Brain morphometry in former American football players: Findings from the DIAGNOSE CTE research project.

Exposure to repetitive head impacts (RHIs) in contact sports is associated with neurodegenerative disorders including chronic traumatic encephalopathy (CTE) which currently can be diagnosed only at postmortem. American football players are at higher risk of developing CTE given their exposure to RHIs. One promising approach for diagnosing CTE in vivo is to explore known neuropathological abnormalities at postmortem in living individuals using structural magnetic resonance imaging (MRI). MRI brain morphometry was evaluated in 170 male former American football players ages 45-74 years (n = 114 professional; n = 56 college) and 54 same-age unexposed asymptomatic male controls (n = 58 age range 45-74). Cortical thickness and volume of regions of interest were selected based on established CTE pathology findings and were assessed using FreeSurfer. Group differences and interactions with age and exposure factors were evaluated using a generalized least squares model. A separate logistic regression and independent multinomial model were performed to predict each Traumatic Encephalopathy Syndrome (TES) diagnosis core clinical features and provisional level of certainty for CTE pathology using brain regions of interest. Former college and professional American football players (combined) showed significant cortical thickness and/or volume reductions compared to unexposed asymptomatic controls in the hippocampus amygdala entorhinal cortex parahippocampal gyrus insula temporal pole and superior frontal gyrus. Post-hoc analyses identified group-level differences between former professional players and unexposed asymptomatic controls in the hippocampus amygdala entorhinal cortex parahippocampal gyrus insula and superior frontal gyrus. Former college players showed significant volume reductions in the hippocampus amygdala and superior frontal gyrus compared to the unexposed asymptomatic controls. We did not observe age-by-group interactions for brain morphometric measures. Interactions between morphometry and exposure measures were limited to a single significant positive association between the age of first exposure to organized tackle football and right insular volume. We found no significant relationship between brain morphometric measures and the TES diagnosis core clinical features and provisional level of certainty for CTE pathology outcomes. These findings suggest that MRI morphometrics detects abnormalities in individuals with a history of RHI exposure that resemble the anatomic distribution of pathological findings from postmortem CTE studies. The lack of findings associating MRI measures with exposure metrics (except for one significant relationship) or TES diagnosis and core clinical features suggests that brain morphometry must be complemented by other types of measures to characterize individuals with RHIs.

Inflammatory biomarkers for neurobehavioral dysregulation in former American football players: findings from the DIAGNOSE CTE Research Project.

BACKGROUND: Traumatic encephalopathy syndrome (TES) is defined as the clinical manifestation of the neuropathological entity chronic traumatic encephalopathy (CTE). A core feature of TES is neurobehavioral dysregulation (NBD), a neuropsychiatric syndrome in repetitive head impact (RHI)-exposed individuals, characterized by a poor regulation of emotions/behavior. To discover biological correlates for NBD, we investigated the association between biomarkers of inflammation (interleukin (IL)-1ß, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) in cerebrospinal fluid (CSF) and NBD symptoms in former American football players and unexposed individuals. METHODS: Our cohort consisted of former American football players, with (n = 104) or without (n = 76) NBD diagnosis, as well as asymptomatic unexposed individuals (n = 55) from the DIAGNOSE CTE Research Project. Specific measures for NBD were derived (i.e., explosivity, emotional dyscontrol, impulsivity, affective lability, and a total NBD score) from a factor analysis of multiple self-report neuropsychiatric measures. Analyses of covariance tested differences in biomarker concentrations between the three groups. Within former football players, multivariable linear regression models assessed relationships among log-transformed inflammatory biomarkers, proxies for RHI exposure (total years of football, cumulative head impact index), and NBD factor scores, adjusted for relevant confounding variables. Sensitivity analyses tested (1) differences in age subgroups (< 60, ≥ 60 years); (2) whether associations could be identified with plasma inflammatory biomarkers; (3) associations between neurodegeneration and NBD, using plasma neurofilament light (NfL) chain protein; and (4) associations between biomarkers and cognitive performance to explore broader clinical symptoms related to TES. RESULTS: CSF IL-6 was higher in former American football players with NBD diagnosis compared to players without NBD. Furthermore, elevated levels of CSF IL-6 were significantly associated with higher emotional dyscontrol, affective lability, impulsivity, and total NBD scores. In older football players, plasma NfL was associated with higher emotional dyscontrol and impulsivity, but also with worse executive function and processing speed. Proxies for RHI exposure were not significantly associated with biomarker concentrations. CONCLUSION: Specific NBD symptoms in former American football players may result from multiple factors, including neuroinflammation and neurodegeneration. Future studies need to unravel the exact link between NBD and RHI exposure, including the role of other pathophysiological pathways.

