The Influence of Vitamin D Levels on Dental Caries: A Retrospective Study of the United States Population.

(1) Background: This study examines vitamin D's impact on dental caries to inform prevention strategies, given its critical role in bone and calcium regulation, vital for dental health. (2) Methods: Data from 18,683 participants of the National Health and Nutrition Examination Survey (NHANES) 2011-2016 were analyzed. NHANES collects U.S. population data through interviews, physical exams, and tests, including vitamin D levels and dental health assessed using both the decayed, missing, and filled teeth (DMFT) index and the presence of untreated dental caries. Vitamin D levels were measured according to serum 25(OH)D concentrations, and the analyses adjusted for confounders such as body mass index (BMI) and socioeconomic status (SES) using Chi-square, Mann-Whitney U, Kruskal-Wallis tests, as well as logistic and Poisson regression. (3) Results: This study found a mean DMFT score of 7.36 and a 33.2% prevalence of untreated dental caries. A higher caries prevalence was correlated with a lower SES (p < 0.001), the male gender (p < 0.001), and a higher BMI (p < 0.001). Severe vitamin D deficiency (<25 nmol/L) doubled the risk of dental caries, with odds ratios of 2.261 and 1.953 after adjusting for demographic factors and BMI. (4) Conclusions: Our study confirms a significant relationship between low vitamin D levels and an increased risk of dental caries nationwide, even after accounting for sociodemographic factors, emphasizing the importance of maintaining sufficient vitamin D levels for preventing caries.

DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF-κB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription-factor activity.

DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors of a wide-range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed DrugMap , an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NFκB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NFκB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription factor activity.

Evaluating the Analgesic Efficacy of Superficial Cervical Plexus Block for Head and Neck Surgeries: A Comparative Randomized Control Study.

INTRODUCTION: In the present study, the advantages of superficial cervical plexus block (SCPB) were evaluated using a landmark-guided method. Our primary aim was to evaluate the analgesic efficacy of SCPB in various head and neck surgeries by observing intra- and postoperative requirements of the total dose of the systemic analgesic, visual analog scale (VAS) score, and the total duration of analgesia; vital parameters and associated perioperative complications were also observed. MATERIALS AND METHODS: Sample size was calculated using reference by taking the parameter pain score at 12 hours using MedCalc software v. 19.5.1 (MedCalc Software, Ostend, Belgium) with a mean difference of score 3±3.5 between two groups, 80% power, and 95% confidence interval (CI); the sample size for each group was 21. There were 30 patients in each group of ASA I, II, and III who were posted for mandibular, tympanomastoid and clavicular surgeries. Group A received general anaesthesia with systemic analgesia and Group B received general anaesthesia followed by SCPB with an injection of bupivacaine 0.25% 10ml on each side according to the site of surgery. VAS score, intra and postoperative analgesic requirement in 24 hours, time of first demand bolus, and peri-operative complications were noted. RESULTS: Intraoperative fentanyl requirement for group A was 97.5±13.75 µg as compared to group B (70.16±13.09 µg), postoperative injection paracetamol requirement was also significantly higher in group A (2566.66±504 mg) as compared to group B (833.33±874.28 mg). The total duration of analgesia was significantly higher in Group B (1191.33±375.36 min) as compared to Group A (122.0±50.88 min) with a p-value <0.0001. No significant complications were noted in any patient. CONCLUSION: SCPB provides better perioperative analgesia by decreasing intraoperative as well as postoperative systemic analgesic requirements and their associated side effects, with no significant perioperative complications in various head and neck region surgeries.

Assessing Barriers and Facilitators to Lung Cancer Screening: Initial Findings from a Patient Navigation Intervention.

Low-dose computed tomography-based lung cancer screening represents a complex clinical undertaking that could require multiple referrals, appointments, and time-intensive procedures. These steps may pose difficulties and raise concerns among patients, particularly minority, under-, and uninsured populations. The authors implemented patient navigation to identify and address these challenges. They conducted a pragmatic randomized controlled trial of telephone-based navigation for lung cancer screening in an integrated, urban safety-net health care system. Following standardized protocols, bilingual (Spanish and English) navigators educated, motivated, and empowered patients to traverse the health system. Navigators made systematic contact with patients, recording standardized call characteristics in a study-specific database. Call type, duration, and content were recorded. Univariable and multivariable multinomial logistic regression was performed to investigate associations between call characteristics and reported barriers. Among 225 patients (mean age 63 years, 46% female, 70% racial/ethnic minority) assigned navigation, a total of 559 barriers to screening were identified during 806 telephone calls. The most common barrier categories were personal (46%), provider (30%), and practical (17%). System (6%) and psychosocial (1%) barriers were described by English-speaking patients, but not by Spanish-speaking patients. Over the course of the lung cancer screening process, provider-related barriers decreased 80% (P = 0.008). The authors conclude that patients undergoing lung cancer screening frequently report personal and health care provider-related barriers to successful participation. Barrier types may differ among patient populations and over the course of the screening process. Further understanding of these concerns may increase screening uptake and adherence. Clinical Trial Registration number: (NCT02758054).

