FXR agonists INT-787 and OCA increase RECK and inhibit liver steatosis and inflammation in diet-induced ob/ob mouse model of NASH.

BACKGROUND AND AIMS: We have previously shown in a model of hepatic ischaemia/reperfusion injury that the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) restores reversion-inducing-cysteine-rich protein with Kazal motifs (RECK), an inverse modulator of metalloproteases (MMPs) and inhibitor of the sheddases ADAM10 and ADAM17 involved in inflammation and fibrogenesis. Here, the effects of FXR agonists OCA and INT-787 on hepatic levels of RECK, MMPs, ADAM10 and ADAM17 were compared in a diet-induced ob/ob mouse model of non-alcoholic steatohepatitis (NASH). METHODS: Lep ob/ob NASH mice fed a high-fat diet (HFD) or control diet (CD) for 9 weeks (wks) were treated with OCA or INT-787 0.05% dosed via HFD admixture (30 mg/kg/day) or HFD for further 12 wks. Serum alanine transaminase (ALT) and inflammatory cytokines, liver RECK, MMP-2 and MMP-9 activity as well as ADAM10, ADAM17, collagen deposition (Sirius red), hepatic stellate cell activation (α-SMA) and pCK+ reactive biliary cells were quantified. RESULTS: Only INT-787 significantly reduced serum ALT, IL-1ß and TGF-ß. A downregulation of RECK expression and protein levels observed in HFD groups (at 9 and 21 wks) was counteracted by both OCA and INT-787. HFD induced a significant increase in liver MMP-2 and MMP-9; OCA administration reduced both MMP-2 and MMP-9 while INT-787 markedly reduced MMP-2 expression. OCA and INT-787 reduced both ADAM10 and ADAM17 expression and number of pCK+ cells. INT-787 was superior to OCA in decreasing collagen deposition and α-SMA levels. CONCLUSION: INT-787 is superior to OCA in controlling specific cell types and clinically relevant anti-inflammatory and antifibrotic molecular mechanisms in NASH.

A Longitudinal RCT on the Effectiveness of a Psychological Intervention for Hospital Healthcare Workers During the COVID-19 Pandemic: What We Learned to Date.

The COVID-19 pandemic has led to significant psychological distress among frontline healthcare workers (HCWs), with a particular increase in trauma-related symptoms. This study investigated the longitudinal course of trauma-associated symptoms and behaviors in HCWs and the effectiveness of a brief dialectical behavior therapy (DBT)-informed intervention in mitigating these symptoms over 12 months. The trial included 225 HCWs randomly assigned to one of three groups: no intervention (control), in-person DBT-informed intervention, or online DBT-informed intervention. Over time, a natural decrease in PTSD symptoms was observed in all groups. Contrary to expectations, no difference was found between the control and intervention groups. However, for participants with severe PTSD symptoms, the intervention significantly mitigated their distress. No differences emerged between in-person and online interventions, suggesting equal effectiveness. Females reported higher trauma-related symptoms, while no differences emerged among different professional roles. These findings underscore the importance of targeted interventions for HCWs experiencing severe symptoms and highlight the potential of online modalities. Further research is needed to optimize the deployment of mental health resources within the healthcare setting, particularly during crises.

The Role of Lung Ultrasound in Low-Resource Settings During the Coronavirus (SARS-CoV-2) Pandemic.

Lung ultrasound (LUS) has proven to be a helpful diagnostic tool for evaluating lung involvement in respiratory pathologies. The usage of this imaging technique became even more widespread during the SARS-CoV-2 pandemic. The latest generation ultrasound scanners are conveniently portable and this permits ultrasound examinations to be performed even in extreme environments where no other diagnostic tool is available. Our team has developed the first guide that assists the clinician while operating in low-resource settings, in managing a SARS-CoV-2 patient based on the clinical examination and the LUS findings.

Fishhook Injury to the Upper Eyelid: A Novel Surgical Approach.

BACKGROUND: Fishhook injuries are an uncommon trauma, and removing a penetrating fishhook is a complicated maneuver, especially if the wound involves delicate anatomical structures like the ocular region. DISCUSSION: Several techniques that have been discussed in literature are reviewed and the authors present a novel approach that has been successfully performed on a patient with a fishhook penetrating his upper eyelid after a fishing accident. CONCLUSION: Emergency physicians should be aware of all the possible approaches to fishhook penetrating injuries. If the fishhook does not involve the globe and an ophthalmologist is not available, the injury may be managed in the emergency department.

MCD Diet Rat Model Induces Alterations in Zinc and Iron during NAFLD Progression from Steatosis to Steatohepatitis.

