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Competing Interests: Dr Romero is an associate editor for the Journal of the American Heart Association and a section editor for Stroke. He is the chair of the Diversity, Equity and Inclusion Committee of the American Stroke Association. He has received compensation for head computed tomography imaging ratings for Brainomix. He is a DSMB member for the CoVasc-ICH clinical trial (Colchicine for the Prevention of Vascular Events after an Acute Intracerebral Hemorrhage). The other authors report no conflicts.

Background: Secondary prevention interventions to reduce post-stroke cognitive impairment (PSCI) can be aided by the early identification of high-risk individuals who would benefit from risk factor modification., Aims: To develop and evaluate a predictive model to identify patients at increased risk of PSCI over 5 years using data easily accessible from electronic health records., Methods: Cohort study that included primary care patients from two academic medical centers. Patients were aged 45 years or older, without prior stroke or prevalent cognitive impairment, with primary care visits and an incident ischemic stroke between 2003 and 2016 (development/internal validation cohort) or 2010 and 2022 (external validation cohort). Predictors of PSCI were ascertained from the electronic health record. The outcome was incident dementia/cognitive impairment within 5 years and beginning 3 months following stroke, ascertained using International Classification of Diseases, Ninth/Tenth Revision (ICD-9/10) codes. For model variable selection, we considered potential predictors of PSCI and constructed 400 bootstrap samples with two-thirds of the model derivation sample. We ran 10-fold cross-validated Cox proportional hazards models using a least absolute shrinkage and selection operator (LASSO) penalty. Variables selected in >25% of samples were included., Results: The analysis included 332 incident diagnoses of PSCI in the development cohort (n = 3741), and 161 and 128 incident diagnoses in the internal (n = 1925) and external (n = 2237) validation cohorts, respectively. The C-statistic for predicting PSCI was 0.731 (95% confidence interval (CI): 0.694-0.768) in the internal validation cohort, and 0.724 (95% CI: 0.681-0.766) in the external validation cohort. A risk score based on the beta coefficients of predictors from the development cohort stratified patients into low (0-7 points), intermediate (8-11 points), and high (12-23 points) risk groups. The hazard ratios (HRs) for incident PSCI were significantly different by risk categories in internal (high, HR: 6.2, 95% CI: 4.1-9.3; Intermediate, HR: 2.7, 95% CI: 1.8-4.1) and external (high, HR: 6.1, 95% CI: 3.9-9.6; Intermediate, HR: 2.8, 95% CI: 1.9-4.3) validation cohorts., Conclusion: Five-year risk of PSCI can be accurately predicted using routinely collected data. Model output can be used to risk stratify and identify individuals at increased risk for PSCI for preventive efforts., Data Access Statement: Mass General Brigham data contain protected health information and cannot be shared publicly. The data processing scripts used to perform analyses will be made available to interested researchers upon reasonable request to the corresponding author., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.M.A. reports sponsored research support from Bristol Myers Squibb / Pfizer Alliance. S.J.A. reports sponsored research support from Bristol Myers Squibb / Pfizer Alliance and American Heart Association and has consulted for Bristol Myers Squibb, Pfizer, Premier and Fitbit. D.E.S. reports sponsored research support from Bristol Myers Squibb/Pfizer Alliance and has consulted for Bristol Myers Squibb, Fitbit, Johnson and Johnson, Medtronic, and Pfizer. C.D.A. has received sponsored research support from Bayer AG. All relationships with industry are unrelated to this work.

Background: Clozapine is the most effective antipsychotic for treatment-resistant psychosis. However, clozapine is underutilised in part because of potential agranulocytosis. Accumulating evidence indicates that below-threshold haematological readings in isolation are not diagnostic of life-threatening clozapine-induced agranulocytosis (CIA)., Aims: To examine the prevalence and timing of CIA using different diagnostic criteria and to explore demographic differences of CIA in patients registered on the UK Central Non-Rechallenge Database (CNRD)., Method: We analysed data of all patients registered on the UK Clozaril ® Patient Monitoring Service Central Non-Rechallenge Database (at least one absolute neutrophil count (ANC) < 1.5 × 10 9 /L and/or white blood cell count < 3.0 × 10 9 /L) between May 2000 and February 2021. We calculated prevalence rates of agranulocytosis using threshold-based and pattern-based criteria, stratified by demographic factors (gender, age and ethnicity). Differences in epidemiology based on rechallenge status and clozapine indication were explored. The proportion of patients who recorded agranulocytosis from a normal ANC was explored., Results: Of the 3029 patients registered on the CNRD with 283 726 blood measurements, 593 (19.6%) were determined to have threshold-based agranulocytosis and 348 (11.4%) pattern-based agranulocytosis. In the total sample (75 533), the prevalence of threshold-based agranulocytosis and pattern-based agranulocytosis was 0.8% and 0.5%, respectively. The median time to threshold-based agranulocytosis was 32 weeks (IQR 184) and 15 (IQR 170) weeks for pattern-based agranulocytosis. Among age groups, the prevalence of pattern-based agranulocytosis and threshold-based agranulocytosis was highest in the >48 age group. Prevalence rates were greatest for White (18%) and male individuals (13%), and lowest for Black individuals (0.1%). The proportion of people who were determined to have pattern-based agranulocytosis without passing through neutropenia was 70%., Conclusions: Threshold-based definition of agranulocytosis may over-diagnose CIA. Monitoring schemes should take into consideration neutrophil patterns to correctly identify clinically relevant CIA. In marked contrast to previous studies, CIA occurred least in Black individuals and most in White individuals.

