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Autophagy, a cellular self-digestion process, involves the degradation of targeted cell components such as damaged organelles, unfolded proteins, and intracellular pathogens by lysosomes. It is a major quality control system of the cell and plays an important role in cell differentiation, survival, development, and homeostasis. Alterations in the cell autophagic machinery have been implicated in several disease conditions, including neurodegeneration, autoimmunity, cancer, infection, inflammatory diseases, and aging. In non-alcoholic fatty liver disease, including its inflammatory form, non-alcoholic steatohepatitis (NASH), a decrease in cell autophagic activity, has been implicated in the initial development and progression of steatosis to NASH and hepatocellular carcinoma (HCC). We present an overview of autophagy as it occurs in mammalian cells with an insight into the emerging understanding of the role of autophagy in NASH and NASH-related HCC.

Metabolic dysfunction-associated steatohepatitis (MASH) is one of the major risk factors for chronic liver disease and hepatocellular carcinoma (HCC). The incidence of MASH in Western countries continues to rise, driving HCC as the third cause of cancer-related death worldwide. HCC has become a major global health challenge, partly from the obesity epidemic promoting metabolic cellular disturbances but also from the paucity of biomarkers for its early detection. Over 50% of HCC cases are clinically present at a late stage, where curative measures are no longer beneficial. Currently, there is a paucity of both specific and sensitive biological markers for the early-stage detection of HCC. The search for biological markers in the diagnosis of early HCC in high-risk populations is intense. We described the potential role of surrogates for a liver biopsy in the screening and monitoring of patients at risk for nesting HCC.

Acute cholecystitis is increasingly managed by laparoscopic cholecystectomy. Some reports have shown conversion and complication rates that are increased in comparison to elective laparoscopic cholecystectomy. This study reviews the combined experience of two hospitals where the intention was to perform early laparoscopic cholecystectomy for acute cholecystitis. A total of 152 cases of laparoscopic cholecystectomy for acute cholecystitis (evidence of acute inflammation clinically and pathologically) were identified. Conversion to open cholecystectomy was required in 14 cases (9%) in the total series. Laparoscopic cholecystectomy was performed within 2 days of admission in 76% (115 of 152) of patients. Conversion was significantly less likely in patients undergoing laparoscopic cholecystectomy within 2 days of admission (4 of 115) compared to those undergoing surgery beyond 2 days (10 of 37; P <0.0001). Eleven patients (7%) had postoperative complications; however, there were no cases of injury to the biliary system and no perioperative deaths. This series shows that laparoscopic cholecystectomy can be performed safely in patients with acute cholecystitis and suggests that early laparoscopic cholecystectomy is preferable to delaying surgery. Although the conversion rate to open surgery is higher than for elective cholecystectomy, the majority of patients (91%) still derive the well-recognized benefits of laparoscopic cholecystectomy. Early laparoscopic cholecystectomy is an acceptable approach to acute cholecystitis for the experienced laparoscopic surgeon.

Objectives We used the Global Burden of Disease (GBD) 2015 study results to explore the burden of high body mass index (BMI) in the Eastern Mediterranean Region (EMR). Methods We estimated the prevalence of overweight and obesity among children (2–19 years) and adults (≥20 years) in 1980 and 2015. The burden of disease related to high BMI was calculated using the GBD comparative risk assessment approach. Results The prevalence of obesity increased for adults from 15.1% (95% UI 13.4–16.9) in 1980 to 20.7% (95% UI 18.8–22.8) in 2015. It increased from 4.1% (95% UI 2.9–5.5) to 4.9% (95% UI 3.6–6.4) for the same period among children. In 2015, there were 417,115 deaths and 14,448,548 disability-adjusted life years (DALYs) attributable to high BMI in EMR, which constitute about 10 and 6.3% of total deaths and DALYs, respectively, for all ages. Conclusions This is the first study to estimate trends in obesity burden for the EMR from 1980 to 2015. We call for EMR countries to invest more resources in prevention and health promotion efforts to reduce this burden.

IgG and mucous glycoprotein are proteins that accelerate nucleation of cholesterol crystals from bile. A relative increase in biliary deoxycholate level appears to be a risk factor for cholesterol gallstone formation. To determine the relationship between deoxycholate and IgG, glyco and tauro conjugated deoxycholates were measured in human gallbladder bile. Cholesterol gallstone patients had a higher concentration of biliary IgG compared to the pigmented stone group and control patients and this appeared to be associated with the simultaneous presence of two conditions: supersaturated bile with cholesterol and high deoxycholate/cholate ratio. To support this observation, animal studies were performed to determine whether a shift in bile salt profile toward deoxycholate plus changes in the cholesterol saturation had an effect on the secretion of IgG by porcine gallbladder epithelium. Cholesterol supersaturated model bile with high content of TDC produces gallbladder epithelial alterations which increase the concentration of intraluminal IgG and mucous glycoprotein. Experimental data supports the observation that both, increased relative proportion of deoxycholates and cholesterol supersaturation of gallbladder bile, results in higher concentration of the potent nucleator IgG in man.

