Comprehensive computational investigation for ligand recognition and binding dynamics of SdiA: a degenerate LuxR -type receptor in Klebsiella pneumoniae.

SdiA is a LuxR-type receptor that controls the virulence of Klebsiella pneumoniae, a Gram-negative bacterium that causes various infections in humans. SdiA senses exogenous acyl-homoserine lactones (AHLs) and autoinducer-2 (AI-2), two types of quorum sensing signals produced by other bacterial species. However, the molecular details of how SdiA recognizes and binds to different ligands and how this affects its function and regulation in K. pneumoniae still need to be better understood. This study uses computational methods to explore the protein-ligand binding dynamics of SdiA with 11 AHLs and 2 AI-2 ligands. The 3D structure of SdiA was predicted through homology modeling, followed by molecular docking with AHLs and AI-2 ligands. Binding affinities were quantified using MM-GBSA, and complex stability was assessed via Molecular Dynamics (MD) simulations. Results demonstrated that SdiA in Klebsiella pneumoniae exhibits a degenerate binding nature, capable of interacting with multiple AHLs and AI-2. Specific ligands, namely C10-HSL, C8-HSL, 3-oxo-C8-HSL, and 3-oxo-C10-HSL, were found to have high binding affinities and formed critical hydrogen bonds with key amino acid residues of SdiA. This finding aligns with the observed preference of SdiA for AHLs having 8 to 10 carbon-length acyl chains and lacking hydroxyl groups. In contrast, THMF and HMF demonstrated poor binding properties. Furthermore, AI-2 exhibited a low affinity, corroborating the inference that SdiA is not the primary receptor for AI-2 in K. pneumoniae. These findings provide insights into the protein-ligand binding dynamics of SdiA and its role in quorum sensing and virulence of K. pneumoniae.

Understanding mastitis: Microbiome, control strategies, and prevalence - A comprehensive review.

Mastitis significantly affects the udder tissue in dairy cattle, leading to inflammation, discomfort, and a decline in both milk yield and quality. The condition can be attributed to an array of microbial agents that access the mammary gland through multiple pathways. The ramifications of this ailment are not merely confined to animal welfare but extend to the financial viability of the livestock industry. This review offers a historical lens on mastitis, tracing its documentation back to 1851, and examines its global distribution with a focus on regional differences in prevalence and antimicrobial resistance (AMR) patterns. Specific microbial genes and communities implicated in both mastitis and AMR are explored, including Staphylococcus aureus, Streptococcus agalactiae,Streptococcus dysagalactiae, Streptococcus uberis Escherichia coli, Klebsiella pneumoniae, Mycoplasma bovis, Corynebacterium bovis, among others. These microorganisms have evolved diverse strategies to elude host immune responses and neutralize commonly administered antibiotics, complicating management efforts. The review aims a comprehensive overview of the current knowledge and research gaps on mastitis and AMR, and to highlight the need for a One Health approach to address this global health issue. Such an approach entails multi-disciplinary cooperation to foster judicious antibiotic use, enhance preventive measures against mastitis, and bolster surveillance and monitoring of AMR in pathogens responsible for mastitis.

Geographic Variation in Oxaliplatin Chemotherapy and Survival in Patients With Colon Cancer.

Geographic disparity in colon cancer survival has received less attention, despite the fact that health care delivery varied across regions. To examine geographic variation in colon cancer survival and explore factors affecting this variation, including the use of oxaliplatin chemotherapy, we studied cases with resected stage-III colon cancer in 2004-2009, identified from the Surveillance, Epidemiology and End Results-Medicare linked database. Cox proportional hazard model was used to estimate the effect of oxaliplatin-containing chemotherapy on survival across regions. Propensity score adjustments were made to control for potential selection bias and confounding. Rural regions showed lowest 3-year survival, whereas big metro regions showed better 3-year survival rate than any other region (67.3% in rural regions vs. 69.5% in big metro regions). Hazard ratio for patients residing in metro region was comparable with those residing in big metro region (1.27, 95% confidence interval: 0.90-1.80). However, patients residing in urban area were exhibiting lower mortality than those in other regions, although not statistically significant. Patients who received oxaliplatin chemotherapy were 23% significantly less likely to die of cancer than those received 5-fluorouracil only chemotherapy (adjusted hazard ratio = 0.77, 95% confidence interval: 0.63-0.95). In conclusion, there were some differences in survival across geographic regions, which were not statistically significant after adjusting for sociodemographic, tumor, chemotherapy, and other treatment characteristics. Oxaliplatin chemotherapy was associated with improved survival outcomes compared with 5-fluorouracil only chemotherapy across regions. Further studies may evaluate other factors and newer chemotherapy regimens on mortality/survival of older patients.

