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Abstract Background Equitable access to healthcare for rural, tribal, and underprivileged people has been an emerging area of interest for researchers, academicians, and policymakers worldwide. Improving equitable access to healthcare requires innovative interventions. This calls for clarifying which operational model of a service innovation needs to be strengthened to achieve transformative change and bring sustainability to public health interventions. The current study aimed to identify the components of an operational model of mobile medical units (MMUs) as an innovative intervention to provide equitable access to healthcare. Methods The study empirically examined the impact of scalability, affordability, replicability (SAR), and immunization performance on the sustainability of MMUs to develop a framework for primary healthcare in the future. Data were collected via a survey answered by 207 healthcare professionals from six states in India. Partial least squares structural equation modeling (PLS-SEM) was conducted to empirically determine the interrelationships among various constructs. Results The standardized path coefficients revealed that three factors (SAR) significantly influenced immunization performance as independent variables. Comparing the three hypothesized relationships demonstrates that replicability has the most substantial impact, followed by scalability and affordability. Immunization performance was found to have a significant direct effect on sustainability. For evaluating sustainability, MMUs constitute an essential component and an enabler of a sustainable healthcare system and universal health coverage. Conclusion This study equips policymakers and public health professionals with the critical components of the MMU operational model leading toward sustainability. The research framework provides reliable grounds for examining the impact of scalability, affordability, and replicability on immunization coverage as the primary public healthcare outcome.

Background: Improving equitable access to healthcare requires innovative interventions and strengthening a service innovation operational model to achieve transformative change and bring sustainability to public health interventions. The current study aims to identify the components of the Mobile Medical Units (MMUs) operational model as an innovative intervention to provide equitable and inclusive access to healthcare. Methods: The study used qualitative research to identify the components of the operational model of MMUs for primary healthcare in future. Data has been collected via semi-structured in-depth interviews with 103 healthcare professionals from six states representing India's Tier I, Tier II, and Tier III regions. A thematic analysis was performed to examine emergent salient themes. Results: The study identified and examined scalability, affordability, replicability, and sustainability as the four critical components of the operational model of MMUs. The findings of the study indicated that MMUs with these four components played a vital role in COVID-19 immunization, especially in resource-limited settings. The study found that MMUs are a cost-effective and scalable healthcare delivery model that can be easily replicated in primary healthcare service delivery. Conclusion: The findings underscore the significant role of MMUs in addressing healthcare disparities, particularly in resource-limited settings. The adaptability and cost-effectiveness of MMUs make them an ideal solution for primary healthcare delivery, especially in Tier I, II, and III regions of India. It lays a foundation for future research and policy-making, emphasizing the need for innovative, equitable, and sustainable healthcare delivery models like MMUs to transform and strengthen healthcare systems globally.

Abstract Ribavirin is an inosine monophosphate dehydrogenase inhibitor. Studies suggest ribavirin aerosol could be a safe and efficacious treatment option in the fight against coronaviruses. However, current treatment is long (12–18 h per day, 3–7 days), limiting clinical utility. A reduction in treatment time would reduce treatment burden. We aimed to evaluate safety and pharmacokinetics (PK) of four, single‐dose regimens of ribavirin aerosol in healthy volunteers. Thirty‐two subjects were randomized, to four cohorts of aerosolized ribavirin (active) or placebo. Cohort 1 received 50 mg/ml ribavirin/placebo (10 ml total volume); cohort 2, 50 mg/ml ribavirin/placebo (20 ml total volume); cohort 3, 100 mg/ml ribavirin/placebo (10 ml total volume); and cohort 4, 100 mg/ml ribavirin/placebo (20 ml total volume). Intense safety monitoring and PK sampling took place on days 1, 2, 3, and 40. Subjects were (mean ± SD, active vs. placebo) aged 57 ± 4.5 vs. 60 ± 2.5 years; 83% vs. 88% were female; and 75% vs. 50% were Caucasian. Some 12.5% (3/24) and 25% (2/8) experienced at least one treatment‐emergent adverse event (TEAE) (two moderate; five mild) in the active and placebo groups, respectively. No clinically significant safety concerns were reported. Mean maximum observed concentration (Cmax) and area under the curve (AUC) values were higher in cohort 4, whereas cohorts 2 and 3 showed similar PK values. Ribavirin absorption reached Cmax within 2 h across cohorts. Four single‐dose regimens of ribavirin aerosol demonstrated systemic exposure with minimal systemic effects. Results support continued clinical development of ribavirin aerosol as a treatment option in patients with coronaviruses.

