Plasma trimethylamine N-oxide (TMAO): associations with cognition, neuroimaging, and dementia.

BACKGROUND: The gut-derived metabolite Trimethylamine N-oxide (TMAO) and its precursors - betaine, carnitine, choline, and deoxycarnitine - have been associated with an increased risk of cardiovascular disease, but their relation to cognition, neuroimaging markers, and dementia remains uncertain. METHODS: In the population-based Rotterdam Study, we used multivariable regression models to study the associations between plasma TMAO, its precursors, and cognition in 3,143 participants. Subsequently, we examined their link to structural brain MRI markers in 2,047 participants, with a partial validation in the Leiden Longevity Study (n = 318). Among 2,517 participants, we assessed the risk of incident dementia using multivariable Cox proportional hazard models. Following this, we stratified the longitudinal associations by medication use and sex, after which we conducted a sensitivity analysis for individuals with impaired renal function. RESULTS: Overall, plasma TMAO was not associated with cognition, neuroimaging markers or incident dementia. Instead, higher plasma choline was significantly associated with poor cognition (adjusted mean difference: -0.170 [95% confidence interval (CI) -0.297;-0.043]), brain atrophy and more markers of cerebral small vessel disease, such as white matter hyperintensity volume (0.237 [95% CI: 0.076;0.397]). By contrast, higher carnitine concurred with lower white matter hyperintensity volume (-0.177 [95% CI: -0.343;-0.010]). Only among individuals with impaired renal function, TMAO appeared to increase risk of dementia (hazard ratio (HR): 1.73 [95% CI: 1.16;2.60]). No notable differences were observed in stratified analyses. CONCLUSIONS: Plasma choline, as opposed to TMAO, was found to be associated with cognitive decline, brain atrophy, and markers of cerebral small vessel disease. These findings illustrate the complexity of relationships between TMAO and its precursors, and emphasize the need for concurrent study to elucidate gut-brain mechanisms.

Emergency Cesarean Section in a Dichorionic Diamniotic Twin Pregnancy With Hydrops Fetalis: A Report of a Critical Case.

This case report describes the emergent scenario of a 41-year-old primipara at 31.2 weeks of gestation, presenting with abdominal and back pain in the context of a dichorionic diamniotic twin pregnancy complicated by hydrops fetalis. The patient, with a history of hypertension, hyperthyroidism, and a cervical stitch in place, underwent an emergency lower segment cesarean section. The ultrasound revealed an intrauterine left footling in one twin, contributing to the suspected hydrops fetalis. Neonatal complications arose, particularly with Baby B, necessitating immediate resuscitation and intensive care. Successful outcomes were achieved through a well-coordinated multidisciplinary approach involving obstetricians, neonatologists, and anesthesiologists. This case underscores the importance of prompt recognition, timely interventions, and collaborative care in managing complex pregnancies, shedding light on the challenges associated with dichorionic diamniotic twin pregnancies and emphasizing the need for ongoing research to refine perinatal strategies.

Association of blood cell-based inflammatory markers with gut microbiota and cancer incidence in the Rotterdam study.

The immune response-gut microbiota interaction is implicated in various human diseases, including cancer. Identifying the link between the gut microbiota and systemic inflammatory markers and their association with cancer will be important for our understanding of cancer etiology. The current study was performed on 8090 participants from the population-based Rotterdam study. We found a significant association (false discovery rate [FDR] ≤0.05) between lymphocytes and three gut microbial taxa, namely the family Streptococcaceae, genus Streptococcus, and order Lactobacillales. In addition, we identified 95 gut microbial taxa that were associated with inflammatory markers (p < 0.05). Analyzing the cancer data, we observed a significant association between higher systemic immune-inflammation index (SII) levels at baseline (hazard ratio (HR): 1.65 [95% confidence interval (CI); 1.10-2.46, p ≤ 0.05]) and a higher count of lymphocytes (HR: 1.38 [95% CI: 1.15-1.65, p ≤ 0.05]) and granulocytes (HR: 1.69 [95% CI: 1.40-2.03, p ≤ 0.05]) with increased risk of lung cancer after adjusting for age, sex, body mass index (BMI), and study cohort. This association was lost for SII and lymphocytes after additional adjustment for smoking (SII = HR:1.46 [95% CI: 0.96-2.22, p = 0.07] and lymphocytes = HR: 1.19 [95% CI: 0.97-1.46, p = 0.08]). In the stratified analysis, higher count of lymphocyte and granulocytes at baseline were associated with an increased risk of lung cancer in smokers after adjusting for age, sex, BMI, and study cohort (HR: 1.33 [95% CI: 1.09-1.62, p ≤0.05] and HR: 1.57 [95% CI: 1.28-1.92, p ≤0.05], respectively). Our study revealed a positive association between gut microbiota, higher SII levels, and higher lymphocyte and granulocyte counts, with an increased risk of developing lung cancer.