Tropylium Ion, an Intriguing Moiety in Organic Chemistry.

The tropylium ion is a non-benzenoid aromatic species that works as a catalyst. This chemical entity brings about a large number of organic transformations, such as hydroboration reactions, ring contraction, the trapping of enolates, oxidative functionalization, metathesis, insertion, acetalization, and trans-acetalization reactions. The tropylium ion also functions as a coupling reagent in synthetic reactions. This cation's versatility can be seen in its role in the synthesis of macrocyclic compounds and cage structures. Bearing a charge, the tropylium ion is more prone to nucleophilic/electrophilic reactions than neutral benzenoid equivalents. This ability enables it to assist in a variety of chemical reactions. The primary purpose of using tropylium ions in organic reactions is to replace transition metals in catalysis chemistry. It outperforms transition-metal catalysts in terms of its yield, moderate conditions, non-toxic byproducts, functional group tolerance, selectivity, and ease of handling. Furthermore, the tropylium ion is simple to synthesize in the laboratory. The current review incorporates the literature reported from 1950 to 2021; however, the last two decades have witnessed a phenomenal upsurge in the utilization of the tropylium ion in the facilitation of organic conversions. The importance of the tropylium ion as an environmentally safe catalyst in synthesis and a comprehensive summary of some important reactions catalyzed via tropylium cations are described.

Ultrasound-Assisted Synthesis of Piperidinyl-Quinoline Acylhydrazones as New Anti-Alzheimer's Agents: Assessment of Cholinesterase Inhibitory Profile, Molecular Docking Analysis, and Drug-like Properties.

Alzheimer's disease (AD) is one of the progressive neurological disorders and the main cause of dementia all over the world. The multifactorial nature of Alzheimer's disease is a reason for the lack of effective drugs as well as a basis for the development of new structural leads. In addition, the appalling side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with the marketed treatment modalities and many failed clinical trials significantly limit the use of drugs and alarm for a detailed understanding of disease heterogeneity and the development of preventive and multifaceted remedial approach desperately. With this motivation, we herein report a diverse series of piperidinyl-quinoline acylhydrazone therapeutics as selective as well as potent inhibitors of cholinesterase enzymes. Ultrasound-assisted conjugation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes (4a,b) and (un)substituted aromatic acid hydrazides (7a-m) provided facile access to target compounds (8a-m and 9a-j) in 4-6 min in excellent yields. The structures were fully established using spectroscopic techniques such as FTIR, 1H- and 13C NMR, and purity was estimated using elemental analysis. The synthesized compounds were investigated for their cholinesterase inhibitory potential. In vitro enzymatic studies revealed potent and selective inhibitors of AChE and BuChE. Compound 8c showed remarkable results and emerged as a lead candidate for the inhibition of AChE with an IC50 value of 5.3 ± 0.51 µM. The inhibitory strength of the optimal compound was 3-fold higher compared to neostigmine (IC50 = 16.3 ± 1.12 µM). Compound 8g exhibited the highest potency and inhibited the BuChE selectively with an IC50 value of 1.31 ± 0.05 µM. Several compounds, such as 8a-c, also displayed dual inhibitory strength, and acquired data were superior to the standard drugs. In vitro results were further supported by molecular docking analysis, where potent compounds revealed various important interactions with the key amino acid residues in the active site of both enzymes. Molecular dynamics simulation data, as well as physicochemical properties of the lead compounds, supported the identified class of hybrid compounds as a promising avenue for the discovery and development of new molecules for multifactorial diseases, such as Alzheimer's disease (AD).

