Computational analysis of affinity dynamics between the variants of SARS-CoV-2 spike protein (RBD) and human ACE-2 receptor.

The novel coronavirus SARS-CoV-2 resulted in a significant worldwide health emergency known as the COVID-19 pandemic. This crisis has been marked by the widespread of various variants, with certain ones causing notable apprehension. In this study, we harnessed computational techniques to scrutinize these Variants of Concern (VOCs), including various Omicron subvariants. Our approach involved the use of protein structure prediction algorithms and molecular docking techniques, we have investigated the effects of mutations within the Receptor Binding Domain (RBD) of SARS-CoV-2 and how these mutations influence its interactions with the human angiotensin-converting enzyme 2 (hACE-2) receptor. Further we have predicted the structural alterations in the RBD of naturally occurring SARS-CoV-2 variants using the tr-Rosetta algorithm. Subsequent docking and binding analysis employing HADDOCK and PRODIGY illuminated crucial interactions occurring at the Receptor-Binding Motif (RBM). Our findings revealed a hierarchy of increased binding affinity between the human ACE2 receptor and the various RBDs, in the order of wild type (Wuhan-strain) < Beta < Alpha < Gamma < Omicron-B.1.1.529 < Delta < Omicron-BA.2.12.1 < Omicron-BA.5.2.1 < Omicron-BA.1.1. Notably, Omicron-BA.1.1 demonstrated the highest binding affinity of -17.4 kcal mol-1 to the hACE2 receptor when compared to all the mutant complexes. Additionally, our examination indicated that mutations occurring in active residues of the Receptor Binding Domain (RBD) consistently improved the binding affinity and intermolecular interactions in all mutant complexes. Analysis of the differences among variants has laid a foundation for the structure-based drug design targeting the RBD region of SARS-CoV-2.

A Retrospective Study Comparing Laparoscopic Transabdominal Cerclage: Pre-Pregnancy Versus in Pregnancy With Their Reproductive Outcomes and Safety.

OBJECTIVES: To compare the efficacy of laparoscopic transabdominal cerclage (TAC) pre-pregnancy and laparoscopic TAC in pregnancy in treating cervical insufficiency. METHOD: A retrospective analytical study comparing outcomes of laparoscopic TAC pre-pregnancy with laparoscopic TAC in pregnancy. A total of 178 patients who underwent laparoscopic TAC at our hospital were enrolled in the study. In total, 122 patients underwent interval cerclage, and 56 patients underwent cerclage during pregnancy. RESULTS: A total of 178 patients who met the inclusion criteria were included in the analysis. Second-trimester abortions decreased by 50%, with an overall increase in full-term live births (32.53%) in patients undergoing laparoscopic TAC pre-pregnancy. The fetal survival rate was around 90% and 85% with laparoscopic TAC pre-pregnancy and laparoscopic TAC in pregnancy, respectively. Although the obstetric outcomes of laparoscopic TAC pre-pregnancy and in pregnancy were comparable, laparoscopic TAC pre-pregnancy was safer than laparoscopic TAC in pregnancy due to the complications associated with the procedure during pregnancy. CONCLUSIONS: Laparoscopic TAC pre-pregnancy yielded better reproductive outcomes than laparoscopic TAC in pregnancy and was associated with fewer perioperative complications.

Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma.

