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Kun-Rui Rao,1,* Ru-Yi Bao,1,* Hu Ming,1 Jian-Wei Liu,1 Yi-Fei Dong1,2 1Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 2Key Laboratory of Molecular Biology in Jiangxi Province, Nanchang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi-Fei Dong, Department of Cardiovascular Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China, Email yf_dong66@126.comBackground: Hypertension patients with primary aldosteronism (PA) have a higher risk of cardiovascular complications than blood pressure-matched essential hypertension (EH) patients. The cause may be closely related to inflammation. We explored the correlations between leukocyte-related inflammation parameters and plasma aldosterone concentration (PAC) in PA patients and clinical characteristics-matched EH patients.Methods: A total of 346 PA and 346 sex, age and 24-h blood pressure-matched EH patients at the 2nd Affiliated Hospital of Nanchang University from January 2020 to June 2021 were enrolled in this study. The differences and correlations of aldosterone and leukocyte parameters between the two groups were analyzed.Results: Compared with EH patients, the lymphocyte count was significantly lower (P = 0.004), the neutrophil–lymphocyte ratio (NLR) (P = 0.023) and the monocyte–lymphocyte ratio (MLR) (P = 0.037) were significantly higher in PA patients. Linear regression analysis and multivariate regression analysis identified that lymphocyte count, NLR and MLR were significantly and independently correlated with PAC in PA patients, and the correlations were stronger with increasing levels of aldosterone. However, in EH patients, only NLR maintained an independent correlation with PAC.Conclusion: Leukocyte-related inflammation parameters, including lymphocyte count, NLR, and MLR, were significantly and independently correlated with PAC in PA patients. The correlations were stronger with increasing levels of aldosterone. However, the above correlations were not always present in patients with EH matched for clinical characteristics.Keywords: aldosterone, inflammation, leukocytes, primary aldosteronism, essential hypertension

Objective: We demonstrated previously that chronic maternal micronutrient restriction altered the body composition in rat offspring and may predispose offspring to adult-onset diseases. Chromium (Cr) regulates glucose and fat metabolism. The objective of this study is to determine the long-term effects of maternal Cr restriction on adipose tissue development and function in a rat model.Research Design and Methods: Female weanling WNIN rats received, ad libitum, a control diet or the same with 65% restriction of Cr (CrR) for 3 months and mated with control males. Some pregnant CrR mothers were rehabilitated from conception or parturition and their pups weaned to control diet. Whereas some CrR offspring were weaned to control diet, others continued on CrR diet. Various parameters were monitored in the offspring at three monthly intervals up to 15-18 months of age.Results: Maternal Cr restriction significantly increased body weight and fat percentage, especially the central adiposity in both male and female offspring. Further, the expression of leptin and 11 beta-hydroxysteroid dehydrogenase 1 genes were significantly increased in CrR offspring of both the sexes. Adipocytokine levels were altered in plasma and adipose tissue; circulating triglyceride and FFA levels were increased, albeit in female offspring only. Rehabilitation regimes did not correct body adiposity but restored the circulating levels of lipids and adipocytokines.Conclusions: Chronic maternal Cr restriction increased body adiposity probably due to increased stress and altered lipid metabolism in WNIN rat offspring, which may predispose them to obesity and associated diseases in later life. [ABSTRACT FROM AUTHOR]

Aim: Corneal blindness accounts for 3.42% of blindness in Malaysia; the rate of eye donation is low. The aim of the study was to assess the awareness about eye donation and willingness to donate eyes among attendants of patients at various clinics in Melaka, Malaysia. Materials and Methods: This observational study was conducted on attendants who accompanied patients (n = 400) visiting various outpatient departments of the General Hospital and two peripheral clinics in Melaka between August and October 2007. The participants answered a questionnaire (Malay and English versions) which included demographic profile, awareness of eye donation, knowledge regarding facts of eye donation, and willingness to donate eyes. Univariate and multivariate logistic regression was performed at 5% level of significance. Results: Awareness of eye donation was observed in 276 (69%) participants. Multivariate analysis showed that awareness was more among females when compared to males (P = 0.009). Of the 276 participants who were aware of eye donation, only 34.42% were willing to donate eyes. Willingness was more among the Indian race (P = 0.02) and males (P = 0.02). Educational status did not influence the willingness to donate eyes. Conclusions: Although majority of participants were aware of eye donation, willingness to donate eyes was poor.

A prospective observational study was done to assess ocular survival, visual outcome and prognostic factors of open globe injury. Eighty eyes of penetrating trauma between 2004 and 2006 were categorized according to the ocular trauma classification system. Primary repair was done and outcomes were assessed at one, three and six months. The final vision was categorized as per World Health Organization classification of visual impairment. Factors at presentation were evaluated for prognostic value towards visual outcome. Sixty-nine eyes with minimum one month follow-up were included for analysis. Statistical analysis was done using Univariate and Multivariate analysis. We found Grade IV visual acuity (< 5/200) at presentation (64%) as the most important factor contributing to poor visual outcome. Statistically insignificant factors were time since injury, cataract, and presence of intraocular foreign body. Ocular survival was 97%. We concluded that initial visual acuity, hyphema, zone and length of injury, retinal detachment and vitreous hemorrhage are statistically significant factors affecting outcome in open globe injuries.

