Cancer-Associated Fibroblast Induces Acinar-to-Ductal Cell Transdifferentiation and Pancreatic Cancer Initiation Via LAMA5/ITGA4 Axis.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by desmoplastic stroma surrounding most tumors. Activated stromal fibroblasts, namely cancer-associated fibroblasts (CAFs), play a major role in PDAC progression. We analyzed whether CAFs influence acinar cells and impact PDAC initiation, that is, acinar-to-ductal metaplasia (ADM). ADM connection with PDAC pathophysiology is indicated, but not yet established. We hypothesized that CAF secretome might play a significant role in ADM in PDAC initiation. METHODS: Mouse and human acinar cell organoids, acinar cells cocultured with CAFs and exposed to CAF-conditioned media, acinar cell explants, and CAF cocultures were examined by means of quantitative reverse transcription polymerase chain reaction, RNA sequencing, immunoblotting, and confocal microscopy. Data from liquid chromatography with tandem mass spectrometry analysis of CAF-conditioned medium and RNA sequencing data of acinar cells post-conditioned medium exposure were integrated using bioinformatics tools to identify the molecular mechanism for CAF-induced ADM. Using confocal microscopy, immunoblotting, and quantitative reverse transcription polymerase chain reaction analysis, we validated the depletion of a key signaling axis in the cell line, acinar explant coculture, and mouse cancer-associated fibroblasts (mCAFs). RESULTS: A close association of acino-ductal markers (Ulex europaeus agglutinin 1, amylase, cytokeratin-19) and mCAFs (α-smooth muscle actin) in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1Cre (KPC) and LSL-KrasG12D/+; Pdx1Cre (KC) autochthonous progression tumor tissue was observed. Caerulein treatment-induced mCAFs increased cytokeratin-19 and decreased amylase in wild-type and KC pancreas. Likewise, acinar-mCAF cocultures revealed the induction of ductal transdifferentiation in cell line, acinar-organoid, and explant coculture formats in WT and KC mice pancreas. Proteomic and transcriptomic data integration revealed a novel laminin α5/integrinα4/stat3 axis responsible for CAF-mediated acinar-to-ductal cell transdifferentiation. CONCLUSIONS: Results collectively suggest the first evidence for CAF-influenced acino-ductal phenotypic switchover, thus highlighting the tumor microenvironment role in pancreatic carcinogenesis inception.

Malondialdehyde-Acetaldehyde Extracellular Matrix Protein Adducts Attenuate Unfolded Protein Response During Alcohol and Smoking-Induced Pancreatitis.

BACKGROUND & AIMS: Epidemiological studies have established alcohol and smoking as independent risk factors for recurrent acute pancreatitis and chronic pancreatitis. However, the molecular players responsible for the progressive loss of pancreatic parenchyma and fibroinflammatory response are poorly characterized. METHODS: Tandem mass tag-based proteomic and bioinformatics analyses were performed on the pancreata of mice exposed to alcohol, cigarette smoke, or a combination of alcohol and cigarette smoke. Biochemical, immunohistochemistry, and transcriptome analyses were performed on the pancreatic tissues and primary acinar cells treated with cerulein in combination with ethanol (50 mmol/L) and cigarette smoke extract (40 µg/mL) for the mechanistic studies. RESULTS: A unique alteration in the pancreatic proteome was observed in mice exposed chronically to the combination of alcohol and cigarette smoke (56.5%) compared with cigarette smoke (21%) or alcohol (17%) alone. The formation of toxic metabolites (P < .001) and attenuated unfolded protein response (P < .04) were the significantly altered pathways on combined exposure. The extracellular matrix (ECM) proteins showed stable malondialdehyde-acetaldehyde (MAA) adducts in the pancreata of the combination group and chronic pancreatitis patients with a history of smoking and alcohol consumption. Interestingly, MAA-ECM adducts significantly suppressed expression of X-box-binding protein-1, leading to acinar cell death in the presence of alcohol and smoking. The stable MAA-ECM adducts persist even after alcohol and smoking cessation, and significantly delay pancreatic regeneration by abrogating the expression of cyclin-dependent kinases (CDK7 and CDK5) and regeneration markers. CONCLUSIONS: The combined alcohol and smoking generate stable MAA-ECM adducts that increase endoplasmic reticulum stress and acinar cell death due to attenuated unfolded protein response and suppress expression of cell cycle regulators. Targeting aldehyde adducts might provide a novel therapeutic strategy for the management of recurrent acute pancreatitis and chronic pancreatitis.