Computational Study of Base-Catalyzed Thiohemiacetal Decomposition in Pseudomonas mevalonii HMG-CoA Reductase.

Thiohemiacetals are key intermediates in the active sites of many enzymes catalyzing a variety of reactions. In the case of Pseudomonas mevalonii 3-hydroxy-3-methylglutaryl coenzyme A reductase (PmHMGR), this intermediate connects the two hydride transfer steps where a thiohemiacetal is the product of the first hydride transfer and its breakdown forms the substrate of the second one, serving as the intermediate during cofactor exchange. Despite the many examples of thiohemiacetals in a variety of enzymatic reactions, there are few studies that detail their reactivity. Here, we present computational studies on the decomposition of the thiohemiacetal intermediate in PmHMGR using both QM-cluster and QM/MM models. This reaction mechanism involves a proton transfer from the substrate hydroxyl to an anionic Glu83 followed by a C-S bond elongation stabilized by a cationic His381. The reaction provides insight into the varying roles of the residues in the active site that favor this multistep mechanism.

Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway.

Multiple anticancer drugs have been proposed to cause cell death, in part, by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs, exactly how the resultant ROS function and are sensed is poorly understood. It remains unclear which proteins the ROS modify and their roles in drug sensitivity/resistance. To answer these questions, we examined 11 anticancer drugs with an integrated proteogenomic approach identifying not only many unique targets but also shared ones-including ribosomal components, suggesting common mechanisms by which drugs regulate translation. We focus on CHK1 that we find is a nuclear H2O2 sensor that launches a cellular program to dampen ROS. CHK1 phosphorylates the mitochondrial DNA-binding protein SSBP1 to prevent its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS-sensing pathway-required to resolve nuclear H2O2 accumulation and mediate resistance to platinum-based agents in ovarian cancers.

Copper and iron metal resistant rhizospheric bacteria boost the plant growth and bacoside A content in Bacopa monnieri under stress conditions.

Bacteria that enhance plant growth and development and are found in the vicinity of roots are referred to as plant growth-promoting rhizobacteria. Some beneficial bacteria help plant tolerance to many hazardous chemical elements. In this context, Cupriavidus basilensis , Novosphingobium humi , Bacillus zanthoxyli , Bacillus sp., Paenibacillus alvei , Ancylobacter aquaticus and Ralstonia syzygii metal-tolerant rhizospheric bacteria were isolated from rhizospheric soil associated with Bacopa monnieri . The beneficial effects of rhizospheric bacteria on B. monnieri plant physiology and biochemical responses were investigated under pot conditions at two levels (100µM and 500µM) of CuSO4 or FeCl3 . N. humi , A. aquaticus and R. syzygii bacterial strains were associated with significantly increased height and biomass under normal and stress conditions. An assay for indole acetic acid in isolated rhizospheric bacteria found differential secretion except Bacillus zanthoxyli . Bacoside A is a major phytocompound in B. monnieri with medicinal value; maximum induction was observed in the R. syzygii treatment. High concentration of copper and iron salts negatively influenced height, biomass and photosynthetic pigments; however N. humi , A. aquaticus , Bacilllus sp. and R. syzygii beneficial bacterial helped plants under stress conditions. Moreover, a significant enhancement in chlorophyll a and b was noticed in C. basilensis , B. zanthoxyli , Bacilllus sp., P. alvei and R. syzygii treatments, without much influence on carotenoid levels. Therefore, the present study emphasises the importance of isolating plant growth-promoting rhizobacteria for use in bacopa plants exposed to metals such as copper and iron in soil.

Identification of chemotherapy targets reveals a nucleus-to-mitochondria ROS sensing pathway.