Abstract Heart transplantation remains the definitive treatment for end stage heart failure. Because availability is limited, risk stratification of candidates is crucial for optimizing both organ allocations and transplant outcomes. Here we utilize proteomics prior to transplant to identify new biomarkers that predict post-transplant survival in a multi-institutional cohort. Microvesicles were isolated from serum samples and underwent proteomic analysis using mass spectrometry. Monte Carlo cross-validation (MCCV) was used to predict survival after transplant incorporating select recipient pre-transplant clinical characteristics and serum microvesicle proteomic data. We identified six protein markers with prediction performance above AUROC of 0.6, including Prothrombin (F2), anti-plasmin (SERPINF2), Factor IX, carboxypeptidase 2 (CPB2), HGF activator (HGFAC) and low molecular weight kininogen (LK). No clinical characteristics demonstrated an AUROC > 0.6. Putative biological functions and pathways were assessed using gene set enrichment analysis (GSEA). Differential expression analysis identified enriched pathways prior to transplant that were associated with post-transplant survival including activation of platelets and the coagulation pathway prior to transplant. Specifically, upregulation of coagulation cascade components of the kallikrein-kinin system (KKS) and downregulation of kininogen prior to transplant were associated with survival after transplant. Further prospective studies are warranted to determine if alterations in the KKS contributes to overall post-transplant survival.

Abstract Background The direct factor Xa inhibitor rivaroxaban is approved for the treatment of venous thromboembolism (VTE), based on the results of large phase III trials. Objectives To confirm rivaroxaban's effectiveness and safety in routine clinical care of patients with VTE. Methods Data were obtained from prospective, noninterventional registries: the FIRST registry (United Kingdom), DRESDEN NOAC registry (Germany), and SWIVTER (Switzerland). Baseline characteristics of these registries and effectiveness and safety outcome rates for the FIRST and DRESDEN NOAC registries were compared. Results A total of 1841 rivaroxaban‐treated patients with acute VTE (57.9% male, 76.6% deep vein thrombosis [DVT]; 23.4% pulmonary embolism ± DVT; median age, 61 years) were included: 1217 from the FIRST registry, 418 from the DRESDEN NOAC registry, and 206 from SWIVTER. Median time between VTE diagnosis and initiation of rivaroxaban was 1.4 ± 1.81 days (25th–75th percentile 1–1; range, 0–15 days). On‐treatment outcome rates for the FIRST and DRESDEN NOAC registries were 0.74 per 100 patient‐years (95% confidence interval [CI], 0.35–1.54) versus 0.96 per 100 patient‐years (95% CI, 0.46–2.01) for VTE recurrence; 1.16 per 100 patient years (95% CI, 0.64–2.09) versus 2.51 per 100 patient‐years (95% CI, 1.58–3.98) for ISTH major bleeding and 1.69 per 100 patient‐years (95% CI, 1.21–2.35) versus 1.73 per 100 patient‐years (95% CI, 1.27–2.36) for all‐cause mortality (intention‐to‐treat analysis), respectively. Conclusion Overall treatment outcomes were consistent with the results of the phase III rivaroxaban trials in VTE treatment, indicating that the use of rivaroxaban offers acceptable treatment results also in routine care. However, we observed significant differences in patient characteristics and management patterns across Switzerland, the United Kingdom, and Germany, limiting direct comparisons of unadjusted outcome event rates between registries.

Journalists and ethnographic researchers, such as anthropologists, sociologists or media scholars, have comparable ways of establishing initial contacts with people from their fields of interest. Due to the ongoing COVID-19 pandemic and consequential travel restrictions and social distancing, it has become increasingly difficult to access a field. Taking inspiration from social anthropologist Ulf Hannerz (2004, p. 226), who compared journalists and anthropologists as “neighboring groups engaged in a somehow parallel pursuit,” this article explores what researchers may learn from practitioners who conduct research without being on-site. Fed by various practical journalists’ experiences, the article aims to investigate how information and communication technologies (ICTs) and digitally mediated methods, such as online search tools and social media, can be used to establish contacts and gain trust remotely. Here, the relevance of these methods for accessing a field in general goes beyond the limitations imposed during the COVID-19 pandemic and can be of interest to all those who face difficulties of field access of any kind. Ultimately, this article reflects on corresponding ethical challenges that may arise while conducting research remotely.

BackgroundAllograft pathologies, such as valvular, coronary artery, or aortic disease, may occur early and late after cardiac transplantation. Cardiac surgery after heart transplantation (CASH) may be an option to improve quality of life and allograft function and prolong survival. Experience with CASH, however, has been limited to single-center reports.MethodsWe performed a retrospective, multicenter study of heart transplant recipients with CASH between January 1984 and December 2020. In this study, 60 high-volume cardiac transplant centers were invited to participate.ResultsData were available from 19 centers in North America (n = 7), South America (n = 1), and Europe (n = 11), with a total of 110 patients. A median of 3 (IQR 2–8.5) operations was reported by each center; five centers included ≥ 10 patients. Indications for CASH were valvular disease (n = 62), coronary artery disease (CAD) (n = 16), constrictive pericarditis (n = 17), aortic pathology (n = 13), and myxoma (n = 2). The median age at CASH was 57.7 (47.8–63.1) years, with a median time from transplant to CASH of 4.4 (1–9.6) years. Reoperation within the first year after transplantation was performed in 24.5%. In-hospital mortality was 9.1% (n = 10). 1-year survival was 86.2% and median follow-up was 8.2 (3.8–14.6) years. The most frequent perioperative complications were acute kidney injury and bleeding revision in 18 and 9.1%, respectively.ConclusionCardiac surgery after heart transplantation has low in-hospital mortality and postoperative complications in carefully selected patients. The incidence and type of CASH vary between international centers. Risk factors for the worse outcome are higher European System for Cardiac Operative Risk Evaluation (EuroSCORE II) and postoperative renal failure.