Geographic variation in medication adherence in commercial and Medicare part D populations.

BACKGROUND: Previous literature has emphasized the importance of cost sharing, health literacy, socioeconomic status, cognitive function, disease burden, and polypharmacy as some of the determinants of medication adherence. Little research has been published examining disparities in adherence rates when comparing different regions of the United States. OBJECTIVE: To examine the impact of geography, socioeconomic status, and other demographic variables on medication adherence rates in a large national sample of Medicare Part D and commercially insured beneficiaries. METHODS: This study focused on users of oral antidiabetic, antihypertensive, and/or antilipidemic medications. Beneficiaries who had at least 2 antidiabetic, antihypertensive, or antilipidemic prescription fills in 2010, 2011, or 2012 and who were enrolled in a large commercial or Medicare Part D prescription drug plan for at least 80% of one of these years (9.6 months) were included in this study. Results were stratified by year and by benefit type. Logistic regression was used to test for the adherence differences among the 9 U.S. regions as defined by the U.S. Census Bureau. Additional variables included in the model to control for population differences were age, gender, socioeconomic status, and yearly out-of-pocket medication expenses. RESULTS: After meeting all inclusion and exclusion criteria, 379,533 beneficiaries were in the 2012 Medicare cohort, and 659,553 beneficiaries were in the 2012 commercial cohort. New England was statistically the most adherent geographic region in both cohorts (Medicare odds ratio [OR] = 1.512, CI = 1.399-1.635); commercial OR = 1.193, CI = 1.109-1.284). Younger age beneficiaries, lower income beneficiaries, and females were less adherent in both groups. CONCLUSIONS: In the commercial and Medicare populations, geography, socioeconomic status, age, and gender all impact the likelihood of a beneficiary being adherent to chronic medications for hypertension, diabetes, and hyperlipidemia. While this study does not elucidate the specific factors (i.e., health literacy, disease severity) driving geographic and other differences in medication adherence observed between groups, it does highlight the limitations of quality metrics and wellness initiatives that assume relative homogeneity in beneficiary characteristics across the United States.

Economic evaluation of pediatric cancer treatment: a systematic literature review.

OBJECTIVE: Although there is a growing national focus on health care cost containment and accountability in resource utilization, childhood cancer therapy costs continue to increase without proportionate survival improvements. Economic evaluations (EEs) such as cost and/or cost effectiveness analysis may identify areas to improve resource efficiency. This review aims to identify and characterize the EE studies performed in this field. METHODS: We performed a structured literature search of the Medline, PubMed, and the National Health Service EE databases from 2000 to 2011. Concepts for the search included "cost analyses," "child," and "cancer." Studies were limited to original research, comparison of 2 or more treatments using monetary units, English language, and originating from economically developed countries. Identified studies were assessed by the Drummond checklist and characterized by the therapy studied, data sources, and research perspectives. RESULTS: Forty studies met inclusion criteria. Eleven studied chemotherapy, surgery, or radiation. Twenty-nine studied supportive measures such as growth factor support or treatment of infection. The median Drummond score was 6 of 10 (range, 2-9). Only 15 (36%) included treatment outcomes when comparing costs. Methodological limitations were common. CONCLUSIONS: A wide variety of topics and methodological limitations made comparisons between studies difficult. Strategies for increasing the generalizability of future EE studies are presented. Substantial opportunity exists for EE research in childhood cancer.

Geographic variation and sociodemographic disparity in the use of oxaliplatin-containing chemotherapy in patients with stage III colon cancer.