Single-incision needle-knife biopsy for the diagnosis of GI subepithelial tumors: a systematic review and meta-analysis.

BACKGROUND AND AIMS: A histologic diagnosis of GI subepithelial tumors (SETs) is important because of the malignant potential of these lesions. The current modalities of choice, including EUS-guided FNA and biopsy (EUS-FNA/FNB) have demonstrated suboptimal diagnostic success. Single-incision with needle-knife (SINK) biopsy has emerged as an alternative diagnostic approach to increase tissue acquisition and diagnostic success. The aim of this study was to perform a systematic review and meta-analysis to evaluate the technical success, diagnostic success, and adverse events of SINK biopsy. METHODS: We searched multiple databases including PubMed, EMBASE, CINAHL, Cochrane, Web of Science, and Google Scholar from inception to July 2022. The primary outcomes assessed were the technical success and diagnostic success of SINK in GI SETs. The secondary outcomes assessed were adverse events and whether immunohistochemical analysis could be successfully performed on tissue samples obtained via SINK. RESULTS: Seven studies with a total of 219 SINK biopsy procedures were included in this meta-analysis. The technical success rate was 98.1% (95% CI, 94.9%-99.3%; P = .000; I2 = .0%), and the diagnostic success rate was 87.9% (95% CI, 82.6%-91.7%; P = .000; I2 = .0%). The immunohistochemical success rate was 88.3% (95% CI, 78.7%-93.9%; P = .000; I2 = 3.5%). The rate of adverse events was 7.5% (95% CI, 4.3%-12.7%; P = .00; I2 = 7.2%), and bleeding was the most common adverse event. CONCLUSION: SINK biopsy is a safe diagnostic procedure with a high technical and diagnostic success in patients with GI SET. Further randomized controlled trials and direct comparison studies are needed to validate these findings.

New Alternative? Self-Assembling Peptide in Gastrointestinal Bleeding: A Systematic Review and Meta-Analysis.

BACKGROUND: Gastrointestinal bleeding (GIB) is a common and potentially fatal condition with all-cause mortality ranging from 3 to 10%. Endoscopic therapy traditionally involves mechanical, thermal, and injection therapies. Recently, self-assembling peptide (SAP) has become increasingly available in the United States. When applied to an affected area, this gel forms an extracellular matrix-type structure allowing for hemostasis. This is the first systematic review and meta-analysis to assess the safety and efficacy of this modality in GIB. METHODS: We performed a comprehensive literature search of major databases from inception to Nov 2022. The primary outcomes assessed were the success of hemostasis, rebleeding rates, and adverse events. The secondary outcomes assessed were successful hemostasis with monotherapy with SAP and combined therapy, which may include mechanical, injection, and thermal therapies. Pooled estimates were calculated using random-effects models with a 95% confidence interval (CI). RESULTS: The analysis included 7 studies with 427 patients. 34% of the patients were on anticoagulation or antiplatelet agents. SAP application was technically successful in all patients. The calculated pooled rate of successful hemostasis was 93.1% (95% confidence interval (CI) 84.7-97.0, I2 = 73.6), and rebleeding rates were 8.9% (95% CI 5.3-14.4, I2 = 55.8). The pooled rates of hemostasis with SAP monotherapy and combined therapy were similar. No adverse events were noted related to SAP. CONCLUSION: SAP appears to be a safe and effective treatment modality for patients with GIB. This modality provides an added advantage of improved visualization over the novel spray-based modalities. Further, prospective, or randomized controlled trials are needed to validate our findings.

