Lead optimization based design, synthesis, and pharmacological evaluation of quinazoline derivatives as multi-targeting agents for Alzheimer's disease treatment.

The complexity and multifaceted nature of Alzheimer's disease (AD) have driven us to further explore quinazoline scaffolds as multi-targeting agents for AD treatment. The lead optimization strategy was utilized in designing of new series of derivatives (AK-1 to AK-14) followed by synthesis, characterization, and pharmacological evaluation against human cholinesterase's (hChE) and ß-secretase (hBACE-1) enzymes. Amongst them, compounds AK-1, AK-2, and AK-3 showed good and significant inhibitory activity against both hAChE and hBACE-1 enzymes with favorable permeation across the blood-brain barrier. The most active compound AK-2 revealed significant propidium iodide (PI) displacement from the AChE-PAS region and was non-neurotoxic against SH-SY5Y cell lines. The lead molecule (AK-2) also showed Aß aggregation inhibition in a self- and AChE-induced Aß aggregation, Thioflavin-T assay. Further, compound AK-2 significantly ameliorated Aß-induced cognitive deficits in the Aß-induced Morris water maze rat model and demonstrated a significant rescue in eye phenotype in the Aꞵ-phenotypic drosophila model of AD. Ex-vivo immunohistochemistry (IHC) analysis on hippocampal rat brains showed reduced Aß and BACE-1 protein levels. Compound AK-2 suggested good oral absorption via pharmacokinetic studies and displayed a good and stable ligand-protein interaction in in-silico molecular modeling analysis. Thus, the compound AK-2 can be regarded as a lead molecule and should be investigated further for the treatment of AD.

Androsin alleviates non-alcoholic fatty liver disease by activating autophagy and attenuating de novo lipogenesis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease with therapeutic options on the horizon. Picrorhiza kurroa, enriched with iridoid glycosides like picroside I and picroside II is known for its hepatoprotective activity and anti-inflammatory properties. Androsin, the other phytochemical present in P. kurroa has been shown to have anti-inflammatory and anti-asthmatic properties. However, its role in NAFLD is yet to be investigated. PURPOSE: This study aims to identify the potent hepatoprotective agent from P. kurroa that can attenuate NAFLD in HFrD-fed ApoE-/- mice, and elucidate the underlying mechanisms governing its effects. METHODS: Classical purification methods were used to isolate seven compounds, including picroside I, picroside II and androsin from the roots of P. kurroa. NAFLD-induced ApoE-/- mice were administered orally with either picroside I, picroside II, or androsin for 7 weeks. Animals were scanned non-invasively by ultrasonography at 1st and 14th week. Gross histomorphometry was examined by HE and Sirius red staining. mRNA transcript and protein profile associated with autophagy, lipogenesis, inflammation, and fibrosis was done through RT-PCR and Western blot analysis. RESULTS: In-vitro and in-vivo studies revealed that among the seven evaluated compounds, androsin shows the most potent in-vitro activity. Oral dosing of androsin (10 mg/kg) protected the liver against HFrD-induced NAFLD in ApoE-/- mice model. Biochemical analysis revealed a reduction in ALT and AST enzymes and a significant reduction in cholesterol levels. Hepatocyte ballooning, hepatic lipid deposition, inflammation, and fibrosis were reduced. Androsin treatment significantly reduced fibrosis (α-SMA, collagens, TGF-ß) and inflammation (ILs, TNF-α, NFκB) in ApoE-/- mice. Mechanistically, androsin activated AMPKα and down-regulated the expression of SREBP-1c, resulting in ameliorating hepatic lipogenesis. CONCLUSION: Our results support autophagy as one of the therapeutic strategies to reduce steatosis and hepatic damage. We found that androsin treatment significantly ameliorated hepatic steatosis, serum lipid levels, and hepatic injury in ApoE-/- induced by HFrD. Androsin administration mitigated lipogenesis by inhibiting SREBP1c/FASN pathway and activating autophagy through AMPKα/PI3K/Beclin1/LC3 pathway.

Structure-Guided Design, Synthesis, and Biological Evaluation of Peripheral Anionic Site Selective and Brain Permeable Novel Oxadiazole-Piperazine Conjugates against Alzheimer's Disease with Antioxidant Potential.

Alzheimer's disease (AD) is a multifactorial and emerging neurological disorder, which has invoked researchers to develop multitargeted ligands. Herein, hybrid conjugates of 5-phenyl-1,3,4-oxadiazole and piperazines were rationally designed, synthesized, and pharmacologically evaluated against hAChE, hBChE, and hBACE-1 enzymes for the management of AD. Among the series, compound 5AD comprising pyridyl substitution at terminal nitrogen of piperazine contemplated as a paramount lead compound (hAChE, IC50 = 0.103 ± 0.0172 µM, hBChE, IC50 ≥ 10 µM, and hBACE-1, IC50 = 1.342 ± 0.078 µM). Compound 5AD showed mixed-type enzyme inhibition in enzyme kinetic studies against the hAChE enzyme. In addition, compound 5AD revealed a significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE and excellent blood-brain barrier (BBB) permeability in a parallel artificial membrane permeation assay (PAMPA). Besides, 5AD also exhibited anti-Aß aggregation activity in self- and AChE-induced thioflavin T assay. Further, compound 5AD has shown significant improvement in learning and memory (p < 0.001) against the in vivo scopolamine-induced cognitive dysfunction mice model. The ex vivo study implied that after treatment with compound 5AD, there was a decrease in AChE and malonaldehyde (MDA) levels with an increase in catalase (CAT, oxidative biomarkers) in the hippocampal brain homogenate. Hence, compound 5AD could be regarded as a lead compound and further be explored in the treatment of AD.

Does This Infant Have a Dislocated Hip?: The Rational Clinical Examination Systematic Review.

Importance: Delayed diagnosis of a dislocated hip in infants can lead to complex childhood surgery, interruption to family life, and premature osteoarthritis. Objective: To evaluate the diagnostic accuracy of clinical examination in identifying dislocated hips in infants. Data Sources: Systematic search of CINAHL, Embase, MEDLINE, and the Cochrane Library from the inception of each database until October 31, 2023. Study Selection: The 9 included studies reported the diagnostic accuracy of the clinical examination (index test) in infants aged 3 months or younger and a diagnostic hip ultrasound (reference test). The Graf method of ultrasound assessment was used to classify hip abnormalities. Data Extraction and Synthesis: The Rational Clinical Examination scale was used to assign levels of evidence and the Quality Assessment of Diagnostic Accuracy Studies tool was used to assess bias. Data were extracted using the individual hip as the unit of analysis; the data were pooled when the clinical examinations were evaluated by 3 or more of the included studies. Main Outcomes and Measures: Sensitivity, specificity, and likelihood ratios (LRs) of identifying a dislocated hip were calculated. Results: Among infants screened with a clinical examination and a diagnostic ultrasound in 5 studies, the prevalence of a dislocated hip (n = 37 859 hips) was 0.94% (95% CI, 0.28%-2.0%). There were 8 studies (n = 44 827 hips) that evaluated use of the Barlow maneuver and the Ortolani maneuver (dislocate and relocate an unstable hip); the maneuvers had a sensitivity of 46% (95% CI, 26%-67%), a specificity of 99.1% (95% CI, 97.9%-99.6%), a positive LR of 52 (95% CI, 21-127), and a negative LR of 0.55 (95% CI, 0.37-0.82). There were 3 studies (n = 22 472 hips) that evaluated limited hip abduction and had a sensitivity of 13% (95% CI, 3.3%-37%), a specificity of 97% (95% CI, 87%-99%), a positive LR of 3.6 (95% CI, 0.72-18), and a negative LR of 0.91 (95% CI, 0.76-1.1). One study (n = 13 096 hips) evaluated a clicking sound and had a sensitivity of 13% (95% CI, 6.4%-21%), a specificity of 92% (95% CI, 92%-93%), a positive LR of 1.6 (95% CI, 0.91-2.8), and a negative LR of 0.95 (95% CI, 0.88-1.0). Conclusions and Relevance: In studies in which all infant hips were screened for developmental dysplasia of the hip, the prevalence of a dislocated hip was 0.94%. A positive LR for the Barlow and Ortolani maneuvers was the finding most associated with an increased likelihood of a dislocated hip. Limited hip abduction or a clicking sound had no clear diagnostic utility.

Cultural factors and family influences on adolescent oral health: qualitative research in a socially disadvantaged population.

AIM: This qualitative study sought to assess the influence of cultural factors and family on oral health behaviour of 12- to 15-year-old adolescents from the socially disadvantaged population. DESIGN: A qualitative design was developed with focus group discussions (FGDs) among 12- to 15-year-old adolescents. Four focus groups (n = 32 participants) were created from a selected sample to capture oral health beliefs and practices, oral health-seeking behaviour along with other relevant information. Focus group discussions were audio-recorded, transcribed verbatim and translated. Data were analysed thematically and structural coding was applied. RESULTS: Three key themes that emerged from FGDs were importance of oral health; role of family in oral health behaviour; and beliefs influencing access, prevention and treatment of oral diseases. Cultural background, family values and beliefs were imperative in moulding the behaviour of adolescents towards oral health. The use of traditional oral hygiene aides was a norm in this population. CONCLUSIONS: Findings of the study provide greater insights into the authoritative role of family and cultural barriers in the uptake of dental services. The study also highlights the potential value of qualitative research and emphasizes the need to integrate oral health-associated cultural beliefs and attitudes of the adolescents towards a wider evidence base.

Risk factors and associated pathway for rural and urban unmet dental prosthetic needs among older adults in Central India.

AIM: This study was undertaken to evaluate the risk factors and associated pathways for unmet dental prosthetic needs among older adult population in Central India. METHODS: A total of 11,145 randomly selected older adults participated in the study; 4613 from urban region and 6532 form rural region. Oral examinations were conducted at individual households for recording dental caries, periodontal disease, prosthetic status and needs. Structural Equation Modelling (SEM) was used to examine relationship between a set of exogenous variables and unmet dental prosthetic needs with variables that remained significant in the adjusted multilevel logistic model. Path coefficients were calculated for all variables with 95% confidence interval. Goodness of fit of the model was assessed by several indices. RESULTS: A total of 8433 (75.7%) participants had never visited a dentist and 9139 (82%) had unmet dental prosthetic needs. Dental caries was observed among 3207 (69.5%) and 4644 (71.1%) study participants from urban and rural regions respectively (p < .05). Low utilization of dental services was associated with high dental prosthetic needs in upper arch and lower arch (PC = -0.05, 0.001) and DMFT was associated with lower utilization of dental services (PC = -0.09, 0.001). DMFT was also associated with age, annual income, level of education, paternal education, type of family, tobacco consumption and CPI score in the hypothesized model. The fit indices used indicated that the model was adequate. CONCLUSIONS: Dental prosthetic needs in the proposed pathway model was associated with low utilization of dental services, dental caries, periodontal disease and other socio-demographic factors.

Global perspective on child and adolescent oral health: a systematic review and meta-analysis of oral impacts on daily performance.

OBJECTIVE: Several prevalence studies have estimated the region-specific impact of oral diseases on oral health-related quality of life. However, none of them reported and compared the same from a global perspective. This meta-analysis aims to evaluate pooled epidemiologic data about child-oral impacts on daily performance (C-OIDP) globally. METHODS: A search was conducted in PubMed, Science Direct, SciELO, Semantic scholar, and Cochrane databases up to January 2023. Studies evaluating OIDP among 11-18-year-olds were included in the review. Quality of the included studies was evaluated using the health states quality index for cross-sectional studies. The meta-analysis used R package software version 4.3.0. A common effect model was used to calculate the pooled prevalence. The protocol was registered in the PROSPERO (CRD-NIHR) database with Reference ID CRD42023393798. RESULTS: The systematic literature search yielded 257 unique citations. After screening titles and abstracts, 214 irrelevant citations were excluded, leaving 55 for full-text review. Overall, 43 studies from 23 countries were included. The meta-analysis reported a pooled prevalence impact C-OIDP of 53.36% (CI: 52.78-53.95, 43 studies, 16,622 participants). The prevalence of C-OIDP scores among South America, Asia, Europe, Africa and Oceania was 83%, 63%, 58%, 33% and 47%, respectively. The maximum prevalence was reported in South America while the least prevalence was noted in the African population. CONCLUSION: Oral diseases affect the oral health-related quality of life of more than half of children and adolescents globally. Huge variations were noted in the prevalence of oral impacts across different regions. These findings can be utilized by policymakers to draft measures required for reducing impacts of oral diseases and improving the health-related quality of life.

Safety and outcomes of different endovascular treatment techniques for anterior circulation ischaemic stroke in the elderly: data from the Imperial College Thrombectomy Registry.

BACKGROUND: Although previous studies investigated the main predictors of outcomes after endovascular thrombectomy (EVT) in patients aged 80 years and older, less is known about the impact of the procedural features on outcomes in elderly patients. The aim of this study was to investigate the influence of EVT technical procedures on the main 3-month outcomes in a population of patients aged 80 years and older. METHODS: This observational, prospective, single-centre study included consecutive patients with acute LVO ischaemic stroke of the anterior circulation. The study outcomes were functional independence at 3 months after EVT (defined as a mRS score of 0-2), successful reperfusion (mTICI ≥ 2b), incidence of haeamorrhagic transformation, and 90-day all cause of mortality. RESULTS: Our cohort included 497 patients with acute ischaemic stroke due to LVO treated with EVT. Among them, 105 (21.1%) patients were aged ≥ 80 years. In the elderly group, multivariable regression analysis showed that thromboaspiration technique vs stent-retriever was the single independent predictor of favourable post-procedural TICI score (OR = 7.65, 95%CI = 2.22-26.32, p = 0.001). CONCLUSIONS: Our study suggests that EVT for LVO stroke in the elderly could be safe. The use of thromboaspiration was associated with positive reperfusion outcome in this population. Further studies in larger series are warranted to confirm the present results and to evaluate the safety and efficacy of EVT in the elderly and oldest adults.

Outcomes of mechanical thrombectomy in acute stroke patients with atrial fibrillation detected after stroke versus known atrial fibrillation.

We aim to compare the outcomes in patients with atrial fibrillation detected after stroke (AFDAS) and their counterparts with known AF (KAF) presenting with large vessel occlusion (LVO) treated with mechanical thrombectomy (MT). This observational, prospective study included consecutive patients with acute LVO ischemic stroke of the anterior circulation with AFDAS, KAF and without AF. The primary study outcome was functional independence at 90 days after stroke. The secondary study outcomes were variation of the NIHSS score at 24 h, rate of successful reperfusion, death at 90 days and rate of immediate complications post-procedure. Overall, our cohort included 518 patients with acute ischemic stroke and LVO treated with MT, with 289 (56.8%) without a diagnosis of AF; 107 (21%) with AFDAS; 122 (22.2%) with KAF. There was no significant difference in terms of functional independence at 90 days after stroke between the three groups. Regarding the secondary study outcome, the rate of symptomatic intracranial haemorrhage (sICH) and/or parenchymal hematoma (PH) were significantly higher in the group of patients without AF (respectively, P = 0.030 and < 0.010). Logistic regression analysis showed that the subtypes of AF were not statistically significantly associated with functional independence at 90 days after stroke and with the likelihood of any ICH. Our results suggest that the subtypes of AF are not associated with clinical and safety outcomes of MT in patients with acute stroke and LVO. Further studies are needed to confirm our findings.

Plate fixation versus flexible intramedullary nails for management of closed femoral shaft fractures in the pediatric population: A systematic review and meta-analysis of the adverse outcomes.

Purpose: Fractures of the femoral diaphysis are associated with a risk of morbidity in children. Various fixation methods have been developed, but with only limited evidence to support their use. This systematic review assesses the evidence regarding clinical outcomes of closed femoral diaphyseal fractures in children treated with plate fixation or flexible intramedullary nails. Methods: A PROSPERO-registered, PRISMA-compliant systematic review and meta-analysis were conducted. MEDLINE, Embase, and Web of Science (WoS) databases were searched from inception to February 2023. Inclusion criteria included clinical studies reporting adverse outcomes following surgical treatment of pediatric closed femoral diaphyseal fractures using plate fixation and flexible intramedullary nails. The ROBINS-I and RoB 2 tools evaluated the risk of bias. Results: Thirteen papers (2 prospective randomized controlled trials and 11 retrospective cohorts) reported 805 closed diaphyseal femoral fractures in 801 children (559 males, 242 females). There were 360 plate fixations and 445 flexible intramedullary nails. Two cases of osteomyelitis and one nonunion were reported. Meta-analysis showed that plate fixation had a lower risk of soft tissue infection (relative risk 0.26 (95% confidence interval 0.07-0.92)). There was no difference in the following outcomes: malunion (relative risk 0.68 (95% confidence interval 0.32-1.44)); unplanned reoperation (relative risk 0.59 (95% confidence interval 0.31-1.14)), and leg-length difference (relative risk 1.58 (95% confidence interval 0.66-3.77)). The risk of bias was high in all studies. Conclusions: An analysis of 805 fractures with minimal differences in meta-analyses is considered high quality even when the quality of the evidence is low. The findings are limited by important flaws in the methodology in the published literature. Well-designed multicentre prospective studies using standardized core outcomes are required to advise treatment recommendations. Level of evidence: III.

Effect of premature loss of primary teeth on prevalence of malocclusion in permanent dentition: A systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis aimed to assess the effect of premature loss of primary teeth in children of mixed dentition age on the prevalence of malocclusion in permanent dentition. MATERIAL AND METHODS: A search was conducted in Medline through PubMed, Cochrane databases, Google Scholar, and Directory of Open Access Journals (DOAJ) through March 2023. All observational studies that evaluated the association between premature loss of primary teeth and malocclusion in permanent dentition were included for analysis. Quality of studies was evaluated using the Newcastle-Ottawa tool. Meta-analysis was conducted using Cochrane Review Manager (RevMan) Version 5.3. The association between different categories of malocclusion and premature loss of primary teeth was assessed using a random-effects model. Heterogeneity was explored through sensitivity analysis. Certainty of evidence was evaluated using GRADE analysis. RESULTS: This meta-analysis showed that the premature loss of primary teeth significantly increases the prevalence of overall malocclusion in permanent dentition (OR=2.54, P=0.003; I2: 83%). Subgroup analysis showed an insignificant relationship of premature loss of primary teeth with Class I malocclusion (OR=1.14, P=0.45; I2: 63%) and Class II malocclusion (OR=1.63, P=0.18; I2: 87%) but statistically significant relationship with Class III malocclusion (OR=3.73, P=0.006; I2: 71%). Sensitivity analysis reflected a significant reduction in I2 values. CONCLUSION: This meta-analysis provides substantial evidence supporting the relationship between premature loss of primary teeth and malocclusion in permanent dentition. Notably, Class III malocclusions exhibited a significant association with premature loss of primary teeth.

Neuromodulation of spinal reflex pathway for the treatment of detrusor overactivity by medial plantar nerve stimulation at surface of sole of foot in patients with spinal cord injury.

Objectives: Suprasacral spinal cord lesions are prone to have neurogenic detrusor overactivity leading to urinary incontinence. Current medical management has known side-effects and often surgical managements are irreversible. Electrical stimulation to modulate spinal reflex pathway having same nerve root as urinary bladder is reported in the literature. This study aimed to reduce detrusor overactivity in patients with spinal cord injury (SCI) using surface electrical stimulation of medial plantar nerve at the sole of foot. Materials and Methods: Twenty adults with SCI having episode of at least 1 leak/day due to detrusor overactivity as diagnosed by cystometrogram (CMG), were on clean intermittent catheterization and ankle jerk was present consented for the study. Participants were asked to maintain bladder diary a week before and during 2 weeks of treatment. CMG was done on day-0 and day-14. cmcUroModul@tor®, an inhouse developed electrical stimulator was used for ½ h daily for period of 2 weeks. Patient satisfaction feedback questionnaire was taken on completion of treatment. CMG data were analyzed using Wilcoxon signed-ranked test while bladder diary was analyzed using binomial distribution. P < 0.05 was considered as statistically significant. Institutional Review Board (IRB) and ethics committee of Christian Medical College, Vellore, approved the study (CMC/IRB/11061). Results: Statistical significant improvement in maximum detrusor pressure (P = 0.03) and cystometric capacity (P = 0.04) was observed. Of 20 subjects, 18 showed improvement in bladder diary. Conclusion: Neuromodulation of medial plantar nerve at sole of foot by surface electrical stimulation is non-invasive, cost-effective, and alternative simple treatment modality for urinary incontinence due to detrusor overactivity.

Critical Evaluation of Lateral Calcaneal Artery Fascio-Cutaneous Flap in Re-Surfacing Posterior Heel Defects: A Review of 24 Cases.

Purpose and background: To assess feasibility and functional acceptability of lateral calcaneal artery fascio-cutaneous flap (LCAFCF) in providing cover to posterior heel defects in single stage. Aims and objectives: To provide stable and sensate cover to small and moderate posterior heel defects. Materials and methods: This review was conducted in department of Burns & Plastic Surgery of Postgraduate Institute of Medical Sciences (PGIMS), Rohtak, Haryana between October 2021 and September 2022 to analyse the clinical outcome of LCAFCF in 24 patients (18 males, 6 females) aged between 20 and 35 years who had chronic dry wounds n = 9, failed primary reconstruction by reverse sural flap n = 1, granulated wounds n = 8, exposed achilles tendons n = 4 and scarred tissue restricting ankle joint movements n = 2 in region of posterior heel following trauma, while riding motor-cycle. Course of lateral calcaneal artery was marked with hand-held doppler. Flap size ranged from 3 to 3.5 cm in width and 5.5-7.5 cm length. The donor sites were split skin grafted. Sutures were removed on 22nd day of surgery. Mean follow up was 13 months. Results: All flaps survived. Two had partial loss of skin graft and two developed hyperkeratosis on grafted site. Sensations in flap, regain of movements of ankle joint, comfort of walking and driving were acceptable. Conclusions: LCAFCF is handy, safe and reliable flap for re-surfacing difficult wounds of posterior heel, therefore should be included in surgical armamentarium.

Outcomes of mechanical thrombectomy in orally anticoagulated patients with anterior circulation large vessel occlusion: a propensity-matched analysis of the Imperial College Thrombectomy Registry.

BACKGROUND: Mechanical thrombectomy (MT) remains an effective treatment for patients with acute ischemic stroke receiving oral anticoagulation (OAC) and large vessel occlusion (LVO). However, to date, it remains unclear whether MT is safe in patients on treatment with OAC. AIMS: In our study, we performed a propensity-matched analysis to investigate the safety and efficacy of MT in patients with acute ischemic stroke receiving anticoagulants. A propensity score method was used to target the causal inference of the observational study design. METHODS: This observational, prospective, single-centre study included consecutive patients with acute LVO ischemic stroke of the anterior circulation. Demographic, neuro-imaging and clinical data were collected and compared according to the anticoagulation status at baseline, patients on OAC vs those not on OAC. The primary study outcomes were the occurrence of any intracerebral haemorrhage (ICH) and symptomatic ICH. The secondary study outcomes were functional independence at 90 days after stroke (defined as modified Rankin Scale (mRS) scores of 0 through 2), mortality at 3 months and successful reperfusion rate according to the modified treatment in cerebral infarction (mTICI) score. RESULTS: Overall, our cohort included 573 patients with acute ischemic stroke and LVO treated with MT. After propensity score matching, 495 patients were matched (99 OAC group vs 396 no OAC group). There were no differences in terms of clinical characteristics between the two groups, except for the rate of intravenous thrombolysis less frequently given in the OAC group. There was no significant difference in terms of the rate of any ICH and symptomatic ICH between the two groups. With regards to the secondary study outcome, there was no significant difference in terms of the rate of successful recanalization post-procedure and functional independence at 3 months between the two groups. Patients in the OAC group showed a reduced mortality rate at 90 days compared to the patients with no previous use of anticoagulation (20.2% vs 21.2%, p = 0.031). Logistic regression analysis did not reveal a statistically significant influence of the anticoagulation status on the likelihood of any ICH (OR = 0.95, 95% CI = 0.46-1.97, p = 0.900) and symptomatic ICH (OR = 4.87, 95% CI = 0.64-37.1, p = 0.127). Our analysis showed also that pre-admission anticoagulant use was not associated with functional independence at 90 days after stroke (OR = 0.76, 95% CI = 0.39-1.48, p = 0.422) and rate of successful reperfusion (OR = 0.81, 95% CI = 0.38-1.72, p = 0.582). CONCLUSION: According to our findings anticoagulation status at baseline did not raise any suggestion of safety and efficacy concerns when MT treatment is provided according to the standard guidelines. Confirmation of these results in larger controlled prospective cohorts is necessary.

Clinical Classification of Urethrocutaneous Fistulas Developing after Hypospadias Repair.

Background Clinical classification of the urethrocutaneous fistulas (UCFs) was designed to help the surgeons in (1) categorizing the fistulas, (2) selecting appropriate treatments, (3) keeping record at presentation and discharge, and (4) transferring information while referring a patient with recurrent fistula to a higher center. Methods This retrospective study comprised of 68 patients with UCFs who reported in the "Hypospadias and VVFs Clinic" between 2004 and 2016. The study was performed to determine the incidence or etiology of the UCFs. It was rather performed to classify fistulas into different categories depending on the number of fistulas: A (5 fistulas), B (16 fistulas), C-a (28 fistulas), C-b (4 fistulas), D (4 fistulas), and E (11 fistulas). Category A fistulas healed conservatively. Category B fistulas underwent transection of the fistula tracts (tractotomy), purse-string closure, or multilayered closure (fistulorrhaphy). Category C-a fistulas were reenforced by preputial or penile skin flaps or waterproofing flaps. Category C-b fistulas underwent re-tubularization of their neourethral plates and eccentric closure of peno-preputial skin. The urethral plates of category D fistulas were re-tubularized after 3 to 6 months and cover was provided by the Cecil-Culp procedure. Category E fistulas had associated hairy urethra, stricture distal urethra, stricture with diverticulum, perifistular scar-induced chordee, long narrow urethral plate, balanitis xerotica obliterans (BXO), and short reconstructed neourethra. Accordingly, appropriate corrective measures were taken. Miscellaneous category F was excluded from the study. Results Except for one in category D, none of the patients had any recurrence of fistula. One patient of category E had residual diverticulum. Conclusion The designed clinical classification of UCFs is simple. Treatment was in accordance with reconstructive ladder wherein complexity of treatment paralleled with increasing complexity of fistulas.

Design and development of benzyl piperazine linked 5-phenyl-1,2,4-triazole-3-thione conjugates as potential agents to combat Alzheimer's disease.

Our present work demonstrates the molecular hybridization-assisted design, synthesis, and biological evaluation of 22 benzylpiperazine-linked 1,2,4-triazole compounds (PD1-22) as AD modifying agents. All the compounds were tested for their in vitro hChEs, hBACE-1, and Aß-aggregation inhibition properties. Among them, compound PD-08 and PD-22 demonstrated good hChE and hBACE-1 inhibition as compared to standards donepezil and rivastigmine. Both compounds displaced PI from PAS at 50 µM concentration which was comparable to donepezil and also demonstrated anti-Aß aggregation properties in self- and AChE-induced thioflavin T assay. Both compounds have shown excellent BBB permeation via PAMPA-BBB assay and were found to be non-neurotoxic at 80 µM concentration against differentiated SH-SY5Y cell lines. Compound PD-22 demonstrated an increase in rescued eye phenotype in Aß-phenotypic drosophila AD model and amelioration of behavioral deficits in the Aß-induced rat model of AD. The in-silico docking studies of compound PD-22 revealed a good binding profile towards CAS and PAS residues of AChE and the catalytic dyad of the BACE-1. The 100 ns molecular dynamics simulation studies of compound PD-22 complexed with AChE and BACE-1 enzymes suggested stable ligand-protein complex throughout the simulation run. Based on our findings compound PD-22 could further be utilized as a lead to design a promising candidate for AD therapy.

A reaction network scheme for hidden Markov model parameter learning.

With a view towards artificial cells, molecular communication systems, molecular multiagent systems and federated learning, we propose a novel reaction network scheme (termed the Baum-Welch (BW) reaction network) that learns parameters for hidden Markov models (HMMs). All variables including inputs and outputs are encoded by separate species. Each reaction in the scheme changes only one molecule of one species to one molecule of another. The reverse change is also accessible but via a different set of enzymes, in a design reminiscent of futile cycles in biochemical pathways. We show that every positive fixed point of the BW algorithm for HMMs is a fixed point of the reaction network scheme, and vice versa. Furthermore, we prove that the 'expectation' step and the 'maximization' step of the reaction network separately converge exponentially fast and compute the same values as the E-step and the M-step of the BW algorithm. We simulate example sequences, and show that our reaction network learns the same parameters for the HMM as the BW algorithm, and that the log-likelihood increases continuously along the trajectory of the reaction network.

Carbon dioxide flushing versus saline flushing of thoracic aortic stents (INTERCEPTevar): protocol for a multicentre pilot randomised controlled trial.

