest., (© Association of Otolaryngologists of India 2021.)

In the present study, effect of exposure of bisphenol A (BPA) and combined exposure of BPA + HSD has been investigated on the glucose homeostasis and associated renal complications in Drosophila. Exposure of 1.0 mM BPA alone induced type 2 diabetes like condition (T2D) in adult male D. melanogaster via oxidative stress. Elevated TGF-β signaling was evident by increased expression of baboon (babo) in BPA exposed organism that stimulated the modulation of extracellular matrix (ECM) component collagen IV resulting in the fibrosis of the Malpighian tubules (MTs). Combined exposure of BPA + HSD (high sucrose diet) resulted in the increased magnitude of T2D and MTs dysfunction parameters. Taken together, the study illustrates that BPA has diabetogenic potential in exposed Drosophila that caused adverse effects on their MTs and combined exposure with BPA and HSD could aggravate the renal tubular dysfunction. The study further suggests the use of Drosophila model to study the environmental chemicals induced diabetes mediated renal dysfunction., 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 © 2022 Elsevier B.V. All rights reserved.)

Background: Rheumatoid arthritis (RA) is associated with increased risk of sepsis and higher infection-related mortality compared to the general population. However, the evidence on the prognostic impact of RA in sepsis has been inconclusive. We aimed to estimate the population-level association of RA with short-term mortality in sepsis., Methods: We used statewide data to identify hospitalizations aged ≥18 years in Texas with sepsis, with and without RA during 2014-2017. Hierarchical logistic models with propensity adjustment (primary model), propensity score matching, and multivariable logistic regression without propensity adjustment were used to estimate the association of RA with short-term mortality among sepsis hospitalizations., Results: Among 283,025 sepsis hospitalizations, 7,689 (2.7%) had RA. Compared to sepsis hospitalizations without RA, those with RA were older (aged ≥65 years, 63.9% vs. 56.4%) and had higher burden of comorbidities (mean Deyo comorbidity index, 3.2 vs. 2.7). Short-term mortality of sepsis hospitalizations with and without RA was 26.8% vs. 31.4%. Following adjustment for confounders, short-term mortality was lower among RA patients (adjusted odds ratio [aOR], 0.910; 95% confidence interval [CI], 0.856-0.967), with similar findings on alternative models. On sensitivity analyses, short-term mortality was lower in RA patients among sepsis hospitalizations aged ≥65 years and those with septic shock, but not among those admitted to intensive care unit (ICU; aOR, 0.990; 95% CI, 0.909-1.079)., Conclusions: RA was associated, unexpectedly, with lower short-term mortality in septic patients. However, this "protective" association was driven by those patients without ICU admission. Further studies are warranted to confirm these findings and to examine the underlying mechanisms.

Mucormycosis is an uncommon but a fatal fungal infection that usually affects patients with altered immunity. The Rhizopus Oryzae is most common type and responsible for nearly 60% of mucormycosis cases in humans and also accounts for 90% of the Rhino-orbital-cerebral (ROCM) form. Our aim and objective was to study, the site of mucormycosis in nose and paranasal sinuses, adjacent site like orbit palate or intracranial involvement, co-morbid condition and management to be done in confirm mucormycosis patients. The most common sinuses involved are the ethmoid, maxillary followed by the frontal and sphenoid sinus. Diabetes mellitus is often associated with mucormycosis of the paranasal sinuses, as is corona virus infection; uncontrolled diabetes further increases the risk. Intra-orbital involvement is common, but intracranial involvement is rare. Extensive steroid and broad-spectrum antibiotic use for Covid-19 management may cause or exacerbate fungal disease. All the patients required surgical intervention along with medical treatment., Competing Interests: Conflict of InterestDr Sunil kumar Pippal (Professor and Head) declares that there is no conflict of interest. Dr Dinesh Kumar declares that there is no conflict of interest. Dr Lavi Ukawat declares that there is no conflict of interest., (© Association of Otolaryngologists of India 2021.)