ABSTRACT Ehrlichia chaffeensis evades innate host defenses by reprogramming the mononuclear phagocyte through mechanisms that involve the exploitation of multiple evolutionarily conserved cellular signaling pathways, including Notch. This immune evasion strategy is directed in part by tandem repeat protein (TRP) effectors. Specifically, the TRP120 effector activates and regulates Notch signaling through interactions with the Notch receptor and the negative regulator, F-Box and WD repeat domain-containing 7 (FBW7). However, the specific molecular interactions and motifs required for E. chaffeensis TRP120-Notch receptor interaction and activation have not been defined. To investigate the molecular basis of TRP120 Notch activation, we compared TRP120 with endogenous canonical/noncanonical Notch ligands and identified a short region of sequence homology within the tandem repeat (TR) domain. TRP120 was predicted to share biological function with Notch ligands, and a function-associated sequence in the TR domain was identified. To investigate TRP120-Notch receptor interactions, colocalization between TRP120 and endogenous Notch-1 was observed. Moreover, direct interactions between full-length TRP120, the TRP120 TR domain containing the putative Notch ligand sequence, and the Notch receptor LBR were demonstrated. To molecularly define the TRP120 Notch activation motif, peptide mapping was used to identify an 11-amino acid short linear motif (SLiM) located within the TRP120 TR that activated Notch signaling and downstream gene expression. Peptide mutants of the Notch SLiM or anti-Notch SLiM antibody reduced or eliminated Notch activation and NICD nuclear translocation. This investigation reveals a novel molecularly defined pathogen encoded Notch SLiM mimetic that activates Notch signaling consistent with endogenous ligands. IMPORTANCE E. chaffeensis infects and replicates in mononuclear phagocytes, but how it evades innate immune defenses of this indispensable primary innate immune cell is not well understood. This investigation revealed the molecular details of a ligand mimicry cellular reprogramming strategy that involved a short linear motif (SLiM), which enabled E. chaffeensis to exploit host cell signaling to establish and maintain infection. E. chaffeensis TRP120 is a moonlighting effector that has been associated with cellular activation and other functions, including ubiquitin ligase activity. Herein, we identified and demonstrated that a SLiM present within each tandem repeat of TRP120 activated Notch signaling. Notch is an evolutionarily conserved signaling pathway responsible for many cell functions, including cell fate, development, and innate immunity. This study is significant because it revealed the first molecularly defined pathogen encoded SLiM that appears to have evolved de novo to mimic endogenous Notch ligands. Understanding Notch activation during E. chaffeensis infection provides a model to study pathogen exploitation of signaling pathways and will be useful in developing molecularly targeted countermeasures for inhibiting infection by a multitude of disease-causing pathogens that exploit cell signaling through molecular mimicry.

Background We compared the in-hospital complications, outcomes, cost, and length of stay (LOS) between angiography-guided percutaneous coronary intervention (PCI) and intravascular ultrasound (IVUS)-guided PCI in patients with ST-elevation myocardial infarction (STEMI) in the USA. Methods A nationwide inpatient database was queried to identify patients >18 years with STEMI who underwent angiography-guided and IVUS-guided PCI from January 2016 to December 2016. We compared the in-hospital mortality, complications, cost, and LOS between the two groups. Results We identified 100,485 patients who underwent angiography-guided PCI and 5,460 patients who underwent IVUS-guided PCI. In-hospital mortality was not statistically different (odds ratio [OR] 0.76, 95% CI 0.46 − 1.22, P = 0.24). Patients who underwent PCI with IVUS were more likely to have coronary artery dissection (OR 4.26, 95% CI 2.34 − 7.7, p =

Right ventricular infarction can precipitate severe right-to-left shunting and refractory hypoxia from a previously dormant patent foramen ovale. Right ventricle mechanical circulatory support and patent foramen ovale closure can play a crucial role in the treatment of hypoxia and right ventricular recovery. We report a case of successful percutaneous patent foramen ovale closure on right ventricle mechanical circulatory support in a patient with right ventricular shock. (Level of Difficulty: Intermediate.)

