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Metabolic Dysfunction-Associated Steatotic Liver Disease in Adults: A Review
No full textImportance Metabolic dysfunction-associated steatotic liver disease (MASLD) includes a range of liver conditions, progressing from isolated steatosis (characterized by fat accumulation in the liver without inflammation) to metabolic dysfunction-associated steatohepatitis (MASH), which involves fat accumulation and inflammation in the liver. The presence of MASLD is associated with increased morbidity and mortality due to liver-related complications, hepatocellular carcinoma, cardiovascular disease, and certain extrahepatic cancers. Observations The most common chronic liver disease worldwide, MASLD affects approximately 30% to 40% of the general adult population globally (with varying prevalence across continents), including approximately 60% to 70% of individuals with type 2 diabetes and approximately 70% to 80% of those with obesity. It is typically diagnosed based on an ultrasonographic finding of hepatic steatosis, along with at least 1 of 5 features of the metabolic syndrome (abdominal overweight or obesity, prediabetes or type 2 diabetes, hypertension, elevated level of plasma triglycerides, and low level of high-density lipoprotein cholesterol) for women who consume less than 140 g/wk of alcohol (<2 standard drinks/d) and for men who consume less than 210 g/wk (<3 standard drinks/d) and have no other known causes of steatosis such as use of a particular medication (eg, corticosteroids, tamoxifen, or methotrexate), hepatitis C, or iron overload. Other risk factors for MASLD include older age (>= 50 years) and male sex (male:female ratio approximately 2). The Fibrosis-4 index (a scoring system incorporating age, serum levels of aspartate aminotransferase and alanine aminotransferase, and platelet count) and vibration-controlled transient elastography (a noninvasive imaging technique) are commonly used to stage hepatic fibrosis in patients with MASLD. Cardiovascular disease is the leading cause of death, followed by certain extrahepatic cancers (primarily gastrointestinal, breast, and gynecologic cancer) and liver-related complications, including cirrhosis, hepatic decompensation (ascites, hepatic encephalopathy, or variceal bleeding), and hepatocellular carcinoma. First-line treatment of MASLD involves behavioral modifications (including hypocaloric low-carbohydrate and low-fat diets, physical exercise, and avoidance of alcohol) and management of type 2 diabetes, obesity, hypertension, and hyperlipidemia. Bariatric surgery should be considered for patients with MASLD and a body mass index greater than 35. Resmetirom (a liver-directed, thyroid hormone receptor beta-selective agonist) and subcutaneous semaglutide (a glucagon-like peptide-1 receptor agonist) are conditionally approved by the US Food and Drug Administration (FDA) for the treatment of adults with MASH who have moderate to advanced fibrosis. Conclusions A highly prevalent condition among adults worldwide, MASLD is associated with liver-related complications, hepatocellular carcinoma, cardiovascular disease, and certain extrahepatic cancers. First-line treatment includes behavioral modifications, including a weight-reducing diet, physical exercise, and avoidance of alcohol. Resmetirom and semaglutide are conditionally FDA-approved medications for the treatment of adults with MASH and moderate to advanced fibrosis
OCT-Based Differentiation of First Acute Optic Neuritis: An International Study of 111 Patients With NMOSD and MOGAD
No full textBackground and objectives: Severe optic neuritis (ON) is a common clinical manifestation in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD). Given distinct prognoses and often the necessity of early plasma exchange in NMOSD, prompt differentiation is crucial. In this study, we investigated the utility of optical coherence tomography (OCT) in differentiating between first acute NMOSD-ON and MOGAD-associated optic neuritis (MOGAD-ON), as well as specific factors associated with disc edema. Methods: In this retrospective multicenter study, 111 adult patients with MOGAD or aquaporin-4 antibody-positive NMOSD who experienced a first ON and underwent OCT within 2 weeks of symptom onset were included from 14 centers across 8 countries. Peripapillary retinal nerve fiber layer (pRNFL) thickness in μm was analyzed, including the average of both eyes in cases of bilateral manifestation. Results: Eighty-three