We report a case of a 16-year-old girl, who was struck by lightning, and experienced blurred vision in the right eye (RE) immediately following the episode. She reported for ophthalmic evaluation two months later. Examination revealed relative afferent pupillary defect in the RE. Posterior subcapsular cataract was noted in both eyes. Fundus examination revealed macular holes and multiple areas of RPE hyperpigmentation in the periphery in both eyes. Fundus fluorescein angiography showed increased choroidal transmission with early fluorescence and late fading in the foveal region and retinal pigment epithelium (RPE) stippling in the periphery in both eyes. This is the first case report of such nature in India to the best of our knowledge.

Abstract Background In many developing countries, such as India, information on human resources in the health sector is incomplete and unreliable. This prevents effective workforce planning and management. This paper aims to address this deficit by producing a more complete picture of India’s health workforce. Methods Both the Census of India and nationally representative household surveys collect data on self-reported occupations. A representative sample drawn from the 2001 census was used to estimate key workforce indicators. Nationally representative household survey data and official estimates were used to compare and supplement census results. Results India faces a substantial overall deficit of health workers; the density of doctors, nurses and midwifes is a quarter of the 2.3/1000 population World Health Organization benchmark. Importantly, a substantial portion of the doctors (37%), particularly in rural areas (63%) appears to be unqualified. The workforce is composed of at least as many doctors as nurses making for an inefficient skill-mix. Women comprise only one-third of the workforce. Most workers are located in urban areas and in the private sector. States with poorer health and service use outcomes have a lower health worker density. Conclusions Among the important human resources challenges that India faces is increasing the presence of qualified health workers in underserved areas and a more efficient skill mix. An important first step is to ensure the availability of reliable and comprehensive workforce information through live workforce registers.

Abstract Background To date, the clinical presentation and prognosis of mixed ductal/lobular mammary carcinomas has not been well studied, and little is known about the outcome of this entity. Thus, best management practices remain undetermined due to a dearth of knowledge on this topic. Methods In this paper, we present a clinicopathologic analysis of patients at our institution with this entity and compare them to age-matched controls with purely invasive ductal carcinoma (IDC) and historical data from patients with purely lobular carcinoma and also stain-available tumor specimens for E-cadherin. We have obtained 100 cases of ductal and 50 cases of mixed ductal/lobular breast carcinoma. Results Clinically, the behavior of mixed ductal/lobular tumors seemed to demonstrate some important differences from their ductal counterparts, particularly a lower rate of metastatic spread but with a much higher rate of second primary breast cancers. Conclusions Our data suggests that mixed ductal/lobular carcinomas are a distinct clinicopathologic entity incorporating some features of both lobular and ductal carcinomas and representing a pleomorphic variant of IDC.

Abstract Introduction Immortalization is a key step in malignant transformation, but immortalization alone is insufficient for transformation. Human mammary epithelial cell (HMEC) transformation is a complex process that requires additional genetic changes beyond immortalization and can be accomplished in vitro by accumulation of genetic changes and expression of H-ras. Methods HMEC were immortalized by serial passaging and transduction with the catalytic subunit of the human telomerase gene (hTERT). The immortalized cells were passaged in vitro and studied by a combination of G- banding and Spectral Karyotyping (SKY). H-ras transduced, hTERT immortalized cells were cloned in soft agar and injected into nude mice. Extensive analysis was performed on the tumors that developed in nude mice, including immunohistochemistry and western blotting. Results Immortal HMEC alone were not tumorigenic in γ-irradiated nude mice and could not grow in soft agar. Late passage hTERT immortalized HMEC from a donor transduced with a retroviral vector containing the mutant, autoactive, human H-ras61L gene acquired anchorage independent growth properties and the capacity for tumorigenic growth in vivo. The tumors that developed in the nude mice were poorly differentiated epithelial carcinomas that continued to overexpress ras. These cells were resistant to doxorubicin mediated G1/S phase arrest but were sensitive to treatment with a farnesyltransferase inhibitor. Conclusion Some of the cytogenetic changes are similar to what is observed in premalignant and malignant breast lesions. Despite these changes, late passage immortal HMEC are not tumorigenic and could only be transformed with overexpression of a mutant H-ras oncogene.