Primary Open Angle Glaucoma (POAG) is the most common form of glaucoma that leads to irreversible vision loss. Dysfunction of trabecular meshwork (TM) tissue, a major regulator of aqueous humor (AH) outflow resistance, is associated with intraocular pressure (IOP) elevation in POAG. However, the underlying pathological mechanisms of TM dysfunction in POAG remain elusive. In this regard, transient receptor potential vanilloid 4 (TRPV4) cation channels are known to be important Ca2+ entry pathways in multiple cell types. Here, we provide direct evidence supporting Ca2+ entry through TRPV4 channels in human TM cells and show that TRPV4 channels in TM cells can be activated by increased fluid flow/shear stress. TM-specific TRPV4 channel knockout in mice elevated IOP, supporting a crucial role for TRPV4 channels in IOP regulation. Pharmacological activation of TRPV4 channels in mouse eyes also improved AH outflow facility and lowered IOP. Importantly, TRPV4 channels activated endothelial nitric oxide synthase (eNOS) in TM cells, and loss of eNOS abrogated TRPV4-induced lowering of IOP. Remarkably, TRPV4-eNOS signaling was significantly more pronounced in TM cells compared to Schlemm's canal cells. Furthermore, glaucomatous human TM cells show impaired activity of TRPV4 channels and disrupted TRPV4-eNOS signaling. Flow/shear stress activation of TRPV4 channels and subsequent NO release were also impaired in glaucomatous primary human TM cells. Together, our studies demonstrate a central role for TRPV4-eNOS signaling in IOP regulation. Our results also provide evidence that impaired TRPV4 channel activity in TM cells contributes to TM dysfunction and elevated IOP in glaucoma.

Caveolar peroxynitrite formation impairs endothelial TRPV4 channels and elevates pulmonary arterial pressure in pulmonary hypertension.

Recent studies have focused on the contribution of capillary endothelial TRPV4 channels to pulmonary pathologies, including lung edema and lung injury. However, in pulmonary hypertension (PH), small pulmonary arteries are the focus of the pathology, and endothelial TRPV4 channels in this crucial anatomy remain unexplored in PH. Here, we provide evidence that TRPV4 channels in endothelial cell caveolae maintain a low pulmonary arterial pressure under normal conditions. Moreover, the activity of caveolar TRPV4 channels is impaired in pulmonary arteries from mouse models of PH and PH patients. In PH, up-regulation of iNOS and NOX1 enzymes at endothelial cell caveolae results in the formation of the oxidant molecule peroxynitrite. Peroxynitrite, in turn, targets the structural protein caveolin-1 to reduce the activity of TRPV4 channels. These results suggest that endothelial caveolin-1-TRPV4 channel signaling lowers pulmonary arterial pressure, and impairment of endothelial caveolin-1-TRPV4 channel signaling contributes to elevated pulmonary arterial pressure in PH. Thus, inhibiting NOX1 or iNOS activity, or lowering endothelial peroxynitrite levels, may represent strategies for restoring vasodilation and pulmonary arterial pressure in PH.

Adoption of Reverse Total Shoulder Arthroplasty for Surgical Treatment of Proximal Humerus Fractures Differs by Patient Race.

BACKGROUND: Reverse total shoulder arthroplasty (rTSA) has gained popularity for the operative treatment of proximal humerus fractures (PHF). The purpose of this study was to compare racial differences in surgical management of PHF between open reduction and internal fixation (ORIF), hemiarthroplasty, and rTSA. Our hypothesis was that there would be no difference in fixation by race. METHODS: The National Surgical Quality Improvement Program (NSQIP) database was queried for ORIF, rTSA, and hemiarthroplasty between 2006 and 2020 for patients with a PHF. Race, ethnicity, age, sex, body mass index (BMI), and American Society of Anesthesiologists (ASA) class were recorded. Chi squared tests were performed to assess relationships between patient factors and operative intervention. Factors significant at the 0.10 level in univariable analyses were included in a multivariable multinomial model to predict operative intervention. RESULTS: 7,499 patients underwent surgical treatment for a PHF, including 526 (7%) undergoing hemiarthroplasty, 5,011 (67%) undergoing ORIF, and 1,962 (26%) undergoing rTSA. 27% of white patients with PHF underwent rTSA compared to 21% of Black patients, 16% of Asian patients, and 14% of Native American and Alaskan Native patients (p<0.001). In the multivariable analysis, utilization of rTSA increased over time (OR 1.2 per year since 2006, p < 0.001) and hemiarthroplasty decreased over time (OR 0.86 per year since 2006, p < 0.001). Non-white patients had significantly lower odds of undergoing rTSA versus ORIF (OR 0.75, 95% CI 0.58-0.97), as did male patients (OR 0.77, 95% CI 0.66-0.88). Patients over 65 (OR 3.86, 95% CI 3.39-4.38), patients with higher ASA classifications (ASA2: OR 3.24, 95% CI 1.86-5.66, ASA3: OR 4.77, 95% CI 2.74-8.32, ASA4: OR 5.25, 95% CI 2.89-9.54), and patients who were overweight (OR 1.33, 95% CI 1.14-1.55) or obese (OR 1.52, 95% CI 1.32-1.75) had higher odds of undergoing rTSA versus ORIF. DISCUSSION: As utilization of rTSA increases, understanding disparities in surgical treatment of PHF is crucial to improving outcomes and equitable access to emerging orthopedic technologies. While patient factors such as age, BMI, and comorbidities are known to directly impact outcomes and thus may be predictive of the type of surgical intervention, patient race should not dictate treatment.