Pediatric Intensive Care Units (PICUs) provide multidisciplinary care to critically ill children and their families. Grief is present throughout the trajectory of illness and can peak around the time of death or non-death losses. The objective of this study was to assess how PICUs around the world implement grief and bereavement care (GBC) as part of an integrated model of care. This is a multicenter cross-sectional, prospective survey study. Questionnaires with multiple-choice and open-ended questions focusing on unit infrastructure, personnel, policies, limited patient data, and practices related to GBC for families and health care professionals (HCPs) were completed by on-site researchers, who were HCPs on the direct care of patients. PICU fulfillment of GBC goals was evaluated using a custom scoring based on indicators developed by the Initiative for Pediatric Palliative Care (IPPC). We compared average total and individual items fulfillment scores according to the respective country's World Bank income. Patient characteristics and details of unit infrastructure were also evaluated as potential predictors of total GBC fulfillment scores. Statistical analysis included multilevel generalized linear models (GLM) with a Gaussian distribution adjusted by child age/gender and clustering by center, using high income countries (HICs) as the comparative reference. Additionally, we applied principals of content analysis to analyze and summarize open-ended answers to contextualize qualitative data. The study included 34 PICUs from 18 countries: high-income countries (HICs): 32.4%, upper middle-income countries (UMICs): 44.1%, low middle-income and low-income countries (LMI/LICs): 23.5%. All groups reported some compliance with GBC goals; no group reported perfect fulfillment. We found statistically significant differences in GBC fulfillment scores between HICs and UMICs (specifically, HCP grief support), and between HICs and LMICs (specifically, family grief support and HCP grief support). PICUs world-wide provide some GBC, independent of income, but barriers include lack of financial support, time, and training, overall unit culture, presence of a palliative care consultation service, and varying cultural perceptions of child death. Disparities in GBC for families and HCPs exist and were related to the native countries' income level. Identifying barriers to support families and HCPs, can lead to opportunities of improving GBC in PICUs world-wide.

The adequate assessment and management of pain remains a challenging task in the Pediatric Intensive Care Unit (PICU). Our goal is to describe how pain is assessed and managed in PICUs around the world and to examine how human and material resources impact achievement of this goal. An international multicenter cross-sectional observational study was designed with the participation of 34 PICUs located in urban, suburban, and rural areas of 18 countries. We evaluated how PICUs around the world assessed and managed pain according to the Initiative for Pediatric Palliative Care recommendations, and how human and material resources impacted achievement of this goal. Data was collected for this study from 2016 to 2018 using questionnaires completed by medical doctors and nurses. In this paper, we focus on the indicators related to how pain is managed and assessed. The average achievement of the goal of pain relief across all centers was 72.2% (SD: 21.1). We found a statistically significant trend of more effective pain management scores, routine assessment, proper documentation, and involvement of pain management experts by increasing country income. While there are efforts being made worldwide to improve the knowledge in pain assessment and management, there is a lack of resources to do so appropriately in low-middle-income countries. There is a mismatch between the existing guidelines and policies, which are mainly designed in high income countries, and the resources available in lower resourced environments.

Aim: To describe the impact of extracorporeal membrane oxygenation (ECMO) assisted CPR (E-CPR) on cerebral oxygen delivery during in-hospital cardiac arrest (IHCA). Methods: Retrospective case series from a tertiary academic medical center. Regional cerebral oxygen saturation (rSO2) was measured continuously using cerebral oximetry in six patients who experienced IHCA. During CPR, the time of E-CPR initiation was recorded, and rSO2 values were subsequently analyzed for a period beginning 5 min before and ending 2.5 min after the initiation of E-CPR. Results: The average rSO2 value in the 2.5 min period following E-CPR initiation increased by 20.8% as compared to the 5-min period before E-CPR initiation. Conclusions: ECMO can be employed in parallel with cerebral rSO2 monitoring during CPR for adult IHCA patients. E-CPR is associated with rapid and significant increases in brain oxygen delivery.

Cerebral amyloid angiopathy-related inflammation (CAA-ri) is an immune-mediated disorder of the central nervous system characterized by an inflammatory response to amyloid-beta (Aβ) deposition within cerebral blood vessel walls. Immunosuppressive therapy is the mainstay of treatment. We present a case of CAA-ri in a subject already on immunosuppressive therapy after orthotopic heart transplantation (OHT). A 57-year-old man 8 months post-OHT for sarcoid cardiomyopathy developed headaches and staring spells while hospitalized for disseminated mycobacterial infection. His brain MRI revealed bi-hemispheric T2-weighted fluid-attenuated inversion recovery white matter hyperintensities and widespread microhemorrhages. Two weeks later, he developed gait ataxia and alterations in mental status, and repeat brain MRI showed more extensive confluent white matter hyperintensities. Leptomeningeal and cortex biopsy revealed changes consistent with amyloid angiitis, with perivascular and intramural histiocyte and lymphocyte collections. Mass spectroscopy confirmed Aβ deposition. Notably, the patient was on immunosuppression with daily 5 mg oral prednisone and tacrolimus before biopsy. After high-dose intravenous followed by oral corticosteroids, he demonstrated significant clinical and radiographic improvement. No relapse was noted despite the relatively rapid tapering of the prednisone therapy over 3 months, as mandated by his systemic infection. Despite the lack of a standard treatment protocol for CAA-ri, case series have reinforced the benefit of prolonged courses of glucocorticoids as single agent or in combination with other immunomodulatory agents. Hence, management of CAA-ri in patients with disseminated mycobacterial infections or OHT is challenging. Our case is unique, as review of existing literature has not revealed any similar cases of patients on chronic immunosuppression at the time of CAA-ri diagnosis, which one would expect to protect against this disorder. In addition, CAA-ri in association with cardiopulmonary sarcoidosis was not previously reported; however, a common immunopathogenic mechanism may exist.