Circulating metabolites associated with kidney function decline and incident CKD: a multi-platform population-based study.

Background: Investigation of circulating metabolites associated with kidney function and chronic kidney disease (CKD) risk could enhance our understanding of underlying pathways and identify new biomarkers for kidney function. Methods: We selected participants from the population-based Rotterdam Study with data on circulating metabolites and estimated glomerular filtration rate based on serum creatinine (eGFRcreat) available at the same time point. Data on eGFR based on serum cystatin C (eGFRcys) and urine albumin-to-creatinine ratio (ACR) were also included. CKD was defined as eGFRcreat <60 ml/min per 1.73 m2. Data on circulating metabolites (ntotal = 1381) was obtained from the Nightingale and Metabolon platform. Linear regression, linear mixed, and Cox proportional-hazards regression analyses were conducted to study the associations between metabolites and kidney function. We performed bidirectional two-sample Mendelian randomization analyses to investigate causality of the identified associations. Results: We included 3337 and 1540 participants with data from Nightingale and Metabolon, respectively. A total of 1381 metabolites (243 from Nightingale and 1138 from Metabolon) were included in the analyses. A large number of metabolites were significantly associated with eGFRcreat, eGFRcys, ACR, and CKD, including 16 metabolites that were associated with all four outcomes. Among these, C-glycosyltryptophan (HR 1.50, 95%CI 1.31;1.71) and X-12026 (HR 1.46, 95%CI 1.26;1.68) were most strongly associated with CKD risk. We revealed sex differences in the associations of 11-ketoetiocholanolone glucuronide and 11-beta-glucuronide with the kidney function assessments. No causal associations between the identified metabolites and kidney function were observed. Conclusion: Our study indicates that several circulating metabolites are associated with kidney function which are likely to have potential as biomarkers, rather than as molecules involved in the pathophysiology of kidney function decline.

Plasma circulating microRNAs associated with blood-based immune markers: a population-based study.

MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression and different immune-related pathways. There is a great interest in identifying miRNAs involved in immune cell development and function to elucidate the biological mechanisms underlying the immune system, its regulation, and disease. In this study, we aimed to investigate the association of circulating miRNAs with blood cell compositions and blood-based immune markers. Circulating levels of 2083 miRNAs were measured by RNA-sequencing in plasma samples of 1999 participants from the population-based Rotterdam Study collected between 2002 and 2005. Full blood count measurements were performed for absolute granulocyte, platelet, lymphocyte, monocyte, white, and red blood cell counts. Multivariate analyses were performed to test the association of miRNAs with blood cell compositions and immune markers. We evaluated the overlap between predicted target genes of candidate miRNAs associated with immune markers and genes determining the blood immune response markers. First, principal component regression analysis showed that plasma levels of circulating miRNAs were significantly associated with red blood cell, granulocyte, and lymphocyte counts. Second, the cross-sectional analysis identified 210 miRNAs significantly associated (P < 2.82 × 10-5) with neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index. Further genetic look-ups showed that target genes of seven identified miRNAs (miR-1233-3p, miR-149-3p, miR-150-5p, miR-342-3p, miR-34b-3p, miR-4644, and miR-7106-5p) were also previously linked to NLR and PLR markers. Collectively, our study suggests several circulating miRNAs that regulate the innate and adaptive immune systems, providing insight into the pathogenesis of miRNAs in immune-related diseases and paving the way for future clinical applications.

