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Ishwar Singh Malhi, Mohammed Bilal Khan Manchester Medical School, Faculty of Biology, Medicine and Health University of Manchester, Manchester, UKCorrespondence: Ishwar Singh Malhi; Mohammed Bilal KhanManchester Medical School, Faculty of Biology, Medicine and Health University of Manchester, Manchester, UKEmail ishwar.malhi@student.manchester.ac.uk; mohammed.khan-19@student.manchester.ac.ukWe would like to extend our gratitude to the contributing writers of this article in providing an insight into the attitudes of recently admitted undergraduate medical students on learning communications skills from Chitwan Medical College, Bharatpur, and would like to present some of our comments on the study.1The article demonstrates that there is a need to integrate communication skills into the current college curriculum, finding that a large proportion of students were not aware of the importance of communication skills for a physician (n=24), with almost half unsure about the ability to learn the skill itself (n=40).1 Nevertheless, as highlighted in the paper, the small sample size based on a single university’s applicants (n=99) impedes the ability to compare and contrast the study, in turn limiting its generalizability. Moreover, the characteristics of participants within the questionnaire included their prior educational institutions, yet the relevance of this has not been identified. Further investigations into whether there is a connection to the aforementioned would highlight any significance.View the original paper by Timilsina and colleagues

Diabetic myonecrosis is a rare complication of poorly controlled diabetes mellitus which commonly affects the thigh and is managed conservatively. Spontaneous ischemic necrosis of muscle is noted without a reduction in vascular supply. Pyomyositis caused by Staphylococcus aureus infection is another rare complication. Atypical presentation of myonecrosis and pyomyositis can occur in the form of simultaneous or sequential involvement of multiple muscle groups. We present a rare case of myonecrosis with pyomyositis in a 39-year-old male patient with a background of type 2 diabetes mellitus who presented with a 5-day history of worsening pain of the right thigh radiating to the right ankle, associated with groin swelling and fever. It is important for clinicians to have a low threshold of suspicion of this rare condition due to the other diverse and similar diagnoses, as well as to prevent further complications and morbidity.

Background: The management of thromboembolic risk and the necessity for timely hemorrhage control make anticoagulant-related gastrointestinal (GI) bleeding clinically challenging., Objective: This study aimed to evaluate clinical outcomes (such as bleeding control and mortality) and the effectiveness of anticoagulation reversal techniques in patients with anticoagulant-related GI bleeding in emergency settings., Methodology: This prospective, observational study conducted at Lady Reading Hospital, Peshawar, from January to December 2023, included patients aged 18 or older with GI bleeding on warfarin or direct oral anticoagulants (DOACs). Key clinical data, including demographics and comorbidities, were collected. The study followed a multidisciplinary approach with emergency physicians, gastroenterologists, and surgeons. Pharmacologic management (Vitamin K for warfarin and idarucizumab for DOACs) was initiated based on clinical judgment, with endoscopic interventions performed within 24 hours if needed, and surgical intervention considered if other methods failed or complications arose. Outcomes such as bleeding control, transfusion needs, and mortality were tracked. Data were collected prospectively via case report forms, and patients were followed for up to six months post-discharge. Statistical analysis was performed using SPSS version 27 (IBM Corp., Armonk, NY), with descriptive statistics for all variables. Continuous variables were compared using independent t-tests, and categorical data were assessed using chi-square tests. Adjusted odds ratios were calculated for mortality and bleeding control outcomes, accounting for confounders.  Results: A total of 384 patients were included, with 180 (46.88%) on warfarin and 204 (53.12%) on DOACs. Bleeding control was significantly better in the DOAC group (170/204, 83.33% vs. 130/180, 72.22%, P = 0.03), while mortality was higher in patients on warfarin (20, 11.11% vs. 10, 4.90%, P = 0.02). Patients on warfarin also had longer hospital stays (6.89 vs. 5.52 days, P = 0.01) and times to intervention (5.28 vs. 4.64 hours, P = 0.03). Although demographic characteristics (e.g., age and gender) and comorbidities (e.g., hypertension and diabetes) were comparable between groups, DOACs showed safer profiles during hospitalization. Long-term follow-up outcomes, including readmission rates, recurrent bleeding, and post-discharge mortality, were similar across both groups., Conclusions: The study demonstrates that DOACs offer better outcomes in bleeding control and mortality compared to warfarin in anticoagulant-related GI bleeding, emphasizing the importance of tailored treatment strategies. These findings highlight the potential benefits of DOACs in emergency settings, supporting the need for customized management plans to optimize patient outcomes., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. The Institutional Review Board and Ethical Committee of Lady Reading Hospital, Medical Teaching Institution (MTI) issued approval 1816/LRH/MTI; dated 06/07/2022. 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, Ullah et al.)