UNLABELLED: This study examined the geographic variation and sociodemographic disparities in the use of oxaliplatin chemotherapy, which has not been widely studied in the past. Our results suggest that chemotherapy use varies across geographic regions. Patterns of use that relate specifically to oxaliplatin-containing chemotherapy can inform providers and researchers how newer regimens are being used as standard chemotherapy in a real-world setting. BACKGROUND: According to the National Cancer Comprehensive Network (NCCN), oxaliplatin with 5-fluorouracil and leucovorin (5-FU/LV) is the recommended adjuvant chemotherapy for patients with resected stage III colon cancer. Age and race are considered strong predictors of chemotherapy receipt, whereas geographic disparity has received minimal attention. The purpose of this study was to examine geographic variation and sociodemographic disparity in the use of chemotherapy in patients with stage III colon cancer, focusing specifically on oxaliplatin. METHODS: A retrospective cohort of 4106 Medicare patients was identified from the Surveillance, Epidemiology and End Results (SEER)/Medicare linked database. Descriptive statistics show how oxaliplatin-containing chemotherapy was used in various geographic regions among different age and racial groups. Multiple logistic regression analysis was performed to examine the relationship between receipt of oxaliplatin-containing chemotherapy and geographic region while adjusting for other sociodemographic and tumor characteristics. RESULTS: Only 49% of the patients with stage III disease received adjuvant chemotherapy within 3 to 6 months of colon cancer-specific surgery. Patients aged 66 to 70 years were 78% more likely to receive chemotherapy than were those aged 80 years and older (P<.001). Patients in less urban regions were approximately 42% less likely to receive oxaliplatin chemotherapy than those residing in a big metro region (odds ratio [OR], 0.58; P=.008). CONCLUSION: Chemotherapy use varies across geographic regions, especially for new chemotherapy drugs like oxaliplatin. Further research is needed to identify the causes of this geographic disparity and ways to provide high-quality cancer care to all patients according to their preferences and needs.

Economic impact of stereotactic radiosurgery for malignant intracranial brain tumors.

Brain metastases occur frequently in cancer patients and can lead to neurological complications that result in decreased quantity and quality of life. Treatment alternatives include whole-brain radiation therapy, neurosurgery and the newest modality, stereotactic radiosurgery (SRS). This article reviews economic evaluations of SRS in the metastatic setting compared with other treatment options. Studies were included if they were published in peer-reviewed journals, primarily focused on patients with malignant brain metastasis and included a cost analysis between interventions. Uncertainty surrounding the cost-effectiveness of SRS is due to a lack of efficacy information between treatment alternatives, methodological limitations and design differences between the available studies. When cost-effectiveness ratios are available, SRS appears to be a reasonable option in resource-limited settings, with incremental cost-effectiveness ratios just below the US$50,000 range. However, better-designed economic analysis in the setting of randomized clinical trials or observational studies needs to be conducted to fully understand the economic value of SRS.

Do A-waves help predict intravenous immunoglobulin response in multifocal motor neuropathy without block?

INTRODUCTION: Are there electrophysiological findings that predict response to intravenous immunoglobulin (IVIg) in patients with lower motor neuron (LMN) syndromes without multifocal conduction block (MCB)? METHODS: We enrolled 9 patients with LMN syndromes without MCB to receive 18 weeks of IVIg therapy. Response was measured at weeks 2 and 18 using the Appel Amyotrophic Lateral Sclerosis (AALS) score (includes grip and pincer strength measures), ALS Functional Rating Scale (ALSFRS), and electrophysiological measures, including motor unit estimates (MUNEs). RESULTS: No change occurred in AALS or ALSFRS scores posttreatment. Grip/pincer strength increased in 7 patients (P = 0.028) after initial treatment (responders); 2 showed no improvement (non-responders). No electrophysiological measure changed after treatment in either group but MUNEs trended higher (P = 0.055). "Abnormal A-waves" (complex, repetitive biphasic, or present in multiple nerves) occurred in pretreatment studies more often in responders (P = 0.028). DISCUSSION: "Abnormal A-waves" may signal IVIg-responsive LMN syndromes even if conduction block is absent.

ALSFRS and appel ALS scores: discordance with disease progression.

Progression of disease and effectiveness of therapy in patients with amyotrophic lateral sclerosis (ALS) are determined by both questionnaire- and examination-based measures. To determine whether both types of measurement tools are equally predictive at all stages of disease, we compared questionnaire-based ALS Functional Rating Scale (ALSFRS) scores to the examination-based Appel ALS (AALS) scores at different stages of disease. Same-day scores were obtained during 174 visits in 62 patients with definite or probable ALS. Using normalized scores, correlation between the scales and predictability were best in mildly affected patients. Predictions of ALSFRS based on AALS scores were less than half as precise in the later stages of disease. Both scales showed significant change with disease progression, but ALSFRS consistently underestimated disease severity defined by AALS (P < 0.001). Questionnaire-based measurements should be compared against objective scales at all stages of disease severity before they are accepted as primary endpoint measures.