ANN-Based Bridge Support Fixity Quantification Using Thermal Response Data from Real-Time Wireless Sensing.

Bridges are critical infrastructures that support our economic activities and daily lives. Aging bridges have been a major issue for decades, prompting researchers to improve resilience and performance through structural health monitoring. While most research focuses on superstructure damage, the majority of bridge failures are associated with support or joint damages, indicating the importance of bridge support. Indeed, bridge support affects the performance of both the substructure and superstructure by maintaining the load path and allowing certain movements to mitigate thermal and other stresses. The support deterioration leads to a change in fixity in the superstructure, compromising the bridge's integrity and safety. Hence, a reliable method to determine support fixity level is essential to detecting bearing health and enhancing the accuracy of the bridge health monitoring system. However, such research is lacking because of its complexity. In this study, we developed a support fixity quantification method based on thermal responses using an Artificial Neural Network (ANN) model. A finite element (FE) model of a representative highway bridge is used to derive thermal displacement data under different bearing stiffnesses, superstructure damage, and thermal loading. The thermal displacement behavior of the bridge under different support fixity conditions is presented, and the model is trained on the simulated response. The performance of the developed FE model and ANN was validated with field monitoring data collected from two in-service bridges in Connecticut using a real-time Wireless Sensor Network (WSN). Finally, the support stiffnesses of both bridges were predicted using the ANN model for validation.

Laparoscopic repair of iatrogenic celiac artery injury during median arcuate ligament release: A retrospection and tips at troubleshooting.

ABSTRACT: Median arcuate ligament (MAL) syndrome or celiac artery (CA) compression syndrome previously treated mainly by vascular surgeons using the open approach is now being increasingly performed by general surgeons with training in advanced laparoscopy. Although this approach has all the advantages of minimal access surgery, the procedure is fraught with serious complications like injury to major vascular structures during dissection. Vascular injury by far is the major cause of conversion to open procedure. Herein, we report a laparoscopic repair of iatrogenic CA injury by intra-corporeal suturing during MAL release. We also elaborate the causes, the preventive measures that can be applied to avoid such catastrophic occurrences in future. To the best of our knowledge, this is the first report of a laparoscopic repair of CA bleed during MAL release.

Molecular characterization and antifungal activity of lipopeptides produced from Bacillus subtilis against plant fungal pathogen Alternaria alternata.