Background Gallbladder carcinoma (GBC) is a rare but highly aggressive malignancy, often discovered incidentally during cholecystectomy for symptomatic cholelithiasis. Despite significant geographic variation, the association between gallstones and GBC is well-documented, with chronic inflammation from gallstones potentially contributing to carcinogenesis. Objective This study aims to determine the prevalence of incidental GBC in patients undergoing cholecystectomy for symptomatic cholelithiasis at a tertiary care hospital in Peshawar, Pakistan. Materials and methods This retrospective cohort study was conducted at the General Surgery Department, Hayatabad Medical Complex, Peshawar, from February 2, 2021, to July 1, 2024. A total of 230 patients, aged 18-55 years and diagnosed with symptomatic cholelithiasis, were included. Cholecystectomy was performed, and all excised gallbladders were histopathologically examined for carcinoma. Statistical analysis was conducted using IBM SPSS (version 26), with a significance threshold of p ≤ 0.05. Results Out of 230 patients, 7 (3.04%) were found to have incidental GBC upon histopathological examination. Among these, five had adenocarcinoma, and two had papillary carcinoma. The carcinoma was confined to the mucosa (T1a) in four cases, while three cases had deeper invasion (T1b). Patients with incidental carcinoma had a significantly longer symptom duration (mean: 14.2 ± 3.1 months) and were older on average (mean age: 49.2 ± 4.3 years) compared to non-carcinoma patients (p = 0.001 and p = 0.002, respectively). No malignancy was suspected intraoperatively in any case. Conclusion Incidental GBC was present in 3.04% of patients undergoing cholecystectomy for symptomatic cholelithiasis, with longer symptom duration and older age as significant risk factors. The findings underscore the importance of histopathological examination of cholecystectomy specimens in regions with high gallstone prevalence, as early detection of incidental carcinoma can facilitate timely oncological intervention., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Institutional Review Board (IRB) Hayatabad Medical Complex Peshawar issued approval 1679. 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, Alam et al.)

It is widely recognized that fuzzy number theory relies on the characteristic function. However, within the fuzzy realm, the characteristic function transforms into a membership function contingent upon the interval [0,1]. This implies that real numbers and intervals represent exceptional cases of fuzzy numbers. By considering this approach, this paper introduces a new L P space and novel refinements for integral variations of Hölder's inequality which is known as Hölder's-like inequality over fuzzy domain. Numerous prevailing inequalities associated with Hölder's-like inequality can be enhanced through the newly acquired inequalities, as demonstrated through an application. By using newly defined special means, some new versions of integral inequalities have obtained where differentiable mappings are real-valued convex-like (or convex fuzzy) mappings Lastly, nontrivial numerical examples are also included to validate the accuracy of the presented inequalities as they vary with the parameter ꙍ ., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Loredana Ciurdariu reports article publishing charges was provided by Politehnica University Timisoara Department of Mathematics. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

As a springboard to explore novel potent inhibitors of cholinesterase enzymes (AChE and BChE) responsible for causing Alzheimer disorder, the current study was conducted to synthesize pyrrole derived triazole based Schiff base scaffolds by facile synthetic route. These compounds were validated by 1 HNMR, 13 CNMR and HREI-MS. All these scaffolds (1-16) were examined for their inhibitory activity against AChE and BChE in contrast to Donepezil (10.20 ± 0.10 and 10.80 ± 0.20 µM) and Allanzanthone (12.40 ± 0.10 and 13.10 ± 0.10 µM). All pyrrole derived triazole based Schiff base scaffolds (1-16) showed varied range of inhibitory potentials against acetylcholinesterase and butyrylcholinesterase enzymes with lowest inhibition concentration values ranging from 5.10 ± 0.40-27.10 ± 0.10 µM (for AChE) and 5.60 ± 0.30-28.40 ± 0.30 µM (for BChE). SAR analysis of these derivatives revealed analog 7 as lead molecule against targeted enzyme, while analog 6 and 11 were ranked as second and third most potent scaffolds. Binding affinity and selectivity of potent molecules against targeted enzymes were examined by molecular docking and obtained results showed that potent molecule have versatile significant binding interactions with stated enzymes. Furthermore, safety profiles of potent analogues were predicted via ADMET protocols., (© 2024. The Author(s).)

This study examines the impacts of various pollutants on foliar biochemical parameters, including relative water content (RWC), total chlorophyll, leaf extract pH, and ascorbic acid content, and their relationship with the Air Pollution Tolerance Index (APTI). RWC, a crucial indicator of plant resilience, showed a significant positive correlation with APTI values (r = 0.4503, p < 0.05). Species with higher RWC, such as Carica papaya and Cassia fistula, demonstrated enhanced tolerance to pollutants, with RWC values reaching up to 85%. Chlorophyll content, which is vital for photosynthesis, exhibited a significant reduction in polluted areas, with levels ranging from 0.28 to 3.23 mg/g (p < 0.05). Notably, Cassia fistula had high APTI values but lower chlorophyll content, reflecting the complex relationship between tolerance and chlorophyll levels. Leaf extract pH was significantly lower in polluted areas, with pH values consistently below 7, correlating with higher APTI values (p < 0.05). Ascorbic acid content, an important antioxidant, was significantly higher in plants exposed to pollution, with positive correlations to APTI (r = 0.9214) and pH levels (r = 0.62). Principal Component Analysis (PCA) identified that pH, ascorbic acid, and APTI were positively correlated, while total chlorophyll and RWC showed opposing trends. Sensitivity analysis indicated that RWC (95.84% impact on Carica papaya and 85.92% on Cassia fistula) and pH were the primary factors influencing APTI and Metal Accumulation Index (MAI) values. The findings underscore the role of RWC, chlorophyll, pH, and ascorbic acid as biomarkers for plant responses to pollution and highlight the effectiveness of species with high MAI values in heavy metal accumulation and environmental monitoring., Competing Interests: Declaration of competing interest There is no competing interest related to the publication of this work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ischemic stroke leads to disability and death worldwide and evidence suggests that stroke severity is affected by the time dimension of the stroke. Rev-Erbα regulates the core circadian clock through repression of the positive clock element Bmal1. However, it remains unclear if a Rev-Erbα agonist (SR9009) alleviates stroke pathology in mice. We found that stroke reduces the level of Rev-Erbα and elevates neuroinflammation and stroke severity at zeitgeber time (ZT) ZT06. Therefore, we hypothesized that SR9009 treatment may reduce neuroinflammation and stroke severity in a mouse suture occlusion model. At 12 to 14 weeks, C57BL/6 J (Wild Type, n = 5-10 mice/group) mice were randomly assigned to undergo MCAO stroke for 60 min at either zeitgeber time ZT06 (MCAO-ZT06-sleep phase) or ZT18 (MCAO-ZT18-awake phase). Stroked mice were treated with SR9009 (100 mg/kg) or vehicle at 1 h and 24 h after MCAO. After forty-eight hours of stroke, TTC staining, Western blot, and qRT-PCR were performed. We found that SR9009 treatment alleviates neuroinflammation and infarct volume by Rev-Erb remodeling in ZT06 stroke mice but not in ZT18 stroke mice. Additionally, monocytic and neutrophilic NLRP3 as well as brain NLRP3 levels were reduced by SR9009 treatment in ZT06 stroke though no effects were observed at ZT18 stroke. SR9009 also reduced TNFα expression and increased IL-10 expression in blood and brain in ZT06 stroke mice and no differences were observed at ZT18. There were no significant effects of SR9009 on neurological deficit score and sensorimotor function at ZT06 or ZT18 at 48 h. Our study demonstrates that SR9009 treatment reduces stroke volume, circulating immune response, circadian expression, and that the protection was circadian- and treatment time-dependent., Competing Interests: Declaration of competing interest All authors in this manuscript declare that they have no known competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Adolescence is a crucial life stage for the individual identity formation. The growing employment of social media and screen-exposure among teenagers and the concerning rise in suicide ideation rates in this susceptible group both suggested this study. Thus, we explored the association between adolescents' suicidal ideation and their daily social media screen-exposure., Methods: We surveyed 502 students, aged 13 to 19 years old, recruited in colleges and universities of Punjab, Pakistan. The survey was based on a 28-item self-reported questionnaire and demographic data collection., Results: Approximately 40% of adolescents reporting suicidal ideation showed an extended social media screen-exposure, as well as significant depressive feelings and problematic personality traits. In particular, suicidal ideation increased by 0.39 for each one-unit increase in screen-exposure time and levels of depression increased by 0.21 times by unit of screen-exposure. The correlation coefficients further indicated a moderate positive association between depression and suicidal thoughts as well as personality traits played as mediators between social media screen-exposure time and suicidal ideation among adolescents., Conclusion: Our study found a positive association, even if modest, between the use of social media screens and suicidal ideation among adolescents. This evidence may suggest to adopt specific strategies to address the use of media among youths and prevent mental disorders related to the prolonged and inappropriate use of digital technologies in those users with a vulnerable personality.