Background Combined heart and kidney transplantation (HKTx) is performed in patients with severe heart failure and advanced renal insufficiency. We analyzed the long‐term survival after HKTx, the influence of age and dialysis status, the rates of cardiac rejection, and the influence of sensitization. Methods and Results From June 1992 to December 2016, we performed 100 HKTx procedures. We compared older (≥60 years, n=53) with younger (50%, and compared these survival rates with those from the United Network for Organ Sharing database. There was no difference in 15‐year survival between the 2 age groups (35±12.4% and 49±17.3%, ≥60 versus 0 or antibody‐mediated rejection>0) was 92±2.8% and 84±3.8%, acute cellular rejection (≥2R/3A) 98±1.5% and 94±2.5%, and antibody‐mediated rejection (≥1) 96±2.1% and 93±2.6% at 30 days and 1 year after HKTx. There was no difference in the 5‐year survival among recipients by sensitization status with panel‐reactive antibody levels 50% (82±5.9%, 83±10.8%, and 92±8.0%; P=0.55). There was no difference in 15‐year survival after HKTx between the United Network for Organ Sharing database and our center (38±3.2% and 40±10.1%, respectively; P=0.45). Conclusions HKTx is safe to perform in patients 60 years and older or younger than 60 years and with or without dialysis dependence, with excellent outcomes. The degree of panel‐reactive antibody sensitization did not appear to affect survival after HKTx.

Background/AimsTo investigate the various etiologies, yields, and effects of capsule endoscopy (CE) on management and complications, along with follow up of patients with obscure gastrointestinal (GI) bleeding.MethodsThe study group of patients included those having obscure, overt, or occult GI bleeding. The findings were categorized as (A) obvious/definitive, (B) equivocal, or (C) negative. Any significant alteration in patient management post CE in the form of drug or surgical intervention was noted.ResultsTotal patients included in the study were 68 (48 males and 20 females). The ratio of male:female was 2.4:1. The age ranged between 16 years to 77 years. Mean age for males was 62±14 years, for females 58±16 years. The total yield of CE with definitive lesions was in 44/68 (65.0%) of patients. In descending order (A) angiodysplasia 16/68 (23.53%), (B) Crohn's disease 10/68 (14.70%), (C) non-steroidal anti-inflammatory drug enteropathy 8/68 (11.76%), (D) small bowel ulcers 4/68 (5.88%), (E) jejunal and ileal polyps 2/68 (2.94%), (F) intestinal lymphangiectasis 2/68 (2.94%), and (G) ileal hemangiomas 2/68 (2.94%) were followed. Equivocal findings 12/68 (17.65%) and negative study 12/68 (17.65%) was found. Complications in the form of capsule retention in the distal ileum were noted in 2/68 (2.94%) subjects. Statistically, there was a higher probability of finding the etiology if the CE was done during an episode of bleeding.ConclusionsCE plays an important role in diagnosing etiologies of obscure GI bleeding. Its role in influencing the management outcome is vital.

Increased demand of farm products and depletion of natural resources compel the agriculture community to increase the use of Information and Communication Technology (ICT) in various farming processes. Agricultural Decision Support Systems (DSS) proved useful in this regard. The majority of available Agricultural DSSs are either crop or task specific. Less emphasis has been placed on the development of comprehensive DSS, which are non-specific regarding crops or farming processes. The crop or task specific DSSs are mainly developed with rule based or knowledge transfer based approaches. The DSSs based on these methodologies lack the ability for scaling up and generalization. The Knowledge engineering modeling approach is more suitable for the development of large and generalized DSS. Unfortunately the model based knowledge engineering approach is not much exploited for the development of Agricultural DSS. CommonKADS is one of the popular modeling frameworks used for the development of Knowledge Based System (KBS). The paper presents the organization, agent, task, communication, knowledge and design models based on the CommonKADS approach for the development of scalable Agricultural DSS. A specific web based DSS application is used for demonstrating the multi agent CommonKADS modeling approach. The system offers decision support for irrigation scheduling and weather based disease forecasting for the popular crops of India. The proposed framework along with the required expert knowledge, provides a platform on which the larger DSS can be built for any crop at a given location.

Introduction: Improving tissue oxygenation is one of most important tasks in management of low cardiac output. Central venous oxygen saturation (ScvO2 ) and lactate are established criteria for monitoring the adequacy of tissue oxygenation. The venous-to-arterial carbon dioxide difference [P(v-a)CO2 ] is inversely associated with cardiac output. Aim: To study the use of P(v-a)CO2 /C(a-v)O2 ratio as a marker of low cardiac output during Cardiopulmonary Bypass (CPB) in paediatric cardiac surgical patients. Materials and Methods: The present study was a prospective observational study conducted over a period of nine months from 1st August 2015 to 30th April 2016. A total of 110 children were enrolled, who underwent CPB during cardiac surgery. The CPB time, Mean Arterial Pressure (MAP), flow rate, cross clamp time, were recorded for all the patients as well as Arterial Blood Gas (ABG) and Venous Blood Gas (VBG) were checked at four different points of time: 1) Before CPB, 2) 10 minutes after initiation of CPB, 3) 30 minutes on CPB and 4) off CPB. Results: The results indicated that Receiver Operating Characteristic curve (ROC curve) at 30 minute of CPB time P(v-a)CO2 /C(a-v)O2 was more specific and sensitive than lactate to detect anaerobic metabolism. Decrease platelet count was significant on second postoperative day. Conclusion: The present study suggests the use of P(v-a) CO2 /C(a-v)O2 ratio as a marker to detect low flow on CPB. Our study was single centric and with a small size, studies involving large population and multiple centers are required to support the recent findings.