Harmful algal blooms are increasing globally and pose serious health concerns releasing cyanotoxins. Microcystin-LR (MC-LR), one of the most frequently produced cyanotoxins, has recently been detected in aerosols generated by the normal motions of affected bodies of water. MC-LR aerosol exposure has been linked to a pro-inflammatory influence on the airways of mice; however, little is understood about the underlying mechanism or the potential consequences. This study aimed to investigate the pro-inflammatory effects of aerosolized MC-LR on murine airways. C57BL/6 and BALB/c mice were exposed to MC-LR aerosols, as these strains are predisposed to type 1/type 17 and type 2 immune responses, respectively. Exposure to MC-LR induced granulocytic inflammation in C57BL/6 but not BALB/c mice, as observed by increased expression of cytokines MIP-1α, CXCL1, CCL2, and GM-CSF compared with their respective vehicle controls. Furthermore, the upregulation of interleukins IL-17A and IL-12 is consistent with Th1- and Th17-driven type 1/type 17 inflammation. Histological analysis confirmed inflammation in the C57BL/6 lungs, with elevated neutrophils and macrophages in the bronchoalveolar lavage fluid and increased pro-inflammatory and pro-resolving oxidized lipids. In contrast, BALB/c mice showed no significant airway inflammation. These results highlight the ability of aerosolized MC-LR to trigger harmful airway inflammation, requiring further research, particularly into populations with predispositions to type 1/type 17 inflammation.

Acute inflammation is elicited by lipid and protein mediators in defense of the host following sterile or pathogen-driven injury. A common refrain is that chronic inflammation is a result of incomplete resolution of acute inflammation and behind the etiology of all chronic diseases, including cancer. However, mediators that participate in inflammation are also essential in homeostasis and developmental biology but without eliciting the clinical symptoms of inflammation. This non-inflammatory physiological activity of the so called 'inflammatory' mediators, apparently under the functional balance with anti-inflammatory mediators, is defined as unalamation ( un-ala-mation ). Inflammation in the absence of injury is a result of perturbance in unalamation due to a decrease in the anti-inflammatory mediators rather than an increase in the inflammatory mediators and leads to chronic inflammation. This concept on the etiology of chronic inflammation suggests that treatment of chronic diseases is better achieved by stimulating the endogenous anti-inflammatory mediators instead of inhibiting the 'inflammatory' mediator biosynthesis with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Furthermore, both 'inflammatory' and anti-inflammatory mediators are present at higher concentrations in the tumor microenvironment compared to normal tissue environments. Since cancer is a proliferative disorder rather than a degenerative disease, it is proposed that heightened unalamation , rather than chronic inflammation, drives tumor growth. This understanding helps explain the inefficacy of NSAIDs as anticancer agents. Finally, inhibition of anti-inflammatory mediator biosynthesis in tumor tissues could imbalance unalamation toward local acute inflammation triggering an immune response to restore homeostasis and away from tumor growth., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Maddipati.)

Ethnopharmacological Relevance: Green tea (Camellia sinensis) is a popular beverage consumed all over the world due to its health benefits. Many of these beneficial effects of green tea are attributed to polyphenols, particularly catechins., Aim of the Study: The present study focuses on underlying anti-platelet aggregation, anti-thrombotic, and anti-lipidemic molecular mechanisms of green tea in South Indian smokers., Materials and Methods: We selected 120 South Indian male volunteers for this study to collect the blood and categorised them into four groups; control group individuals (Controls), smokers, healthy control individuals consuming green tea, and smokers consuming green tea. Smokers group subjects have been smoking an average 16-18 cigarettes per day for the last 7 years or more. The subjects (green tea consumed groups) consumed 100 mL of green tea each time, thrice a day for a one-year period., Results: LC-MS analysis revealed the presence of multiple phytocompounds along with catechins in green tea extract. Increased plasma lipid peroxidation (LPO), protein carbonyls, cholesterol, triglycerides, and LDL-cholesterol with decreased HDL-cholesterol levels were observed in smokers compared to the control group and the consumption of green tea showed beneficial effect. Furthermore, docking studies revealed that natural compounds of green tea had high binding capacity with 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA) when compared to their positive controls, whereas (-) epigallocatechin-3-gallate (EGCG) and (-) epicatechin-gallate (ECG) had high binding capacity with sterol regulatory element-binding transcription factor 1 (SREBP1c). Further, our ex vivo studies showed that green tea extract (GTE) significantly inhibited platelet aggregation and increased thrombolytic activity in a dose dependent manner., Conclusion: In conclusion, in smokers, catechins synergistically lowered oxidative stress, platelet aggregation and modified the aberrant lipid profile. Furthermore, molecular docking studies supported green tea catechins' antihyperlipidemic efficacy through strong inhibitory activity on HMG-CoA reductase and SREBP1c. The mitigating effects of green tea on cardiovascular disease risk factors in smokers that have been reported can be attributed majorly to catechins or to their synergistic effects., 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 Elsevier B.V. All rights reserved.)