Introduction: Sepsis is a serious condition that often results in high fatality rates, particularly in intensive care units (ICUs). Its nonspecific clinical characteristics makes early diagnosis and therapy difficult, despite how critical they are. The use of biomarkers like procalcitonin (PCT) and C-reactive protein (CRP) in the diagnosis and prognosis of sepsis has demonstrated encouraging results. In contrast to PCT, which is highly selective for bacterial infections, CRP is an acute-phase protein that reflects systemic inflammation., Objective: This study aimed to assess the diagnostic accuracy and prognostic significance of CRP and PCT in early sepsis detection and outcome prediction., Methodology: This study was a retrospective cohort study that involved 90 patients in the ICU who met the criteria for sepsis-3. CRP and PCT levels, clinical data, and outcomes were obtained from electronic medical records. The diagnostic accuracy was tested using receiver operating characteristic (ROC) curves, while the prognostic relevance was analyzed by Kaplan-Meier survival analysis and Cox proportional hazards regression., Results: The mean CRP level was 102.3 mg/L and PCT level was 5.4 ng/mL. ROC analysis revealed an area under the curve (AUC) of 0.78 for CRP and 0.82 for PCT, indicating better diagnostic performance for PCT. High levels of CRP and PCT were associated with poorer survival, with median survival times of 18 and 15 days, respectively, for high-level groups. Cox regression identified CRP and PCT as significant predictors of mortality, with hazard ratios of 1.50 and 1.68, respectively., Conclusion: Both CRP and PCT are valuable biomarkers for diagnosing and prognosticating sepsis. PCT, with its higher specificity for bacterial infections, demonstrates superior diagnostic accuracy compared to CRP. Elevated levels of both biomarkers are associated with increased mortality risk, highlighting their potential role in early sepsis management and outcome prediction., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Board (IRB) of Lady Reading Hospital-MTI issued approval 948/LRH/MTI. 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, Daud et al.)

We studied the distribution and population status of the Cheer pheasant (Catreus wallichii) in Azad Jammu and Kashmir (AJ&K). Study was mainly conducted in four localities Jhelum Valley (JV), Machiara National Park (MNP), Haveli and Nar Sher Ali Khan (NSAK) from 2016-2020, for five breeding seasons. Population status of Cheer pheasant was determined by the call counts method. In total 105 breeding pairs (210 birds) were estimated highest (134) being recorded from Jhelum valley followed by MNP, Haveli and Nar Sher Ali Khan While applying correction factor 158 birds were recorded. Extensive surveys were carried out in an area of 19.23 km2. Our results indicate an expansion in distribution ranges of Cheer pheasant and population has established in several new sites. Highest Mean population density of 6.11pair/km2 was recorded in Qazi Nag area of Jhelum Valley. The mean population density of Cheer pheasant was slightly higher in the month of May. Furthermore, 58% of the calling birds were detected at elevations ranging from 2300-2600m, while 17% were found at elevations between 1900-2200m. Expansion in distribution ranges of Cheer might be due to reason that bird might have been underestimated in the past or conservation measures and community awareness programs taken by the Department of Wildlife and Fisheries, AJ&K.