patients with MOGAD (51 women; 124 ON eyes; bilateral ON 48.2%) and 28 with NMOSD (24 women; 36 ON eyes; bilateral ON 21.4%) were enrolled. A significant increase in pRNFL thickness (>2SD), suggestive of disc edema, was observed in 73.4% of MOGAD-ON eyes and 11.1% of NMOSD-ON eyes (p < 0.001). The pRNFL thickness cutoff of 117.5 μm provided 92.9% specificity and 71.1% sensitivity in distinguishing between MOGAD-ON and NMOSD-ON (area under the curve = 0.838). There was no association between pRNFL thickening and MOG-IgG titer (high vs low), body mass index, or the delay between ON onset and OCT. Simultaneous bilateral MOGAD-ON was associated with significantly more pronounced pRNFL thickening. Discussion: Acute-stage OCT contributes to the rapid and accurate differentiation between MOGAD-ON and NMOSD-ON prior to antibody confirmation, which can be critical for timely therapeutic decisions
When suicide mimics homicide: a forensic analysis of three cases involving multiple sharp-force injuries
No full textSuicide by multiple sharp-force injuries represents an uncommon and diagnostically complex occurrence in forensic pathology. The presence of numerous stab or incised wounds can mimic homicidal patterns, especially when typical self-inflicted indicators are absent or unclear. Differentiating between suicide and homicide in such cases requires a multidisciplinary assessment involving autopsy findings, scene investigation, and psychological history. We report three rare cases of suicide involving multiple sharp-force injuries. Case 1: A 44-year-old man with a history of depression and alcohol abuse was found in an advanced state of decomposition at home. Twelve stab wounds were located on the precordial and epigastric regions, with hesitation marks on the forearm and no evidence of third-party involvement. Case 2: A 32-year-old woman with bulimia nervosa was discovered supine in her kitchen, with a blood-stained kitchen knife nearby. Twelve parallel stab wounds were observed in the precordial region and left breast, with pulmonary artery transection and massive haemothorax. No hesitation or defensive wounds were noted. Case 3: A 39-year-old man, recently affected by bereavement-related depression, was found in his garage gripping a kitchen knife. He sustained 25 sharp-force injuries across the neck and abdomen, including jugular vein transection and tracheal perforation. Hesitation wounds were present on the palmar aspects of the fingers. Despite the high number of wounds, several factors (anatomical accessibility, presence of hesitation marks, lack of defence injuries, and psychiatric histories) supported a suicidal manner of death. These cases emphasise the critical need for integrated forensic evaluations in distinguishing suicides from potential homicides
GY971 mitigates inflammation by reducing neutrophil recruitment in cystic fibrosis Ex Vivo and In Vivo models
No full textBackground: There is a prominent need for anti-inflammatory agents for people with Cystic Fibrosis (pwCF), even in the era of CFTR modulators. ETI (Elexacaftor/Tezacaftor/Ivacaftor) reduces but does not eliminate pulmonary inflammation, that chronically damages CF pulmonary tissues and favors recurrent pulmonary exacerbations. Furthermore, although known anti-inflammatory drugs are beneficial to pwCF, their side effects are limiting the clinical use. To address this issue, we developed a new synthetic furocoumarin molecule named GY971, able to reduce the excessive accumulation of neutrophils in the bronchial lumen, by targeting the NF-κB transcription factor (TF). Methods: To assess its efficacy, GY971 was tested in human primary bronchial and nasal epithelial cells obtained ex vivo from different pwCF carrying the F508del mutation and infected with Pseudomonas aeruginosa. Moreover, GY971 was also administered in a zebrafish model infected with P. aeruginosa in vivo. Results: GY971 reduced neutrophil chemotaxis mediators both in CF bronchial epithelial cell lines and in CF primary bronchial and nasal epithelial cells ex vivo. The expression of key inflammatory proteins involved in CF lung disease, including IL-8, IL-1β, TNF-α and IL-6, was significantly reduced using nanomolar concentrations of GY971. Importantly, GY971 does not interfere with the ETI-mediated rescue of CFTR protein and showed no cytotoxic effects. Lastly, in vivo testing with a zebrafish model confirmed its effectiveness: GY971 decreased neutrophil recruitment in treated larvae across different concentrations, supporting earlier results from murine studies. Conclusions: GY971 appears to be a promising molecule for the future development of combinatorial anti-inflammatory treatments together with ETI