Background: A filamentous fungus Penicillium rubens is widely recognized for producing industrially important antibiotic, penicillin at industrial scale., Objective: To better comprehend, the genetic blueprint of the wild-type P. rubens was isolated from India to identify the genetic/biosynthetic pathways for phenoxymethylpenicillin (penicillin V, PenV) and other secondary metabolites., Method: Genomic DNA (gDNA) was isolated, and library was prepared as per Illumina platform. Whole genome sequencing (WGS) was performed according to Illumina NovoSeq platform. Further, SOAPdenovo was used to assemble the short reads validated by Bowtie-2 and SAMtools packages. Glimmer and GeneMark were used to dig out total genes in genome. Functional annotation of predicted proteins was performed by NCBI non-redundant (NR), UniProt, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO) databases. Moreover, secretome analysis was performed by SignalP 4.1 and TargetP v1.1 and carbohydrate-active enzymes (CAZymes) and protease families by CAZy database. Comparative genome analysis was performed by Mauve 2.4.0. software to find genomic correlation between P. rubens BIONCL P45 and Penicillium chrysogenum Wisconsin 54-1255; also phylogeny was prepared with known penicillin producing strains by ParSNP tool., Results: Penicillium rubens BIONCL P45 strain was isolated from India and is producing excess PenV. The 31.09 Mb genome was assembled with 95.6% coverage of the reference genome P. chrysogenum Wis 54-1255 with 10687 protein coding genes, 3502 genes had homologs in NR, UniProt, KEGG, and GO databases. Additionally, 358 CAZymes and 911 transporter coding genes were found in genome. Genome contains complete pathways for penicillin, homogentisate pathway of phenyl acetic acid (PAA) catabolism, Andrastin A, Sorbicillin, Roquefortine C, and Meleagrin. Comparative genome analysis of BIONCL P45 and Wis 54-1255 revealed 99.89% coverage with 2952 common KEGG orthologous protein-coding genes. Phylogenetic analysis revealed that BIONCL P45 was clustered with Fleming's original isolate P. rubens IMI 15378., Conclusion: This genome can be a helpful resource for further research in developing fermentation processes and strain engineering approaches for high titer penicillin production., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

One of the primary concerns in the field of green synthesis of nanoparticles (NPs) utilizing plant materials is the scarcity of high purity, challenges in achieving large-scale production, and limited global accessibility. Hygienic preparation and safe storage of plant extracts are also considerable challenges in this field. So, an investigation was started to overcome these limitations. Virgin coconut oil (VCO) in its purest form is available commercially all over the world. Also, it has high medicinal value with excellent biomedical applications. Very limited work has been reported on oils as bio reducers and stabilizers. In those reports, they used a few chemicals as mediators in the processes of synthesis and cleaning. So, to the best of our knowledge, for the first time, zinc oxide (ZnO) NPs were synthesized using VCO as a reducing and capping agent with zero chemical mediators. A comprehensive investigation of the structural, microstructural, and optical properties was reported. X-ray diffraction confirms the formation of VCO-ZnO NPs with an average crystallite size of 32.81 nm in a hexagonal structure. UV characteristics confirm quantum confinement through a well-defined SPR near 223 nm with fwhm of 67 nm and a direct band gap at 3.96 eV. FTIR reveals the capping of VCO through carboxylic functional groups, particularly the -COO- group of coconut oil at 1770 cm -1 with a shift of about 30 cm -1 compared to plain VCO. TEM confirms the polycrystalline nature with nearly spherical and 10-22 nm particle size. The zeta potential of -15.4 ± 5.0 mV signifies the stability and antiagglomeration properties. FESEM with EDS results confirms morphological excellence, the purity level of synthesized NPs (99.5%), and the prominent scalability of NPs (84.38% yield). Finally, as-synthesized VCO-ZnO NPs showed very good antioxidant (IC 50 78.991, 51.464, and 4.677 μg/mL in DPPH, ABTS, and FRAP assays, respectively), anti-inflammatory (IC 50 22.42 μg/mL in protein denaturation), antimicrobial (MIC 0.156 mg/mL for Pseudomonas and 0.316 mg/mL for S. aureus ), and antidiabetic properties (IC 50 88.45 and 147.67 μg/mL for α-amylase and α-glucosidase assays, respectively)., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: Bone cement implantation syndrome characteristically involves acute alterations in the function of respiratory and cardiovascular systems. We present a case report of cement reaction with unusual presentation, that is, hypoxia, hypertension and tachycardia. A 74-year-old hypertensive male on regular medications sustained a slip and fall, presented with a right intertrochanteric neck of femur fracture, now posted for cemented hemiarthroplasty. Intraoperatively, after applying bone cement, the patient developed sweating, dyspnoea, bilateral wheezing and tachypnoea and desaturation of up to 80%-84%. Respiratory symptoms were associated with tachycardia (140-160 bpm) and hypertension (220/110 mm Hg). The surgeon was alerted about the event, the patient was reassured, and respiration was assisted with positive pressure ventilation with supplementation of 100% oxygen., Discussion: Several mechanisms have been proposed, such as the toxic effect of systemically absorbed methyl methacrylate, exothermic reaction, fat and marrow embolism, high marrow pressure during cementing and anaphylactic reaction. The administration of adrenaline, which can worsen the clinical picture, is the mainstay in managing anaphylaxis., Conclusion: The association of hypertension and tachycardia with bone cement implantation syndrome, previously not reported, can have distinct pathomechanisms and cause a diagnostic and management dilemma., 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.