Over 380 host plant species have been known to develop leaf spots as a result of the fungus Alternaria alternata. It is an aspiring pathogen that affects a variety of hosts and causes rots, blights, and leaf spots on different plant sections. In this investigation, the lipopeptides from the B. subtilis strains T3, T4, T5, and T6 were evaluated for their antifungal activities. In the genomic DNA, iturin, surfactin, and fengycin genes were found recovered from B. subtilis bacterium by PCR amplification. From different B. subtilis strains, antifungal Lipopeptides were extracted, identified by HPLC, and quantified with values for T3 (24 g/ml), T4 (32 g/ml), T5 (28 g/ml), and T6 (18 g/ml). To test the antifungal activity, the isolated lipopeptides from the B. subtilis T3, T4, T5, and T6 strains were applied to Alternaria alternata at a concentration of 10 g/ml. Lipopeptides were found to suppress Alternaria alternata at rates of T3 (75.14%), T4 (75.93%), T5 (80.40%), and T6 (85.88%). The T6 strain outperformed the other three by having the highest antifungal activity against Alternaria alternata (85.88%).

Room-Temperature Synthesis of Biogenic δ-MnO2 NPs for the Dehydrogenative Coupling of Diamines with Alcohols for Benzimidazole and Quinoxaline Synthesis: An Efficient Catalyst for Electrochemical Applications.

An efficient, unique, and eco-friendly biogenic synthesis of single-crystalline δ-phase manganese oxide nanoparticles (MnO2 NPs) using Gliricidia sepium leaves (GSL) extract at room temperature has been revealed for the first time. The active chemicals present in the GSL extract were found to serve as both reducing and stabilizing agents. The catalyst shows an excellent surface area of 301.13 m2 g-1, a mean pore diameter of 4.01 nm, and 39.97% w/w of active metal content. The reactivity of the synthesized catalyst was demonstrated by achieving a one-pot synthesis of benzimidazoles and quinoxalines via an acceptorless dehydrogenative coupling strategy utilizing biorenewable alcohols. The release of hydrogen gas was observed as the only side product and proven by its successful utilization for alkene reduction which supports the mechanistic elucidation. The release of hydrogen gas as a useful byproduct highlights the scientific importance of the present methodology. Additionally, gram-scale synthesis and catalyst recyclability studies are deliberated. Importantly, the δ-MnO2 NP catalyst exhibited superior catalytic activity and high durability toward hydrogen evolution reaction in alkaline media, highlighting the dual use of the catalyst. The δ-MnO2 NPs attain the current density of 10 mA/cm2 at an overpotential of 154 mV with a Tafel slope of 119 mV/dec.

Declining fertility and increasing use of traditional methods of family planning: a paradox in Uttar Pradesh, India?

Uttar Pradesh (UP), with more than 220 million people, is the most populous state in India. Despite a high unmet need for modern family planning methods, the state has experienced a substantial decline in fertility. India has also seen a decline during this period which can be attributed to the increased prevalence of modern methods of family planning, particularly female sterilisation, but in UP, the corresponding increase was marginal. At the same time, Traditional Family Planning Methods (TMs) increased significantly in UP in contrast to India, where it was marginal. The trends in UP raise questions about the drivers in fertility decline and question the conventional wisdom that fertility declines are driven by modern methods, and the paper aims to understand this paradox. Fertility trends and family planning practices in UP were analysed using data from different rounds of National Family Health Surveys (NFHS) and the two UP Family Planning Surveys conducted by the UP Technical Support Unit to understand whether the use of TMs played a role in the fertility decline. As per NFHS-4, the prevalence of TM in India (6%) was less than half that of UP (13%). The UP Family Planning Survey in 25 High Priority Districts estimated that 22% of women used TMs. The analysis also suggested that availability and accessibiility of modern contraceptives might have played a role in the increased use of TMs in UP. If there are still couples who make a choice in favour of TMs, they should be well informed about the risks associated with the use of traditional methods as higher failure rate is observed among TMs users.

Outcome Analysis Comparing Muscle and Fasciocutaneous Free Flaps for Heel Reconstruction: Meta-Analysis and Case Series.