Persistent Reverse End Diastolic Flow in Fetal Middle Cerebral Artery: A Rare Finding with Poor Outcomes.

Doppler findings of persistent reverse end-diastolic flow (PREDF) in a fetal middle cerebral artery (MCA) are a very rare sonographic finding and are a marker of poor fetal condition. This finding often leads to intrauterine fetal death or early neonatal death. Reverse end-diastolic flow in the middle cerebral artery is an advanced hemodynamic event. Fetal cerebral circulation normally has a high impedance; in the event of fetal hypoxemia, impedance decreases, resulting in the central redistribution of blood flow to vital organs, which maintains the oxygen delivery to the brain. Reverse flow in the middle cerebral arteries describes the loss of this autoregulatory process. PREDF is a sequence that occurs due to increased extracranial or intracranial pressure. Previous case reports mentioned intracranial hemorrhage, fetal growth restriction, fetal anemia, and fetal hepatic abnormalities as problems leading to PREDF. This condition presumably arises due to cerebral edema associated with severe hypoxemia. We reported Doppler findings of PREDF MCA in a 33-year-old female patient at 30 weeks gestation who was referred to the hospital with severe preeclampsia accompanied by fetal growth restriction and oligohydramnios. A cesarean section was performed due to severe preeclampsia and a low bishop score. Hypotheses on various etiologies and their association with intrauterine/neonatal death as well as the best management still require further investigation.

Health effects and cost-effectiveness of a multilevel physical activity intervention in low-income older adults; results from the PEP4PA cluster randomized controlled trial.

BACKGROUND: Older adults are the least active population in the U.S. Low-income communities have fewer physical activity (PA) resources, contributing to less PA and increased chronic disease risk. This study assessed the effect of the multilevel, peer-led, Peer Empowerment Program 4 Physical Activity (PEP4PA) on moderate-to-vigorous PA (MVPA) and health outcomes, over 2 years of follow up. METHODS: In a cluster-randomized controlled trial, 12 senior or community centers serving low-income older adults were assigned to a PA intervention (n = 6) or usual programming (n = 6) condition. PEP4PA included self-monitoring, health coaching, group walks, social support, and community advocacy to improve walking conditions. The primary outcome was daily minutes of MVPA (7-day accelerometer). Secondary outcomes included Perceived Quality of Life (PQoL), 6-Minute Walk Test (6-MWT), blood pressure (BP), and depressive symptoms at baseline, 6, 12, 18 and 24 months. Mixed effects regression models estimated the effects on outcomes between groups over time and included random effects for repeated measures and center clustering. Effect modification by sex and income status was assessed. We calculated the incremental cost per daily minute of MVPA gained in the intervention group relative to the control group to assess cost effectiveness. RESULTS: We enrolled 476 older adults (50 + years). Participants were on average 71 years old, 76% female, 60% low income, and 38% identified as racial or ethnic minorities. Compared to the control group, intervention participants sustained roughly a 10 min/day increase in MVPA from baseline at all time points and increased mean PQoL scores from unsatisfied at baseline to satisfied at 12, 18 and 24 months. Males and higher-income groups had greater improvements in MVPA. No significant effects were observed for 6-MWT or depressive symptoms, and BP results were mixed. The incremental cost per minute MVPA gained per person was $0.25, $0.09, $0.06, and $0.05 at 6, 12, 18 and 24 months, respectively. CONCLUSIONS: PEP4PA achieved increases in MVPA and PQoL in low-income older adults, over 2 years of follow up. The peer-led, community-based intervention provides a sustainable and cost-effective model to improve health behaviors in underserved, aging populations. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT02405325 ) March 20, 2015.

CHAP-child: an open source method for estimating sit-to-stand transitions and sedentary bout patterns from hip accelerometers among children.