CaB 2 O 4 nanorods doped with different concentrations of Cu were prepared by using co-precipitation method. The recorded Thermoluminescence (TL) and Optically stimulated luminescence (OSL) of CaB 2 O 4 :Cu samples for different concentrations of Cu irradiated with 6 Gy of X-Ray shows that 0.05 at.wt% of Cu concentrations have higher sensitivity. The TL and OSL kinetic parameters of glow curves were evaluated using "tgcd" and conventional fitting methods. The TL glow curve of the CaB 2 O 4 :Cu have three individual glow peaks with maximum peak temperatures at 404.50, 453.04 and 484.02 K respectively. The OSL glow curves of the CaB 2 O 4 :Cu nanoparticles follow non-first order kinetics which can be fitted with the sum of two first order decay curves., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The 21-point Brain Care Score (BCS) is a novel tool designed to motivate individuals and care providers to take action to reduce the risk of stroke and dementia by encouraging lifestyle changes. Given that late-life depression is increasingly recognized to share risk factors with stroke and dementia, and is an important clinical endpoint for brain health, we tested the hypothesis that a higher BCS is associated with a reduced incidence of future depression. Additionally, we examined its association with a brain health composite outcome comprising stroke, dementia, and late-life depression., Methods: The BCS was derived from the United Kingdom Biobank baseline evaluation in participants with complete data on BCS items. Associations of BCS with the risk of subsequent incident late-life depression and the composite brain health outcome were estimated using multivariable Cox proportional hazard models. These models were adjusted for age at baseline and sex assigned at birth., Results: A total of 363,323 participants were included in this analysis, with a median BCS at baseline of 12 (IQR: 11-14). There were 6,628 incident cases of late-life depression during a median follow-up period of 13 years. Each five-point increase in baseline BCS was associated with a 33% lower risk of incident late-life depression (95% CI: 29%-36%) and a 27% lower risk of the incident composite outcome (95% CI: 24%-30%)., Discussion: These data further demonstrate the shared risk factors across depression, dementia, and stroke. The findings suggest that a higher BCS, indicative of healthier lifestyle choices, is significantly associated with a lower incidence of late-life depression and a composite brain health outcome. Additional validation of the BCS is warranted to assess the weighting of its components, its motivational aspects, and its acceptability and adaptability in routine clinical care worldwide., Competing Interests: CA receives sponsored research support from the US National Institutes of Health, the American Heart Association, and Bayer AG, and has consulted for ApoPharma. GF receives sponsored research support from the National Institute of Mental Health Clinical Global Mental Health Research T32 Fellowship, receives royalties or licenses from Johns Hopkins University Press, University of Chicago Press, Belvoir Press, and the American Psychiatric Press, is on a Data Safety Monitoring Board or Advisory Board of Healthy Hearts Healthy Minds DSMB, is a Board of Directors member at the Rosalynn Carter Institute, and has stock or stock options from Revival Therapeutics Consultant. LG-M receives sponsored research support from the American Heart grant number 963719. JR receives sponsored research support from the US National Institutes of Health and the American Heart Association, and receives payments for expert testimony and consulting fees from the National Football League. EM is an employee of Regeneron Genetics Center. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.​ The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Singh, Rivier, Papier, Chemali, Gutierrez-Martinez, Parodi, Mayerhofer, Senff, Clocchiatti-Tuozzo, Nunley, Newhouse, Ouyang, Westover, Tanzi, Lazar, Pikula, Ibrahim, Brouwers, Howard, Howard, Yechoor, Littlejohns, Sheth, Rosand, Fricchione, Anderson and Falcone.)

The Brain Health crisis stands as one of humankind's most pressing threats, with age-related noncommunicable brain diseases, particularly stroke, and dementia, affecting hundreds of millions annually and jeopardizing the economic well-being of populations worldwide. Epidemiological studies indicate that ≈40% of dementia and 60% of stroke cases are attributable to modifiable risk factors. In this Comments and Opinions article, we underscore the pivotal role of blood pressure (BP) control in reducing suffering, enhancing economic well-being, and promoting healthy longevity for populations worldwide. Emphasizing that BP control is crucial for both brain and heart health, it advocates for heightened awareness, positioning hypertension as a primary focus for preventing dementia and stroke with potential global impact. Despite its significance, BP control encounters global challenges, with proportions of the population maintaining adequately controlled hypertension ranging from 23% to 90%. The World Health Organization estimated that 46% of the 1.28 billion people with hypertension are unaware of their elevated BP. Given the notable disparities in BP management, addressing BP management also contributes to combating significant health inequalities. The next time you are faced with a patient anxious about the prospect of experiencing a fate similar to a parent with dementia or a sister with a stroke, we suggest a straightforward answer for health care providers: start ensuring BP control. BP is a matter of brain health, and it is a matter of our economic future., Competing Interests: Disclosures Dr Rosand receives sponsored research support from the US National Institutes of Health and the American Heart Association, receives payments for consulting and expert testimony from the National Football League, consulting for Eli Lilly, serves as an Editorial Board Member for Elsevier, served on the Scientific Advisory Board for Takeda, and has a leadership or fiduciary role at Columbia University.