Collagen hydrolysis, catalyzed by Zn(II)-dependent matrix metalloproteinases (MMPs), is a critical physiological process. Despite previous computational investigations into the catalytic mechanisms of MMP-mediated collagenolysis, a significant knowledge gap in understanding remains regarding the influence of conformational sampling and entropic contributions at physiological temperature on enzymatic collagenolysis. In our comprehensive multilevel computational study, employing quantum mechanics/molecular mechanics (QM/MM) metadynamics (MetD) simulations, we aimed to bridge this gap and provide valuable insights into the catalytic mechanism of MMP-1. Specifically, we compared the full enzyme-substrate complex in solution, clusters in solution, and gas-phase to elucidate insights into MMP-1-catalyzed collagenolysis. Our findings reveal significant differences in the catalytic mechanism when considering thermal effects and the dynamic evolution of the system, contrasting with conventional static potential energy surface QM/MM reaction path studies. Notably, we observed a significant stabilization of the critical tetrahedral intermediate, attributed to contributions from conformational flexibility and entropy. Moreover, we found that protonation of the scissile bond nitrogen occurs via proton transfer from a Zn(II)-coordinated hydroxide rather than from a solvent water molecule. Following C-N bond cleavage, the C-terminus remains coordinated to the catalytic Zn(II), while the N-terminus forms a hydrogen bond with a solvent water molecule. Subsequently, the release of the C-terminus is facilitated by the coordination of a water molecule. Our study underscores the pivotal role of protein conformational dynamics at physiological temperature in stabilizing the transition state of the rate-limiting step and key intermediates, compared to the corresponding reaction in solution. These fundamental insights into the mechanism of collagen degradation provide valuable guidance for the development of MMP-1-specific inhibitors.

Background An enhanced recovery approach in surgery helps early postoperative discharge. With the decreasing trend of morbidity and mortality in recent times in patients undergoing complex procedures such as pancreaticoduodenectomy, readmissions are the next major concern. The causes and outcomes of these readmissions should be investigated for their impact on patient care and prevention. Methodology A total of 997 patients discharged after pancreaticoduodenectomy from a tertiary care center in northern India, between 1989 and 2021, were studied retrospectively to assess the readmission rate for sequelae after pancreaticoduodenectomy. The causes, interventions, outcomes, and predictive factors were studied. Results A total of 103 (10.3%) patients required readmission for sequelae after pancreaticoduodenectomy, and 52 (50.4%) patients required interventions. The most common cause for readmission in our study was intra-abdominal collection (n = 23, 22.3%). Of these 103 patients, 63 (61.2%) had good outcomes, 36 (34.9%) had fair outcomes, and four (3.9%) had bad outcomes. Overall, 53 (51.5%) of 103 patients were readmitted within 30 days of discharge, most commonly with intra-abdominal collection (16 of 53, 30.1%). Of these 53 patients, 22 (41.5%) required interventions, 34 (64.1%) had good outcomes, and 27 (50.9%) were readmitted within seven days of discharge. Of these 27 patients, 12 (44.4%) required interventions, with 24 (88.8%) experiencing good outcomes. Of the 103 patients, 12 (11.6%) were readmitted between 31 and 90 days, mostly due to external stent, T-tube, or percutaneous transhepatic biliary drainage-related problems. Overall, 38 (36.9%) of 103 patients were readmitted after 90 days, mostly with incisional hernia and strictured hepaticojejunostomy. Of these 38 patients, 26 (68.4%) required intervention, and 23 (60.5%) had good outcomes. A previous history of cholangitis (odds ratio (OR) = 1.771, 95% confidence interval (CI) = 1.17-2.67, p = 0.007), postoperative fever (OR = 1.628, 95% CI = 1.081-2.452, p = 0.02), wound infection (OR = 2.011, 95% CI = 1.332-3.035, p = 0.001), and wound dehiscence (OR = 2.136, 95% CI = 1.333-3.423, p = 0.002) predicted readmission on univariate analysis. Multivariate analysis showed a previous history of cholangitis (OR = 1.755, CI = 1.158-2.659, p = 0.008) and wound infection (OR = 1.995, 95% CI = 1.320-2.690, p = 0.001) as factors independently predicting readmission. Conclusions Readmitted patients have high intervention rates and good recovery rates. Readmissions should not be considered a scale for poor healthcare. Patient education, proper management of postoperative complications, and a properly designed discharge care system can help tackle this problem., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethics Committee (IEC), Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India issued approval 2022-08-MCh-EXP-45 PGI/BE/152/2022. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Singh et al.)