Evaluation of sustainable e-waste collection method for urban and rural region of India.

Electronic waste is one of the most challenging waste streams to manage. It has become a significant concern in developing countries due to the ever-increasing volume of generation coupled with deficient growth in collection and processing infrastructure. For the various stakeholders, it is of paramount importance to adopt a robust and sustainable collection method for hazard mitigation. The prevalent e-waste collection methods are categorized under four major heads, namely take-back, retail store, door-to-door and curbside collection. The e-waste collection problems are analysed from various perspective, based on literature that cited developing country-specific survey and data that includes India. Economic sustainability and potential risk are included as attributes in the evaluation scheme. We attempt to establish a decision-making model. Discussion with the field experts and decision-makers (DMs) provided the weights for various attributes and sub-attributes. A fuzzy linguistic scale is used to take care of ambiguity in DMs' opinion. Fuzzy- Analytical Hierarchy Process (FAHP) is used to determine the importance of various attributes and sub-attributes, while Fuzzy-VlseKriterijumska Optimizacija I Kompromisno Resenje (FVIKOR) is used to determine the rank of the alternatives. Based on the analysis, 'take-back collection' and 'retail store based collection' are found the most suitable options for urban and rural regions respectively. The attributes, social awareness and economical sustainability are found to have the highest significance in both cases. Implementation of a collection method is an expensive activity, and the proposed Fuzzy-Multi Attribute Decision Making attempts to capture various attributes and their complex interplay to arrive at a decision on optimum e-waste collection option(s) in a specific locality.

Adenoma and polyp detection rates during insertion versus withdrawal phase of colonoscopy: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Colonoscopy is the preferred modality for colorectal cancer screening because it has both diagnostic and therapeutic capabilities. Current consensus states that colonoscopy should be performed with initial rapid passage of the instrument to the cecum, followed by thorough evaluation for and removal of all polyps during a deliberate slow withdrawal. Reports have suggested that polyps that are seen but not removed during insertion are sometimes quite difficult to find during withdrawal. METHODS: We performed a comprehensive literature search of several major databases (from inception to March 2020) to identify randomized controlled trials comparing inspection and polypectomy during the insertion phase as opposed to the traditional practice of inspection and polypectomy performed entirely during the withdrawal phase. We examined differences in terms of adenoma detection rate (ADR), polyps detected per patient (PDPP), cecal intubation time (CIT), withdrawal time, and total procedure time. RESULTS: Seven randomized controlled trials, including 3834 patients, were included in our final analysis. The insertion/withdrawal cohort had 1951 patients and the withdrawal-only cohort 1883 patients. Pooled odds of adenoma detection in the insertion/withdrawal cohort was .99 (P = .8). ADR was 47.2% in the insertion/withdrawal cohort and 48.6% in the withdrawal-only cohort. Although total procedure and withdrawal times were shorter in the insertion/withdrawal cohort, PDPP in both cohorts were not statistically significant (1.4 vs 1.5, P = .7). CONCLUSIONS: Additional inspection and polypectomy during the insertion and withdrawal phases of colonoscopy offer no additional benefit in terms of ADR or PDPP.

Application of DEA-Based Malmquist Productivity Index on Health Care System Efficiency of ASEAN Countries.