Background: Spontaneous intracerebral hemorrhage (ICH) in the cerebellum has a poor short-term prognosis, whereas data on the long-term case fatality and recurrent vascular events are sparse. Herewith, we aimed to assess the long-term case fatality and recurrence rate of vascular events after a first cerebellar ICH., Methods: In this international cohort study, we included patients from 10 hospitals (the United States and Europe from 1997 to 2017) aged ≥18 years with a first spontaneous cerebellar ICH who were discharged alive. Data on long-term case fatality and recurrence of vascular events (recurrent ICH [supratentoria or infratentorial], ischemic stroke, myocardial infarction, or major vascular surgery) were collected for survival analysis and absolute event rate calculation., Results: We included 405 patients with cerebellar ICH (mean age [SD], 72 [13] years, 49% female). The median survival time was 67 months (interquartile range, 23-100 months), with a cumulative survival rate of 34% at 10-year follow-up (median follow-up time per center ranged: 15-80 months). In the 347 patients with data on vascular events 92 events occurred in 78 patients, after initial cerebellar ICH: 31 (8.9%) patients had a recurrent ICH (absolute event rate, 1.8 per 100 patient-years [95% CI, 1.2-2.6]), 39 (11%) had an ischemic stroke (absolute event rate, 2.3 [95% CI, 1.6-3.2]), 13 (3.7%) had a myocardial infarction (absolute event rate, 0.8 [95% CI, 0.4-1.3]), and 5 (1.4%) underwent major vascular surgery (absolute event rate, 0.3 [95% CI, 0.1-0.7]). The median time to a first vascular event during follow-up was 27 months (interquartile range, 8.7-50 months), with a cumulative hazard of 47% at 10 years., Conclusions: The long-term prognosis of patients who survive a first spontaneous cerebellar ICH is poor and comparable to that of patients who survive a first supratentorial ICH. Further identification of patients at high risk of vascular events following the initial cerebellar ICH is needed. Including patients with cerebellar ICH in randomized controlled trials on secondary prevention of patients with ICH is warranted., Competing Interests: Disclosures Dr Anderson has received sponsored research support from Bayer AG and has consulted for ApoPharma unrelated to this work. Dr Rosand reports compensation from National Football League and Takeda Development Center Americas for consultant services, unrelated to this work. The other authors report no conflicts.

Wastewater-based epidemiology (WBE) has been used for monitoring infectious diseases like polio, hepatitis, etc. since the 1940s. It is also being used for tracking the SARS-CoV-2 at the population level. This article aims to compile and assess the information for the qualitative and quantitative detection of the SARS-CoV-2 in wastewater. Based on the globally published studies, we highlight the importance of monitoring SARS-CoV-2 presence/detection in the wastewater and concurrently emphasize the development of early surveillance techniques. SARS-CoV-2 RNA sheds in the human feces, saliva, sputum and mucus that ultimately reaches to the wastewater and brings viral RNA into it. For the detection of the virus in the wastewater, different detection techniques have been optimized and are in use. These are based on serological, biosensor, targeted PCR, and next generation sequencing for whole genome sequencing or targeted amplicon sequencing. The presence of the SARS-CoV-2 RNA in wastewater could be used as a potential tool for early detection and devising the strategies for eradication of the virus before it is spread in the community. Additionally, with the right and timely understanding of viral behavior in the environment, an accurate and instructive model that leverages WBE-derived data may be created. This might help with the creation of technological tools and doable plans of action to lessen the negative effects of current viral epidemics or future potential outbreaks on public health and the economy. Further work toward whether presence of viral load correlates with its ability to induce infection, still needs evidence. The current increasing incidences of JN.1 variant is a case in point for continued early detection and surveillance, including wastewater., Competing Interests: The authors declare 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 Gogoi, Singh, Kalyan, Koch, Gogoi, Kshattry, Mahanta, Imran, Pandey and Bharali.)

Background: Despite increasing incidence, there is little data on abnormal eating behaviours or disorders in Indian youth, especially medical students. Additionally, little literature exists measuring the association of social media use with abnormal eating behaviours., Aim: To assess the prevalence of abnormal eating behaviours amongst medical students, social media usage, and any association of social media usage with eating behaviours., Materials and Methods: An online cross-sectional questionnaire-based study was conducted with 272 participants at a medical college, and two scales: the Three-Factor Eating Questionnaire-Revised 21items (TFEQ-R21) and the Scale of Effects of social media on Eating Behaviour (SESMEB) were used., Results: 22% of the participants reported abnormal eating behaviours. A significant difference in the effect of social media on eating behaviour according to the year of study [f = 3.08, P = 0.02] was seen with the final years having the lowest and the first years having the highest SESMEB scores. Students using more than 4 social media platforms had a higher SESMEB score [t = -2.02, P < 0.04]. A positive correlation was seen between TFEQ domains such as uncontrolled eating [r = 0.38, P = 0.01], emotional eating [r = 0.30, P = 0.01], and TFEQ total score [r = 0.40, P = 0.01] with SESMEB scores., Conclusion: This study finds a significant correlation between increased social media usage and developing abnormal eating behaviours in medical students. It highlights the need for the creation of policies regulating social media use with eating behaviours in mind., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Industrial Psychiatry Journal.)