Background Choosing the components of free flap (fasciocutaneous or muscle) is one of the crucial but controversial decisions in heel reconstruction. This meta-analysis aims to provide an up-to-date comparison of fasciocutaneous flaps (FCFs) and muscle flaps (MFs) for heel reconstruction and to ascertain if one flap has an advantage over the other. Methods Following the Preferred Reporting Item for Systematic Reviews and Meta-Analyses guidelines, a systematic literature review was performed identifying studies on heel reconstruction with FCF and MF. Primary outcomes were survival, time of ambulation, sensation, ulceration, gait, need for specialized footwear, revision procedures, and shear. Meta-analyses and Trial Sequential Analysis (TSA) were performed to estimate the pooled risk ratios (RRs) and standardized mean difference (SMD) with fixed effects and random effects models, respectively. Results Of 757 publications identified, 20 were reviewed including 255 patients with 263 free flaps. The meta-analysis showed no statistically significant difference between MF and FCF in terms of survival (RR, 1; 95% confidence interval [CI], 0.83, 1.21), gait abnormality (RR, 0.55; 95% CI, 0.19, 1.59), ulcerations (RR, 0.65; 95% CI, 0.27, 1.54), footwear modification (RR, 0.52; 95% CI, 0.26, 1.09), and revision procedures (RR, 1.67; 95% CI, 0.84, 3.32). FCF had superior perception of deep pressure (RR, 1.99; 95% CI, 1.32, 3.00), light touch, and pain (RR, 5.17; 95% CI, 2.02, 13.22) compared with MF. Time to full weight-bearing (SMD, -3.03; 95% CI, -4.25, -1.80) was longer for MF compared with FCF. TSA showed inconclusive results for comparison of the survival of flaps, gait assessment, and rates of ulceration. Conclusion Patients reconstructed with FCF had superior sensory recovery and early weight bearing on their reconstructed heels, hence faster return to daily activities compared with MFs. In terms of other outcomes such as footwear modification and revision procedure, both flaps had no statistically significant difference. The results were inconclusive regarding the survival of flaps, gait assessment, and rates of ulceration. Future studies are required to investigate the role of shear on the stability of the reconstructed heels.

Novel laparo-endoscopic hybrid technique of management of a rare case of duodeno-duodenal intussusception.

We herein report a rare case of duodeno-duodenal intussusception (IS) presenting with obstruction caused by tubulovillous adenoma in an adult with malrotation that was managed by a novel laparoendoscopic hybrid technique. This was done by passing transjejunal nasogastric tube (NG) through one of the ports and manoeuvring it towards the IS. Two hundred and fifty millilitre of saline was flushed by aseptosyringe with pressure connected to the NG. This hydrostatic reduction technique resulted in distension of the jejunal and duodenal loop achieving reduction of IS. Intraoperative endoscopy was performed to exactly localise the mass lesion. The duodenum was kocherised and was delivered through a 4-cm transverse incision. Anterior duodenotomy was performed; the mass was excised; and duodenotomy was closed transversely. An extensive literature search did not show any case report of duodenoduodenal IS being managed by this technique. The combination of novel retrograde decompression and intraoperative endoscopy helped us to manage this rare case by this novel technique.

Self-healing cutaneous nodules with fever and arthritis: worrisome presentation of a benign disorder.

A 4-year-old boy with extensive papules and nodules with arthritis was evaluated and followed up. In spite of the initial worrisome presentation, the lesions showed near-complete resolution over a 2-year follow-up period. Click here for the corresponding questions to this CME article.

A Novel Mouse Model of TGFß2-Induced Ocular Hypertension Using Lentiviral Gene Delivery.