Sight depends on the tight cooperation between photoreceptors and pigmented cells, which derive from common progenitors through the bifurcation of a single gene regulatory network into the neural retina (NR) and retinal-pigmented epithelium (RPE) programs. Although genetic studies have identified upstream nodes controlling these networks, their regulatory logic remains poorly investigated. Here, we characterize transcriptome dynamics and chromatin accessibility in segregating NR/RPE populations in zebrafish. We analyze cis-regulatory modules and enriched transcription factor motives to show extensive network redundancy and context-dependent activity. We identify downstream targets, highlighting an early recruitment of desmosomal genes in the flattening RPE and revealing Tead factors as upstream regulators. We investigate the RPE specification network dynamics to uncover an unexpected sequence of transcription factors recruitment, which is conserved in humans. This systematic interrogation of the NR/RPE bifurcation should improve both genetic counseling for eye disorders and hiPSCs-to-RPE differentiation protocols for cell-replacement therapies in degenerative diseases. The gene regulatory network controlling the bifurcation of common progenitors into the neural retina and retinal-pigmented epithelium programs remains poorly understood. Here the authors study transcriptome dynamics and chromatin accessibility during this process in zebrafish, revealing network redundancy, as well as context-dependent and sequential transcription factor activity.

Normal pressure hydrocephalus (NPH) leads to cognitive impairment (CI) as part of its triad of symptoms. Assessment of CI before and after a tap test can be used to inform diagnosis, differentiate NPH symptoms from alternative or concomitant causes of CI, and suggest the potential benefits of valve placement. The aims of this study are: to describe cognitive performance in patients with NPH diagnosis before and after a tap test, and to compare CI between patients with NPH meeting criteria for a dementia diagnosis (D +) and those without criteria for dementia (D−) at both baseline and after the tap-test. We performed a Before-and-after study evaluating clinical features and performance on cognitive tests (CERAD, ADAS-COG, SVF, PVF, ROCF and IFS). We included 76 NPH patients, with a median age of 81 years. 65 patients (87.8%) improved cognitive performance after tap test. ROCF (p = 0.018) and IFS (p < 0.001) scores significantly change after the tap test. Dementia was concomitant in 68.4% of patients. D + group showed higher proportion of patients with altered performance in IFS, PVF, SVF, and ROCF than D- group at baseline (p < 0.05). A significant improvement in SVF and IFS was observed exclusively in the D− group after tap test. Our results suggest that executive function and praxis are the cognitive domains more susceptible to improvement after a tap test in a 24-h interval in NPH patients. Moreover, the D− group showed a higher proportion of improvement after the tap test in executive function and verbal fluency test compared with the D + group.

•Updating strategies can be optimized with prioritization processes that help identify CGs, CG sections, CQs, or recommendations in the greatest need for updating.•We recently developed the UpPriority tool, a pragmatic tool for prioritizing CG questions for updating. The tool was based on a published methodological systematic review and a multistep process involving relevant stakeholders.•We applied the UpPriority tool to a set of CGs using a step-by-step process that included: 1) establishment of the UpPriority Implementation Working Group, 2) mapping of the CG questions and recommendations, 3) development of a survey to prioritize CQs, 4) assessment of CQ's priority according to six items, 5) calculation and ranking of priority scores, 6) decision of prioritized CQs for updating, and 7) development of the priority report. We assessed the tool implementation process (appraisers’ experience when using the tool) and the inter-observer reliability of the tool, and we provided suggestions for improvement.•The UpPriority is a useful tool to identify which CQs within a CG need to be prioritized for update in a real-world scenario. We aim to 1) use the UpPriority tool to identify which clinical questions (CQs) within the clinical guidelines (CGs) need to be prioritized for updating and 2) assess the implementation of the tool in a real-world set of CGs. We systematically assessed CQs from a sample of CGs developed in the Spanish National Health System CG program. We applied the UpPriority tool to each CG using a step-by-step process that included: 1) establishment of the UpPriority Implementation Working Group, 2) mapping of the original CG questions and recommendations, 3) development of a survey to prioritize CQs, 4) assessment of CQ's priority according to six items, 5) calculation and ranking of priority scores, 6) decision of prioritized CQs for updating, and 7) development of the priority report. We assessed the tool implementation process (appraisers’ experience when using the tool) and the inter-observer reliability of the tool, and we provided suggestions for improvement. We included four CGs with a total of 107 CQs on the following topics: chronic heart failure (10 CQs), inherited retinal dystrophies (39 CQs), menopause (20 CQs), and open-angle glaucoma (38 CQs). We included a total of 30 participants, most of them clinicians that were members of the original CG development groups. CQs were classified in three groups: 1) high priority (CQs prioritized for updating [16/107; 15.0%]), 2) medium priority (CQs that could be prioritized for updating [47/107; 43.9%]), and low priority (CQs that were not prioritized for updating [44/107; 41.1%]). The mean time each appraiser needed to assess the CQs with the tool was 3.8 hours (range 0.5 to 10). Agreement among the appraisers varied among the CGs. Appraisers considered that the tool was useful. We suggest some areas for consideration when using the tool including: 1) identification of key appraisers, 2) customization of training materials, 3) establishment of priority thresholds, and 4) provision of methodological support. The UpPriority is a useful tool to identify which CQs within a CG need to be prioritized for update in a real-world scenario. Recruitment and training of topic experts are the main challenges when using the tool.

El estudio se enfoca en examinar el derecho a la autodeterminación en situaciones terminales de enfermedad, subrayando su conexión con el principio de dignidad humana arraigado en la legislación ecuatoriana. Cuando las personas enfrentan sufrimientos físicos y emocionales insostenibles debido a enfermedades terminales, el suicidio puede ser contemplado como una opción para buscar una muerte con dignidad. Los profesionales médicos a menudo se encuentran con pacientes que no pueden tomar decisiones informadas sobre su atención médica, lo que resalta la importancia de evaluar la competencia de estos pacientes en términos de su capacidad para tomar decisiones relacionadas con su salud, incluyendo la comprensión, la libertad y la voluntariedad.