Introduction: The 21-point Brain Care Score (BCS) was developed through a modified Delphi process in partnership with practitioners and patients to promote behavior changes and lifestyle choices in order to sustainably reduce the risk of dementia and stroke. We aimed to assess the associations of the BCS with risk of incident dementia and stroke., Methods: The BCS was derived from the United Kingdom Biobank (UKB) baseline evaluation for participants aged 40-69 years, recruited between 2006-2010. Associations of BCS and risk of subsequent incident dementia and stroke were estimated using Cox proportional hazard regressions, adjusted for sex assigned at birth and stratified by age groups at baseline., Results: The BCS (median: 12; IQR:11-14) was derived for 398,990 UKB participants (mean age: 57; females: 54%). There were 5,354 incident cases of dementia and 7,259 incident cases of stroke recorded during a median follow-up of 12.5 years. A five-point higher BCS at baseline was associated with a 59% (95%CI: 40-72%) lower risk of dementia among participants aged <50. Among those aged 50-59, the figure was 32% (95%CI: 20-42%) and 8% (95%CI: 2-14%) for those aged >59 years. A five-point higher BCS was associated with a 48% (95%CI: 39-56%) lower risk of stroke among participants aged <50, 52% (95%CI, 47-56%) among those aged 50-59, and 33% (95%CI, 29-37%) among those aged >59., Discussion: The BCS has clinically relevant and statistically significant associations with risk of dementia and stroke in approximately 0.4 million UK people. Future research includes investigating the feasibility, adaptability and implementation of the BCS for patients and providers worldwide., Competing Interests: CA receives sponsored research support from the US National Institutes of Health, the American Heart Association, and Bayer AG, and has consulted for ApoPharma. GrF receives sponsored research support from the National Institute of Mental Health Clinical Global Mental Health Research T32 Fellowship, receives royalties or licenses from Johns Hopkins University Press, University of Chicago Press, Belvoir Press, and the American Psychiatric Press, is on a Data Safety Monitoring Board or Advisory Board of Healthy Hearts Healthy Minds DSMB, is a Board of Directors member at the Rosalynn Carter Institute, and has stock or stock options from Revival Therapeutics Consultant. JR receives sponsored research support from the US National Institutes of Health and the American Heart Association, receives payments for consulting and expert testimony from the National Football League, and has a leadership or fiduciary role at Columbia University and Lancet Neurology. KP was supported by Cancer Research UK [grant number C570/A16491 and C16077/A29186]. LG-M receives sponsored research support from the American Heart [grant number 963719]. MC is supported by the Wellcome Trust [grant number 205339/Z/16/Z]. The remaining authors declare 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 © 2023 Singh, Oreskovic, Carr, Papier, Conroy, Senff, Chemali, Gutierrez-Martinez, Parodi, Mayerhofer, Marini, Nunley, Newhouse, Ouyang, Brouwers, Westover, Rivier, Falcone, Howard, Howard, Pikula, Ibrahim, Sheth, Yechoor, Lazar, Anderson, Tanzi, Fricchione, Littlejohns and Rosand.)

Introduction: Acral lentiginous melanoma (ALM) is a rare type of melanoma associated with delayed diagnosis and poor survival rates. This study examines ALM incidence rates in comparison to all other melanoma types., Methods: We used data from the Centers for Disease Control and Prevention's National Program of Cancer Registries and the National Cancer Institute's Surveillance, Epidemiology, and End Results Program, which together cover 99% of the US population. We calculated age-adjusted rates and rate ratios for ALM and all other malignant melanomas by sex, race and ethnicity, stage, and year of diagnosis (2010-2019)., Results: ALM incidence rates were significantly lower among non-Hispanic Black persons (1.8 per 1,000,000); non-Hispanic Asian/Pacific Islander (API) persons (1.7 per 1,000,000); and Hispanic Black, American Indian/Alaska Native (AI/AN), and API persons (1.5 per 1,000,000) compared to non-Hispanic White persons (2.3 per 1,000,000). Rates were significantly higher among Hispanic White persons (2.8 per 1,000,000) compared to non-Hispanic White persons. For all other melanoma types, incidence rates were significantly higher among non-Hispanic White persons compared to persons in each of the other racial and ethnic categories. The percentage of melanomas that were ALM ranged from 0.8% among non-Hispanic White persons to 19.1% among Hispanic Black, AI/AN, and API persons., Conclusion: These findings suggest that awareness of the potential for ALM in patients of all races and ethnicities could be balanced with an understanding of the rarity of the disease and the potential for the development of other melanoma types in racial and ethnic minority groups., 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.)

Introduction: In the subcontinent of India as well as for the other nations, the most usual cancer that affects the oral cavity the "squamous cell carcinoma". The main side effects of the intervention of the SCC are the large defect and disfigurement. This study sought to investigate the various interventions of the SCC in a designated cancer institute., Material and Methods: A retrospective clinical study of the records was done between 2000-2020 years. The operated cases were analysed for various patient demographics as well as the site of the lesion and number distributions. The change in the techniques and the preference flaps over the periods was noted, and the values were compared for every 5 years., Results: A1001 patients were treated between the intended periods. Though there were larger number of men, the variation was not significant. Common sites were floor of the mouth (FOM) and tongue. The common interventions were primary closure, soft tissue free flaps and bone flaps. The shift was seen towards the free flaps., Conclusion: The Free flaps were the common applications in the constructions. Bone free flaps overtook the other procedures that were commonly applied. The quality of life and the aesthetics are seen to be better with the free flaps., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Pharmacy and Bioallied Sciences.)