This study assesses and compares the productive efficiency of the national healthcare system of the ASEAN region which includes Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand and Vietnam amidst rising mortality rate from noncommunicable diseases (NCDs) in the Sustainable Development Goals (SDGs) era. Nonparametric data envelopment analysis technique based on the Malmquist Productivity Index is performed and its components, total factor productivity change, technical change and technological change are compared across the region. Two different models are considered in assessing and comparing the technical efficiency of the national healthcare system across the region with life expectancy at birth and mortality rate from NCDs as parallel health care output for both the models. The mean value of total factor productivity is 0.983 and 0.974 which suggests that national healthcare system productivity efficiency decays by 1.7% for Model I and 2.6% for Model II, respectively. This suggests that the health care system inefficiencies across the ASEAN region have not made life expectancy to improve as much as it should be and curtailed the mortality rate from growing chronic NCDs within a decade. The region is likely to lag behind in achieving SDGs 3 target 4 on reducing by one-third premature mortality from chronic NCDs unless the health care system's technical efficiency is improved across the region. The finding suggests a microlevel study on each country to identify major sources of healthcare system inefficiency in a bid to ameliorate it.

Performance of echocardiography for detection of portopulmonary hypertension among liver transplant candidates: Meta-analysis.

BACKGROUND: Evaluation of pulmonary arterial pressure is crucial among cirrhotic patients, considering that moderate portopulmonary hypertension (POPH) is a contraindication for liver transplantation. Although right heart catheterization (RHC) is the most accurate method to diagnose POPH, it is invasive. OBJECTIVE: The aim of the study is to evaluate the performance of echocardiography in detecting POPH in liver transplant candidates. METHODS: A Literature search was performed, and pooled sensitivity, specificity, positive likelihood ratio (LR), negative LR, and area under the summary receiver operating curve (AUC) were calculated. Subgroup analyses were performed based on different cutoff values for echocardiography and diagnostic criteria of RHC. RESULTS: Sensitivity, specificity, positive LR, negative LR, and AUC of echocardiography for detection of POPH were 0.86 (0.74, 0.94), 0.87 (0.84, 0.90), 7.17 (3.59, 14.31), 0.22 (0.13, 0.38), and 0.807 while they were 0.82 (0.74, 0.89), 0.81 (0.78, 0.84), 117.75 (16.03, 865.08), 0.28 (0.16, 0.50), and 0.876for detection of moderate POPH, respectively. Performance of echocardiography was not significantly different in the subgroup analyses of stringency of POPH criteria and pulmonary arterial systolic pressure (ePASP) cutoffs. CONCLUSIONS: Our meta-analysis supports utilization of echocardiography for screening of POPH. However, RHC remains essential in highly suspicious cases. Echocardiographic data other than ePASP should be evaluated in future studies.

A Combination of MUC5AC and CA19-9 Improves the Diagnosis of Pancreatic Cancer: A Multicenter Study.

OBJECTIVES: Pancreatic cancer (PC) is a lethal malignancy that lacks specific diagnostic markers. The present study explores the diagnostic potential of the most differentially overexpressed secretory mucin MUC5AC alone and in combination with CA19-9 using multi-center training and validation sets. METHODS: The expression of MUC5AC in benign pancreatic pathologies, PC precursor lesions, primary PC tissues and metastatic lesions was evaluated by immunohistochemistry. Circulating MUC5AC levels were measured using sandwich ELISA assay developed in-house, and CA19-9 was measured using radioimmunoassay. A combined training set (n=346) was used to evaluate the diagnostic (n=241) and predictive (n=105, total samples 201 from pre- and post-surgical and chemotherapy set) significance of MUC5AC. Results were further validated with a pre-defined cut-off value using independent sets from the Mayo Clinic (n=94) and the University of Pittsburgh Medical Center (n=321). RESULTS: Tissue expression analyses indicated the de novo expression of MUC5AC in pancreatic intraepithelial precursor lesions 1A (PanIN1A); the expression was maintained through all stages of progression to invasive adenocarcinoma. The median circulating MUC5AC levels in patients with resectable early-stage PC (EPC) (stage 1/2; 67.2 ng/ml, IQR: 23.9-382.1) and unresectable late-stage PC (LPC) (stage 3/4; 389.7 ng/ml, IQR: 87.7-948.6) were significantly higher compared with (P-value ≤0.0001) benign controls (BC) (7.2 ng/ml, IQR: 0.4-26.5) and (P-value ≤0.0001) chronic pancreatitis (CP) controls (8.4 ng/ml, IQR: 1.5-19.2). In the diagnostic training set (n=241), MUC5AC efficiently differentiated EPC from healthy controls (HC) (83%/80% sensitive (SN)/specific (SP)), BC (67%/87% SN/SP), and CP (83%/77% SN/SP). Independent validation sets from the Mayo Clinic and UPMC confirmed the diagnostic potential of MUC5AC to differentiate EPC from BC (68%/73%; 65%/83%) and CP (68%/79%; 65%/72%). Furthermore, MUC5AC and CA19-9 combination significantly improved (p-value < 0.001) the diagnostic accuracy for differentiating resectable cases from controls. CONCLUSIONS: MUC5AC is a valuable diagnostic biomarker, either alone or in combination with CA19-9, to differentiate PC from CP and benign controls.