Introduction: Recent Food and Drug Administration (FDA) draft guidelines are intended to improve representation and formalize the assessment of race and ethnicity in drug development, but how regulators and industry stakeholders plan to implement and enforce new requirements is still being determined., Materials and Methods: Here, a 10-question survey was developed to assess the experiences of industry stakeholders in developing diversity plans. These survey results informed an analysis of postmarketing studies to understand how diversity requirements have been enforced to date., Results and Discussion: Among 13 survey responders, experience submitting and receiving feedback on diversity plans was limited. A variety of challenges have been associated with developing these plans, including questions regarding regulatory guidance. Sponsors have utilized several data sources, including real-world datasets, to define enrollment goals. Diversity-related postmarketing studies most commonly related to oncologic diseases, and endpoints frequently related to efficacy. Most marketing applications associated with diversity-related postmarketing studies received Orphan drug designation (ODD) and Accelerated Approval., Conclusions: These results show that industry experience with diversity plans remains limited in the absence of finalized regulatory guidance. Sponsors are beginning to develop strategies for submitting diversity plans, which include identifying key functions and data sources to support enrollment goals, although definitive conclusions were difficult to draw from the small responder pool. In the postmarketing setting, studies are already underway to improve the understanding of racial and ethnic differences in responses to approved drugs. Development programs relating to oncology, which has historically suffered from a lack of diverse representation, have been a primary focus of such studies thus far., (© 2024. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

The rapid rise of antimicrobial resistance (AMR) is a global concern, being triggered by the overuse or misuse of antibiotics in poultry farming sector. We evaluated Lactococcus lactis subsp. lactis BIONCL17752 strain, and characterized its probiotic potential to endure hostile gastrointestinal conditions. Genome sequencing analysis revealed probiotics traits, and gene clusters involved in bacteriocins, lactococcin A, and sactipeptides production. The absence of genes for antibiotic resistance, virulence, and biogenic amine production indicates the potential of probiotic strain. The BIONCL17752 strain was explored for antibiotic-free feed supplement for growth promotor in broiler chicken. The feed supplemented with 4 × 10 9  CFU/kg of probiotic strain, in combination with various concentrations of fructooligosaccharides (FOS) 1.0, 2.5, and 5.0 kg/tonne in starter, grower, and finisher diets, respectively. A significant improvement of body weight 152 to 171 g/bird (p < 0.05), and a low feed conversion ratio (FCR) of 1.62, was achieved without using synthetic antibiotics for growth promotion. The results of biochemical, hematological, and histological examinations showed normal features, indicating that the treatment had no harmful effects on the bird's health. Reduced levels of cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) in serum are an indication of the health benefits for the treated birds. Microbial community analysis of fecal samples of poultry birds exhibited a higher abundance of Bacteroidetes, Firmicutes, Proteobacteria, Actinobacteria, and Fusobacteria. Probiotic treatment resulted in reduced Firmicutes and increased Bacteroidetes (F/B ratio) in the broiler's gut which highlights the benefits of probiotic dietary supplements. Importantly, the probiotic-fed group exhibited a high abundance of carbohydrate-active enzymes (CAZyme) such as glycoside hydrolases (GH), glycoside transferases (GT), and carbohydrate-binding module (CBM) hydrolases which are essential for the degradation of complex sugar molecules. The probiotic potential of the BIONCL17752 strain contributes to broilers' health by positively affecting intestinal microbiota, achieving optimal growth, and lowering mortality, demonstrating the economic benefits of probiotic treatment in organic poultry farming., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Despite large theoretical energy densities, metal-sulfide electrodes for energy storage systems face several limitations that impact the practical realization. Here, we present the solution-processable, room temperature (RT) synthesis, local structures, and application of a sulfur-rich Mo 3 S 13 chalcogel as a conversion-based electrode for lithium-sulfide batteries (LiSBs). The structure of the amorphous Mo 3 S 13 chalcogel is derived through operando Raman spectroscopy, synchrotron X-ray pair distribution function (PDF), X-ray absorption near edge structure (XANES), and extended X-ray absorption fine structure (EXAFS) analysis, along with ab initio molecular dynamics (AIMD) simulations. A key feature of the three-dimensional (3D) network is the connection of Mo 3 S 13 units through S-S bonds. Li/Mo 3 S 13 half-cells deliver initial capacity of 1013 mAh g -1 during the first discharge. After the activation cycles, the capacity stabilizes and maintains 312 mAh g -1 at a C/3 rate after 140 cycles, demonstrating sustained performance over subsequent cycling. Such high-capacity and stability are attributed to the high density of (poly)sulfide bonds and the stable Mo-S coordination in Mo 3 S 13 chalcogel. These findings showcase the potential of Mo 3 S 13 chalcogels as metal-sulfide electrode materials for LiSBs., (© 2024 Wiley-VCH GmbH.)