Non-Hispanic Asian (Asian) and non-Hispanic Native Hawaiian and Pacific Islander (NHPI) persons represent growing segments of the U.S. population (1). Epidemiologic cancer studies often aggregate Asian and NHPI persons (2,3); however, because Asian and NHPI persons are culturally, geographically, and linguistically diverse (2,4), subgroup analyses might provide insights into the distribution of health outcomes. To examine the frequency and percentage of new cancer cases among 25 Asian and NHPI subgroups, CDC analyzed the most current 2015-2019 U.S. Cancer Statistics data.* The distribution of new cancer cases among Asian and NHPI subgroups differed by sex, age, cancer type, and stage at diagnosis (for screening-detected cancers). The percentage of cases diagnosed among females ranged from 47.1% to 68.2% and among persons aged <40 years, ranged from 3.1% to 20.2%. Among the 25 subgroups, the most common cancer type varied. For example, although breast cancer was the most common in 18 subgroups, lung cancer was the most common cancer among Chamoru, Micronesian race not otherwise specified (NOS), and Vietnamese persons; colorectal cancer was the most common cancer among Cambodian, Hmong, Laotian, and Papua New Guinean persons. The frequency of late-stage cancer diagnoses among all subgroups ranged from 25.7% to 40.3% (breast), 38.1% to 61.1% (cervical), 52.4% to 64.7% (colorectal), and 70.0% to 78.5% (lung). Subgroup data illustrate health disparities among Asian and NHPI persons, which might be reduced through the design and implementation of culturally and linguistically responsive cancer prevention and control programs, including programs that address social determinants of health., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Virulent Enterobacterale strains expressing serine and metallo-β-lactamases (MBL) genes have emerged responsible for conferring resistance to hard-to-treat infectious diseases. One strategy that exists is to develop β-lactamase inhibitors to counter this resistance. Currently, serine β-lactamase inhibitors (SBLIs) are in therapeutic use. However, an urgent global need for clinical metallo-β-lactamase inhibitors (MBLIs) has become dire. To address this problem, this study evaluated BP2, a novel beta-lactam-derived β-lactamase inhibitor, co-administered with meropenem. According to the antimicrobial susceptibility results, BP2 potentiates the synergistic activity of meropenem to a minimum inhibitory concentration (MIC) of ≤1 mg/L. In addition, BP2 is bactericidal over 24 h and safe to administer at the selected concentrations. Enzyme inhibition kinetics showed that BP2 had an apparent inhibitory constant (K i app ) of 35.3 µM and 30.9 µM against New Delhi Metallo-β-lactamase (NDM-1) and Verona Integron-encoded Metallo-β-lactamase (VIM-2), respectively. BP2 did not interact with glyoxylase II enzyme up to 500 µM, indicating specific (MBL) binding. In a murine infection model, BP2 co-administered with meropenem was efficacious, observed by the >3 log 10 reduction in K. pneumoniae NDM cfu/thigh. Given the promising pre-clinical results, BP2 is a suitable candidate for further research and development as an (MBLI).

β-lactams are the most prescribed class of antibiotics due to their potent, broad-spectrum antimicrobial activities. However, alarming rates of antimicrobial resistance now threaten the clinical relevance of these drugs, especially for the carbapenem-resistant Enterobacterales expressing metallo-β-lactamases (MBLs). Antimicrobial agents that specifically target these enzymes to restore the efficacy of last resort β-lactam drugs, that is, carbapenems, are therefore desperately needed. Herein, we present a cyclic zinc chelator covalently attached to a β-lactam scaffold (cephalosporin), that is, BP1. Observations from in vitro assays (with seven MBL expressing bacteria from different geographies) have indicated that BP1 restored the efficacy of meropenem to ≤ 0.5 mg/L, with sterilizing activity occurring from 8 h postinoculation. Furthermore, BP1 was nontoxic against human hepatocarcinoma cells (IC 50 > 1000 mg/L) and exhibited a potency of (K i app ) 24.8 and 97.4 μM against Verona integron-encoded MBL (VIM-2) and New Delhi metallo β-lactamase (NDM-1), respectively. There was no inhibition observed from BP1 with the human zinc-containing enzyme glyoxylase II up to 500 μM. Preliminary molecular docking of BP1 with NDM-1 and VIM-2 sheds light on BP1's mode of action. In Klebsiella pneumoniae NDM infected mice, BP1 coadministered with meropenem was efficacious in reducing the bacterial load by >3 log 10 units' postinfection. The findings herein propose a favorable therapeutic combination strategy that restores the activity of the carbapenem antibiotic class and complements the few MBL inhibitors under development, with the ultimate goal of curbing antimicrobial resistance.

The recent surge in beta-lactamase resistance has created superbugs, which pose a current and significant threat to public healthcare. This has created an urgent need to keep pace with the discovery of inhibitors that can inactivate these beta-lactamase producers. In this study, the in vitro and in vivo activity of 1,4,7-triazacyclononane-1,4,7 triacetic acid (NOTA)-a potential metallo-beta-lactamase (MBL) inhibitor was evaluated in combination with meropenem against MBL producing bacteria. Time-kill studies showed that NOTA restored the efficacy of meropenem against all bacterial strains tested. A murine infection model was then used to study the in vivo pharmacokinetics and efficacy of this metal chelator. The coadministration of NOTA and meropenem (100 mg/kg.bw each) resulted in a significant decrease in the colony-forming units of Klebsiella pneumoniae NDM-1 over an 8-h treatment period (>3 log10 units). The findings suggest that chelators, such as NOTA, hold strong potential for use as a MBL inhibitor in treating carbapenem-resistant Enterobacterale infections., (© The Author(s) 2022. Published by Oxford University Press on behalf of FEMS.)

CaB 4 O 7 nanoparticles doped with different concentrations of Dy 3+ were prepared by using solution combustion method. The recorded Thermoluminescence (TL) and Optically stimulated luminescence (OSL) of CaB 4 O 7 :Dy samples for different concentrations of Dy 3+ irradiated with 6 Gy of X-Ray shows concentration quenching effect above 0.05 at.wt% of Dy 3+ concentrations. The TL and OSL kinetic parameters of glow curves were evaluated using "tgcd" and conventional fitting methods. The TL glow curve of the CTB:(0.05%)Dy have five individual glow peaks with maximum peak temperatures at 410, 470, 525, 563 and 593 K. TL Dose response of the X-Ray irradiated CTB:(0.05%)Dy is also found to be linear in the range of 1 Gy to 50 Gy. The OSL glow curves of the CTB:Dy nanoparticles follow non-first order kinetics and can be fitted with the sum of three first order decay curves. Fading characteristics of the TL and OSL signals are studied for 40 days and found to be very stable., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study compares three different mating techniques in Sprague-Dawley rats, using the pregnancy rate as the main indicator of success. It provides recommendations for timed-pregnancy experiments to achieve an appropriate sample size for the study of human pregnancy disorders. The implementation of a preconditioning phase, determination of the estrous cycle, the use of two mating strategies (Lee-Boot and Whitten effect), female: male mating ratios, and cohabitation duration should be considered as they improve the mating success rate., (Copyright © 2022 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier B.V. All rights reserved.)