Rickettsial infections continue to cause serious morbidity and mortality in severe human cases around the world. Host cell adhesion and invasion is an essential requisite for intracellular growth, replication, and subsequent dissemination of pathogenic rickettsiae. Heparan sulfate proteoglycans [HSPGs] facilitate the interactions between fibroblast growth factor(s) and their tyrosine kinase receptors resulting in receptor dimerization/activation and have been implicated in bacterial adhesion to target host cells. In the present study, we have investigated the contributions of fibroblast growth factor receptors [FGFRs] in rickettsial entry into the host cells. Inhibition of HSPGs by heparinase and FGFRs by AZD4547 (a selective small-molecule inhibitor) results in significant reduction in rickettsial internalization into cultured human microvascular endothelial cells (ECs), which represent the primary targets of pathogenic rickettsiae during human infections. Administration of AZD4547 during R. conorii infection in a murine model of endothelial-target spotted fever rickettsiosis also diminishes pulmonary rickettsial burden in comparison to mock-treated controls. Silencing of FGFR1 expression using a small interfering RNA also leads to similar inhibition of R. rickettsii invasion into ECs. Consistent with these findings, R. rickettsii infection of ECs also results in phosphorylation of tyrosine 653/654, suggesting activation of FGFR1. Using isobaric tag for relative and absolute quantitation [iTRAQ]-based proteomics approach, we further demonstrate association of β-peptide of rickettsial outer membrane protein OmpA with FGFR1. Mechanistically, FGFR1 binds to caveolin-1 and mediates bacterial entry via caveolin-1 dependent endocytosis. Together, these results identify host cell FGFR1 and rickettsial OmpA as another novel receptor-ligand pair contributing to the internalization of pathogenic rickettsiae into host endothelial cells and the potential application of FGFR-inhibitor drugs as adjunct therapeutics against spotted fever rickettsioses.

Endothelial cell interactions with lipopolysaccharide (LPS) involve both activating and repressing signals resulting in pronounced alterations in their transcriptome and proteome. Noncoding RNAs are now appreciated as posttranscriptional and translational regulators of cellular signaling and responses, but their expression status and roles during endothelial interactions with LPS are not well understood. We report on the expression profile of long noncoding (lnc) RNAs of human microvascular endothelial cells in response to LPS. We have identified a total of 10,781 and 8310 lncRNA transcripts displaying either positive or negative regulation of expression, respectively, at 3 and 24 h posttreatment. A majority of LPS-induced lncRNAs are multiexonic and distributed across the genome as evidenced by their presence on all chromosomes. Present among these are a total of 44 lncRNAs with known regulatory functions, of which 41 multiexonic lncRNAs have multiple splice variants. We have further validated splice variant-specific expression of EGO (NONHSAT087634) and HOTAIRM1 (NONHSAT119666) at 3 h and significant upregulation of lnc-IL7R at 24 h. This study illustrates the genome-wide regulation of endothelial lncRNA splice variants in response to LPS and provides a foundation for further investigations of differentially expressed lncRNA transcripts in endothelial responses to LPS and pathophysiology of sepsis/septic shock.

Accurate estimation of evapotranspiration (ETo) is a key factor in weather-based irrigation scheduling methods. To estimate ETo using the Hargreaves equation, just the data on the minimum and maximum temperature and solar radiation are required. However, this procedure cannot offer consistent accuracy for different climate conditions. To attain the accuracy, calibration of the equation constants (CHand EH) for different climate conditions have successfully been attempted by many researchers. Because these calibration procedures are lengthy and location-specific, there is a need of a generalized calibration method to make the Hargreaves equation more pertinent and effective. In this paper, fuzzy logic based calibration method for the Hargreaves equation is proposed and validated. The fuzzy inference system is developed to compute appropriate values of the constants CHand EH on the basis of past data on humidity and wind velocity of a selected location. The underlying relationship between weather conditions and the best values of the constants CHand EH are used to establish a fuzzy rule base. The performance of the method is checked at eight geographically different locations of India with diverse climate conditions. The Mean Absolute Error (MAE) in ETovalues estimated by the calibrated modified Hargreaves equation and the Penman-Monteith (PM) equation is in the range of 0.3220-1.0325. It is far more lower than if the error is calculated using the original Hargreaves equation. It confirms the correctness of the calibration method for different climate conditions.