Nonheme Fe(II) and 2-oxoglutarate (2OG)-dependent histone lysine demethylases 2A (KDM2A) catalyze the demethylation of the mono- or dimethylated lysine 36 residue in the histone H3 peptide (H3K36me1/me2), which plays a crucial role in epigenetic regulation and can be involved in many cancers. Although the overall catalytic mechanism of KDMs has been studied, how KDM2 catalysis takes place in contrast to other KDMs remains unknown. Understanding such differences is vital for enzyme redesign and can help in enzyme-selective drug design. Herein, we employed molecular dynamics (MD) and combined quantum mechanics/molecular mechanics (QM/MM) to explore the complete catalytic mechanism of KDM2A, including dioxygen diffusion and binding, dioxygen activation, and substrate oxidation. Our study demonstrates that the catalysis of KDM2A is controlled by the conformational change of the second coordination sphere (SCS), specifically by a change in the orientation of Y222, which unlocks the 2OG rearrangement from off-line to in-line mode. The study demonstrates that the variant Y222A makes the 2OG rearrangement more favorable. Furthermore, the study reveals that it is the size of H3K36me3 that prevents the 2OG rearrangement, thus rendering the enzyme inactivity with trimethylated lysine. Calculations show that the SCS and long-range interacting residues that stabilize the HAT transition state in KDM2A differ from those in KDM4A, KDM7B, and KDM6A, thus providing the basics for the enzyme-selective redesign and modulation of KDM2A without influencing other KDMs.

Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common cause of pulmonary hypertension (PH) worldwide and is strongly associated with adverse clinical outcomes. The American Heart Association recently highlighted a call to action regarding the distinct lack of evidence-based treatments for PH due to poorly understood pathophysiology of PH attributable to HFpEF (PH-HFpEF). Prior studies have described cardiophysiological mechanisms to explain the development of isolated postcapillary PH (ipc-PH); however, the consequent increase in pulmonary vascular (PV) resistance (PVR) may lead to the less understood and more fatal combined pre- and postcapillary PH (cpc-PH). Metabolic disease and inflammatory dysregulation have been suggested to predispose PH, yet the molecular mechanisms are unknown. Although PH-HFpEF has been studied to partly share vasoactive neurohormonal mediators with primary pulmonary arterial hypertension (PAH), clinical trials that have targeted these pathways have been unsuccessful. The increased mortality of patients with PH-HFpEF necessitates further study into viable mechanistic targets involved in disease progression. We aim to summarize the current pathophysiological and clinical understanding of PH-HFpEF, highlight the role of known molecular mechanisms in the progression of PV disease, and introduce a novel concept that lipid metabolism may be attenuating and propagating PH-HFpEF. NEW & NOTEWORTHY Our review addresses pulmonary hypertension (PH) attributable to heart failure (HF) with preserved ejection fraction (HFpEF; PH-HFpEF). Current knowledge gaps in PH-HFpEF pathophysiology have led to a lack of therapeutic targets. Thus, we address identified knowledge gaps in a comprehensive review, focusing on current clinical epidemiology, known pathophysiology, and previously studied molecular mechanisms. We also introduce a comprehensive review of polyunsaturated fatty acid (PUFA) lipid inflammatory mediators in PH-HFpEF.

Background: An increasing incidence of colorectal cancer (CRC) is being reported in developing countries, including India. Most Indian studies on CRC are retrospective and single-centered. The present study is an attempt to understand the current clinical profile and stage of newly diagnosed CRCs across multiple centers in Tamil Nadu, India., Methods: A multi-centric observational survey was conducted between September 1, 2021, and August 31, 2022, under the aegis of the Indian Society of Gastroenterology - Tamil Nadu chapter. Patients 18 years of age and older with a recent diagnosis of CRC fulfilling the inclusion criteria were prospectively recruited at the participating centers. Their demographic, clinical, biochemical, endoscopic, histopathologic, radiologic and risk factor details were systematically collected and analyzed., Results: Across 23 centers in Tamil Nadu, 1208 patients were recruited. The male:female ratio was 1.49:1, while mean (SD) age was 57.7 (13.5) years. A majority (81.9%) were Tamils and 78.5% belonged to lower socioeconomic classes. The predominant symptoms were hematochezia (30.2%) and a change in bowel habits (27.5%). The most common locations were the rectum (34.3%) and rectosigmoid (15.1%). Synchronous CRCs were seen in 3.3% and synchronous colorectal polyps in 12.8%. Predisposing factors for CRC were seen in 2%. A past history of any cancer among CRC patients was obtained in 3.1% and a family history of any cancer was found in 7.6%. Patients who were either overweight or obese constituted 46.4% of the study population. At presentation, the predominant stages were stage III (44.7%) and stage IV (20.8%)., Conclusions: A majority of patients with newly diagnosed CRC in Tamil Nadu belonged to the lower socioeconomic classes. About 60% had CRCs located within the reach of the flexible sigmoidoscope. Two-thirds of the patients exceeded stage II disease at presentation., Trial Registration: Not applicable., (© 2024. Indian Society of Gastroenterology.)