Relationship of acute axonal damage, Wallerian degeneration, and clinical disability in multiple sclerosis.

BACKGROUND: Axonal damage and loss substantially contribute to the incremental accumulation of clinical disability in progressive multiple sclerosis. Here, we assessed the amount of Wallerian degeneration in brain tissue of multiple sclerosis patients in relation to demyelinating lesion activity and asked whether a transient blockade of Wallerian degeneration decreases axonal loss and clinical disability in a mouse model of inflammatory demyelination. METHODS: Wallerian degeneration and acute axonal damage were determined immunohistochemically in the periplaque white matter of multiple sclerosis patients with early actively demyelinating lesions, chronic active lesions, and inactive lesions. Furthermore, we studied the effects of Wallerian degeneration blockage on clinical severity, inflammatory pathology, acute axonal damage, and long-term axonal loss in experimental autoimmune encephalomyelitis using Wallerian degeneration slow (Wld S ) mutant mice. RESULTS: The highest numbers of axons undergoing Wallerian degeneration were found in the perilesional white matter of multiple sclerosis patients early in the disease course and with actively demyelinating lesions. Furthermore, Wallerian degeneration was more abundant in patients harboring chronic active as compared to chronic inactive lesions. No co-localization of neuropeptide Y-Y1 receptor, a bona fide immunohistochemical marker of Wallerian degeneration, with amyloid precursor protein, frequently used as an indicator of acute axonal transport disturbance, was observed in human and mouse tissue, indicating distinct axon-degenerative processes. Experimentally, a delay of Wallerian degeneration, as observed in Wld S mice, did not result in a reduction of clinical disability or acute axonal damage in experimental autoimmune encephalomyelitis, further supporting that acute axonal damage as reflected by axonal transport disturbances does not share common molecular mechanisms with Wallerian degeneration. Furthermore, delaying Wallerian degeneration did not result in a net rescue of axons in late lesion stages of experimental autoimmune encephalomyelitis. CONCLUSIONS: Our data indicate that in multiple sclerosis, ongoing demyelination in focal lesions is associated with axonal degeneration in the perilesional white matter, supporting a role for focal pathology in diffuse white matter damage. Also, our results suggest that interfering with Wallerian degeneration in inflammatory demyelination does not suffice to prevent acute axonal damage and finally axonal loss.

Endoscopic Bubble Trouble: Hyperbaric Oxygen Therapy for Cerebral Gas Embolism During Upper Endoscopy.

Gas embolism is a rare but potentially devastating complication of endoscopic procedures. We describe 3 cases of gas embolism which were associated with endoscopic procedures (esophagogastroduodenoscopy and endoscopic retrograde cholangiopancreatography). We treated these at our hyperbaric medicine center with 3 different outcomes: complete resolution, death, and disability. We review the literature regarding this unusual complication of endoscopy and discuss the need for prompt identification and referral for hyperbaric oxygen therapy. Additional adjunctive therapies are also discussed.

Duodenocaval Fistula: Unmasking the Rare Culprit of Gastrointestinal Hemorrhage.