An ischemic stroke (IS) is caused due to the lack of blood flow to cerebral tissue. Most of the studies have focused on how stroke affects the localized tissue, but it has been observed that a stroke can cause secondary complications in distant organs, such as Bone Marrow (BM). Our study focused on the effect of ischemic strokes on the bone marrow microenvironment. Bone marrow (BM) is a vital organ that maintains inflammatory homeostasis and aids in the repair of damaged tissue after injury/IS. We used the middle cerebral artery occlusion (MCAO) model of ischemic stroke on adult mice (6 months) and investigated the changes in the BM environment. BM cells were used for western blot and RT-PCR, and the BM supernatant was used for cytokine analysis and extracellular vesicle (EVs) isolation. We observed a significant increase in the total cell number within the BM and an increase in TNF-alpha and MCP-1, which are known for inducing a pro-inflammatory environment. Western blots analysis on the whole BM cell lysate demonstrated elevated levels of inflammatory factors (IL-6, TNF-alpha, and TLR-4) and senescence markers (p21 p16). EVs isolated from the BM supernatant showed no change in size or concentration; however, we found that the EVs carried increased miRNA-141-3p and miRNA-34a. Proteomic analysis on BM-derived EVs showed an alteration in the protein cargo of IS. We observed an increase in FgB, C3, Fn1, and Tra2b levels. The signaling pathway analysis showed mitochondrial function is most affected within the bone marrow. Our study demonstrated that IS induces changes in the BM environment and EVs secreted in the BM., Competing Interests: Declaration of competing interest The authors also declare that there is no other conflict of interest regarding the publication of this manuscript., (Published by Elsevier Inc.)

The present study addresses advanced monitoring techniques for particles and airborne molecular contaminants (AMCs) in cleanroom environments, which are crucial for ensuring the integrity of semiconductor manufacturing processes. We focus on quantifying particle levels and a representative AMC, hydrogen chloride (HCl), having known detrimental effects on equipment longevity, product yield, and human health. We have developed a compact laser sensor based on open-path cavity ring-down spectroscopy (CRDS) using a 1742 nm near-infrared diode laser source. The sensor enables the high-sensitivity detection of HCl through absorption by the 2-0 vibrational band with an Allan deviation of 0.15 parts per billion (ppb) over 15 min. For quantifying particle number concentrations, we examine various detection methods based on statistical analyses of Mie scattering-induced ring-down time fluctuations. We find that the ring-down distributions' 3rd and 4th standard moments allow particle detection at densities as low as ~10 5 m -3 (diameter > 1 μm). These findings provide a basis for the future development of compact cleanroom monitoring instrumentation for wafer-level monitoring for both AMC and particles, including mobile platforms.

Since the end of the twentieth century, the world has observed a considerable upsurge in carbon emissions as several countries have surfaced as industrial centers and production monsters worldwide. The present study contributes to the existing literature examining the effects of carbon-based emissions, industrial value added, trade openness, transport services, railway lines, and globalization index on per capita GDP growth in China. The study covers a period of 40 years, from 1982 to 2021, introducing the impact of railway transport on GDP growth in contemporary environmental empirics. A vector error correction model (VECM) was applied to achieve the study's envisaged objectives. The findings of this study reveal that carbon emissions are responsible for the reduction of per capita GDP growth in China. On the contrary, industrial value added, transport services, railway lines, and globalization index positively support the per capita GDP growth-dependent variable. The study proposes that pragmatic policies are needed to control pollution resulting from carbon emissions. The eventual effect of maintaining greenhouse gases is expected to assist in achieving sustainable growth of per capita GDP leading to the accomplishment of sustainable development goals in the economy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Bangladesh is currently experiencing significant infrastructural development in road networking system through the construction or reconstruction of multiple roads and highways. Consequently, there is a rise in traffic intensity on roads and highways, along with a significant contamination of adjacent agricultural soils with heavy metals. The purpose of this study was to evaluate the ecological risk, health risk and the abundance of seven heavy metals (Cu, Mn, Pb, Cd, Cr, As, and Ni) in three distance gradients (0, 300, and 500 m) of agricultural soil along the Dhaka-Chattogram highway. The concentration of heavy metals was measured with an Atomic Absorption Spectrophotometer (AAS) on a total of 36 soil samples that were taken from 12 different sampling sites. Based on the findings, Cd had a high contamination factor for all distance gradients, whereas Cr had a moderate contamination factor in 67% of the study areas. According to the Pollution Load Index (PLI), Cd, Cr, and Pb were the predominant pollutants. Principal component analysis (PCA) result shows these metals mainly came from anthropogenic sources. The considerable positive correlations between Cu-Pb, Cu-Cd, Pb-Cd, and Cr-Ni all pointed to shared anthropogenic origins. As per Potential Ecological Risk Assessment (PERI) analysis, Pb, Cd, Cr, and Ni each contribute significantly and pose a moderate threat. The Target Hazard Quotient (THQ) values for all pathways of exposure to Pb and Cr in soils were more than 1, which would pose a significant risk to human health in the following order: THQ adult female  > THQ adult male  > THQ children . This study will help to evaluate the human health risk and develop a better understanding of the heavy metal abundance scenario in the agricultural fields adjacent to this highway., 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.)