BACKGROUND: Hip-worn accelerometer cut-points have poor validity for assessing children's sedentary time, which may partly explain the equivocal health associations shown in prior research. Improved processing/classification methods for these monitors would enrich the evidence base and inform the development of more effective public health guidelines. The present study aimed to develop and evaluate a novel computational method (CHAP-child) for classifying sedentary time from hip-worn accelerometer data. METHODS: Participants were 278, 8-11-year-olds recruited from nine primary schools in Melbourne, Australia with differing socioeconomic status. Participants concurrently wore a thigh-worn activPAL (ground truth) and hip-worn ActiGraph (test measure) during up to 4 seasonal assessment periods, each lasting up to 8 days. activPAL data were used to train and evaluate the CHAP-child deep learning model to classify each 10-s epoch of raw ActiGraph acceleration data as sitting or non-sitting, creating comparable information from the two monitors. CHAP-child was evaluated alongside the current practice 100 counts per minute (cpm) method for hip-worn ActiGraph monitors. Performance was tested for each 10-s epoch and for participant-season level sedentary time and bout variables (e.g., mean bout duration). RESULTS: Across participant-seasons, CHAP-child correctly classified each epoch as sitting or non-sitting relative to activPAL, with mean balanced accuracy of 87.6% (SD = 5.3%). Sit-to-stand transitions were correctly classified with mean sensitivity of 76.3% (SD = 8.3). For most participant-season level variables, CHAP-child estimates were within ± 11% (mean absolute percent error [MAPE]) of activPAL, and correlations between CHAP-child and activPAL were generally very large (> 0.80). For the current practice 100 cpm method, most MAPEs were greater than ± 30% and most correlations were small or moderate (≤ 0.60) relative to activPAL. CONCLUSIONS: There was strong support for the concurrent validity of the CHAP-child classification method, which allows researchers to derive activPAL-equivalent measures of sedentary time, sit-to-stand transitions, and sedentary bout patterns from hip-worn triaxial ActiGraph data. Applying CHAP-child to existing datasets may provide greater insights into the potential impacts and influences of sedentary time in children.

Drive for muscularity and tendencies of muscle dysmorphia among Pakistani bodybuilders: A prevalence study.

OBJECTIVE: To assess the relationship between drive for muscularity and muscle dysmorphic tendencies in Pakistani bodybuilders. METHODS: The cross-sectional study was conducted in Lahore, Pakistan, from June to September 2017, and comprised male bodybuilders in their early and middle adulthood. Data was collected using an indigenous Drive for Muscularity Inventory and the Body Dysmorphic Disorder factors of the Yale-Brown Obsessive Compulsive Scale. Data was analysed using SPSS 21. RESULTS: There were 211 subjects with a mean age of 26.25±5.946 years. There was a positive relationship between drive for muscularity and tendencies of muscle dysmorphia (p<0.05). Of the total, 130(62%) bodybuilders had a moderate level of drive for muscularity. Unmarried bodybuilders aged 18-25 years had more drive for muscularity compared to married bodybuilders age 26 years and above (p<0.001). CONCLUSIONS: The drive for muscularity and muscle dysmorphic tendencies were found prevalent in Pakistani culture.

Haplotype diversity of 17 Y-STRs in Sheikh population of Punjab.

Y chromosomal short tandem repeat (Y-STR) haplotype diversity of 180 genetically unrelated male individuals from Sheikh population of Punjab Pakistan was studied by amplifying 17 Y-STR markers through the AmpFISTR®Yfiler™ PCR amplification kit. The analysis of data revealed mean discrimination capacity of 0.6438 and matching probability of 0.3561. Sheikh population was also compared with 11 other populations in order to determine its population relationships which indicated that Punjabi Sheikhs have low genetic resemblance with Indian-Balmiki, UAE [Arab], Yousafzai Pathan from Pakistan, and Pathans from Afghanistan. The data of this study could have valuable application in forensic cases, in population genetics studies, and in strengthening the Y-STR database.

Genetic polymorphism of Y-chromosomal STRs in Gujjar population of Punjab.