Downregulation of ATF-4 Attenuates the Endoplasmic Reticulum Stress-Mediated Neuroinflammation and Cognitive Impairment in Experimentally Induced Alzheimer's Disease Model.

Protein aggregation is invariably associated with the inflammation as a factor in Alzheimer's disease (AD). We investigated the interaction between downstream factors of endoplasmic reticulum (ER) stress pathway and inflammation, with implications in cognitive impairment in AD. Amyloid-ß (Aß)(1-42) was administered by bilateral intracerebroventricular (icv) injection in the brain of adult male Wistar rats to experimentally develop AD. The cognitive impairment was assessed by measuring behavioral parameters such as Morris water maze and novel object recognition tests. Levels of pro-inflammatory cytokines such as interleukin (IL)-1ß and tumor necrosis factor (TNF)-α and anti-inflammatory cytokines IL-4 and IL-10 were measured by the enzyme-linked immunosorbent assay (ELISA) in different rat brain regions. Inflammatory marker proteins such as cyclo-oxygenase (COX)-2 and phosphorylation of nuclear factor kappa B (NF-КB) (p65) were measured by the western blotting. Gene expression of ER stress downstream factors such as ATF-4, CHOP, and GADD-34 was analyzed by qRT-PCR. Histological studies were performed to check Aß accumulation and neuronal degeneration. Integrated stress response inhibitor (ISRIB) was used to confirm the specific role of ER stress-mediated inflammation in cognitive impairment. Administration of Aß(1-42) resulted in alteration in levels of inflammatory cytokines, inflammatory proteins, and mRNA levels of ER stress downstream factors. ISRIB treatment resulted in attenuation of Aß(1-42)-induced ER stress, inflammation, neurodegeneration, and cognitive impairment in rats. These results indicate that ER stress-mediated inflammation potentiates the cognitive impairment in AD. An understanding of cascade of events, interaction of ER stress which was a hallmark of the present investigation together with inflammation and modulation of downstream signalling factors could serve as potent biomarkers to study AD progression. Schematic representation of interaction between ER stress and inflammation. Administration of Aß(1-42) resulted in ER stress which caused the activation of factors of PERK pathway, inflammation, neuronal degeneration, and cognitive impairment. ISRIB treatment caused downregulation of ATF-4 and attenuation of inflammation indicating a role of ER stress-mediated inflammation in the cognitive impairment in AD. The site of action of ISRIB is shown in blue color.

Managers' leadership competencies and sustainable development goals in turbulent markets: the enabling role of resource commitment.

Research on the sustainable development goals (SDGs) has brought attention to the significance of small and medium enterprises (SMEs) due to their substantial contributions to economic growth. However, SMEs still need to develop integrated frameworks to assess the implications of sustainable operations while managing scarce resources. In this study, we investigate how top managers of SMEs utilize leadership competencies to balance and allocate resources for SDGs in a turbulent environment. To test the model, the analysis was conducted on 254 SMEs operating in an emerging market. The findings indicate that resource commitment plays a partially mediating role between leadership competencies and SDGs, while environmental uncertainty does not moderate the relationship between leadership competencies and resource commitment. These insights suggest that SMEs with competent leaders commit resources to SDGs regardless of environmental conditions. This research recommends that SMEs focus on cultivating competent leaders to navigate resource constraints and contribute to the SDGs in a turbulent environment. Further implications are discussed.

Outcomes of Radioactive Iodine (131I) Therapy among Hyperthyroid patients.