Glaucoma is a multifactorial disease leading to irreversible blindness. Primary open-angle glaucoma (POAG) is the most common form and is associated with the elevation of intraocular pressure (IOP). Reduced aqueous humor (AH) outflow due to trabecular meshwork (TM) dysfunction is responsible for IOP elevation in POAG. Extracellular matrix (ECM) accumulation, actin cytoskeletal reorganization, and stiffening of the TM are associated with increased outflow resistance. Transforming growth factor (TGF) ß2, a profibrotic cytokine, is known to play an important role in the development of ocular hypertension (OHT) in POAG. An appropriate mouse model is critical in understanding the underlying molecular mechanism of TGFß2-induced OHT. To achieve this, TM can be targeted with recombinant viral vectors to express a gene of interest. Lentiviruses (LV) are known for their tropism towards TM with stable transgene expression and low immunogenicity. We, therefore, developed a novel mouse model of IOP elevation using LV gene transfer of active human TGFß2 in the TM. We developed an LV vector-encoding active hTGFß2C226,228S under the control of a cytomegalovirus (CMV) promoter. Adult C57BL/6J mice were injected intravitreally with LV expressing null or hTGFß2C226,228S. We observed a significant increase in IOP 3 weeks post-injection compared to control eyes with an average delta change of 3.3 mmHg. IOP stayed elevated up to 7 weeks post-injection, which correlated with a significant drop in the AH outflow facility (40.36%). Increased expression of active TGFß2 was observed in both AH and anterior segment samples of injected mice. The morphological assessment of the mouse TM region via hematoxylin and eosin (H&E) staining and direct ophthalmoscopy examination revealed no visible signs of inflammation or other ocular abnormalities in the injected eyes. Furthermore, transduction of primary human TM cells with LV_hTGFß2C226,228S exhibited alterations in actin cytoskeleton structures, including the formation of F-actin stress fibers and crossed-linked actin networks (CLANs), which are signature arrangements of actin cytoskeleton observed in the stiffer fibrotic-like TM. Our study demonstrated a mouse model of sustained IOP elevation via lentiviral gene delivery of active hTGFß2C226,228S that induces TM dysfunction and outflow resistance.

A simultaneous liquid chromatographic analysis of niclosamide and bicalutamide in rat plasma by protein precipitation extraction.

OBJECTIVE: The aim of the study was to develop a simple, sensitive and cost-efficient bioanalytical method for the simultaneous determination of niclosamide and bicalutamide in rat plasma with appropriate validation. MATERIAL AND METHODS: Real-time estimation was carried out using Ultra Flow Liquid Chromatography. The solvent system consisting of 20mM sodium acetate buffer at pH 4.0 and acetonitrile (65: 35% v/v) is used as the mobile phase. The analytes were extracted by protein precipitation with acetonitrile and separated on an Eclipse plus C18 Column (25cm×5cm×4.6µm) with L1 packing in isocratic mode with a flow rate of 1ml/min at 254nm. The developed method was validated on the basis of the bioanalytical guidelines of the US American FDA. RESULT: The retention times of niclosamide and bicalutamide were 4.19min and 8.61min, respectively, with a running time of 15minutes. The calibration ranges are 50-600ng/ml for niclosamide and 100-1200ng/ml for bicalutamide. Regression equations for niclosamide and bicalutamide were y=55746x - 1E+06 and y=22051x-576888 with regression coefficient (R2) 0.9952 & 0.9982 using the unweighted and weighted linear regression with a weighting factor of 1/xo, 1/x, 1/√x, and 1/x2. The accuracy of niclosamide and bicalutamide were 46.01ng/ml to 584.10ng/ml and 82.30ng/ml to 1149.13ng/ml, respectively. The percentage recoveries for niclosamide and bicalutamide were 86.51-90.29% & 88.64-93.99%, respectively. CONCLUSIONS: The result of the present study show that the method developed is a simple, fast and precise method and is used in bioavailability and bioequivalence studies as well as during routine therapeutic drug monitoring of niclosamide and bicalutamide.

Suicidality among gender minorities in Karnataka, South India.