The primary motive of the current work is to achieve smaller mean particle size with narrow size distribution that can enhance the bioavailability of azithromycin (ARZ), an essential requirement due to its poor water solubility. Recrystallization of ARZ was evaluated using cooling as well as antisolvent crystallization approaches in the presence of ultrasonic irradiation with detailed study into effect of different parameters such as ultrasonic power, time and temperature. Ultrasound assisted antisolvent crystallization at low temperatures (<10℃) yielded best size reduction up to 80% with narrower distribution and also gave better yield of the product, that too within 5 min of sonication. With scale up considerations, recirculation mode of operation was also evaluated which offered promising results for the size reduction. Images captured using optical microscope and SEM revealed a nearly uniform rod/plate-shaped geometry. Increase in amorphous nature of ARZ was confirmed based on XRD analysis. FTIR analysis showed no significant changes in the functional groups when compared to the original sample. Overall, the work demonstrated an improved reprocessing approach based on the use of ultrasound with insights into effect of operating parameters and effect of ultrasound on various characteristics., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Rodent models have contributed greatly to our understanding of preeclampsia (PE) progression in humans, however to-date no model has been able to effectively replicate the clinical presentation of the disease. This study aimed to provide a thorough physiological characterization of the arginine vasopressin (AVP)-induced rat model of PE to determine its applicability in studying the pathophysiology of PE. Female Sprague Dawley rats (n = 24) were separated into four groups (n = 6 per group) viz., pregnant AVP, pregnant saline, non-pregnant AVP, and non-pregnant saline. All animals received a continuous dose of either AVP (150 ng/h) or saline via subcutaneous mini osmotic pumps for 18 days. Full physiological characterization of the model included measuring systolic and diastolic blood pressure, and collecting urine and blood samples for biochemical analysis. AVP infusion significantly increased blood pressure and urinary protein levels in the pregnant rats ( p < 0.05). Biochemical markers measured, differed significantly in the AVP-treated vs the pregnant saline groups ( p < 0.05). Placental and individual pup weight decreased significantly in the pregnant AVP vs pregnant saline group ( p < 0.05). The physiological and hematological data confirm the usefulness of this rat model in the study of PE, since AVP-induced vasoconstriction increases peripheral resistance and successfully mimics the pathological changes associated with PE development in humans. Abbreviations: PE: preeclampsia; AVP: arginine vasopressin; ISSHP: International Society for the Study of Hypertension in Pregnancy; ACOG: American College of Obstetricians and Gynecologists; RUPP: reduced uterine perfusion pressure; sFlt-1: soluble fms-like tyrosine kinase; VEGF: vascular endothelial growth factor; PlGF: placental growth factor; AVP: arginine vasopressin; PAVP: pregnant AVP-treated; PS: pregnant saline; GD: gestational day; ALT: alanine transaminase; NAVP: non-pregnant AVP-treated; NS: non-pregnant saline; AST: aspartate aminotransferase; HDL: high-density lipoprotein; RBC: red blood cell; RAAS: renin-angiotensin aldosterone system; HELLP: hemolysis, elevated liver enzymes, low platelet.

We provide a novel single restriction enzyme (RE; BsaHI) digestion approach for detecting distinct pathotypes of Newcastle disease virus (NDV). After scanning 4,000 F gene nucleotide sequences in the NCBI database, we discovered a single RE (BsaHI) digestion site in the cleavage site. APMV-I "F gene" class II-specific primer-based reverse transcriptase PCR was utilized to amplify a 535-bp fragment, which was then digested with the RE (BsaHI) for pathotyping avian NDV field isolates and pigeon paramyxovirus-1 isolates. The avirulent (lentogenic and mesogenic strains) produced 189- and 346-bp fragments, respectively, but the result in velogenic strains remained undigested with 535-bp fragments. In addition, 45 field NDV isolates and 8 vaccine strains were used to confirm the approach. The sequence-based analysis also agrees with the data obtained utilizing the single RE (BsaHI) digestion approach. The proposed technique has the potential to distinguish between avirulent and virulent strains in a short time span, making it valuable in NDV surveillance and monitoring research. IMPORTANCE The extensive use of the NDV vaccine strain and the existence of avirulent NDV strains in wild birds makes it difficult to diagnose Newcastle Disease virus (NDV). The intracerebral pathogenicity index (ICPI) and/or sequencing-based identification, which are required to determine virulent NDV, are time-consuming, costly, difficult, and cruel techniques. We evaluated 4,000 F gene nucleotide sequences and discovered a restriction enzyme (RE; BsaHI) digestion technique for detecting NDV and vaccine pathotypes in a short time span, which is cost-effective and useful for field cases as well as for large-scale NDV monitoring and surveillance. The data acquired using the single RE BsaHI digestion technique agree with the sequence-based analysis.