Multiple chemotherapies are proposed to cause cell death in part by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs exactly how the resultant ROS function and are sensed is poorly understood. In particular, it's unclear which proteins the ROS modify and their roles in chemotherapy sensitivity/resistance. To answer these questions, we examined 11 chemotherapies with an integrated proteogenomic approach identifying many unique targets for these drugs but also shared ones including ribosomal components, suggesting one mechanism by which chemotherapies regulate translation. We focus on CHK1 which we find is a nuclear H 2 O 2 sensor that promotes an anti-ROS cellular program. CHK1 acts by phosphorylating the mitochondrial-DNA binding protein SSBP1, preventing its mitochondrial localization, which in turn decreases nuclear H 2 O 2 . Our results reveal a druggable nucleus-to-mitochondria ROS sensing pathway required to resolve nuclear H 2 O 2 accumulation, which mediates resistance to platinum-based chemotherapies in ovarian cancers.

Comparison of 4D computed tomography and F-18 fluorocholine PET for localisation of parathyroid lesions in primary hyperparathyroidism: A systematic review and meta-analysis.

Minimally invasive parathyroidectomy (MIP) is the standard of care for primary hyperparathyroidism (PHPT). Four dimensional computed tomography(4DCT) and F-18 Fluorocholine positron emission tomography/computed tomography (FCH PET/CT) localize adenomas accurately to perform MIP. We aimed to conduct a systematic review and metanalysis to evaluate the diagnostic performance of 4DCT and FCH PET/CT scan for quadrant wise localisation in PHPT patients and to do head-to-head comparison between these two modalities. DESIGN, PATIENTS AND MEASUREMENT : After searching through PubMed and EMBASE databases, 46 studies (using histology as a gold standard) of 4DCT and FCH PET/CT were included. RESULTS: Total number of patients included were 1651 and 952 for 4DCT scan (studies n = 26) and FCH PET/CT scan (studies n = 24) respectively. In per patient analysis, FCH PET/CT and 4DCT had pooled sensitivities of 92% (88-94) and 85% (73-92) respectively and in per lesion analysis, 90% (86-93) and 79% (71-84), respectively. In the subgroup with negative conventional imaging/persistent PHPT, FCH PET/CT had comparable sensitivity to 4DCT (84% [74-90] vs. 72% [46-88]). As per patient wise analysis, FCH PET/CT had better detection rates than 4DCT ([92.4 vs. 76.85], odds ratio -3.89 [1.6-9.36] p = .0024) in the subpopulation where both FCH PET/CT and 4DCT were reported. CONCLUSION: Both 4DCT and FCH PET/CT scan performed well in newly diagnosed patients, patients with persistent disease and in those with inconclusive conventional imaging results. FCH PET/CT scan had a higher pooled sensitivity than 4DCT in detecting patients with PHPT in head to head comparison.

Automated fitting of transition state force fields for biomolecular simulations.

The generation of surrogate potential energy functions (PEF) that are orders of magnitude faster to compute but as accurate as the underlying training data from high-level electronic structure methods is one of the most promising applications of fitting procedures in chemistry. In previous work, we have shown that transition state force fields (TSFFs), fitted to the functional form of MM3* force fields using the quantum guided molecular mechanics (Q2MM) method, provide an accurate description of transition states that can be used for stereoselectivity predictions of small molecule reactions. Here, we demonstrate the applicability of the method for fit TSFFs to the well-established Amber force field, which could be used for molecular dynamics studies of enzyme reaction. As a case study, the fitting of a TSFF to the second hydride transfer in Pseudomonas mevalonii 3-hydroxy-3-methylglutaryl coenzyme A reductase (PmHMGR) is used. The differences and similarities to fitting of small molecule TSFFs are discussed.

Multicenter Randomized Clinical Trial of a Mailed Outreach Strategy for Hepatocellular Carcinoma Surveillance.