Y-STR polymorphism of Gujjar population was determined by using AmpFISTR®YfilerTM PCR amplification kit. A total 176 haplotypes were obtained after the analysis of 17 Y-STR loci in 176 genetically unrelated individuals. Haplotype diversity and discrimination capacity attained was 0.99730 and 0.652201325, respectively. The comparison of Gujjar population with 16 other populations revealed that Gujjars have low genetic distance from Punjabi, Sindhi, and Pakhtun population of Pakistan; Azad Kashmir, Saraswat Brahmin from India; Bangladeshi population; north and south of Afghanistan; and Uttar Pradesh India which hints toward the migrational route Gujjars took over the centuries. This data is of significant value for population studies and forensic applications.

Applications and impact of computer technologies in management of multimorbidity.

OBJECTIVE: To highlight clinical scenarios and healthcare practitioners' difficulties where computer applications can help in multimorbidity management. METHODS: The cross-sectional study was conducted from December 2017 to January 2019 in the twin cities of Rawalpindi and Islamabad, Pakistan, and comprised local physicians/practitioners. Data was collected using a self-generated questionnaire which was distributed among the subjects. It identified four problems as most commonly faced: treatment/dose management, time management, forgetting to ask necessary questions about disease, and 'others', such as bad handwriting errors and ethical issues. Data was analysed using SPSS 17. RESULTS: Of the 53 subjects, 33(62%) marked problems related to treatment management, 35(66%) marked problems related to shortage of time, 34(64%) marked those related to difficulty in asking relevant questions about disease, 15(28%) marked the 'other' option. CONCLUSIONS: Computer technologies are significantly helpful in managing the problems of treating multimorbidity by adopting standard database.

Ovarian reserve parameters and response to controlled ovarian stimulation in infertile patients.

OBJECTIVE: To determine the ovarian reserve parameters in patients presenting for IVF and intracytoplasmic sperm injection (ICSI) treatment and its association with the number of follicles retrieved and number of oocyte retrieved and fertilized. METHODS: A retrospective cross sectional study was conducted at Australian Concept Infertility Medical Centre from January 2017 to August 2017. Around 120 couples presenting to infertility clinics selected for IVF and ICSI with Females (25-45) had their FSH, AMH and AFC done. After ovulation induction, its response was determined by number of follicles retrieved, quality of oocytes retrieved or fertilized and inseminated. SPSS version 20 was used for the purpose of data analysis. RESULTS: The median age of the patients was 34 (29-38) years. A moderate negative correlation of age and FSH levels was observed with quality of oocytes, Number of oocyte inseminated, number of oocyte fertilized and number of follicle restored. However, a positive correlation of AMH and AFC levels were found with quality of oocytes, Number of oocyte inseminated, number of oocyte fertilized and number of follicle restored. The correlation of AMH levels with number of oocyte inseminated (rho 0.729, p-value <0.001), number of oocyte fertilized (rho 0.721, <0.001) and number of follicle restored (rho 0.723, p-value <0.001) were found strongly correlated. CONCLUSION: Our study concluded that AMH and AFC have a strong correlation with number of follicles restored and number of oocytes retrieved whereas FSH and age has a weak correlation with the number of follicles restored and number of oocytes retrieved.

Potential biomarkers for the diagnosis of respiratory tract infection and lungs cancer.

Major hurdle faced by many physicians in treating various respiratory tract infections and lung carcinomas is their late or mis-diagnosis. In most respiratory tract infections the manner of infection is not completely understood. Similarly, various lung carcinomas are diagnosed at advance stages at which not only the treatment possibilities are narrowed but the chances of survival are also reduced. So, for the sake of better treatment, the quick and improved diagnostic strategies are suggested. Protein biomarkers fully fit the description in this regard as they have shown great potential in specific diagnosis of many respiratory diseases and also have shown capability in timely pin pointing different stages of lung carcinomas. Many serum biomarkers are presently being used for diagnosis but the efficiency for diagnosis of these biomarkers is lower when used alone. So, physicians are suggested to use the combination of different biomarkers. Moreover, genetic biomarkers are also currently studied to indicate the exact stage of disease, the possible damage occurred, the severity of disease and also for the analysis of the possible body response to the therapeutics.

Regularity of the edge ideals of perfect [ν,h]-ary trees and some unicyclic graphs.