Vascular cognitive impairment and dementia (VCID) are a growing threat to public health without any known treatment. The bilateral common carotid artery stenosis (BCAS) mouse model is valid for VCID. Previously, we have reported that remote ischemic postconditioning (RIPostC) during chronic cerebral hypoperfusion (CCH) induced by BCAS increases cerebral blood flow (CBF), improves cognitive function, and reduces white matter damage. We hypothesized that physical exercise (EXR) would augment CBF during CCH and prevent cognitive impairment in the BCAS model. BCAS was performed in C57/B6 mice of both sexes to establish CCH. One week after the BCAS surgery, mice were randomized to treadmill exercise once daily or no EXR for four weeks. CBF was monitored with an LSCI pre-, post, and 4 weeks post-BCAS. Cognitive testing was performed for post-BCAS after exercise training, and brain tissue was harvested for histopathology and biochemical test. BCAS led to chronic hypoperfusion resulting in impaired cognitive function and other functional outcomes. Histological examination revealed that BCAS caused changes in neuronal morphology and cell death in the cortex and hippocampus. Immunoblotting showed that BCAS was associated with a significant downregulate of AMPK and pAMPK and NOS3 and pNOS3. BCAS also decreased red blood cell (RBC) deformability. EXR therapy increased and sustained improved CBF and cognitive function, muscular strength, reduced cell death, and loss of white matter. EXR is effective in the BCAS model, improving CBF and cognitive function, reducing white matter damage, improving RBC deformability, and increasing RBC NOS3 and AMPK. The mechanisms by which EXR improves CBF and attenuates tissue damage need further investigation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objectives: Intrathecal (IT) medications are routinely introduced through catheterization of the intraventricular space or subarachnoid space. There has been sporadic use of IT medications delivered directly to the ventricle either by intermittent injection through an external ventricular drain (EVD) or by an Ommaya reservoir with a ventricular catheter. IT medication delivery through EVD has many drawbacks, including the necessary opening of a sterile system, delivery of medication in a bolus form, and requirements to clamp the EVD after medication delivery. Despite these setbacks, IT medications delivered through EVD have been used across a wide range of applications, including antibiotic delivery treatment of vasospasm with nicardipine and delivery of tissue plasminogen activator., Methods: We used a newly developed active fluid exchange device to treat various severe conditions involved in the cerebral ventricles. Here, we present our treatment protocols and advice on the techniques related to successful active fluid exchange therapy., Results: Seventy patients have been treated with our system with various conditions, including subarachnoid hemorrhage, intraventricular hemorrhage, ventriculitis, and cerebral abscess. Total complication rate was 14% with only 1 catheter occlusion and low rates of hemorrhage, infection, and spinal fluid leak., Conclusion: Current continuous IT medication dosages and protocols are based on reports and consensus statements evaluating intermittent instillation of medication boluses. The pharmacokinetics of continuous dosing and the therapeutic and safety profiles of the medications need to be studied in a prospective manner to evaluate the true optimal dosing standards. Furthermore, the ability to deliver continuous, sterile medications directly through an IT route will open new avenues of pharmacotherapy that were previously closed. This report serves as a basic guide for the safe and effective use of the IRRA flow active fluid exchange catheter to deliver IT medications., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Hypertension and aging are leading risk factors for stroke and vascular contributions to cognitive impairment and dementia (VCID). Most animal models fail to capture the complex interplay between these pathophysiological processes. In the current study, we examined the development of cognitive impairment in 18-month-old spontaneously hypertensive rats (SHR) before and following ischemic stroke. Sixty SHRs were housed for 18 months with cognitive assessments every 6 months and post-surgery. MRI scans were performed at baseline and throughout the study. On day 3 post-stroke, rats were randomized to receive either angiotensin II type 2 receptor (AT2R) agonist Compound 21 (C21) or plain water for 8 weeks. SHRs demonstrated a progressive cognitive decline and significant MRI abnormalities before stroke. Perioperative mortality within 72 h of stroke was low. Stroke resulted in significant acute brain swelling, chronic brain atrophy, and sustained sensorimotor and behavioral deficits. There was no evidence of anhedonia at week 8. C21 enhanced sensorimotor recovery and ischemic lesion resolution at week 8. SHRs represent a clinically relevant animal model to study aging and stroke-associated VCID. This study underscores the importance of translational disease modeling and provides evidence that modulation of the AT2R signaling via C21 may be a useful therapeutic option to improve sensorimotor and cognitive outcomes even in aged animals., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: The ancient science of life known as Ayurveda uses a variety of formulations or herbal compounds to treat a wide range of illnesses. Male infertility accounts for half of all infertility worldwide, and numerous etiological variables play a role. A pharmacologically active tobacco component called nicotine has a negative impact on male fertility and the reproductive system. Musalyadi Churna (MSC) is one of the polyherbal compound formulations mentioned in Ayurveda Classics for aphrodisiac therapy and recommended for the treatment of male infertility., Objective: The current study aims to evaluate the spermatogenic potential of MSC along with its protective effect against testicular degeneration induced by nicotine in rat models., Materials and Methods: Sixty adult Sprague-Dawley male rats were used in the experiment, which were divided into ten groups of six rats each. Nicotine was administered orally as disease control. The standard and vehicle control were also included along with study drug groups in which MSC was administered orally to the rats. The study was conducted for 70 days for each group with assessment of body weight and food consumption. After treatment, rats were weighed and sacrificed for evaluation of parameters like organ weight, epididymal sperm count, and sperm morphology along with histological assessment. The data were statistically evaluated using analysis of variance test and Bonferroni multiple-comparison range test to compare different treatment groups., Results and Conclusion: In the present study, MSC possesses substantial spermatogenic efficacy, and the result indicates that the study drug possesses a protective effect against nicotine-induced impaired testicular functions in rats, but further research to elucidate its exact mechanism of action is essential., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Pharmacy and Bioallied Sciences.)