Duodenocaval fistula is an extremely rare and life-threatening cause of gastrointestinal hemorrhage and septicemia. Diagnosing this condition is challenging due to its nonspecific symptoms, leading to significant delays in diagnosis and contributing to its remarkably high mortality rate. We present a unique case of duodenocaval fistula associated with prior radiation, peptic ulcer disease, and antiangiogenic cancer therapy, nearly resulting in the death of a young patient.

Effect of work from home and employee mental health through mediating role of workaholism and work-family balance.

BACKGROUND: The current global outbreak caused by COVID-19 has produced a unique situation with severe health and financial consequences. The fast and quick global impact called for an immediate response. A key public health action was the decision to amend the law to allow employees to work from home (WFH) whenever it was possible. In response to public health restrictions to stop the spread of COVID-19, organizations quickly switched to WFH without fully comprehending the effects of continued WFH on mental and physical health. Working from anywhere and at any time has made the separation between business and personal life more difficult. These modifications may cause employees' workdays to be longer and to experience greater work-life conflict. Overwork and work addiction provide a greater risk to the public's health and can harm various facets of mental and physical health, such as depression, anxiety, and sleep difficulties. There hasn't been much research on the underlying processes that link workaholism to poor mental health, especially among Indian academics. PURPOSE: There is a rise in the number of people who are worried about their mental health in academic settings. The primary purpose of this study is to determine whether academicians in India can potentially have a healthy work-family balance, which may mitigate the negative impacts of workaholism and poor mental health especially due to the Work from Home system. METHODOLOGY: A population-based study was conducted on academicians (n = 456) at private and public universities in Delhi NCR, India. Workaholism, work-family balance, and mental health difficulties were all measured using self-reported scales in the study. By using path analysis, the proposed mediation model was evaluated. The survey responses had an accuracy rate of 80%. Based on the conceptual research framework, PLS-SEM path modeling is used to find the causal connection between the indicators and latent components. FINDINGS: The findings indicated that workaholism has been associated with mental health in two different ways: directly and through work-family balance. The path analysis found a statistically significant relationship between work from home and mental health through workaholism and work-family balance. Increased levels of anxiety, depression, stress, headaches, exhaustion, and reduced job satisfaction were some of the mental health consequences of Work from Home. PRACTICAL IMPLICATION: This study provides real-world guidance to human resource managers on how to prioritize composite-level interventions at all levels of the university to create highly satisfied employees, provide a good working environment, and improve employees' mental health. ORIGINALITY/VALUE: Many researches have been done on the relationship between work-from-home and employee mental health, but relatively few have looked at how work-life balance and workaholism play a role in how work-from-home affects employees' mental health. This study fills a need in the academic and practitioner literature by investigating the relationship between work-from-home from home and employee mental health as well as the mediating function of work-family balance and workaholism with regard to Indian higher education institutions.

Using the Rendezvous Technique Through Choledochoduodenostomy for Malignant Biliary Obstruction.

Endoscopic transpapillary biliary stenting via endoscopic retrograde cholangiopancreatography is the preferred therapy for benign and malignant distal biliary obstruction. In cases of failed endoscopic retrograde cholangiopancreatography, endoscopic ultrasound-guided choledochoduodenostomy has been shown to be as effective as percutaneous methods with an improved safety profile. Despite its efficacy, it is complicated by stent occlusion in 9%-26% of cases. To our knowledge, this is the first case in which biliary obstruction was relieved by performing a rendezvous procedure utilizing a pre-existing choledochoduodenostomy.

A quasi-experimental study on health insurance coverage and health services in Nigeria.