Introduction: Calcium pyrophosphate crystal deposition disease (CPPD) is the most common form of crystal arthropathy second only to gout. Common clinical presentation is an acute monoarticular arthritis commonly occurring in knee joints. We presented a case of bilateral olecranon bursitis in a calcium pyrophosphate crystal deposition disease. Case Report: A 42-year-old female patient is presented with golf ball sized painless swellings in the posterior aspect of her elbows. Elbow joints were clinically normal except for restriction of terminal flexion. X-ray showed mild erosion at the tip of olecranon. Excision biopsy of the swelling showed positive birefringent calcium pyrophosphate dehydrate crystals on the inner wall of the specimen on polarized light microscopy. Conclusion: Bilateral olecranon bursitis may be part of the extraarticular manifestations of calcium pyrophosphate dihydrate crystal deposition disease with good prognosis following in toto bursa excision

Microvascular endothelial cells (ECs) represent the primary target cells during human rickettsioses and respond to infection via the activation of immediate⁻early signaling cascades and the resultant induction of gene expression. As small noncoding RNAs dispersed throughout the genome, microRNAs (miRNAs) regulate gene expression post-transcriptionally to govern a wide range of biological processes. Based on our recent findings demonstrating the involvement of fibroblast growth factor receptor 1 (FGFR1) in facilitating rickettsial invasion into host cells and published reports suggesting miR-424 and miR-503 as regulators of FGF2/FGFR1, we measured the expression of miR-424 and miR-503 during R. conorii infection of human dermal microvascular endothelial cells (HMECs). Our results revealed a significant decrease in miR-424 and miR-503 expression in apparent correlation with increased expression of FGF2 and FGFR1. Considering the established phenomenon of endothelial heterogeneity and pulmonary and cerebral edema as the prominent pathogenic features of rickettsial infections, and significant pathogen burden in the lungs and brain in established mouse models of disease, we next quantified miR-424 and miR-503 expression in pulmonary and cerebral microvascular ECs. Again, R. conorii infection dramatically downregulated both miRNAs in these tissue-specific ECs as early as 30 min post-infection in correlation with higher FGF2/FGFR1 expression. Changes in the expression of both miRNAs and FGF2/FGFR1 were next confirmed in a mouse model of R. conorii infection. Furthermore, miR-424 overexpression via transfection of a mimic into host ECs reduced the expression of FGF2/FGFR1 and gave a corresponding decrease in R. conorii invasion, while an inhibitor of miR-424 had the expected opposite effect. Together, these findings implicate the rickettsial manipulation of host gene expression via regulatory miRNAs to ensure efficient cellular entry as the critical requirement to establish intracellular infection.

Eosinophilic gastroenteritis is characterized histologically by eosinophilic infiltration of the gut wall and clinically manifests by gastrointestinal (GI) symptoms. A high index of suspicion is required for the early diagnosis of this uncommon disease in patients who have concomitant GI symptoms and peripheral eosinophilia. This unusual case who initially had duodenal ulcer with duodenal stenosis, responded to Helicobacter pylori treatment and dilatation. He was symptom free for 2 years. Subsequently, developed evanescent eosinophilic gastritis and recurrent H. pylori infection with refractory prepyloric ulceration, but no duodenal stenosis. Eosinophilic gastritis and H. pylori infection initially responded to treatment, but subsequently the patient developed nonhealing prepyloric ulcer and refractory H. pylori infection and had persistent symptoms; all these necessitated surgical intervention consisting of antrectomy with gastrojejunostomy.

Abstract Cystatin 9 (CST9) is a member of the type 2 cysteine protease inhibitor family, which has been shown to have immunomodulatory effects that restrain inflammation, but its functions against bacterial infections are unknown. Here, we report that purified human recombinant (r)CST9 protects against the deadly bacterium Francisella tularensis (Ft) in vitro and in vivo. Macrophages infected with the Ft human pathogen Schu 4 (S4), then given 50 pg of rCST9 exhibited significantly decreased intracellular bacterial replication and increased killing via preventing the escape of S4 from the phagosome. Further, rCST9 induced autophagy in macrophages via the regulation of the mammalian target of rapamycin (mTOR) signaling pathways. rCST9 promoted the upregulation of macrophage proteins involved in antiinflammation and antiapoptosis, while restraining proinflammatory-associated proteins. Interestingly, the viability and virulence of S4 also was decreased directly by rCST9. In a mouse model of Ft inhalation, rCST9 significantly decreased organ bacterial burden and improved survival, which was not accompanied by excessive cytokine secretion or subsequent immune cell migration. The current report is the first to show the immunomodulatory and antimicrobial functions of rCST9 against Ft. We hypothesize that the attenuation of inflammation by rCST9 may be exploited for therapeutic purposes during infection.

Introduction: Tendinopathy is a major medical problem associated with sports and physical activity in active people over 25 years of age. We study about the effect of PRP in the patients of chronic Tendinopathy. Methods: From the patients of chronic tendinopathy who failed medical treatment for last 3 months, platelet rich plasma is prepared from patient's own blood. After giving platelet rich plasma injection, patient is advised to take rest for 3 weeks with analgesics. Physiotherapy is started after 3 weeks of injection as this is causing pain for first 3 weeks. Patients are advised to join their duty after 3 weeks of injection. All the patients were followed up in OPD at 3 weeks, 6 weeks, 3 months and 6 months. At every follow up, range of motion, visual analogue scale and functional activity score recorded. Results: The follow up shows that most of the patients do not get relief within 3 weeks after injection. Follow up shows that 16 patients out of 50 got relief within 6 weeks after injection. Result shows that 46 patients out of 50 get relief within 6 months after injection. That means 94% of patients are having relief within 6 months of injection. Conclusion:The findings of this study shows that platelet rich plasma injection under ultrasound guidance at the tendon is effective mode of treatment for patients and takes time but result in gradual decrease in symptoms.