Generative adversarial networks (GANs) have gained significant attention in the field of image synthesis, particularly in computer vision. GANs consist of a generative model and a discriminative model trained in an adversarial setting to generate realistic and novel data. In the context of image synthesis, the generator produces synthetic images, whereas the discriminator determines their authenticity by comparing them with real examples. Through iterative training, the generator allows the creation of images that are indistinguishable from real ones, leading to high-quality image generation. Considering their success in computer vision, GANs hold great potential for medical diagnostic applications. In the medical field, GANs can generate images of rare diseases, aid in learning, and be used as visualization tools. GANs can leverage unlabeled medical images, which are large in size, numerous in quantity, and challenging to annotate manually. GANs have demonstrated remarkable capabilities in image synthesis and have the potential to significantly impact digital histopathology. This review article focuses on the emerging use of GANs in digital histopathology, examining their applications and potential challenges. Histopathology plays a crucial role in disease diagnosis, and GANs can contribute by generating realistic microscopic images. However, ethical considerations arise because of the reliance on synthetic or pseudogenerated images. Therefore, the manuscript also explores the current limitations and highlights the ethical considerations associated with the use of this technology. In conclusion, digital histopathology has seen an emerging use of GANs for image enhancement, such as color (stain) normalization, virtual staining, and ink/marker removal. GANs offer significant potential in transforming digital pathology when applied to specific and narrow tasks (preprocessing enhancements). Evaluating data quality, addressing biases, protecting privacy, ensuring accountability and transparency, and developing regulation are imperative to ensure the ethical application of GANs., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Ischemic stroke is caused by obstructed cerebral blood flow, which results in neurological injury and poor outcomes. Pro-inflammatory signaling from both residential and infiltrating immune cells potentiates cerebral injury and worsens patient outcomes after stroke. While the occurrence of a stroke exhibits a time-of-day-dependent pattern, it remains unclear whether disrupted circadian rhythms modulate post-stroke immunity. In this study, we hypothesized that stroke timing differentially affects immune activation in mice. Following middle cerebral artery occlusion (MCAO), circadian genes BMAL1, CLOCK, Cry1, and Cry2 elevated at ZT06, with a significant difference between ZT06 and ZT18. Conversely, expression of the negative limb circadian clock gene, Per1, decreased at ZT06 and ZT18 in stroke mice compared to sham. Paralleling these circadian gene expression changes, we observed a significant increase in TNF-α and a decrease in IL-10 expression at 48 h post-MCAO, when the procedure was performed at ZT06 (MCAO-ZT6), which corresponds to a deep sleep period, as compared to when the stroke was induced at ZT12 (MCAO-ZT12), ZT18 (MCAO-ZT18), or ZT0 (MCAO-ZT12). Similarly, increased pro-inflammatory, decreased anti-inflammatory monocytes, and increased NLRP3 were observed in blood, while changes in the expression of CD11b and Iba1 were noted within brain tissue at 48 h of MCAO-ZT06, as compared to MCAO-ZT18. Consistent with the increased immune response, infarct volume and sensorimotor deficits were greater in MCAO-ZT06 mice compared to MCAO-ZT18 mice at 48 h. Finally, we found reduced weight and length of the spleen while splenocytes showed significant time-dependent changes in Tregs, Bregs, and monocytes in MCAO-ZT06 mice. Taken together, this study demonstrates that circulating and splenic immune responses following ischemic stroke exhibit a circadian expression pattern which may contribute to time-of-day-dependent stroke outcomes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study explores the relationship between structural alterations of nirmatrelvir, such as homologation and deuteration, and metabolic stability of newly synthesized derivatives. We developed a reliable synthetic protocol toward dideutero-nirmatrelvir and its homologated analogues with high isotopic incorporation. Deuteration of the primary metabolic site of nirmatrelvir provides a 3-fold improvement of its human microsomal stability but is accompanied by an increased metabolism rate at secondary sites. Homologation of the lactam ring allows the capping group modification to decrease and delocalize the molecule's lipophilicity, reducing the metabolic rate at secondary sites. The effect of deuteration was less pronounced for the 6-membered lactam than for its 5-membered analogue in human microsomes, but the trend is reversed in the case of mouse microsomes. X-ray data revealed that the homologation of the lactam ring favors the orientation of the drug's nitrile warhead for interaction with the catalytic sulfur of the SARS-CoV-2 M pro , improving its binding. Comparable potency against SARS-CoV-2 M pro from several variants of concern and selectivity over human cysteine proteases cathepsin B, L, and S was observed for the novel deuterated/homologated derivative and nirmatrelvir. Synthesized compounds displayed a large interspecies variability in hamster, rat, and human hepatocyte stability assays. Overall, we aimed to apply a rational approach in changing the physicochemical properties of the drug to refine its biochemical and biological parameters., Competing Interests: The authors declare the following competing financial interest(s): The Governors of the University of Alberta has filed a patent application that also contains a few of the molecules in this manuscript and currently some authors are listed as inventors., (© 2023 The Authors. Published by American Chemical Society.)

Biological bioprostheses such as grafts, patches, and heart valves are often derived from biological tissue like the pericardium. These bioprostheses can be of xenogenic, allogeneic, or autologous origin. Irrespective of their origin, all types are pre-treated via crosslinking to render the tissue non-antigenic and mechanically strong or to minimize degradation. The most widely used crosslinking agent is glutaraldehyde. However, glutaraldehyde-treated tissue is prone to calcification, inflammatory degradation, and mechanical injury, and it is incapable of matrix regeneration, leading to structural degeneration over time. In this work, we are investigating an alternative crosslinking method for an intraoperative application. The treated tissue's crosslinking degree was evaluated by differential scanning calorimetry. To confirm the findings, a collagenase assay was conducted. Uniaxial tensile testing was used to assess the tissue's mechanical properties. To support the findings, the treated tissue was visualized using two-photon microscopy. Additionally, fourier transform infrared spectroscopy was performed to study the overall protein secondary structure. Finally, a crosslinking procedure was identified for intraoperative processing. The samples showed a significant increase in thermal and enzymatic stability after treatment compared to the control, with a difference of up to 22.2 °C and 100%, respectively. Also, the tissue showed similar biomechanics to glutaraldehyde-treated tissue, showing greater extensibility, a higher failure strain, and a lower ultimate tensile strength than the control. The significant difference in the structure band ratio after treatment is proof of the introduction of additional crosslinks compared to the untreated control with regard to differences in the amide-I region. The microscopic images support these findings, showing an alteration of the fiber orientation after treatment. For collagen-based biomaterials, such as pericardial tissue, the novel phenolic crosslinking agent proved to be an equivalent alternative to glutaraldehyde regarding tissue characteristics. Although long-term studies must be performed to investigate superiority in terms of longevity and calcification, our novel crosslinking agent can be applied in concentrations of 1.5% or 2.0% for the treatment of biomaterials.