Severe aplastic anemia (SAA) is a rare, fatal disease characterized by severe cytopenias and loss of hematopoietic stem cells (HSCs). Immune-mediated destruction and inflammation are known drivers of SAA, however, the underlying mechanisms driving persistent inflammation are unknown. Current treatments for SAA rely on immunosuppressive therapies or HSC transplantation, however, these treatments are not always effective. Using an established mouse model of SAA, we observed a significant increase in apoptotic cells within the bone marrow (BM) and impaired efferocytosis in SAA mice, relative to radiation controls. Single-cell transcriptomic analysis revealed heterogeneity among BM monocytes and unique populations emerged during SAA characterized by increased inflammatory signatures and significantly increased expression of Sirpa and Cd47. CD47, a "don't eat me" signal, was increased on both live and apoptotic BM cells, concurrent with markedly increased expression of signal regulatory protein alpha (SIRPα) on monocytes. Functionally, SIRPα blockade improved cell clearance and reduced accumulation of CD47-positive apoptotic cells. Lipidomic analysis revealed a reduction in the precursors of specialized pro-resolving lipid mediators (SPMs) and increased prostaglandins in the BM during SAA, indicative of impaired inflammation resolution. Specifically, 18-HEPE, a precursor of E-series resolvins, was significantly reduced in SAA-induced mice relative to radiation controls. Treatment of SAA mice with Resolvin E1 (RvE1) improved efferocytic function, BM cellularity, platelet output, and survival. Our data suggest that impaired efferocytosis and inflammation resolution contributes to SAA progression and demonstrate that SPMs, such as RvE1, offer new and/or complementary treatments for SAA that do not rely on immune suppression., (© 2024. The Author(s).)

The primary aim of this investigation was to synthesise novel adsorbent by incorporating greenly synthesized zinc oxide nanoparticles into chitosan matrix (G-ZnO-Cs). The production of ZnO Nanoparticles via a green approach involved the utilization of extracts derived from Nymphaeaceae fronds. This assertion was substantiated by the application of Field Emission Scanning Electron Microscopy (FESEM) and X-ray Diffraction (XRD) analytical techniques. Several Analytical methods such as Fourier Transform Infrared spectroscopy (FT-IR), Energy Dispersive X-ray Analysis (EDAX), FESEM, Thermogravimetric Analysis (TGA), XRD, Brunauer-Emmett-Teller (BET) analysis, and point-of-zero charge determination were used to characterize G-ZnO-Cs. Further study investigates the impact of five key processing parameters, namely pH, interaction duration, G-ZnO-Cs dosage, temperature, and initial concentration of dyes, on the removal of three organic dyes Reactive Blue 19 (RB 19), Reactive Orange 16 (RO 16), and Congo Red (CR) The adsorption process of Reactive Blue 19 (RB 19), Reactive Orange 16 (RO 16), and Congo Red (CR) dyes on G-ZnO-Cs were determined to comply to the pseudo-second-order (PSO) and Langmuir models, as determined through equilibrium and kinetic experiments. The highest adsorption capabilities for RB 19, RO 16 and CR dye were revealed to be 219.6 mg/g, 129.6 mg/g, and 118.8 mg/g, respectively. The elimination success rate of the fixed-bed column approach for treating huge volumes was highlighted in the conducted research. Moreover, the G-ZnO-Cs composite exhibited significant reusability due to its ability to undergo elution and simultaneous regeneration processes., 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 Elsevier Inc. All rights reserved.)

Folate is a micronutrient essential for DNA synthesis, cell division, fetal growth and development. Folate deficiency leads to genomic instability. Inadequate intake of folate during conception may lead to neural tube defects (NTDs) in the offspring. Folate influences the DNA methylation, histone methylation and homocysteine mediated gene methylation. DNA methylation influences the expression of microRNAs (miRNAs). Folate deficiency may be associated with miRNAs misregulation leading to NTDs. Mitochondrial epigenetics and folate metabolism has proved to be involved in embryogenesis and neural tube development. Folate related genetic variants also cause the occurrence of NTDs. Unmetabolized excessive folate may affect health adversely. Hence estimation of folate levels in the blood plays an important role in high-risk cases., 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 Elsevier Inc. All rights reserved.)