Professionalizzazione dell’amministrazione locale e diritto alla partecipazione politica nella recente giurisprudenza costituzionale sudafricana
No full textIl tema della politicizzazione dell’amministrazione pubblica locale è da tempo al centro di un
rilevante dibattito sia politico sia giuridico in Sudafrica. Il presente contributo ricostruisce i più rilevanti rifessi di tale dibattito sul piano costituzionale, facendo in particolare riferimento alla sentenza della Corte Costituzionale che ha recentemente dichiarato illegittima la norma che vietava a tutti i dipendenti dell’amministrazione pubblica locale di rivestire cariche politiche di partito
Occupational exposures and incidence of asthma over two decades in the European Community Respiratory Health Survey
No full textBackground: While short-term occupational exposures to many agents are associated with increased risk of asthma, the long-term consequences of exposure have not been well understood. We investigated the effects of occupational exposures over two decades on the incidence of asthma. Methods: This population-based, multicentre cohort was assessed at baseline (European Community Respiratory Health Survey (ECRHS)1) and followed up twice over 20 years (ECRHS2 and ECRHS3). This analysis included data for 5591 participants with complete work histories and free of asthma at baseline. Incident adult-onset asthma was defined as either an asthma attack, woken by an attack of shortness of breath and/or current asthma medication in the last 12 months before each timepoint, without asthma at a previous survey. An updated asthma-specific job exposure matrix was used to estimate exposures to asthmagens. Adjusted Poisson models were fitted with generalised estimating equations to estimate asthma incidence. Results: Ever high exposure to high molecular weight sensitisers (rate ratio (RR)=1.31; 95% CI 1.15 to 1.63), irritants (RR=1.29; 1.09-1.54), biocides (RR=1.42; 1.12-1.79), only low exposure to low molecular weight sensitisers (RR=1.26; 1.08-1.47), mites (RR=1.48; 1.12-1.94) and reactive chemicals (RR=1.24; 1.06-1.45) were associated with increased incidence of asthma. Asthma incidence also increased with ever high or cumulative exposure to these exposures and for specific exposure to wood dust, cleaning agents and bleach. The population-attributable fraction for adult-onset asthma due to occupational exposures was 18% (16.9-19.4%). Conclusion: This strengthens the evidence that occupational exposures to sensitisers and chemical irritants contribute substantial risk and a substantive attributable fraction of adult-onset asthma. Control of implicated hazardous exposures and periodic screening of exposed workers should be considered
Placebo Responses in Trials of Functional Neurologic Disorders
No full textFunctional Neurologic Disorders (FNDs) are prevalent in neurology and emergency settings, causing significant disability and economic burden. Diagnosis relies on positive clinical signs rather than exclusion of organic diseases. Treatment includes education, physiotherapy, and cognitive behavioral therapy, although evidence for efficacy is mixed with the few placebo-controlled trials available. The role of placebo in FNDs is debated, with anecdotal cases and a few studies suggesting therapeutic benefits and possible shared pathways between placebo effect and FND symptoms. Ethical concerns relate to deception versus beneficence, especially given limited treatment access
Robust feedback control of collisional plasma dynamics in presence of uncertainties
No full textMagnetic fusion aims to confine high-temperature plasma within a device, enabling the fusion of deuterium and tritium nuclei to release energy. Due to the very large temperatures involved, it is essential to isolate the plasma from the device walls to prevent structural damage and the external magnetic fields play a fundamental role in achieving this confinement. In realistic settings, the physical mechanisms governing plasma behavior are highly complex, involving numerous uncertain parameters and intricate particle interactions, such as collisions, that significantly affect both confinement efficiency and overall stability. In this work, we address particularly these challenges by proposing a robust feedback control strategy