BACKGROUND: The effectiveness of hepatocellular carcinoma (HCC) surveillance is mitigated by underuse in clinical practice, highlighting a need for interventions. We evaluated the effectiveness of mailed HCC surveillance outreach to promote HCC surveillance in patients with cirrhosis. METHODS: We conducted a multicenter pragmatic randomized clinical trial comparing mailed outreach for surveillance ultrasound (n = 1436) and usual care with visit-based surveillance (n = 1436) among patients with cirrhosis at 3 health systems (tertiary care referral center, safety net health system, and Veterans Affairs medical center) from April 2018 to December 2019. The primary outcome of this interim analysis was guideline concordant semiannual HCC surveillance over a 12-month period and a secondary outcome was proportion time covered by surveillance. All patients were included in intention-to-screen analyses. RESULTS: Compared with usual care, the outreach arm had significantly higher semiannual surveillance (35.1% vs 21.9%) and lower no-surveillance (29.8% vs 43.5%) (P < .001), resulting in significant increases in the proportion of time covered by surveillance (41.3% vs 31.0%; P < .001). The intervention increased HCC surveillance across most predefined subgroups; however, there were site-level differences in the intervention effect, with significant increases in semiannual surveillance at the Veterans Affairs and safety net health systems but not at the tertiary care referral center. CONCLUSIONS: Mailed outreach significantly increased semiannual HCC surveillance vs usual care in patients with cirrhosis, with a consistent intervention effect across most examined subgroups. Continued follow-up is ongoing to determine if these increases in surveillance translate into improved downstream outcomes includi.ng early HCC detection and curative treatment receipt. (ClinicalTrials.gov, Numbers: NCT02582918 and NCT03756051).

3D viscoelastic drag forces contribute to cell shape changes during organogenesis in the zebrafish embryo.

The left-right organizer in zebrafish embryos, Kupffer's Vesicle (KV), is a simple organ that undergoes programmed asymmetric cell shape changes that are necessary to establish the left-right axis of the embryo. We use simulations and experiments to investigate whether 3D mechanical drag forces generated by the posteriorly-directed motion of the KV through the tailbud tissue are sufficient to drive such shape changes. We develop a fully 3D vertex-like (Voronoi) model for the tissue architecture, and demonstrate that the tissue can generate drag forces and drive cell shape changes. Furthermore, we find that tailbud tissue presents a shear-thinning, viscoelastic behavior consistent with those observed in published experiments. We then perform live imaging experiments and particle image velocimetry analysis to quantify the precise tissue velocity gradients around KV as a function of developmental time. We observe robust velocity gradients around the KV, indicating that mechanical drag forces must be exerted on the KV by the tailbud tissue. We demonstrate that experimentally observed velocity fields are consistent with the viscoelastic response seen in simulations. This work also suggests that 3D viscoelastic drag forces could be a generic mechanism for cell shape change in other biological processes.

Modifying gap junction communication in cancer therapy.

AIM: Drug delivery is crucial for therapeutic efficacy and gap junction communication channels (GJIC) facilitate movement within the tumour. Pro-drug activation, a modality of cancer therapy leads to Ganciclovir triphosphate (GCV-TP) incorporation into newly synthesized DNA resulting in cell death. The objective was to enhance, with Histone deacetylase inhibitors (HDACi) and All Trans Retinoic Acid (ATRA), GJIC, crucial for drug delivery, and with combination, abrogate the observed detrimental effect of Dexamethasone (DXM). METHODS: Cell lines (NT8E, and HeLa) were pre-treated with Valproic Acid (VPA) (1 mM), 4 Phenyl Butyrate (4PB) (2 mM), ATRA (10 µM) and Dexamethasone (1 µM). Protein quantitated with the Bicinchoninic (BCA) assay for cell lysates, membrane and soluble fractions was assessed with Western blotting for Connexins (43, 26 and 32) and E-Cadherin. A qRT-PCR was done for CX 43-GJA1, CX 26-GJB2, CX 32-GJB1 and E-Cadherin, and normalized with Glyceraldehyde Phosphate dehydrogenase (GAPDH). Further, localization of Connexins (CX) and E-Cadherin, GJIC competence, pre-clinical in-vitro studies and the mechanism of cell death were evaluated. RESULTS: There was no toxicity or change in growth patterns observed with the drugs. In both the cell lines CX 43 localized to the membrane whereas CX 32 and CX 26 were present but not membrane bound. E-Cadherin was present on the membrane in NT8E and completely absent in HeLa cells. Effects of HDACi, DXM and ATRA were seen on the expression of Connexins and E-Cadherin in both the cell lines. NT8E and HeLa cell lines showed enhanced GJIC with 4PB [30 %], VPA [36 %] and ATRA [54 %] with a 60 % increase in cytotoxicity and an abrogation of Dexamethasone inhibition on combination with VPA or ATRA. CONCLUSION: An enhancement of GJIC function by HDACi and ATRA increased cytotoxicity and could be effective in the presence of Dexamethasone, when combined with ATRA or VPA.

30-day readmission prevention program in heart failure patients (RAP-HF) in a community hospital: creating a task force to improve performance in achieving CMS target goals.