Healthy sleep is vital to all functions in the body. It improves physical and mental health, strengthens resistance against diseases, and develops strong immunity against metabolism and chronic diseases. However, a sleep disorder can cause the inability to sleep well. Sleep apnea syndrome is a critical breathing disorder that occurs during sleeping when breathing stops suddenly and starts when awake, causing sleep disturbance. If it is not treated timely, it can produce loud snoring and drowsiness or causes more acute health problems such as high blood pressure or heart attack. The accepted standard for diagnosing sleep apnea syndrome is full-night polysomnography. However, its limitations include a high cost and inconvenience. This article aims to develop an intelligent monitoring framework for detecting breathing events based on Software Defined Radio Frequency (SDRF) sensing and verify its feasibility for diagnosing sleep apnea syndrome. We extract the wireless channel state information (WCSI) for breathing motion using channel frequency response (CFR) recorded in time at every instant at the receiver. The proposed approach simplifies the receiver structure with the added functionality of communication and sensing together. Initially, simulations are conducted to test the feasibility of the SDRF sensing design for the simulated wireless channel. Then, a real-time experimental setup is developed in a lab environment to address the challenges of the wireless channel. We conducted 100 experiments to collect the dataset of 25 subjects for four breathing patterns. SDRF sensing system accurately detected breathing events during sleep without subject contact. The developed intelligent framework uses machine learning classifiers to classify sleep apnea syndrome and other breathing patterns with an acceptable accuracy of 95.9%. The developed framework aims to build a non-invasive sensing system to diagnose patients conveniently suffering from sleep apnea syndrome. Furthermore, this framework can easily be further extended for E-health applications., 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.)

Dengue is caused by the dengue virus (DENVs) infection and clinical manifestations include dengue fever (DF), dengue hemorrhagic fever (DHF), or dengue shock syndrome (DSS). Due to a lack of antiviral drugs and effective vaccines, several therapeutic and control strategies have been proposed. A systemic literature review was conducted according to PRISMA guidelines to select proper references to give an overview of DENV infection. Results indicate that understanding the virus characteristics and epidemiology are essential to gain the basic and clinical knowledge as well as dengue disseminated pattern and status. Different factors and mechanisms are thought to be involved in the presentation of DHF and DSS, including antibody-dependent enhancement, immune dysregulation, viral virulence, host genetic susceptibility, and preexisting dengue antibodies. This study suggests that dissecting pathogenesis and risk factors as well as developing different types of therapeutic and control strategies against DENV infection are urgently needed., Competing Interests: Declaration of Competing Interest We have no conflict of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This work provides numerical simulations of the nonlinear breathing transmission epidemic system using the proposed stochastic scale conjugate gradient neural networks (SCGGNNs) procedure. The mathematical model categorizes the breathing transmission epidemic model into four dynamics based on a nonlinear stiff ordinary differential system: susceptible, exposed, infected, and recovered. Three different cases of the model are taken and numerically presented by applying the stochastic SCGGNNs. An activation function 'log-sigmoid' uses twenty neurons in the hidden layers. The precision of SCGGNNs is obtained by comparing the proposed and database solutions. While the negligible absolute error is performed around 10 -06 to 10 -07 , it enhances the accuracy of the scheme. The obtained results of the breathing transmission epidemic system have been provided using the training, verification, and testing procedures to reduce the mean square error. Moreover, the exactness and capability of the stochastic SCGGNNs are approved through error histograms, regression values, correlation tests, and state transitions., (© 2023. Springer Nature Limited.)

Human diseases may be modeled in animals to allow preclinical assessment of putative new clinical interventions. Recent, highly publicized failures of large clinical trials called into question the rigor, design, and value of preclinical assessment. We established the Stroke Preclinical Assessment Network (SPAN) to design and implement a randomized, controlled, blinded, multi-laboratory trial for the rigorous assessment of candidate stroke treatments combined with intravascular thrombectomy. Efficacy and futility boundaries in a multi-arm multi-stage statistical design aimed to exclude from further study highly effective or futile interventions after each of four sequential stages. Six independent research laboratories performed a standard focal cerebral ischemic insult in five animal models that included equal numbers of males and females: young mice, young rats, aging mice, mice with diet-induced obesity, and spontaneously hypertensive rats. The laboratories adhered to a common protocol and efficiently enrolled 2615 animals with full data completion and comprehensive animal tracking. SPAN successfully implemented treatment masking, randomization, prerandomization inclusion and exclusion criteria, and blinded assessment of outcomes. The SPAN design and infrastructure provide an effective approach that could be used in similar preclinical, multi-laboratory studies in other disease areas and should help improve reproducibility in translational science.