designed to steer the plasma towards a desired spatial region, despite the presence of uncertainties. From a modeling perspective, we consider a collisional plasma described by a Vlasov-Poisson-BGK system, which accounts for a self-consistent electric field and a strong external magnetic field, while incorporating uncertainty in the model. A key feature of the proposed control strategy is its independence from the random parameter, making it particularly suitable for practical applications. A series of numerical simulations confirms the effectiveness of our approach and demonstrates the ability of external magnetic fields to successfully confine plasma away from the device boundaries, even in the presence of uncertain conditions
Evaluating allocations of opportunities
No full textThis paper provides a robust criterion for comparing lists of probability distributions - interpreted as allocations of opportunities - faced by different social groups. Borrowing from decision making under objective ambiguity, we axiomatically argue in favour of comparing those lists of probability distributions on the basis of a uniform - among groups - valuation of their expected utility. We identify an empirically implementable criterion - extended zonotope inclusion - for comparing allocations of opportunities that coincide with the unanimity of all such uniform valuations of expected utility that exhibit aversion to inequality of opportunity. We illustrate our criterion by evaluating allocations of educational opportunities among castes and genders in 14 Indian states
Utility of the Amygdalar Atrophy Scale to Identify Patients With Limbic-Predominant Age-Related TDP-43 Encephalopathy in a Memory Clinic
No full textBackground and Objectives Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a neurodegenerative condition often overlapping clinically with Alzheimer disease (AD). No established in vivo biomarkers exist for LATE. The amygdalar atrophy scale (AAS) is a visual MRI rating tool scoring the amygdala as AAS(0) (no atrophy), AAS(1) (mild-to-moderate atrophy), or AAS(2) (severe atrophy) and is associated with TDP-43 neuropathology in limbic regions. This study describes the clinical, neuroimaging, and longitudinal cognitive profiles of individuals classified using a proposed framework that combines the AAS with established AD biomarkers. Methods This retrospective study included individuals attending the Geneva Memory Center (2014-2022) who underwent T1-weighted MRI, as well as clinical and neuropsychological assessments. Participants were categorized with an etiologic grouping defined as No-AD/No-LATE (AAS(0), negative AD biomarkers), AD (AAS(0), positive AD biomarkers), LATE (AAS(1-2), negative AD biomarkers), or AD/LATE (AAS(1-2), positive AD biomarkers). Group differences were compared using Kruskal-Wallis or chi(2) tests. Differences in MRI brain volumes and cortical thickness between groups were examined with analysis of covariance. Cognitive trajectories using Mini-Mental State Examination (MMSE) scores over 30 months were estimated with linear mixed-effects models accounting for baseline age and education. Results The analytic sample included 469 participants (mean age 71.2 +/- 8.5 years, 53% female). The No-AD/No-LATE group exhibited the highest MMSE scores (N = 181, 27.9 +/- 2.2), outperforming AD (N = 146, 24.2 +/- 4.9), LATE (N = 36, 26.2 +/- 3.2), and AD/LATE (N = 106, 22.5 +/- 5.3) groups (p < 0.001). On the Free and Cued Selective Reminding Test, the No-AD/No-LATE group showed the highest scores (15.1 +/- 1.8); the LATE and AD groups performed similarly (13.3 +/- 3.5 and 12.5 +/- 4.0), both exceeding the AD/LATE group (10.6 +/- 4.1) (p < 0.001). LATE and AD/LATE groups showed lower volumes/thicknesses in TDP-43-related regions compared with AD and No-AD/No-LATE groups. Longitudinally, the LATE group maintained cognitive stability as the No-AD/No-LATE group (beta = -0.010, 95% CI -0.096 to 0.075, p = 0.813), whereas both AD (beta = -0.136, 95% CI -0.184 to -0.088, p < 0.001) and AD/LATE (beta = -0.139, 95% CI -0.196 to -0.082, p < 0.001) groups showed faster decline over time. Discussion Patients identified as LATE by the integration of AAS with AD biomarkers had generally mild amnestic cognitive impairment, significant limbic atrophy, and slow decline over time, all features consistent with previous autopsy series. Moreover, AD/LATE cases were more impaired than those with LATE or AD alone. Prospective and neuropathologic validation is warranted