Background: In patients with spontaneous cerebellar intracerebral hemorrhage (ICH) guidelines advocate evacuation when the hematoma diameter is > 3 cm. We studied outcome in patients with cerebellar ICH > 3 cm who did not undergo immediate hematoma evacuation., Methods: We included consecutive patients with cerebellar ICH > 3 cm at two academic hospitals between 2008 and 2017. Patients who died < 24 h (h) were excluded because of probable confounding by indication. We determined patient characteristics, hematoma volumes, EVD placement, secondary hematoma evacuation, in-hospital and 3-month case-fatality, and functional outcome., Results: Of 130 patients with cerebellar ICH, 98 (77%) had a hematoma > 3 cm of whom 22 (23%) died < 24 h and 28 (29%) underwent hematoma evacuation < 24 h. Thus, 48 patients were initially treated conservatively (mean age 70 ± 13, 24 (50%) female). Of these 48 patients, 7 (15%) underwent secondary hematoma evacuation > 24 h, of whom 1 (14%) had received an EVD < 24 h. Five others also received an EVD < 24 h without subsequent hematoma evacuation. Of the 41 patients without secondary hematoma evacuation, 11 (28%) died and 20 (51%) had a favorable outcome (mRS of 0-3) at 3 months. The 7 patients who underwent secondary hematoma evacuation had a decrease in GCS score of at least two points prior to surgery; two (29%) had deceased at 3 months; and 5 (71%) had a good functional outcome (mRS 0-3)., Conclusions: While cerebellar ICH > 3 cm is often considered an indication for immediate hematoma evacuation, there may be a subgroup of patients in whom surgery can be safely deferred. Further data are needed to assess the optimal timing and indications of surgical treatment in these patients., (© 2021. The Author(s).)

Chronic wound infections caused by antibiotic-resistant bacteria have become a global health concern. This is attributed to the biofilm-forming ability of bacteria on wound surfaces, thus enabling their persistent growth. In most cases, it leads to morbidity and in severe cases mortality. Current conventional approaches used in the treatment of biofilm wounds are proving to be ineffective due to limitations such as the inability to penetrate the biofilm matrix; hence, biofilm-related wounds remain a challenge. Therefore, there is a need for more efficient alternate therapeutic interventions. Hydrogen peroxide (HP) is a known antibacterial/antibiofilm agent; however, prolonged delivery has been challenging due to its short half-life. In this study, we developed a hydrogel for the codelivery of HP and antimicrobial peptides (Ps) against bacteria, biofilms, and wound infection associated with biofilms. The hydrogel was prepared via the Michael addition technique, and the physiochemical properties were characterized. The safety, in vitro , and in vivo antibacterial/antibiofilm activity of the hydrogel was also investigated. Results showed that the hydrogel is biosafe. A greater antibacterial effect was observed with HP-loaded hydrogels (CS-HP; hydrogel loaded with HP and CS-HP-P; hydrogel loaded with HP and peptide) when compared to HP as seen in an approximately twofold and threefold decrease in minimum inhibitory concentration values against methicillin-resistant Staphylococcus aureus (MRSA) bacteria, respectively. Similarly, both the HP-releasing hydrogels showed enhanced antibiofilm activity in the in vivo study in mice models as seen in greater wound closure and enhanced wound healing in histomorphological analysis. Interestingly, the results revealed a synergistic antibacterial/antibiofilm effect between HP and P in both in vitro and in vivo studies. The successfully prepared HP-releasing hydrogels showed the potential to combat bacterial biofilm-related infections and enhance wound healing in mice models. These results suggest that the HP-releasing hydrogels may be a superior platform for eliminating bacterial biofilms without using antibiotics in the treatment of chronic MRSA wound infections, thus improving the quality of human health., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Background and Purpose: The computed tomography angiography spot sign is associated with hematoma expansion, case fatality, and poor functional outcome in spontaneous supratentorial intracerebral hemorrhage (ICH). However, no data are available on the spot sign in spontaneous cerebellar ICH., Methods: We investigated consecutive patients with spontaneous cerebellar ICH at 3 academic hospitals between 2002 and 2017. We determined patient characteristics, hematoma expansion (>33% or 6 mL), rate of expansion, discharge and 90-day case fatality, and functional outcome. Poor functional outcome was defined as a modified Rankin Scale score of 4 to 6. Associations were tested using univariable and multivariable logistic regression., Results: Three hundred fifty-eight patients presented with cerebellar ICH, of whom 181 (51%) underwent a computed tomography angiography. Of these 181 patients, 121 (67%) were treated conservatively of which 15 (12%) had a spot sign. Patients with a spot sign treated conservatively presented with larger hematoma volumes (median [interquartile range]: 26 [7–41] versus 6 [2–13], P=0.001) and higher speed of expansion (median [interquartile range]: 15 [24–3] mL/h versus 1 [5–0] mL/h, P=0.034). In multivariable analysis, presence of the spot sign was independently associated with death at 90 days (odds ratio, 7.6 [95% CI, 1.6–88], P=0.037). With respect to surgically treated patients (n=60, [33%]), 14 (23%) patients who underwent hematoma evacuation had a spot sign. In these 60 patients, patients with a spot sign were older (73.5 [9.2] versus 66.6 [15.4], P=0.047) and more likely to be female (71% versus 37%, P=0.033). In a multivariable analysis, the spot sign was independently associated with death at 90 days (odds ratio, 2.1 [95% CI, 1.1–4.3], P=0.033)., Conclusions: In patients with spontaneous cerebellar ICH treated conservatively, the spot sign is associated with speed of hematoma expansion, case fatality, and poor functional outcome. In surgically treated patients, the spot sign is associated with 90-day case fatality.