The evaporation of liquid hydrocarbon n-heptane is discussed in detail with experimentation and numerical techniques. A maximum wall temperature of 1050 K was reported during an experimental process with a two-phase flow that was stable and had a prominent meniscus at a small fuel flow rate (FFR) ≤ 10 µL/min. At medium to high FFR (30-70 µL/min), the flow field was unstable, with nucleating bubbles and liquid droplets inside the microtube and the maximum temperature recorded was 850 K for 70 µL/min. For the numerical model, the temperature of the wall was used as a boundary condition. Using the numerical model, the evaporative flux at the meniscus, pressure drop, pressure oscillation, and heat transfer coefficient (HTC) were investigated. A single peak in HTC was obtained at a low fuel flow rate, while multiple peaks were obtained for high FFR. At low FFR, the pressure peak was observed to be 102.4 KPa, whereas at high FFR, the pressure peak increased to 105.5 KPa. This shows a 2% increase in pressure peak with an increase in FFR. Similarly, when the FFR increased from 5 µL/min to 70 µL/min, the pressure drop increased from 500 Pa to 2800 Pa. The high amplitude of pressure drops and a high peak of HTC were found, which depend on the mass flow rate. The coefficient of variation for pressure drop depends mainly on the fuel flow rate.

Federated Learning (FL) is an emerging distributed learning paradigm which offers data privacy to contributing nodes in the collaborating environment. By exploiting the Individual datasets of different hospitals in FL setting could be used to develop reliable screening, diagnosis, and treatment predictive models to tackle major challenges such as pandemics. FL can enable the development of very diverse medical imaging datasets and thus provide more reliable models for all participating nodes, including those with low quality data. However, the issue with the traditional Federated Learning paradigm is the degradation of generalization power due to poorly trained local models at the client nodes. The generalization power of the FL paradigm can be improved by considering the relative learning contribution of client nodes. Simple aggregation of learning parameters in the standard FL model faces a diversity issue and results in more validation loss during the learning process. This issue can be resolved by considering the relative contribution of each client node participating in the learning process. The class imbalance at each site is another significant challenge that greatly impacts the performance of the aggregated learning model. This work considers Context Aggregator FL based on the context of loss-factor and class-imbalance issues by incorporating the relative contribution of the collaborating nodes in FL by proposing Validation-Loss based Context Aggregator (CAVL) and Class Imbalance based Context Aggregator (CACI). The proposed Context Aggregator is evaluated on several different Covid-19 imaging classification datasets present on participating nodes. The evaluation results show that Context Aggregator performs better than standard Federating average Learning algorithms and FedProx Algorithm for Covid-19 image classification problems., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This work demonstrates the novel concept of a mixed-dimensional reconfigurable field effect transistor (RFET) by combining a one-dimensional (1D) channel material such as a silicon (Si) nanowire with a two-dimensional (2D) material as a gate dielectric. An RFET is an innovative device that can be dynamically programmed to perform as either an n- or p-FET by applying appropriate gate potentials. In this work, an insulating 2D material, hexagonal boron nitride (hBN), is introduced as a gate dielectric and encapsulation layer around the nanowire in place of a thermally grown or atomic-layer-deposited oxide. hBN flake was mechanically exfoliated and transferred onto a silicon nanowire-based RFET device using the dry viscoelastic stamping transfer technique. The thickness of the hBN flakes was investigated by atomic force microscopy and transmission electron microscopy. The ambipolar transfer characteristics of the Si-hBN RFETs with different gating architectures showed a significant improvement in the device's electrical parameters due to the encapsulation and passivation of the nanowire with the hBN flake. Both n- and p-type characteristics measured through the top gate exhibited a reduction of hysteresis by 10-20 V and an increase in the on-off ratio ( I ON / I OFF ) by 1 order of magnitude (up to 10 8 ) compared to the values measured for unpassivated nanowire. Specifically, the hBN encapsulation provided improved electrostatic top gate coupling, which is reflected in the enhanced subthreshold swing values of the devices. For a single nanowire, an improvement up to 0.97 and 0.5 V/dec in the n- and p-conduction, respectively, is observed. Due to their dynamic switching and polarity control, RFETs boast great potential in reducing the device count, lowering power consumption, and playing a crucial role in advanced electronic circuitry. The concept of mixed-dimensional RFET could further strengthen its functionality, opening up new pathways for future electronics.

Microplastics (MPs) are a growing concern due to its ubiquitous presence and exceptional stability. We examined the abundance, dispersion, and attributes of MPs in the sediment and fish species of the Turag River in Bangladesh, which separated the industrial city Gazipur from the Mega-city Dhaka. Collected samples were digested and the chemical structure was identified using ATR-FTIR spectroscopy. The concentration of MPs in the sediment ranged from 10 to 35 particles kg -1 , with a mean abundance of 19.2 ± 2.44 particles kg -1 and MPs of the fragment type account for 34 % of all. The majority of MPs were discovered in the 3-5 mm size range. MPs concentrations in freshwater fish gut from the Turag River ranged from 0.63 ± 0.18 to 7.0 ± 1.1 microplastics individual -1 . Fiber was found to be the most commonly ingested MPs type (43 %), followed by fragments (41 %), film (12 %), and foam (4 %). The most common type of MPs was transparent (34 %) followed by red (28 %), white (20 %), green (9 %) and black (8 %). The results showed that demersal (1.87 ± 0.39 items individual -1 ) and benthopelagic (1.5 ± 0.26 items individual -1 ) fish species had more MPs than pelagic fish (0.63 ± 0.18 items individual -1 ) species. Polypropylene (PP) was found to be the most dominant polymer type in the sediment sample, and PS (39 %) in the fish sample. Polyethylene (PE) was discovered to be 30 % and PP 25 % in sediment and fish samples, respectively. Other commonly detected polymer types include polyamide (PA), polystyrene (PS), cellulose acetate (CA), and polyethylene terephthalate (PET). In different sampling sites along the Turag River, the pollution load index (PLI) of MPs contamination was found to be in the risk level category I. The PLI values reflected the city's anthropogenic influence. The findings of the study could be used to establish a baseline for MPs pollution in Bangladesh's vast freshwater ecosystem., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)