BACKGROUND: It is argued that Indian gender minorities displayed differential mental health problems and suicide attempts. Hence, the study was intended to understand the prevalence of anxiety, depression and suicidality among this group, specifically those living in a metropolitan city in South India. METHODS: The data was generated from a cross-sectional study that employed a structured questionnaire to collect information about experiences of anxiety, depression and suicidal behavior among gender-diverse individuals in Bangalore, the capital city of Karnataka state. The study used stratified simple random sampling of eligible individuals who were 18 years of age and older and who were enrolled in an HIV prevention program implemented for gender-diverse individuals run by the Karnataka Health Promotion Trust and the University of Manitoba at the time of the study (2012). Bivariate and multivariate analyses were used to assess the relative contribution of various factors that affect suicide ideation or actual attempts among the gender diverse participants. RESULTS: Results showed that 62% whose main source of income was Basti (socially sanctioned practice of begging), 52% of Hijras, 56% who lived with their Gurus, 58% who were not happy with their physical appearance, 55% who consumed alcohol daily, and 63% who experienced high depression had ever thought of or attempted suicide in the month prior to the survey. However, multivariate analysis showed that respondents who were not happy with their physical appearance and thought of changing it had significantly higher odds (AOR = 2.861; CI 1.468,5.576; p = 0.002) of either having thoughts that it was better being dead or wished they died. Similarly, those who experienced high depression, their odds of either having had thoughts of or having attempted suicide increased by three times (AOR = 3.997; CI 1.976, 8.071; p < 0.000). CONCLUSIONS: It is observed that a high percentage of gender minorities had attempted suicide or thought of suicide during the month preceding the data collection. The findings bring new insights on the proximate determinant of physical appearance on the suicidality of gender minorities assigned male at birth and appropriate to account for this while addressing the mental health issues.

Establishing evidence-based decision-making mechanism in a health eco-system and its linkages with health service coverage in 25 high-priority districts of Uttar Pradesh, India.

BACKGROUND: Achievement of successful health outcomes depends on evidence-based programming and implementation of effective health interventions. Routine Health Management Information System is one of the most valuable data sets to support evidence-based programming, however, evidence on systemic use of routine monitoring data for problem-solving and improving health outcomes remain negligible. We attempt to understand the effects of systematic evidence-based review mechanism on improving health outcomes in Uttar Pradesh, India. METHODS: Data comes from decision-tracking system and routine health management information system for period Nov-2017 to Mar-2019 covering 6963 health facilities across 25 high-priority districts of the state. Decision-tracking data captured pattern of decisions taken, actions planned and completed, while the latter one provided information on service coverage outcomes over time. Three service coverage indicators, namely, pregnant women receiving 4 or more times ANC and haemoglobin testing during pregnancy, delivered at the health facility, and receive post-partum care within 48 h of delivery were used as outcomes. Univariate and bivariate analyses were conducted. RESULTS: Total 412 decisions were taken during the study reference period and a majority were related to ante-natal care services (31%) followed by delivery (16%) and post-natal services (16%). About 21% decisions-taken were focused on improving data quality. By 1 year, 67% of actions planned based on these decisions were completed, 26% were in progress, and the remaining 7% were not completed. We found that, over a year, districts witnessing > 20 percentage-point increase in outcomes were also the districts with significantly higher action completion rates (> 80%) compared to the districts with < 10 percentage-point increase in outcomes having completion of action plans around 50-70%. CONCLUSIONS: Findings revealed a significantly higher improvement in coverage outcomes among the districts which used routine health management data to conduct monthly review meetings and had high actions completion rates. A data-based review-mechanisms could specifically identify programmatic gaps in service delivery leading to strategic decision making by district authorities to bridge the programmatic gaps. Going forward, establishing systematic evidence-based review platforms can be an important strategy to improve health outcomes and promote the use of routine health monitoring system data in any setting.

IL-10 Signaling in the Tumor Microenvironment of Ovarian Cancer.