BACKGROUND: Nigeria has the highest maternal mortality rate among sub-Saharan African countries. Recently, universal health insurance coverage has been embraced as a means to enhance population health in low- and middle-income countries. Hitherto, the effect of health insurance coverage on the utilisation of facility-level delivery is largely unknown in the face of the earnest need to lower maternal mortality rates in developing countries. AIM: To empirically investigate the association of health insurance coverage on health services utilisation of facility-level delivery and the extent to which public- and private-sector facility delivery in Nigeria had a disproportionate associational effect with health insurance coverage, in the universal health coverage era. SETTING: A cross-sectional study conducted for Nigeria. METHODS: This study employed a quasi-experimental method using propensity scores along with different matching methods that were applied to the most recent wave of Nigeria's Demographic and Health Survey (2020) data. RESULTS: Evidence suggests that childbearing mothers from insured households had an average of 25% probability of utilising facility-level delivery relative to mothers from uninsured households in the year that preceded the survey. Moreover, private-sector facility delivery had a 31% higher associational effect with health insurance coverage than public-sector facility delivery, which had an estimated probability of 21%. CONCLUSION: Expansion of health insurance coverage in Nigeria will be a desirable way to stimulate the utilisation of facility-level delivery by women of childbearing age. Consequently, coverage expansion has the potential to save many maternal and newborn lives in Nigeria.Contribution: This study has contributed to the urgent attention of the federal government of Nigeria to monitor and revamp the health insurance coverage policies of the country for better facilitation of health services to the Nigerian population.

Endoscopic ultrasound-guided portal pressure gradient measurement: a systematic review and meta-analysis.

Background: Endoscopic ultrasound-guided portal pressure gradient measurement (EUS-PPG) is a new modality where the portal pressure is measured by directly introducing a needle into the hepatic vein and portal vein. This is the first systematic review and meta-analysis to evaluate the efficacy and safety of EUS-PPG. Methods: A comprehensive literature search was performed to identify pertinent studies. The primary outcomes assessed were the technical and clinical success of EUS-PPG. Technical success was defined as successful introduction of the needle into the desired vessel, while clinical success was defined as the correlation of the stage of fibrosis on the liver biopsy to EUS-PPG, or concordance of HVPG and EUS-PPG. The secondary outcomes were pooled rates for total and individual adverse events related to EUS-PPG. Pooled estimates were calculated using random-effects models with a 95% confidence interval (CI). Results: Eight cohort studies with a total of 178 patients were included in our analysis. The calculated pooled rates of technical success and clinical success were 94.6% (95%CI 88.5-97.6%; P=<0.001; I2=0) and 85.4% (95%CI 51.5-97.0%; P=0.042; I2=70), respectively. The rate of total adverse events was 10.9% (95%CI 6.5-17.7%; P=<0.001; I2=4), and 93.7% of them were mild, as defined by the American Society for Gastrointestinal Endoscopy. Abdominal pain (11%) was the most common adverse event, followed by bleeding (3.6%). There were no cases of perforation or death reported in our study. Conclusions: EUS-PPG is a safe and effective modality for diagnosing portal hypertension. Further randomized controlled trials are needed to validate our findings.

Microglial nodules in early multiple sclerosis white matter are associated with degenerating axons.

Microglial nodules in the normal-appearing white matter have been suggested as the earliest stage(s) of multiple sclerosis (MS) lesion formation. Such nodules are characterized by an absence of leukocyte infiltration, astrogliosis or demyelination, and may develop into active demyelinating MS lesions. Although the etiology of MS is still not known, inflammation and autoimmunity are considered to be the central components of this disease. Previous studies provide evidence that Wallerian degeneration, occurring as a consequence of structural damage in MS lesions, might be responsible for observed pathological abnormalities in connected normal-appearing white matter. As innate immune cells, microglia/macrophages are the first to react to even minor pathological changes in the CNS. Biopsy tissue from 27 MS patients and autopsy and biopsy tissue from 22 normal and pathological controls were analyzed to determine the incidence of microglial nodules. We assessed MS periplaque white matter tissue from early disease stages to determine whether microglial nodules are associated with altered axons. With immunohistochemical methods, the spatial relation of the two phenomena was visualized using HLA-DR antibody for MHC II expression by activated microglia/macrophages and by applying antibodies against damaged axons, i.e., SMI32 (non-phosphorylated neurofilaments) and amyloid precursor protein as well as neuropeptide Y receptor Y1, which marks axons undergoing Wallerian degeneration. Our data demonstrate that the occurrence of microglial nodules is not specific to MS and is associated with degenerating as well as damaged axons in early MS. In addition, we show that early MS microglial nodules exhibit both pro- and antiinflammatory phenotypes.