We compute the Castelnuovo-Mumford regularity of the quotient rings of edge ideals of perfect [ν,h]-ary trees and some unicyclic graphs.

Optimization of Electrospinning Parameters for Lower Molecular Weight Polymers: A Case Study on Polyvinylpyrrolidone.

Polyvinylpyrrolidone (PVP) is a synthetic polymer that holds significance in various fields such as biomedical, medical, and electronics, due to its biocompatibility and exceptional dielectric properties. Electrospinning is the most commonly used tool to fabricate fibers because of its convenience and the wide choice of parameter optimization. Various parameters, including solution molarity, flow rate, voltage, needle gauge, and needle-to-collector distance, can be optimized to obtain the desired morphology of the fibers. Although PVP is commercially available in various molecular weights, PVP with a molecular weight of 130,000 g/mol is generally considered to be the easiest PVP to fabricate fibers with minimal challenges. However, the fiber diameter in this case is usually in the micron regime, which limits the utilization of PVP fibers in fields that require fiber diameters in the nano regime. Generally, PVP with a lower molecular weight, such as 10,000 g/mol and 55,000 g/mol, is known to present challenges in fiber preparation. In the current study, parameter optimization for PVP possessing molecular weights of 10,000 g/mol and 55,000 g/mol was carried out to obtain nanofibers. The electrospinning technique was utilized for fiber fabrication by optimizing the above-mentioned parameters. SEM analysis was performed to analyze the fiber morphology, and quantitative analysis was performed to correlate the effect of parameters on the fiber morphology. This research study will lead to various applications, such as drug encapsulation for sustained drug release and nanoparticles/nanotubes encapsulation for microwave absorption applications.

Is there a relationship between somatosensory impairment and the perception of pain in stroke survivors? An exploratory study.

Pain and somatosensory impairments are commonly reported following stroke. This study investigated the relationship between somatosensory impairments (touch detection, touch discrimination and proprioceptive discrimination) and the reported presence and perception of any bodily pain in stroke survivors. Stroke survivors with somatosensory impairment ( N  = 45) completed the Weinstein Enhanced Sensory Test (WEST), Tactile Discrimination Test, and Wrist Position Sense Test for quantification of somatosensation in both hands and the McGill Pain Questionnaire, visual analog scale and the Neuropathic Pain Symptom Inventory (NPSI) for reporting presence and perception of pain. No relationship was observed between somatosensory impairment (affected contralesional hand) of touch detection, discriminative touch or proprioceptive discrimination with the presence or perception of pain. However, a weak to moderate negative relationship between touch detection in the affected hand (WEST) and perception of pain intensity (NPSI) was found, suggesting that stroke survivors with milder somatosensory impairment of touch detection, rather than severe loss, are likely to experience higher pain intensity [rho = -0.35; 95% confidence interval (CI), -0.60 to -0.03; P  = 0.03]. Further, a moderate, negative relationship was found specifically with evoked pain (NPSI) and touch detection in the affected hand (rho = -0.43; 95% CI, -0.72 to -0.02; P  = 0.03). In summary, our findings indicate a weak to moderate, albeit still uncertain, association, which prevents making a definitive conclusion. Nevertheless, our findings contribute to our understanding of the complexities surrounding the experience of pain in survivors of stroke and provide direction for future studies.

A comparable risk of extensively drug-resistant typhoid fever in the pediatric cohort during the COVID-19 pandemic.