Objective: The present study aimed to assess the thyroid outcomes six-months after radioactive Iodine-131 therapy (RIT) among hyperthyroid patients and identify the factors associated with them. Methods: This retrospective observational study was conducted at the department of Nuclear Medicine and Molecular Imaging, Northwest General Hospital & Research Centre during 2013 to 2019. For the study purpose, the thyroid outcomes of 153 hyperthyroid patients were studied retrospectively for six months after RIT. The data was obtained from the medical records. Patient baseline characteristics, clinical features, laboratory investigations, results of thyroid imaging, and therapeutic investigations were acquired and recorded in a structured questionnaire. Results: Out of the 153 screened records of hyperthyroid patients, 19.6% became euthyroid, 9.2% remained hyperthyroid, and 25.5% developed hypothyroidism after six months of RIT. The observed remission rate by the end of six months was 80.95%. Three months post-RIT, gender and RAI doses had a significant effect on thyroid function. The frequency of hypothyroidism was higher among those treated with an RAI dose of ≤ 20 mCi (83.0%) than those treated with a higher dose > 20 mCi (17%). Moreover, most patients receiving > 20 mCi radioiodine became euthyroid (64.5%). Similar outcomes were observed after six months of the therapy, except gender was replaced by etiologies of hyperthyroidism (p=0.009). Conclusion: Radioactive iodine (131-I) therapy is effective for the treatment of hyperthyroidism. However, the appropriate dose is still debatable, as there was a high incidence of hypothyroidism post-therapy.

A Type 1 Diabetes Polygenic Score Is Not Associated With Prevalent Type 2 Diabetes in Large Population Studies.

Context: Both type 1 diabetes (T1D) and type 2 diabetes (T2D) have significant genetic contributions to risk and understanding their overlap can offer clinical insight. Objective: We examined whether a T1D polygenic score (PS) was associated with a diagnosis of T2D in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods: We constructed a T1D PS using 79 known single nucleotide polymorphisms associated with T1D risk. We analyzed 13 792 T2D cases and 14 169 controls from CHARGE cohorts to determine the association between the T1D PS and T2D prevalence. We validated findings in an independent sample of 2256 T2D cases and 27 052 controls from the Mass General Brigham Biobank (MGB Biobank). As secondary analyses in 5228 T2D cases from CHARGE, we used multivariable regression models to assess the association of the T1D PS with clinical outcomes associated with T1D. Results: The T1D PS was not associated with T2D both in CHARGE (P = .15) and in the MGB Biobank (P = .87). The partitioned human leukocyte antigens only PS was associated with T2D in CHARGE (OR 1.02 per 1 SD increase in PS, 95% CI 1.01-1.03, P = .006) but not in the MGB Biobank. The T1D PS was weakly associated with insulin use (OR 1.007, 95% CI 1.001-1.012, P = .03) in CHARGE T2D cases but not with other outcomes. Conclusion: In large biobank samples, a common variant PS for T1D was not consistently associated with prevalent T2D. However, possible heterogeneity in T2D cannot be ruled out and future studies are needed do subphenotyping.

Healthcare and economic burden of heart failure with amyloidosis: An insight from National Readmission Database.

INTRODUCTION: We analyzed trends, causes and predictors of 30-days readmission in cardiac amyloidosis and inspected the impact of these readmissions on mortality, morbidity, and utilization of healthcare resources. METHODS: Heart Failure with cardiac amyloidosis patients were selected from National readmission Database (NRD) using ICD-10 CM codes. Patients younger than 18 years, elective readmissions, readmissions due to trauma, patients with missing data and December 2018 admissions were excluded. Primary outcome was all-cause 30-day readmissions rate, secondary outcomes were factors associated with 30-days readmissions and their effect on morbidity, mortality, and healthcare resource utilization. RESULTS: Out of 4123 total heart failure with cardiac amyloidosis index admissions in 2018, 3374 patients were included in final analysis. 19.6% were readmitted within 30 days. Readmitted patients were younger, sicker, admitted to small or large hospital. Hypertensive heart and Chronic Kidney Disease (CKD Stage I-IV) with Congestive Heart Failure (CHF), hypertensive heart and CKD (Stage V) or End Stage Renal Disease (ESRD) with CHF, hypertensive heart disease with CHF, acute kidney failure, and sepsis were the most common causes of readmissions. Young age, admission to small and large size hospitals were independent predictors of 30-day readmissions. Readmissions had higher mortality, costed 6.6 extra in hospital days to patients and $16380 per admission to healthcare system. CONCLUSIONS: Cardiac amyloidosis readmissions were associated with increased morbidity and mortality of patients and extra burden on the healthcare system. There is a need to identify patients at risk for readmissions to improve patient outcomes and decrease healthcare cost.