We evaluate the effects of the methionine-choline-deficient (MCD) diet on serum and hepatic zinc (Zn) and iron (Fe) and their relationships with matrix metalloproteinases (MMPs) and their modulators (TIMPs and RECK) as well as hepatic fatty acids using male Wistar rats fed 2-, 4- and 8-week MCD diets. Serum and hepatic Zn decrease after an 8-week MCD diet. Serum Fe increases after an 8-week MCD diet and the same occurs for hepatic Fe. An increase in hepatic MMP activity, associated with a decrease in RECK and TIMPs, is found in the MCD 8-week group. Liver Fe shows a positive correlation versus MMPs and RECK, and an inverse correlation versus TIMPs. A positive correlation is found comparing liver Zn with stearic, vaccenic and arachidonic acids, and an inverse correlation is found with linolenic and docosatetraenoic acids. An opposite trend is found between liver Fe versus these fatty acids. During NAFLD progression from steatosis to steatohepatitis, MCD rats exhibit an increase in Zn and a decrease in Fe levels both in serum and tissue associated with alterations in hepatic MMPs and their inhibitors, and fatty acids. The correlations detected between Zn and Fe versus extracellular matrix modulators and fatty acids support their potential role as therapeutic targets.

Presentation and outcome with second-line treatment in AL amyloidosis previously sensitive to nontransplant therapies.

The management of light chain (AL) amyloidosis has improved in recent years thanks to accurate biomarker-based staging systems and response criteria and availability of novel effective therapies. However, previous studies have focused on newly diagnosed patients, and little is known on relapsed patients, despite the fact that trials of new agents are often performed in this setting. In the present study, we report the outcome of 259 patients who responded to up-front therapy. Ninety-two patients (35%) needed second-line therapy after a median of 49 months. Cardiac and renal progression were observed in 22% and 12% of patients who received second-line therapy, respectively. Complete response after up-front treatment and frontline therapy with combined bortezomib, melphalan, and dexamethasone independently prolonged time to second-line therapy. Median survival of relapsing patients was 59 months. Patients who had a "high-risk dFLC progression," which we defined as a difference between involved and uninvolved free light chains (dFLC) of >20 mg/L, a level >20% of baseline value, and a >50% increase from the value reached at best response, had a shorter survival after initiation of second-line therapy on univariate, but not on multivariate, analysis, where cardiac progression was the only independent predictor of survival after starting rescue treatment. Patients with AL amyloidosis who need second-line therapy after response to up-front treatment generally have a good outcome. A "high-risk dFLC progression" should trigger rescue treatment, and cardiac progression should not be awaited.

Radiographic findings in 240 patients with COVID-19 pneumonia: time-dependence after the onset of symptoms.

OBJECTIVE: To analyze the most frequent radiographic features of COVID-19 pneumonia and assess the effectiveness of chest X-ray (CXR) in detecting pulmonary alterations. MATERIALS AND METHODS: CXR of 240 symptomatic patients (70% male, mean age 65 ± 16 years), with SARS-CoV-2 infection confirmed by RT-PCR, was retrospectively evaluated. Patients were clustered in four groups based on the number of days between symptom onset and CXR: group A (0-2 days), 49 patients; group B (3-5), 75 patients; group C (6-9), 85 patients; and group D (> 9), 31 patients. Alteration's type (reticular/ground-glass opacity (GGO)/consolidation) and distribution (bilateral/unilateral, upper/middle/lower fields, peripheral/central) were noted. Statistical significance was tested using chi-square test. RESULTS: Among 240 patients who underwent CXR, 180 (75%) showed alterations (group A, 63.3%; group B, 72%; group C, 81.2%; group D, 83.9%). GGO was observed in 124/180 patients (68.8%), reticular alteration in 113/180 (62.7%), and consolidation in 71/180 (39.4%). Consolidation was significantly less frequent (p < 0.01). Distribution among groups was as follows: reticular alteration (group A, 70.9%; group B, 72.2%; group C, 57.9%; group D, 46.1%), GGO (group A, 67.7%; group B, 62.9%; group C, 71%; group D, 76.9%), and consolidation (group A, 35.5%; group B, 31.4%; group C, 47.8%; group D, 38.5%). Alterations were bilateral in 73.3%. Upper, middle, and lower fields were involved in 36.7%, 79.4%, and 87.8%, respectively. Lesions were peripheral in 49.4%, central in 11.1%, or both in 39.4%. Upper fields and central zones were significantly less involved (p < 0.01). CONCLUSIONS: The most frequent lesions in COVID-19 patients were GGO (intermediate/late phase) and reticular alteration (early phase) while consolidation gradually increased over time. The most frequent distribution was bilateral, peripheral, and with middle/lower predominance. Overall rate of negative CXR was 25%, which progressively decreased over time. KEY POINTS: • The predominant lung changes were GGO and reticular alteration, while consolidation was less frequent. • The typical distribution pattern was bilateral, peripheral, or both peripheral and central and involved predominantly the lower and middle fields. • Chest radiography showed lung abnormalities in 75% of patients with confirmed SARS-CoV-2 infection, range varied from 63.3 to 83.9%, respectively, at 0-2 days and > 9 days from the onset of symptoms.