Objective: The number of extremely drug-resistant (XDR) Salmonella typhi isolates is growing in the northwest of Pakistan, where health-care facilities are already under strain due to the coronavirus disease 2019 (COVID-19) issue. In Khyber Pakhtunkhwa, Pakistan, we currently describe the first widespread appearance of an XDR Salmonella typhi epidemic during the COVID-19 pandemic. This strain of Salmonella typhi is resistant to all first- and second-line drugs and even the third-generation cephalosporin. Methods: Salmonella species isolated from pediatric blood samples shown a high level of resistance to the various antibiotic classes evaluated between November and December 2020. Gender, age, address, and clinical symptoms were among the demographic information that was recorded. A total of 562 blood cultures from symptomatic patients have been collected by the Pathology Laboratory at a tertiary care institution of Rehman Medical Institute, Peshawar. All samples have been processed in accordance with regulatory requirements and incubated in BacT/ALERT 3D. Results: Of the 562 blood samples, 71 included Salmonella typhi, of which 66 (92.9%) and 5 (7%) were multidrug resistant (MDR) and XDR, respectively. Ciprofloxacin (100%), chloramphenicol (100%), ceftriaxone (100%), ampicillin (100%), and cotrimoxazole (93%) were completely resistant to all isolates. Azithromycin and carbapenems were effective against every Salmonella typhi isolate that was MDR or XDR. Males (76%) were more commonly affected than females (24%), and the frequency was substantially higher in children under 15 years of age (88%) than in adults (P = 0.0016). Conclusion: The emergence of XDR Salmonella typhi with a high level of resistance is in fact alarming. Due to the lack of viable treatment alternatives, the current situation necessitates the immediate implementation of efficient preventive measures, such as campaigns for typhoid vaccination and food and water safety.

Acyl pyrazole sulfonamides as new antidiabetic agents: synthesis, glucosidase inhibition studies, and molecular docking analysis.

Diabetes mellitus is a multi-systematic chronic metabolic disorder and life-threatening disease resulting from impaired glucose homeostasis. The inhibition of glucosidase, particularly α-glucosidase, could serve as an effective methodology in treating diabetes. Attributed to the catalytic function of glucosidase, the present research focuses on the synthesis of sulfonamide-based acyl pyrazoles (5a-k) followed by their in vitro and in silico screening against α-glucosidase. The envisaged structures of prepared compounds were confirmed through NMR and FTIR spectroscopy and mass spectrometry. All compounds were found to be more potent against α-glucosidase than the standard drug, acarbose (IC50 = 35.1 ± 0.14 µM), with IC50 values ranging from 1.13 to 28.27 µM. However, compound 5a displayed the highest anti-diabetic activity (IC50 = 1.13 ± 0.06 µM). Furthermore, in silico studies revealed the intermolecular interactions of most potent compounds (5a and 5b), with active site residues reflecting the importance of pyrazole and sulfonamide moieties. This interaction pattern clearly manifests various structure-activity relationships, while the docking results correspond to the IC50 values of tested compounds. Hence, recent investigation reveals the medicinal significance of sulfonamide-clubbed pyrazole derivatives as prospective therapeutic candidates for treating type 2 diabetes mellitus (T2DM).

Comprehensive analysis of root canal morphology in maxillary premolars among the Pakistani subpopulation: a CBCT-based study.

BACKGROUND: Understanding the root canal morphology is essential for the success of root canal treatment. Therefore, this study aimed to evaluate and analyze the root canal configuration of maxillary premolars using Cone Beam Computed Tomography in the Pakistani subpopulation. METHOD: This cross-sectional study utilized CBCT scans from two distinct centres: Aga Khan University in Karachi and Jinnah MRI and Body Scans in Lahore. The CBCT images were visualized using GALAXIS version 1.9 (SICAT GmbH and Co. KG, Bonn, Germany), integrated within the Sirona Dental System (D-64625 Bensheim, Germany). The scanning parameters were standardized at 85 kV, 7 mA, with a 15-s exposure time and a voxel size of 0.16 mm. A total of 707 CBCT scans were collected, encompassing 2180 maxillary premolars. Root canal configurations were classified based on (Ahmed et al. Int Endod J. 2017;50(8):761-70). Statistical analyses were performed using SPSS version 26, employing the Chi-square test with a significance level set at p < 0.05. RESULTS: The distribution of root canal morphologies varied significantly with age and gender. Among maxillary premolars, 50% exhibited the typical configuration of 2MPMB1 L1 (two roots, single canal in each buccal and lingual root), while 26% of maxillary right second premolars displayed 1MPM1 (one root, one canal). Overall, 1MPM1 accounted for 27.4% of the total cases in the second premolars. There was no statistically significant relationship between age and root canal distribution in either first premolars (p = 0.338) or second premolars (p = 0.833). Regarding gender, a significant difference was observed in the distribution of right maxillary 1st premolars (p = 0.022*), with a higher prevalence among females. CONCLUSION: This study offers significant insights into the anatomical variations of root canals in maxillary premolars across diverse regional subpopulations in Pakistan. While specific root canal configurations were prevalent, the findings indicate no statistically significant correlation between age and root canal morphology in maxillary premolars. However, a notable gender disparity was observed in the distribution of the right maxillary first premolars.