Radiofrequency Ablation of Cervical Thyroid Cancer Metastases-Experience of Endocrinology Practices in the United States.

Context: Radiofrequency ablation (RFA) is used in the United States to treat benign thyroid nodules; however, experience with treating cervical recurrence/persistence of papillary thyroid cancer (PTC) is limited. Objective: To evaluate the efficacy RFA for the treatment of cervical recurrence/persistence of PTC in the United States. Methods: This is a retrospective, multicenter study of 8 patients who underwent RFA of 11 cervical metastatic PTC lesions between July 2020 and December 2021. The volume reduction (VR) of the lesions, thyroglobulin (Tg) levels and complications following RFA were assessed. Energy applied per unit volume (E/V) during RFA was also determined. Results: Nine out of 11 (81.8%) lesions had initial volume under 0.5 mL and showed a complete (n = 8) or near-complete (n = 1) response. The 2 lesions with initial volume over 1.1 mL had a partial response, 1 of which had regrowth. There was a median VR of 100% (range 56.3-100%) after a median follow-up period of 453 days (range 162-570 days), with corresponding decline in Tg levels from a median of 0.7 ng/mL (range 0-15.2 ng/mL) to a median of 0.3 ng/mL (range 0-1.3 ng/mL). All patients with an E/V of at least 4483 J/mL or higher had a complete or near-complete response. There were no complications. Conclusion: RFA performed in an endocrinology practice is an efficacious treatment option for selected patients with cervical metastases of PTC, particularly those who cannot or do not want to undergo further surgery.

Prevalence and antimicrobial susceptibility of Acinetobacter spp. in a tertiary care hospital in Peshawar: a cross-sectional study.

Acinetobacter spp. have been a primary cause of nosocomial infections worldwide, causing significant morbidity and mortality, especially in Pakistan. The purpose of this study was to investigate the trend of antimicrobial resistance over a 5-year period in a tertiary care hospital in Pakistan. Methods: A retrospective cross-sectional study regarding the occurrence and antimicrobial resistance of Acinetobacter spp. recovered from clinical specimens that were referred to the Pathology Laboratory of Northwest General Hospital, Peshawar. The data from 2014 to 2019 was recorded and analyzed by the laboratory. Sociodemographic characteristics and laboratory record data was analyzed using SPSS, version 25. A chi-square test was applied to see the significance. Results: Of 59 483 clinical samples, Acinetobacter baumannii strains were detected in 114 of them. The majority of the clinical samples were from blood (89.5%) followed by sputum (7.9%), wound swab (1.8%), and bone marrow (0.9%). A. baumannii has been found in 52 men (67.53%) and 28 women (75.67%), with an overall risk of 0.669 times. In 76 men (98.70%), sensitivity for ertapenem (99.1), colistin (96.49), and tigecycline (78.9%) were also observed which indicated the potential viability of these drugs to treat multidrug-resistant (MDR) Acinetobacter infections. The male-to-female risk ratio was 0.98 for colistin and 0.71 for amikacin. Conclusion: Increased frequency of MDR supports the need for continuous surveillance to determine the prevalence and evolution of MDR Acinetobacter spp. in Pakistan. Colistin, tigecyclines, and ertapenem remain the possible line of drugs to treat MDR Acinetobacter.

Unraveling Neuro-Proteogenomic Landscape and Therapeutic Implications for Human Behaviors and Psychiatric Disorders.

Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioral traits and the disease etiology of neuropsychiatric disorders. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits such as sleeping, smoking, feelings, alcohol intake, mental health, and psychiatric disorders. Integrating with established drug information, we validated 13 out of 13 matched combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets. This consortium effort provides a large-scale proteogenomic resource for biomedical research on human behaviors and other neuro-related phenotypes.

Genetic mechanisms of 184 neuro-related proteins in human plasma.