Stochastic frontier approach to efficiency analysis of health facilities in providing services for non-communicable diseases in eight LMICs.

BACKGROUND: The rising burden of non-communicable diseases presents an increasing public health challenge to many low- and middle-income countries. This problem may be compounded in health systems with lower levels of technical efficiency (TE). METHODS: This study used recent Service Provision Assessments data to estimate the level of TEs of health facilities in eight countries. Initially, the general and disease-specific service readiness indexes are estimated. Finally, the production function is estimated using the exposures and the outcomes of the model. RESULTS: Evidence shows that the general and disease-specific service readiness indexes are significantly associated with an increase in the number of outpatient visits. Outpatient visits may increase by 14% with an increase in health worker density. Similarly, outpatient visits may increase by 0.3% with a unit increase in the general and diabetes service readiness indexes. Furthermore, outpatient visits may increase by 0.4% and 0.8% with an increase in services readiness for cardiovascular and respiratory diseases. respectively. Overall, the level of TE score suggests the need for improvement. CONCLUSIONS: Facility-level service readiness for chronic diseases is quite low. Therefore, improving health outcomes related to chronic diseases requires urgent investment in high-quality health systems in these countries.

Ultrathin, biodegradable polymer-coated everolimus-eluting stents for patients undergoing percutaneous coronary intervention: Final three-year results of the PERFORM-EVER registry.

The registry reports 3-year safety and clinical performance of the ultrathin strut (60 µm) biodegradable polymer-coated Tetrilimus, an everolimus-eluting stent (EES) (Sahajanand Medical Technologies Limited, India), in 'real-world' patients with coronary artery disease. A total of 815 Tetrilimus EES were implanted in 735 lesions in 594 patients. At 3-year follow-up, primary endpoint (target lesion failure, TLF) was reported in 8.6 % patients, including 2.6 % cardiac deaths, 3.5 % myocardial infarction and 2.6 % target lesion revascularization. At three-year, no cases of definite stent thrombosis were reported. The final three-year results of PERFORM-EVER registry endorse the continuous safety and effectiveness Tetrilimus EES.

Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation.

BACKGROUND: In brain tissues from multiple sclerosis (MS) patients, clusters of activated HLA-DR-expressing microglia, also referred to as preactive lesions, are located throughout the normal-appearing white matter. The aim of this study was to gain more insight into the frequency, distribution and cellular architecture of preactive lesions using a large cohort of well-characterized MS brain samples. METHODS: Here, we document the frequency of preactive lesions and their association with distinct white matter lesions in a cohort of 21 MS patients. Immunohistochemistry was used to gain further insight into the cellular and molecular composition of preactive lesions. RESULTS: Preactive lesions were observed in a majority of MS patients (67%) irrespective of disease duration, gender or subtype of disease. Microglial clusters were predominantly observed in the vicinity of active demyelinating lesions and are not associated with T cell infiltrates, axonal alterations, activated astrocytes or blood-brain barrier disruption. Microglia in preactive lesions consistently express interleukin-10 and TNF-α, but not interleukin-4, whereas matrix metalloproteases-2 and -9 are virtually absent in microglial nodules. Interestingly, key subunits of the free-radical-generating enzyme NADPH oxidase-2 were abundantly expressed in microglial clusters. CONCLUSIONS: The high frequency of preactive lesions suggests that it is unlikely that most of them will progress into full-blown demyelinating lesions. Preactive lesions are not associated with blood-brain barrier disruption, suggesting that an intrinsic trigger of innate immune activation, rather than extrinsic factors crossing a damaged blood-brain barrier, induces the formation of clusters of activated microglia.