In 2012, Centers for Medicare and Medicaid Services (CMS) announced it would penalize any hospitals that had 30-day readmission rates for heart failure (HF) patients above 20%. Mather Hospital Northwell Health, a community teaching hospital, organized a proactive task force to meet these goals. We describe our hospital-wide Readmission Prevention in Heart Failure (RAP-HF) project. We focused on the following interventions: early identification of patients at risk for readmission, discipline-specific mitigation planning by the interdisciplinary rounding team, enhanced medication education for heart failure patients, education of family/caregivers on medication and heart failure symptoms, facilitation in scheduling of post-discharge follow up visits and hard-wired communication between hospital and post-discharge care providers. We saw a 25.53% decrease in 30-day readmission rates.

An Ancient Harappan Genome Lacks Ancestry from Steppe Pastoralists or Iranian Farmers.

We report an ancient genome from the Indus Valley Civilization (IVC). The individual we sequenced fits as a mixture of people related to ancient Iranians (the largest component) and Southeast Asian hunter-gatherers, a unique profile that matches ancient DNA from 11 genetic outliers from sites in Iran and Turkmenistan in cultural communication with the IVC. These individuals had little if any Steppe pastoralist-derived ancestry, showing that it was not ubiquitous in northwest South Asia during the IVC as it is today. The Iranian-related ancestry in the IVC derives from a lineage leading to early Iranian farmers, herders, and hunter-gatherers before their ancestors separated, contradicting the hypothesis that the shared ancestry between early Iranians and South Asians reflects a large-scale spread of western Iranian farmers east. Instead, sampled ancient genomes from the Iranian plateau and IVC descend from different groups of hunter-gatherers who began farming without being connected by substantial movement of people.

Popliteal Versus Local Field Block for Pain-Related Postoperative Unplanned Emergency Room Visits After Foot and Ankle Surgery.

Ultrasound-guided popliteal blocks for postoperative pain management have grown in popularity within foot and ankle surgery. The purpose of this study was to evaluate the efficacy of popliteal block in preventing postoperative emergency department visits after foot and ankle surgery. We compared rates of presentation to the emergency department for pain following foot and ankle surgery between surgeries with a popliteal block and those with local field block alone. We identified 101 charts, of which 26 presented to the emergency department for postoperative pain following popliteal block. Our results demonstrated that popliteal blocks did not perform better than local blocks, and that there is no statistically significant difference between the 2 methods of postoperative pain control in terms of rates of presentation to the emergency department for pain. Levels of Evidence: Level III, All statistical analyses were carried out using the R statistical package by the primary author (NS) (R Developmental, Core Team. R: A Language and Environment for Statistical Computing, 2012. http://www.R-project.org ).

Predictors for Surgery-Related Emergency Department Visits within 30 Days of Foot and Ankle Surgeries.

Presentation to an emergency department (ED) after foot and ankle surgeries not only causes inconvenience to patients but also increases healthcare costs. To minimize this, many major institutions have tracked these data as a part of quality improvement measures. Our previous study showed that factors associated with any (surgery-related and unrelated) postoperative ED visits were not easily modifiable by surgeons. Therefore, in the current study, we focused on factors associated specifically with surgery-related postoperative ED visits, because this may provide some insights for surgeons rather than just administrators. We examined 513 foot and ankle surgeries, of which 114 resulted in 30-day postoperative ED visits for surgery-related reasons. Demographic, medical, and surgical factors were evaluated, and risk factors were identified after adjusting for potential clinically relevant covariates. Both inpatient and outpatient surgical settings and outpatient surgical settings alone were analyzed separately. Regardless of the setting, we found that shorter surgery was protective against postoperative ED visits, as was having a previous ED visit within 6 months before surgery. In the outpatient setting, younger age and having no insurance were also proxies for a postoperative ED visit, in addition to the above factors.

Factors associated with emergency room visits within 30 days of outpatient foot and ankle surgeries.

The number of emergency department (ED) visits within 30 days after elective surgery has been utilized as a quality measure by many institutions. The significance of the measure as a postoperative complication in foot and ankle surgery, and risk factors for it, are unknown. We conducted a retrospective cohort study involving 386 patients to determine risk factors associated with ED visits after outpatient foot and ankle surgeries. After adjusting for clinically relevant covariates, we found that previous ED visits within 6 months of surgery, and nonelective surgeries were associated with the postoperative ED visit. Having private insurance was protective against postoperative ED visits. Though these risk factors may not be easily modifiable by surgeons, understanding them may improve patient education and transitional care to prevent overcrowding of the ED.