Understanding the genetic basis of neuro-related proteins is essential for dissecting the disease etiology of neuropsychiatric disorders and other complex traits and diseases. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-reiated proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-reiated traits as well as complex diseases such as hypertension, high cholesterol, immune-related disorders, and psychiatric disorders. Integrating with established drug information, we validated 13 combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets for diseases and comorbidities. This consortium effort provides a large-scale proteogenomic resource for biomedical research.

Prevalence Of Human Adenovirus In Paediatric Patients Presenting With Acute Respiratory Symptoms At Different Hospitals Of Pakistan.

BACKGROUND: Human Adenovirus (HAdV) is one of the most common causes of infection in children. HAdV commonly affects respiratory system, however can also involve other parts of the body like nervous system, eyes and urinary tract. The virus usually causes a mild infection of the lower and upper respiratory tract. Objective of the study was to find the prevalence of HAdV in paediatric patients presenting with Influenza like symptoms and severe acute respiratory illness across Pakistan. METHODS: This cross-sectional study was conducted at the National Institute of Health, Islamabad. Respiratory swabs were collected from 389 children with age less than five years from 14 hospitals in different regions of Pakistan from October 1, 2017 to September 30, 2018. Patients' demographics, signs and symptoms were recorded through a predesigned proforma while Real-time polymerase chain reaction (RT-PCR) was performed for respiratory samples. RESULTS: Out of all 389 samples, HAdV was found in 25 (6.4%) cases. The proportion of HAdV obtained was greater in females 18 (4.6%) than male 7 (1.8%). The influenza-like illness in children attending outpatient department had a higher prevalence of HAdV 13 (3.3%) compared to admitted children 12 (3.1%). Similarly, patients from one to 6 months of age had higher positive outcome than older children. Majority of positive patients were from Islamabad (2.0%) followed by Gilgit (1.8%), Azad Jammu Kashmir (1.0%), Multan (0.5%), and Karachi (0.5%). The most frequent signs and symptoms were cough, fever, sore throat, nasal congestion and shortness of breath. CONCLUSIONS: The present study concludes that HAdV infection is common in Pakistan especially in female patients aged 1-6 months. It's crucial to improve the diagnosis of HAdV infections in our country to prevent complications associated with the virus. Furthermore, genetic analysis may help find different genotypes of HAdV circulating in Pakistan.

Protective effect of rosmarinic acid on the transmembrane transporter Ctr1 expression in cisplatin-treated mice.

AIMS: Cisplatin (cis-diamminedichloroplatinum(II), CP) is a platinum-based anticancer drug widely used in the treatment of solid malignancies. However, its side effects, particularly nephrotoxicity, are limiting factors in its clinic use. Rosmarinic acid (RA), a natural antioxidant compound, is reported to attenuate oxidative stress and associated pathophysiological outcomes. Our study aimed to explore the protective effect of RA against CP-induced acute kidney injury (AKI). MATERIALS AND METHODS: We investigated the effect of RA at the dose of 100 mg/kg on AKI induced by CP (20 mg/kg) in mice. Various parameters of nephrotoxicity such as levels of serum electrolytes, albumin, and globulin were measured using standardized methods. Besides, a specific biomarker of damage to proximal tubular cells, kidney injury molecule-1 (Kim-1), was measured in the serum by ELISA. mRNA expression of Kim-1 and a transmembrane transporter, copper transporter 1 (Ctr1), was analyzed by quantitative reverse transcriptase-polymerase chain reaction. CTR1 expression was also analyzed by western blot technique. RESULTS: RA treatment restored the downregulated CTR1 , a renal transmembrane transporter in CP-treated mice. It was accompanied by a reduction in the level of serum albumin and globulin. Serum electrolytes such as Na+, K+, and Ca2+ in CP-treated mice were found to be restored with RA treatment. Moreover, RA also significantly downregulated the increased expression of nephrotoxicity biomarker KIM-1. CONCLUSIONS: Overall, RA proved to be an effective nephroprotective compound which afforded protection at cellular and subcellular levels with an appreciable modulatory effect on a transmembrane transporter.