Buprenorphine is an opioid drug used in the management of pain and the treatment opioid addiction. Like other opioids, it is believed that it achieves these effects by altering functional neurotransmitter pathways and the expression of important transcription factors; cyclic AMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in the brain. However, there is a lack of scientific evidence to support these theories. This study investigated the pharmacodynamic effects of BUP administration by assessing neurotransmitter and molecular changes in the healthy rodent brain. Sprague-Dawley rats (150-200 g) were intranasally administered buprenorphine (0.3 mg/mL) and sacrificed at different time points: 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h post drug administration. LC-MS was used to quantify BUP and neurotransmitters (GABA, GLUT, DA, NE and 5-HT) in the brain, while CREB and BDNF gene expression was determined using qPCR. Results showed that BUP reached a C max of 1.21 ± 0.0523 ng/mL after 2 h, with all neurotransmitters showing an increase in their concentration over time, with GABA, GLUT and NE reaching their maximum concentration after 8 h. DA and 5-HT reached their maximum concentrations at 1 h and 24 h, respectively post drug administration. Treatment with BUP resulted in significant upregulation in BDNF expression throughout the treatment period while CREB showed patterns of significant upregulation at 2 and 8 h, and downregulation at 1 and 6 h. This study contributes to the understanding of the pharmacodynamic effects of BUP in opioid addiction by proving that the drug significantly influences NT pathways that are implicated in opioid addiction., (Copyright © 2021. Published by Elsevier Masson SAS.)

Introduction: The present study was done to assess the functional outcome and complications of interlocking intramedullary (IM) radius ulna nailing to treat radio-ulna fractures in adults., Methodology: Thirty adult patients with diaphyseal or segmental fractures of radius and ulna were included and treated with IM nailing. Grace and Eversmann rating system was used to assess functional evaluation and grip strength was measured using grasp dynamometer., Results: Mean age of the 30 eligible patients was 33.5 years, and males comprised 77% of the study population. Intra-operative complications like nail impaction and proximal screw locking problem for radius was present in one patient each. Increased swelling in three patients (10%) and posterior interosseous nerve palsy in one patient (3%) were observed post-operatively. In the post-operative period, all patients were able to move fingers, had 100° elbow range of motion and good grip strength. Pronation and supination till 80° was present in 80% and 57% of the patients respectively. Wrist flexion and dorsiflexion till 90° was present in 80% and 57% of the patients. Fracture union was confirmed radiologically in all cases at a mean of 3.6 weeks. Functional outcome was excellent in 73% and good in 13%. Grip strength was judged to be excellent in all cases., Conclusions: Excellent and good functional outcomes were obtained in 86%, and no case developed mal-union or delayed union. Based on our results, IM nail for surgical treatment of radial and ulnar diaphyseal fractures can be used., Competing Interests: None., (© 2021 Delhi Orthopedic Association. All rights reserved.)

Crystallographic and electronic structures of phase pure ternary solid solutions of Ni 1- x Co x O ( x = 0 to 1) have been studied using XRD, EXAFS and XAS measurements. The lattice parameter of the cubic rock-salt (RS) Ni 1- x Co x O solid solutions increases linearly with increasing Co content and follows Vegard's law, in the complete composition range. A linear increase in the bond lengths (Ni/Co-O, Ni-Ni and Ni-Co) with " x ", closely following the bond lengths determined from virtual crystal approximation (VCA), is observed, which implies that there is only a minimal local distortion of the lattice in the mixed crystal. The optical gap of the ternary solid solution determined from diffuse reflectivity measurements shows neither a linear variation with Co composition nor bowing, as observed in many ternary semiconductors. This trend in the variation of optical gaps is explained by probing the conduction band using XAS at the O K-edge. We have observed that the variation in the onset energy of the conduction band edge with " x " is very similar to the variation in the optical gap with " x ", thus clearly indicating the dominant role played by the conduction band position in determining the optical gap. The variation in the intensities of the pre-edge peak in the XANES spectra measured at Ni and Co K-edges, and the L 1/2 peak in XAS spectra measured at Ni and Co L-edges, is found to depend on the unoccupied O 2p-metal-(Ni/Co) 3d hybridized states and the bond lengths., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Indigenous breeds of young chickens in India are believed to be resistant to the classical strain of infectious bursal disease virus (IBDV). However, the mechanism underlying this resistance is obscure. Innate immunity is a key factor in defining the clinical course and pathology of microbial infections. The present study is aimed to compare the pathology of very virulent IBDV (vvIBDV) and immunological host response in experimentally infected - vaccinated and unvaccinated indigenous Aseel and commercial White Leghorn chickens. The viral loads and innate immune gene expression profiles of MDA-5, Mx, IFN-α, and IFN-β in different lymphoid organs were analyzed by quantitative PCR. The histopathological scores in Aseel birds were lower than in White Leghorns despite comparable viral loads. The degrees of histopathological lesions were fewer in vaccinated birds than in unvaccinated birds of both breeds. Analysis of innate immune response genes revealed that the cytoplasmic pattern recognition receptor MDA-5 gene was overexpressed mainly in the cecal tonsils of both vaccinated and nonvaccinated White Leghorn chickens. An increase in the expression of the IFN-α gene was seen in the cecal tonsils of Aseels, and an increase in IFN-β gene expression was seen in the thymuses of White Leghorns following vvIBDV challenge both in vaccinated and nonvaccinated birds. In addition, we observed that the Mx gene plays a minimal role, if any, in vvIBDV infection of the breeds under study. It remains interesting and important that although vvIBDV causes disease in indigenous Aseel birds, the faster clearance and reduced pathology of the virus in Aseel birds compared to White Leghorn chicken indicate some unidentified innate immune factors that are limiting IBDV in this breed. Further studies will be required to correlate kinetics of humoral and cellular immune response in relation to the virus load in different organs to illuminate the mechanism of genetic resistance in native breeds of chicken.