Unlike other malignancies, ovarian cancer (OC) creates a complex tumor microenvironment with distinctive peritoneal ascites consisting of a mixture of several immunosuppressive cells which impair the ability of the patient's immune system to fight the disease. The poor survival rates observed in advanced stage OC patients and the lack of effective conventional therapeutic options have been attributed in large part to the immature dendritic cells (DCs), IL-10 secreting regulatory T cells, tumor-associated macrophages, myeloid-derived suppressor cells, and cancer stem cells that secrete inhibitory cytokines. This review highlights the critical role played by the intraperitoneal presence of IL-10 in the generation of an immunosuppressive tumor microenvironment. Further, the effect of antibody neutralization of IL-10 on the efficacy of DC and chimeric antigen receptor T-cell vaccines will be discussed. Moreover, we will review the influence of IL-10 in the promotion of cancer stemness in concert with the NF-κB signaling pathway with regard to OC progression. Finally, understanding the role of IL-10 and its crosstalk with various cells in the ascitic fluid may contribute to the development of novel immunotherapeutic approaches with the potential to kill drug-resistant OC cells while minimizing toxic side effects.

Arcuate sign-fibular head avulsion fracture and associated injuries in the pediatric and adolescent population.

PURPOSE: To describe the first "arcuate sign" case series in the pediatric population, radiologic features of the associated injuries, management, and how they compare with the adult population. METHODS: Retrospective study included patients under 18 years of age with a classic "arcuate sign" on radiographs. Data collected included patient demographics, mechanism of injury, and management. Radiographs and advanced imaging (MRI, CT) were reviewed by two musculoskeletal radiologists in a blinded fashion and findings recorded. RESULTS: Seven patients (4 males, 3 females) with mean age 15 years (range 14-17 years) were included in the study. All 7 injuries were related to sports, 5/7 (71%) being non-contact injuries. Five patients had MRI done-1 LCL injury, MPFL sprain, and MCL sprain were reported; 3 popliteofibular ligament and popliteus sprains were seen; and 3 bone contusions were present on imaging. None of the patients had meniscus or cruciate ligament tears. One patient had an additional fracture of the lateral tibial plateau at the ilio-tibial band attachment and an associated peroneal nerve injury. Five out of seven (71.4%) were treated non-operatively and were able to return back to activity at a mean of 7.2 weeks from injury. Two out of seven (28.6%) needed operative intervention for the fracture but not arthroscopic repair. CONCLUSION: Pediatric patients with a radiographic arcuate sign tend not to have ACL, PCL, or meniscal injuries, and treatment is predominantly non-operative in contrast to literature reported in adults.

Sodium 4-Phenylbutyrate Reduces Ocular Hypertension by Degrading Extracellular Matrix Deposition via Activation of MMP9.

Ocular hypertension (OHT) is a serious adverse effect of the widely prescribed glucocorticoid (GC) therapy and, if left undiagnosed, it can lead to glaucoma and complete blindness. Previously, we have shown that the small chemical chaperone, sodium-4-phenylbutyrate (PBA), rescues GC-induced OHT by reducing ocular endoplasmic reticulum (ER) stress. However, the exact mechanism of how PBA rescues GC-induced OHT is not completely understood. The trabecular meshwork (TM) is a filter-like specialized contractile tissue consisting of TM cells embedded within extracellular matrix (ECM) that controls intraocular pressure (IOP) by constantly regulating aqueous humor (AH) outflow. Induction of abnormal ECM deposition in TM is a hallmark of GC-induced OHT. Here, we investigated whether PBA reduces GC-induced OHT by degrading abnormal ECM deposition in TM using mouse model of GC-induced OHT, ex vivo cultured human TM tissues and primary human TM cells. We show that topical ocular eye drops of PBA (1%) significantly lowers elevated IOP in mouse model of GC-induced OHT. Importantly, PBA prevents synthesis and deposition of GC-induced ECM in TM. We report for the first time that PBA can degrade existing abnormal ECM in normal human TM cells/tissues by inducing matrix metalloproteinase (MMP)9 expression and activity. Furthermore, inhibition of MMPs activity by chemical-inhibitor (minocycline) abrogated PBA's effect on ECM reduction and its associated ER stress. Our study indicates a non-chaperone activity of PBA via activation of MMP9 that degrades abnormal ECM accumulation in TM.