MicroRNAs (miRNAs) mediate gene silencing by destabilization and/or translational repression of target mRNA. Infection of human microvascular endothelial cells as primary targets of Rickettsia rickettsii, the etiologic agent of Rocky Mountain spotted fever, triggers host responses appertaining to alterations in cellular gene expression. Microarray-based profiling of endothelial cells infected with R. rickettsii for 3 or 24 h revealed differential expression of 33 miRNAs, of which miRNAs129-5p, 200a-3p, 297, 200b-3p, and 595 were identified as the top five up-regulated miRNAs (5 to 20-fold, p ≤ 0.01) and miRNAs 301b-3p, 548a-3p, and 377-3p were down-regulated (2 to 3-fold, p ≤ 0.01). Changes in the expression of selected miRNAs were confirmed by q-RT-PCR in both in vitro and in vivo models of infection. As potential targets, expression of genes encoding NOTCH1, SMAD2, SMAD3, RIN2, SOD1, and SOD2 was either positively or negatively regulated. Using a miRNA-specific mimic or inhibitor, NOTCH1 was determined to be a target of miRNA 200a-3p in R. rickettsii-infected human dermal microvascular endothelial cells (HMECs). Predictive interactome mapping suggested the potential for miRNA-mediated modulation of regulatory gene networks underlying important host cell signaling pathways. This first demonstration of altered endothelial miRNA expression provides new insights into regulatory elements governing mechanisms of host responses and pathogenesis during human rickettsial infections.

BACKGROUND:Pre-exposure chemoprophylaxis (PrECP) using antiretroviral agents is a promising strategy for the prevention of sexual HIV transmission in women. Molecular transporters in the human vaginal tract (VT) may play a pivotal role in determining drug disposition and, consequently, pharmacodynamic outcomes in these efforts. Little is known, however, on the expression of these transporters in vaginal tissues, representing a critical knowledge gap. METHODOLOGY/PRINCIPAL FINDINGS:Our study analyzed the genome-wide transcriptome in 44 vaginal tissue samples from 6 reproductive-age women undergoing gynecologic surgeries. The analysis revealed that, unexpectedly, a large number (43%) of gene isoforms corresponding to membrane transporters were over-expressed (above the median expression level) in all samples. A subset of 12 highly expressed membrane transporters was identified and contained 10 members (83%) of the solute carrier superfamily. The largest difference in membrane transporter gene expression was observed across subjects, but more subtle differential expression also was found along the anterior-posterior axis of the VT. Cross-validation of the microarray analyses with measurements RT-qPCR demonstrated high concordance between these data sets. Immunofluorescence labeling of membrane transporter proteins in vaginal tissues was highly dependent on tissue/cell types. CONCLUSIONS/SIGNIFICANCE:Antiretroviral PrECP drugs currently under evaluation are substrates for molecular transporters that were commonly expressed, but fell into both over- or under-expressed categories in all samples, suggesting a complex role for carrier-mediated processes in determining the disposition of these xenobiotics in vaginal tissues. These findings hold important implications for the successful development of products, either oral or intravaginal, for female-controlled HIV PrECP.

Bacteria release flagellin that elicits innate responses via Toll-like receptor 5 (TLR5). Here, we investigated the fate of apically administrated full length flagellin from virulent and avirulent bacteria, along with truncated recombinant flagellin proteins in intestinal epithelial cells and cellular responses. Flagellin was internalized by intestinal epithelial cell (IEC) monolayers of IEC-18. Additionally, apically applied flagellin was internalized by polarized human Caco-2BBe and T-84 cells in a TLR5 dependent mechanism. More, flagellin exposure did not affect the integrity of intestinal monolayers. With immunofluorescent staining, internalized flagellin was detected in both early endosomes as well as lysosomes. We found that apical exposure of polarized Caco-2BBe and T-84 to flagellin from purified Salmonella, Escherichia coli O83:H1 (isolate from Crohn's lesion) or avirulent E. coli K12 induced comparable levels of basolateral IL-8 secretion. A recombinant protein representing the conserved amino (N) and carboxyl (C) domains (D) of the flagellin protein (ND1/2ECHCD2/1) induced IL-8 secretion from IEC similar to levels elicited by full-length flagellins. However, a recombinant flagellin protein containing only the D3 hypervariable region elicited no IL-8 secretion in both cell lines compared to un-stimulated controls. Silencing or blocking TLR5 in Caco-2BBe cells resulted in a lack of flagellin internalization and decreased IL-8 secretion. Furthermore, apical exposure to flagellin stimulated transepithelial migration of neutrophils and dendritic cells. The novel findings in this study show that luminal-applied flagellin is internalized by normal IEC via TLR5 and co-localizes to endosomal and lysosomal compartments where it is likely degraded as flagellin was not detected on the basolateral side of IEC cultures.