Introduction: Treatment advances for metastatic breast cancer (mBC) have improved overall survival (OS) in some mBC subtypes; however, there remains no cure for mBC. Considering the use of progression-free survival (PFS) and other surrogate endpoints in clinical trials, we must understand patient perspectives on measures used to assess treatment efficacy., Objective: To explore global patient perceptions of the concept of PFS and its potential relation to quality of life (QoL)., Materials and Methods: Virtual roundtables in Europe and the United States and interviews in Japan with breast cancer patients, patient advocates, and thought leaders. Discussions were recorded, transcribed, and analyzed thematically., Results: Lengthened OS combined with no worsening or improvement in QoL remain the most important endpoints for mBC patients. Time when the disease is not progressing is meaningful to patients when coupled with improvements in QoL and no added treatment toxicity. Clinical terminology such as "PFS" is not well understood, and participants underscored the need for patient-friendly terminology to better illustrate the concept. Facets of care that patients with mBC value and that may be related to PFS include relief from cancer-related symptoms and treatment-related toxicities as well as the ability to pursue personal goals. Improved communication between patients and providers on managing treatment-related toxicities and addressing psychosocial challenges to maintain desired QoL is needed., Conclusion: While OS and QoL are considered the most relevant endpoints, patients also value periods of time without disease progression. Incorporation of these considerations into the design and conduct of future clinical trials in mBC, as well as HTA and reimbursement decision-making, is needed to better capture the potential value of a therapeutic innovation., 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 © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction:  Since the onset of COVID-19, physicians and scientists have been working to further understand biomarkers associated with the infection, so that patients who have contracted the virus can be treated. Although COVID-19 is a complex virus that affects patients differently, current research suggests that COVID-19 infections have been associated with increased procalcitonin, a biomarker traditionally indicative of bacterial infections. This paper aims to investigate the relationship between COVID-19 infection severity and procalcitonin levels in the hopes to aid the management of patients with COVID-19 infections., Methods:  Patient data were obtained from the Renaissance School of Medicine at Stony Brook University. The data of the patients who had tested positive for COVID-19 and had an associated procalcitonin value (n=1046) was divided into age splits of 18-59, 59-74, and 74-90. Multiple factors were analyzed to determine the severity of each patient's infection. Patients were divided into low, medium, and high severity dependent on the patient's COVID-19 severity. A one-way analysis of variance (ANOVA) was done for each age split to compare procalcitonin values of the severity groups within the respective age split. Next, post hoc analysis was done for the severity groups in each age split to further compare the groups against each other.  Results: One-way ANOVA testing of the three age splits all had a resulting p<0.0001, displaying that the null hypothesis was rejected. In the post hoc analysis, however, the test failed to reject the null hypothesis when comparing the medium and high severity groups against each other in the 59-74 and 74-90 age splits. The null hypothesis was rejected in all pairwise comparisons in the 18-59 age split. We determined that a procalcitonin value of greater than 0.24 ng/mL would be characterized as a more severe COVID-19 infection when considering patient factors and comorbidities.  Conclusion: The analysis of the data concluded that elevated procalcitonin levels correlated with the severity of COVID-19 infections. This finding can be used to assist medical providers in the management of COVID-19 patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Hussain et al.)

Acetyl substitution on the xylan chain is critical for stable interaction with cellulose and other cell wall polymers in the secondary cell wall. Xylan acetylation pattern is governed by Golgi and extracellular localized acetyl xylan esterase (AXE). We investigated the role of Arabidopsis clade Id from the GDSL esterase/lipase or GELP family in polysaccharide deacetylation. The investigation of the AtGELP7 T-DNA mutant line showed a decrease in stem esterase activity and an increase in stem acetyl content. We further generated overexpressor AtGELP7 transgenic lines, and these lines showed an increase in AXE activity and a decrease in xylan acetylation compared to wild-type plants. Therefore, we have named this enzyme as AtAXE1. The subcellular localization and immunoblot studies showed that the AtAXE1 enzyme is secreted out, associated with the plasma membrane and involved in xylan de-esterification post-synthesis. The cellulose digestibility was improved in AtAXE1 overexpressor lines without pre-treatment, after alkali and xylanases pre-treatment. Furthermore, we have also established that the AtGELP7 gene is upregulated in the overexpressor line of AtMYB46, a secondary cell wall specific transcription factor. This transcriptional regulation can drive AtGELP7 or AtAXE1 to perform de-esterification of xylan in a tissue-specific manner. Overall, these data suggest that AtGELP7 overexpression in Arabidopsis reduces xylan acetylation and improves digestibility properties of polysaccharides of stem lignocellulosic biomass., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)