Emergency accesses in Dermatology Department during the Covid-19 pandemic in a referral third level center in the north of Italy.

During the lockdown period, most planned visits have been postponed and the number of accesses to emergency department (ED) has dramatically reduced. The aim of our study is to analyze the impact of the lockdown on the number, type, and severity of Dermatological ED diagnosis. We performed a retrospective review of all dermatological consultations in the ED of IRCSS San Matteo during the lockdown period in Italy (February 22-May 3 2020) and compared them with those from the same period in 2019. We noticed a sharply reduction in the number of dermatological consultations requested in the ED: from 164 patients in 2019 to 33 in 2020. Some diagnostic categories showed a significant difference with a higher incidence of vasculopathic lesions (0.6% vs 12.1%, P < .0001), urticarial rashes (8.5% vs 21.2%, P = .03), and scabies (3% vs 12.1%, P = .023). We observed an increase in the proportion of patients starting medications, before coming to the ED 26.2% in 2019 vs 66.7% in 2020 (P < .001). Furthermore, we noticed a significant increase in the average complexity of cases presenting to the ED in 2020, as proven by the increased need for biopsies and systemic therapy.

Common cardiovascular risk factors and in-hospital mortality in 3,894 patients with COVID-19: survival analysis and machine learning-based findings from the multicentre Italian CORIST Study.

BACKGROUND AND AIMS: There is poor knowledge on characteristics, comorbidities and laboratory measures associated with risk for adverse outcomes and in-hospital mortality in European Countries. We aimed at identifying baseline characteristics predisposing COVID-19 patients to in-hospital death. METHODS AND RESULTS: Retrospective observational study on 3894 patients with SARS-CoV-2 infection hospitalized from February 19th to May 23rd, 2020 and recruited in 30 clinical centres distributed throughout Italy. Machine learning (random forest)-based and Cox survival analysis. 61.7% of participants were men (median age 67 years), followed up for a median of 13 days. In-hospital mortality exhibited a geographical gradient, Northern Italian regions featuring more than twofold higher death rates as compared to Central/Southern areas (15.6% vs 6.4%, respectively). Machine learning analysis revealed that the most important features in death classification were impaired renal function, elevated C reactive protein and advanced age. These findings were confirmed by multivariable Cox survival analysis (hazard ratio (HR): 8.2; 95% confidence interval (CI) 4.6-14.7 for age ≥85 vs 18-44 y); HR = 4.7; 2.9-7.7 for estimated glomerular filtration rate levels <15 vs ≥ 90 mL/min/1.73 m2; HR = 2.3; 1.5-3.6 for C-reactive protein levels ≥10 vs ≤ 3 mg/L). No relation was found with obesity, tobacco use, cardiovascular disease and related-comorbidities. The associations between these variables and mortality were substantially homogenous across all sub-groups analyses. CONCLUSIONS: Impaired renal function, elevated C-reactive protein and advanced age were major predictors of in-hospital death in a large cohort of unselected patients with COVID-19, admitted to 30 different clinical centres all over Italy.

Proposal for International Standardization of the Use of Lung Ultrasound for Patients With COVID-19: A Simple, Quantitative, Reproducible Method.

Growing evidence is showing the usefulness of lung ultrasound in patients with the 2019 new coronavirus disease (COVID-19). Severe acute respiratory syndrome coronavirus 2 has now spread in almost every country in the world. In this study, we share our experience and propose a standardized approach to optimize the use of lung ultrasound in patients with COVID-19. We focus on equipment, procedure, classification, and data sharing.

Clinical characteristics of coronavirus disease (COVID-19) early findings from a teaching hospital in Pavia, North Italy, 21 to 28 February 2020.

We describe clinical characteristics, treatments and outcomes of 44 Caucasian patients with coronavirus disease (COVID-19) at a single hospital in Pavia, Italy, from 21-28 February 2020, at the beginning of the outbreak in Europe. Seventeen patients developed severe disease, two died. After a median of 6 days, 14 patients were discharged from hospital. