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.

Comparison of McCoy, Macintosh, and Truview laryngoscope for bougie-aided naso-tracheal intubation: A randomized controlled study.

Background: Video laryngoscopes are commonly used along with Macintosh and McCoy laryngoscopes for Nasotracheal intubation (NTI). The purpose of this study was to evaluate the performance of McCoy, Macintosh, and Truview laryngoscopes during bougie-aided NTI with respect to intubation time, success rate, and hemodynamic changes during the procedure. Methods: Forty-five American Society of Anesthesiologists (ASA) I-II adult patients, with Mallampati grade 1-4, requiring NTI, were enrolled after taking written informed consent. ASA III/IV, restricted mouth opening, and body mass index >30 were excluded from the study. Patients were randomly allocated to intubate with one of the three laryngoscopes (McCoy, Macintosh, and Truview) and the anesthesiologists were well experienced with all of them. The primary outcome was intubation time and secondary outcomes included first attempt success rate, external laryngeal manipulation, Cormack-Lehane (CL) grade, and hemodynamic responses. Results: The intubation time of McCoy, Macintosh, and Truview, was 86.87 ± 15.92, 82.87 ± 16.46, and 79.93 ± 14.53 (mean ± standard deviation) seconds, respectively, which is comparable with Truview being the shortest. CL grade 1 was obtained more in the Truview group (53.3%) compared to the other two groups, while CL grade 3 was obtained in 20% each in McCoy and Macintosh groups. Conclusions: McCoy, Macintosh, and Truview laryngoscopes were comparable in performance during bougie-aided NTI, with Truview having the shortest intubation time and better visualization.

A comparative study of perioperative pain, blood loss, and hospital stay in an Indian population undergoing mini-open oblique lumbar interbody fusion versus open transforaminal lumbar interbody fusion.

Background: There are several approaches for lumbar fusion, although there is yet to be a consensus on which approach is the best. This study aimed to evaluate the intraoperative blood loss and acute postoperative pain in single-level mini-open oblique lumbar interbody fusion (OLIF) versus open transforaminal lumbar interbody fusion (TLIF) surgeries for the degenerative spine. Methods: Thirty-two patients were assigned by the surgeon to OLIF or TLIF groups - 16 in mini-open OLIF and 16 in open TLIF groups. The intraoperative blood loss and postoperative hemoglobin, numerical rating scale (NRS) at proposed time intervals for 24 h postoperative, and rescue analgesics used were compared among the groups. The operative duration and hospital stay in both groups were also compared. Results: The OLIF group showed significantly higher postoperative hemoglobin (11.5 vs. 10.5 g %, P = 0.04), lower 24-h postoperative pain scores on movement, (NRS 4 vs. 5.5, P = 0.0001), and shorter hospital stay (4.5 vs. 7 days, P = 0.003) than TLIF group. However, the surgery duration was significantly longer in OLIF than in TLIF (190 vs. 150 min, P = 0.005). Intraoperative hemodynamics, other postoperative pain scores at variable time points, and rescue analgesics given were comparable among groups (P > 0.05). Intraoperative blood loss was lower in OLIF than TLIF (275 vs. 500 mL) but was not statistically significant (P > 0.05). Conclusion: Mini-open OLIF has favorable perioperative outcomes compared to open TLIF. Patients have higher postoperative hemoglobin and lesser pain on movement on the first postoperative day, leading to earlier mobilization and a shorter hospital stay.

Breast lymphomas: Clinical and pathological insights from a tertiary cancer care center in India.

BACKGROUND: Breast lymphomas are a rare group of malignancies that are further subdivided into primary and secondary. AIMS: To study the pathological and clinical course of breast lymphomas. MATERIALS AND METHODS: This is a retrospective analysis of patients treated at our institute over a period of 4.5 years from September 2018 to February 2023. The details of all the patients diagnosed with breast lymphoma were reviewed and analysed for the histomorphological, immunohistochemical, clinical, and treatment details. Appropriate statistical analysis including Kaplan-Meier methods was used. RESULTS: Out of 11 cases of breast lymphoma, five were primary and six were secondary. It was seen predominantly in females (82%) and the age range was 31 to 73 years. Diffuse large B cell lymphoma (DLBCL) was the predominant morphology (73%), along with single rare cases of ALK-negative anaplastic large cell lymphoma, Burkitt lymphoma, and small lymphocytic lymphoma. The treatment details were analyzed for 7 patients. The median follow-up was 28 months. Rituximab along with CHOP regimen or its variants was commonly used as first-line treatment with initial response rates of 71%. The median progression-free survival was 5 months. The median overall survival was 15 months. CONCLUSION: Lymphomas of the breast are rare but it is crucial to differentiate them from the commoner breast carcinomas as the treatment and prognosis vary vastly.

Enhancing biomethanation performance through co-digestion of diverse organic wastes: a comprehensive study on substrate optimization, inoculum selection, and microbial community analysis.

A blend of organic municipal solid waste, slaughterhouse waste, fecal sludge, and landfill leachate was selected in different mixing ratios to formulate the best substrate mixture for biomethanation. Individual substrates were characterized, and the mixing ratio was optimized with the help of a response surface methodology tool to a value of 1:1:1:1 (with a C/N ratio of 28±0.769 and total volatile fatty acid (VFA) concentration of 2500±10.53 mg/L) to improve the overall biomethanation. The optimized blend (C/N ratio: 28.6, VFA: 2538 mg/L) was characterized for physicochemical, biological, and microbial properties and subjected to anaerobic digestion in lab-scale reactors of 1000 mL capacity with and without the addition of inoculum. The biogas yield of individual substrates and blends was ascertained separately. The observed cumulative biogas yield over 21 days from the non-inoculated substrates varied between 142±1.95 mL (24.6±0.3 ml/gVS) and 1974.5±21.72 mL (270.4±3.1 ml/gVS). In comparison, the addition of external inoculation at a 5% rate (w/w) of the substrate uplifted the minimum and maximum cumulative gas yield values to 203±9.9 mL (35.0±1.6 mL/gVS) and 3394±13.4 mL (315.3±1.2 mL/gVS), respectively. The inoculum procured from the Defence Research and Development Organisation (DRDO) was screened in advance, considering factors such as maximizing VFA production and consumption rate, biogas yield, and digestate quality. A similar outcome regarding biogas yield and digestate quality was observed for the equivalent blend. The cumulative gas yield increased from 2673±14.5 mL (373.7±2.2 mL/gVS) to 4284±111.02 mL (391.47±20.02 mL/gVS) over 21 days post-application of a similar dosage of DRDO inoculum. The 16S rRNA genomic analysis revealed that the predominant bacterial population belonged to the phylum Firmicutes, with the majority falling within the orders Clostridiales and Lactobacillales. Ultimately, the study advocates the potential of the blend mentioned above for biomethanation and concomitant enrichment of both biogas yield and digestate quality.

Trends in avascular necrosis and related arthroplasties in hospitalized patients with systemic lupus erythematosus and rheumatoid arthritis.

OBJECTIVE: Avascular necrosis (AVN) is a devastating complication often necessitating arthroplasty, particularly common in systemic lupus erythematosus (SLE). Limited research exists on arthroplasty trends since new steroid-sparing agents. We analyzed trends and characteristics associated with AVN and AVN-related arthroplasties among SLE and RA hospitalizations using two decades of data from the U.S. National Inpatient Sample (NIS). METHODS: This cross-sectional study used NIS (2000-2019) to identify hospitalized adults with SLE and RA, with or without AVN, using ICD codes. AVN was further grouped by arthroplasty status. Primary outcomes were AVN and AVN-related arthroplasty rates and time trends in SLE and RA. Baseline sociodemographics and comorbidities were compared. Analyses used STATA and Joinpoint regression to calculate annual percent change (APC). RESULTS: Overall, 42,728 (1.3 %) SLE and 43,600 (0.5 %) RA hospitalizations had concomitant AVN (SLE-AVN and RA-AVN). Of these, 16,724 (39 %) and 25,210 (58 %) underwent arthroplasties, respectively. RA-AVN increased (APC: 0.98*), with a decrease in arthroplasties (APC: -0.82*). In contrast, SLE-AVN initially increased with a breakpoint in 2011 (APC 2000-2011: 1.94* APC 2011-2019 -2.03), with declining arthroplasties (APC -2.03*). AVN hospitalizations consisted of individuals who were younger and of Black race; while arthroplasties were less likely in individuals of Black race or Medicaid coverage. CONCLUSION: We report a breakpoint in rising SLE-AVN after 2011, which may relate to newer steroid-sparing therapies (i.e., belimumab). AVN-associated arthroplasties decreased in SLE and RA. Fewer AVN-associated arthroplasties were noted for Black patients and those with Medicaid, indicating potential disparities. Further research should examine treatment differences impacting AVN and arthroplasty rates.

Clinical Utility of Tectal Plate Measurements on Magnetic Resonance Imaging in Progressive Supranuclear Palsy.

BACKGROUND: Midbrain atrophy is a characteristic feature of progressive supranuclear palsy (PSP), observed in PSP-Richardson's syndrome (PSP-RS) and to a lesser extent PSP-parkinsonism (PSP-P). OBJECTIVE: Our aim was to critically evaluate the utility of manual magnetic resonance imaging measurements of the midbrain tectal plate as a diagnostic biomarker in PSP. METHODS: Length of the tectal plate and width of the superior and inferior colliculi were measured in 40 PSP (20 PSP-RS and 20 PSP-P) patients and compared with 20 Parkinson's disease and 20 healthy control subjects. RESULTS: Tectal plate length was reduced in both PSP groups compared with Parkinson's disease and control subjects and was most abnormal in PSP-RS followed by PSP-P. Reduced tectal plate length was associated with worse PSP Rating Scale scores. CONCLUSIONS: Simple manual measurements of tectal plate length show utility as a diagnostic biomarker in PSP, particularly for PSP-RS. © 2024 International Parkinson and Movement Disorder Society.

A comparative assessment of biomethane potential of fresh fecal matter and fecal sludge and its correlation with malodor.

Comprehensive and proper management of fecal sludge (FS) is an ongoing concern in many nations. Decentralized fecal sludge treatment plants (FSTPs) are effective in this regard; however, many have experienced strong public opposition based partly on suspicion of malodor. Fecal sludge and freshly generated fecal matter (FM) samples from various FSTPs were collected, characterized, and investigated for biomethane potential. The homogenized samples were anaerobically digested for 28 days. Digestion successfully reduced total suspended solids, biochemical oxygen demand, and threshold odor number values of 97,350-97,420 mg/l, 43,230-43,260 mg/l, and 130-150 for FM, to 49,500-49,650 mg/l, 23,760-23,850 mg/l, and 3338, respectively, for FS samples. The comprehensive gas yield from Bhongir, Boduppal, and Shadnagar FS samples was 40, 55, and 31 ml, respectively. In contrast, cumulative gas generation from the FM was 26,361 ml. Digestion of FS samples also reduced concentrations of volatile solids and coliforms by 66-72% and 99%, respectively. Characterization of gas samples revealed methane and carbon dioxide concentrations as 56% and 22% for FM, and 0.4% and 61% for FS samples, respectively. Hydrogen sulfide and ammonia gas were absent in FS samples, dispelling common societal misconceptions of FSTPs being associated with malodor.

An Innovative Technique for Assessment of Bone Change, Bite Force, and Retention of the Single-Implant-Supported Mandibular Overdenture: A Clinical Study.

This study is the first study to incorporate a novel approach to single-implant-retained mandibular overdenture with a bar attachment on a single implant in the symphysis region. The use of a single-implant-retained bar overdenture significantly improved patients' chewing efficiency, indicating enhanced overdenture retention and stability. Materials and Methods: Ten maxillary and mandibular completely edentulous patients were enrolled in the study. A complete denture was fabricated for them. On completion, bite force, retention force, and bone change were recorded. Bite force was recorded with the strain gauge, retention force with the force measurement gauge, and bone changes with radiographs. Conclusion: Single-implant-supported bar mandibular overdenture (SISBOD) can be a suitable standard economic option for edentulous mandible and can greatly improve the quality of life of patients.

Prevalence of Periodontal Disease among Patients Reporting to Tertiary Care Hospital in Ranchi.

Background: Despite a huge number of advancements in the medical field, periodontitis still remains one of the most prevalent oral diseases worldwide. Aim: Thus, the primary aim of our study was to evaluate the prevalence of periodontal diseases in patients reporting to the tertiary healthcare setup in Ranchi. Materials and Methods: Based on inclusion criteria, subjects aged 18-60 years were selected and a per forma was filled by the observer. The prevalence of periodontal disease was measured using the community periodontal index, simplified oral hygiene index, and stage of periodontitis. Results: Descriptive variables were assessed using frequency, percentage, mean, and standard deviations, while the categorical analysis was performed using the Chi-square tests. Conclusion: General awareness about periodontal health and regular dental visits should be given utmost importance among the rural populations of every developing country.

Plasma glial fibrillary acidic protein in the visual and language variants of Alzheimer's disease.

INTRODUCTION: Glial fibrillary acidic protein (GFAP) in plasma is a proxy for astrocytic activity and is elevated in amyloid-ß (Aß)-positive individuals, making GFAP a potential blood-based biomarker for Alzheimer's disease (AD). METHODS: We assessed plasma GFAP in 72 Aß-positive participants diagnosed with the visual or language variant of AD who underwent Aß- and tau-PET. Fifty-nine participants had follow-up imaging. Linear regression was applied on GFAP and imaging quantities. RESULTS: GFAP did not correlate with Aß- or tau-PET cross-sectionally. There was a limited positive correlation between GFAP and rates of tau accumulation, particularly in the language variant of AD, although associations were weaker after removing one outlier patient with the highest GFAP level. DISCUSSION: Among Aß-positive AD participants with atypical presentations, plasma GFAP did not correlate with levels of AD pathology on PET, suggesting that the associations between GFAP and AD pathology might plateau during the advanced phase of the disease.

Exploring the unusual: a testosterone-secreting ovarian tumor.

Ovarian steroid cell tumors are rare, representing less than 0.1% of all ovarian neoplasms. Among the myriad causes of hirsutism, ovarian tumors account for 1% of the reported cases. We present the case of a 49-year-old parous postmenopausal woman who sought medical attention for hirsutism for 2 years. This case illustrates the unusual and interesting connection between rare ovarian pathology and the clinical manifestation of hirsutism in a postmenopausal patient. Her ultrasonography and MRI showed a right adnexal mass of solid-cystic consistency with thin septations. Her laboratory workup revealed high levels of total testosterone of 256 ng/ml (8.4-48.1ng/ml) and free testosterone of 7.36 pg/ml (0.2-4.1 pg/ml), while DHEAS - 234 µg/dl (35.4-256 µg/dl) and CA125 - 15.8U/L (0.0-35 U/L) were in the normal range. She underwent exploratory laparotomy with a total abdominal hysterectomy and oophorectomy. Histopathological examination and immunohistochemistry conclusively established the presence of a steroid cell tumor, specifically classified as "Not Otherwise Specified"(NOS), in the right ovary.

Atypical Alzheimer's disease: new insights into an overlapping spectrum between the language and visual variants.

Overlap between language and visual variants of atypical Alzheimer's disease (AD) has been reported. However, the extent, frequency of overlap, and its neuroanatomical underpinnings remain unclear. Eighty-two biomarker-confirmed AD patients who presented with either predominant language (n = 34) or visuospatial/perceptual (n = 48) deficits underwent detailed clinical examinations, MRI, and [18F]flortaucipir-PET. Subgroups were defined based on language/visual testing and patterns of volume loss and tau uptake were assessed. 28% of the language group had visual dysfunction (marked in 8%), and 47% of the visual group had language impairment (marked in 26%). Progressive involvement of the parieto-occipital and frontal lobes was noted with greater visual impairment in the language group, and greater left parieto-temporal and frontal involvement with worsening language impairment in the visual group. Only 25% of our cohort showed a pure language or visual presentation, highlighting the high frequency of syndromic overlap in atypical AD and the diagnostic challenge of categorical phenotyping.

Altered structural and functional connectivity in Posterior Cortical Atrophy and Dementia with Lewy bodies.

Posterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) show distinct atrophy and overlapping hypometabolism profiles, but it is unknown how disruptions in structural and functional connectivity compare between these disorders and whether breakdowns in connectivity relate to either atrophy or hypometabolism. Thirty amyloid-positive PCA patients, 24 amyloid-negative DLB patients and 30 amyloid-negative cognitively unimpaired (CU) healthy individuals were recruited at Mayo Clinic, Rochester, MN, and underwent a 3T head MRI, including structural MRI, resting state functional MRI (rsfMRI) and diffusion tensor imaging (DTI) sequences, as well as [18F] fluorodeoxyglucose (FDG) PET. We assessed functional connectivity within and between 12 brain networks using rsfMRI and the CONN functional connectivity toolbox and calculated regional DTI metrics using the Johns Hopkins atlas. Multivariate linear-regression models corrected for multiple comparisons and adjusted for age and sex compared DTI metrics and within-network and between-network functional connectivity across groups. Regional gray-matter volumes and FDG-PET standard uptake value ratios (SUVRs) were calculated and analyzed at the voxel-level using SPM12. We used univariate linear-regression models to investigate the relationship between connectivity measures, gray-matter volume, and FDG-PET SUVR. On DTI, PCA showed degeneration in occipito-parietal white matter, posterior thalamic radiations, splenium of the corpus collosum and sagittal stratum compared to DLB and CU, with greater degeneration in the temporal white matter and the fornix compared to CU. We observed no white-matter degeneration in DLB compared to CU. On rsfMRI, reduced within-network connectivity was present in dorsal and ventral default mode networks (DMN) and the dorsal-attention network in PCA compared to DLB and CU, with reduced within-network connectivity in the visual and sensorimotor networks compared to CU. DLB showed reduced connectivity in the cerebellar network compared to CU. Between-network analysis showed increased connectivity in both cerebellar-to-sensorimotor and cerebellar-to-dorsal attention network connectivity in PCA and DLB. PCA showed reduced anterior DMN-to-cerebellar and dorsal attention-to-sensorimotor connectivity, while DLB showed reduced posterior DMN-to-sensorimotor connectivity compared to CU. PCA showed reduced dorsal DMN-to-visual connectivity compared to DLB. The multimodal analysis revealed weak associations between functional connectivity and volume in PCA, and between functional connectivity and metabolism in DLB. These findings suggest that PCA and DLB have unique connectivity alterations, with PCA showing more widespread disruptions in both structural and functional connectivity; yet some overlap was observed with both disorders showing increased connectivity from the cerebellum.

Guidance on sexual, reproductive, maternal, newborn, child and adolescent health in humanitarian and fragile settings: a scoping review.

INTRODUCTION: Progress related to sexual, reproductive, maternal, newborn, child and adolescent health (SRMNCAH) has stalled. COVID-19, conflict and climate change threaten to reverse decades of progress and to ensure the health and well-being of vulnerable populations in humanitarian and fragile settings (HFS) going forward, there is a need for tailored guidance for women, children and adolescents (WCA). This review seeks to map and appraise current resources on SRMNCAH in HFS. METHODS: In line with the updated Joanna Briggs Institute guidance and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews framework, a manual literature review was conducted of global and regional guidance published between January 2008 and May 2023 from members of the Global Health Cluster, the Global Nutrition Cluster and the Inter-Agency Working Group on Reproductive Health in Crises. A content analysis was conducted. Scores were then calculated according to the Appraisal of Guidelines for Research and Evaluation II scoring tool and subsequently categorised as high quality or low quality. RESULTS: A total of 730 documents were identified. Of these, 141 met the selection criteria and were analysed. Available guidance for delivering SRMNCH services exists, which can inform policy and programming for the general population and WCA. Important gaps related to beneficiaries, health services and health system strengthening strategies were identified. CONCLUSION: The review revealed there is evidence-based guidance available to support interventions targeting WCA in HFS, including: pregnant and lactating women, women of reproductive age, adolescents, newborns, small vulnerable newborns, stillbirths, refugees and internally displaced persons and WCA with disabilities. However, gaps related to beneficiaries, health services and health system strengthening strategies must be addressed in updated guidance that is created, disseminated and monitored in a standardised way that is mindful of the need to respond rapidly in HFS.

An enigmatic pathogenetic mechanism of hypoxia inducible factor - 1/2 alpha in the progression of fibrosis of oral submucous fibrosis and its malignant transformation: A systematic review and meta-analysis.

OBJECTIVE: Oral submucous fibrosis is a frequently reported potentially malignant disorder characterized by fibrosis and a malignant transformation rate of 7-30%. The role of hypoxia-inducible factor-1/2α in malignant transformation mechanisms of oral submucous fibrosis remains uncharted territory owing to a scarcity of studies. Thus the present systematic review and meta-analysis aimed to determine the role of hypoxia-inducible factor-1/2α in the progression of fibrosis of oral submucous fibrosis and its malignant transformation. MATERIAL AND METHODS: Using PubMed, Google Scholar, and Cochrane Library databases, full-text articles that investigated hypoxia-inducible factor-1/2α in oral submucous fibrosis were entailed for review. A modified Newcastle-Ottawa scale was employed to evaluate risk of bias in all articles and Review Manager was utilized for meta-analysis. RESULTS: Eighteen and eight qualified articles respectively were included for qualitative and quantitative data synthesis. Progressive upregulation of hypoxia-inducible factor-1/2α in oral submucous fibrosis is associated with fibrosis-induced carcinogenesis. A Random-effects model uncloaked that oral submucous fibrosis cases with significantly increased expression of hypoxia-inducible factor-1α had an increased associated risk of malignant transformation compared with controls (combined odds ratio 523.83, 95% confidence interval 125.74- 2182.28, p < 0.00001). CONCLUSION: The existing evidence substantiates the notion that hypoxia-inducible factor-1/2α, a fundamental pathogenetic mechanism of progression and malignant transformation of oral submucous fibrosis in the background of fibrosis.

Anterior retropharyngeal approach (ARPA) for high cervical spine.

BACKGROUND: One of the major challenges in operating on the spine lies in taking an anterior approach for the high cervical spine. In patients with a short neck, Klippel-Fiel syndrome or when the C3 vertebra is high in relation to the hyoid bone, it will be difficult to access the C3 body. The transoral route is a highly contaminated zone, and therefore, no instrumentation or grafts can be placed through it. METHOD: The anterior retropharyngeal approach (ARPA) for the high cervical spine. CONCLUSION: The anterior retropharyngeal approach is an excellent approach for the high cervical spine where instrumentation is needed. This route provides wide exposure of the C1-C3 region, avoiding the contaminated of the oral cavity.