Microbial Profile and Antimicrobial Susceptibility Pattern in Diabetic Foot Ulcer Patients Attending a Tertiary Care Hospital.

Background This study aimed to assess the bacterial profile of diabetes patients with an infected foot and their antimicrobial susceptibility pattern in a tertiary care hospital. Methodology We conducted a six-month prospective study at a hospital in Peshawar, Pakistan. Demographics and clinical characteristics such as age, sex, type and duration of diabetes, glycemic control, presence of retinopathy, nephropathy, neuropathy, peripheral vascular disease, ulcer size, outcomes, and the number of admitted days at the facility were collected. Pus or discharges from the ulcer base and debrided necrotic tissue were obtained. Gram staining was performed on the samples which were isolated on chocolate agar and MacConkey agar. Incubation was done for 24 hours at a temperature of 37°C, and isolates were identified using standard bacteriological methods. The Kirby-Bauer testing method was used to assess antibiotic susceptibility. Results A total of 200 patients received a diagnosis of diabetic foot ulcer at the hospital during the study period. The age of the patients ranged from 24 to 92 years, with a mean age of 58.12 years (standard deviation (SD) = 12.494). The mean HbA1c level was 9.33% (SD = 2.050). The mean duration of diabetes mellitus was 12.3 years (SD = 6.181). In total, 96 (66.2%) isolates were gram-negative bacteria, while 49 (33.8%) were gram-positive bacteria. Among the gram-negative bacteria, Pseudomonas spp. was the most reported (15.9%), whereas methicillin-resistant Staphylococcus aureus was the most reported gram-positive bacteria (20.7%). Amikacin was found to be the most effective (45%) in treating diabetic foot ulcers, followed by tineam and meropenem being equally effective at a susceptibility of 44%. The highest resistance of the microbes was to the drug trimethoprim (44.5%). Conclusions The pathogens causing diabetic foot ulcers show sensitivity to many of the routinely used medications. However, resistance is being developed to some of the antibiotics such as trimethoprim. Therefore, the culture of the specimen to identify the causative agent and adequate knowledge of the susceptibility pattern are critical for the appropriate management of diabetic foot ulcers.

Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease.

Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-ß precursor protein processing, amyloid-ß aggregation, lipid metabolism and microglial function in AD.

Inpatient assessment of the neurological outcome of acute stroke patients based on the National Institute of Health Stroke Scale (NIHSS).

Objective: Identify the association between stroke severity and the neurological outcome of an acute stroke using the National Institutes of Health stroke scale (NIHSS). Study design: A descriptive cross-sectional study.Place and duration of study: Northwest hospital Hayatabad Peshawar. Methodology: A cross-sectional descriptive study was done in the general plus stroke unit of the northwest hospital in Peshawar, KPK during Jan 2022 to July 2022.400 admitted patients diagnosed with acute stroke in the past three months were included for NIHSS assessment and were classified as mild, moderate, or severe stroke. After entering all of the data from the collection into SPSS version 16, the information was transferred to an Excel spreadsheet. To further assess the results, the researcher and statistician evaluated all of the cases, radiological findings, and laboratory test data. Results: In this cross-sectional descriptive study, 400 individuals ranging from 30 to 90 years of age were divided into two groups: males and females. The survey was conducted by 49% of men and 51% of women. The stroke severity was assessed to be mild in 22% of cases, moderate in 49%, and severe in 29% of patients. As evaluated by the NIHSS, Patients with acute ischemic stroke were divided into four groups depending on their neurological outcomes: those who improved were 160 (40%), those who remained stable were 124 (31%), and those who deteriorated were 52 (13%), and those who died were 64 (16%). Patients with greater triglyceride levels were 88, while those with lower levels were 312. Acute stroke was also detected in 34% of patients with a covid history, 28% of patients who were covid positive, and 38% of patients who were covid free in this investigation. Conclusion: According to our findings, the NIHSS is a reliable scale for evaluating patients' neurological outcomes and determining the association between acute stroke severity and cognitive functioning (NIHSS).