Substantia Nigra Pathology, Contact Sports Play, and Parkinsonism in Chronic Traumatic Encephalopathy.

Importance: Parkinsonism is associated with traumatic brain injury and chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head impact (RHI) exposure, but the neuropathologic substrates that underlie parkinsonism in individuals with CTE are yet to be defined. Objective: To evaluate the frequency of parkinsonism in individuals with CTE and the association of RHI and neuropathologic substrates with parkinsonism in these individuals. Design, Setting, and Participants: This cross-sectional study included brain donors with neuropathologically diagnosed CTE without other significant neurodegenerative disease and with information on parkinsonism from the Understanding Neurologic Injury and Traumatic Encephalopathy brain bank between July 2015 and May 2022. Exposure: Years of contact sports participation as a proxy for RHI. Main Outcomes and Measures: The main outcomes were frequency of parkinsonism in individuals with CTE and associations between (1) RHI with substantia nigra (SN) Lewy bodies (LBs) and neurofibrillary tangles (NFTs); (2) LBs, NFTs, and arteriolosclerosis with SN neuronal loss; and (3) SN neuronal loss, LBs, NFTs, and arteriolosclerosis with parkinsonism, tested by age-adjusted logistic regressions. Results: Of 481 male brain donors with neuropathologically diagnosed CTE, parkinsonism occurred frequently in individuals with CTE (119 [24.7%]; 362 [75.3%] did not have parkinsonism). Participants with parkinsonism had a higher mean (SD) age at death (71.5 [13.0] years) than participants without parkinsonism (54.1 [19.3] years) (P < .001) and higher rates of dementia (104 [87.4%] vs 105 [29.0%]), visual hallucinations (45 [37.8%] vs 51 [14.1%]), and probable rapid eye movement sleep behavior disorder (52 [43.7%] vs 58 [16.0%]) (P < .001 for all). Participants with parkinsonism had a more severe CTE stage (eg, stage IV: 35 [29.4%] vs 39 [10.8%]) and nigral pathology than those without parkinsonism (NFTs: 50 of 117 [42.7%] vs 103 of 344 [29.9%]; P = .01; neuronal loss: 61 of 117 [52.1%] vs 59 of 344 [17.1%]; P < .001; and LBs: 28 of 116 [24.1%] vs 20 of 342 [5.8%]; P < .001). Years of contact sports participation were associated with SN NFTs (adjusted odds ratio [AOR], 1.04; 95% CI, 1.00-1.07; P = .03) and neuronal loss (AOR, 1.05; 95% CI, 1.01-1.08; P = .02). Nigral neuronal loss (AOR, 2.61; 95% CI, 1.52-4.47; P < .001) and LBs (AOR, 2.29; 95% CI, 1.15-4.57; P = .02) were associated with parkinsonism. However, SN neuronal loss was associated with SN LBs (AOR, 4.48; 95% CI, 2.25-8.92; P < .001), SN NFTs (AOR, 2.51; 95% CI, 1.52-4.15; P < .001), and arteriolosclerosis (AOR, 2.27; 95% CI, 1.33-3.85; P = .002). In American football players, regression analysis demonstrated that SN NFTs and neuronal loss mediated the association between years of play and parkinsonism in the context of CTE (ß, 0.012; 95% CI, 0.001-0.038). Conclusions and Relevance: In this cross-sectional study of contact sports athletes with CTE, years of contact sports participation were associated with SN tau pathology and neuronal loss, and these pathologies were associated with parkinsonism. Repetitive head impacts may incite neuropathologic processes that lead to symptoms of parkinsonism in individuals with CTE.