INTRODUCTION: Thoracic endovascular aortic repair (TEVAR) carries a 3%-6.1% stroke risk, including risk of 'silent' cerebral infarction (SCI). Stent-grafts are manufactured in room air and retain air. Instructions for use recommend saline flushing to 'de-air' the system prior to insertion, but substantial amounts of air are released when deploying them, potentially leading to downstream neuronal injury and SCI. Carbon dioxide (CO2) is more dense and more soluble in blood than air, without risk of bubble formation, so could be used in addition to saline to de-air stents. This pilot trial aims to assess the feasibility of a full-scale randomised controlled trial (RCT) investigating the neuroprotective benefit against SCI with the use of CO2-flushed aortic stent-grafts. METHODS AND ANALYSIS: This is a multicentre pilot RCT, which is taking place in vascular centres in the UK, USA and New Zealand. Patients identified for TEVAR will be enrolled after informed written consent. 120 participants will be randomised (1:1) to TEVAR-CO2 or TEVAR-saline, stratified according to TEVAR landing zone. Participants will undergo preoperative neurocognitive tests and quality of life assessments, which will be repeated at 6 weeks, or first outpatient appointment, and 6 months. Inpatient neurological testing will be performed within 48 hours of return to level 1 care for clinical stroke or delirium. Diffusion-weighted MRI will be undertaken within 72 hours postoperatively (1-7 days) and at 6 months to look for evidence and persistence of SCI. Feasibility will be assessed via measures of recruitment and retention, informing the design of a full-scale trial. ETHICS AND DISSEMINATION: The study coordination centre has obtained approval from the London Fulham Research Ethics Committee (19/LO/0836) and Southern Health and Disability Ethics Committee (NZ) and UK's Health Regulator Authority (HRA). The study has received ethical approval for recruitment in the UK (Fulham REC, 19/LO/0836), New Zealand (21/STH/192) and the USA (IRB 019-264, Ref 378630). Consent for entering into the study will be taken using standardised consent forms by the local study team, led by a local PI. The results of the trial will be submitted for publication in an open access journal. TRIAL REGISTRATION NUMBER: NCT03886675.

Assessment of urban sprawls, amenities, and indifferences of LST and AOD in sub-urban area: a case study of Jammu.

Urbanization, particularly in peri-urban areas, often results in critically transforming the regional land use and land cover (LULC). The increased built-up in peri-urban areas affects the regional accessibility of residents of urban clusters to requisite amenities and severely affects the regional environment, as observed in the case of Jammu district situated in the foothills of the Indian Himalayas. The present study is aimed at assessing the rise of urban sprawls in Jammu district over the past two decades and how the urbanization has affected the lag in the number of amenities corresponding to the urban growth based on qualitative parameters. Further, a parameterization scheme is developed to assess the amenities quality. A comparison is made with Indore, a planned smart city, to assess the status of urbanization and residential quality based on an amenity index. The study also investigates the indifferences observed in some of the climate variables in the urban and sub-urban settings of the Jammu district. The investigation is conducted through a multi-ring buffer analysis approach utilizing the land use land cover (LULC) products based on Landsat 8/7 satellite imagery of 2002, 2013, and 2021. The indifferences in the settings are analyzed using MODIS aerosol optical depth (AOD) and land surface temperature (LST) products. The analysis leads to determination of critical urban parameters including the urban area, density, and growth rate, revealing significant urbanization at 25-27 km from the city center. Significant indifferences are observed in urban and sub-urban areas indicating higher rise in LST and AOD, particularly in the recent decade. These investigations provide critical information to urban and climate solution authorities for planning and management, particularly in critically endangered areas.

Endovascular Thrombectomy with or without Intravenous Thrombolysis for Anterior Circulation Large Vessel Occlusion in the Imperial College London Thrombectomy Registry.

Background and purpose. Mechanical thrombectomy (MT) is the standard of care for eligible patients with a large vessel occlusion (LVO) acute ischemic stroke. Among patients undergoing MT there has been uncertainty regarding the role of intravenous thrombolysis (IVT) and previous trials have yielded conflicting results regarding clinical outcomes. We aim to investigate clinical, reperfusion outcomes and safety of MT with or without IVT for ischemic stroke due to anterior circulation LVO. Materials and Methods. This observational, prospective, single-centre study included consecutive patients with acute LVO ischemic stroke of the anterior circulation. The primary outcomes were the rate of in-hospital mortality, symptomatic intracranial haemorrhage and functional independence (mRS 0-2 at 90 days). Results. We enrolled a total of 577 consecutive patients: 161 (27.9%) were treated with MT alone while 416 (72.1%) underwent IVT and MT. Patients with MT who were treated with IVT had lower rates of in-hospital mortality (p = 0.037), higher TICI reperfusion grades (p = 0.007), similar rates of symptomatic intracranial haemorrhage (p = 0.317) and a higher percentage of functional independence mRS (0-2) at 90 days (p = 0.022). Bridging IVT with MT compared to MT alone was independently associated with a favorable post-intervention TICI score (>2b) (OR, 1.716; 95% CI, 1.076-2.735, p = 0.023). Conclusions. Our findings suggest that combined treatment with MT and IVT is safe and results in increased reperfusion rates as compared to MT alone.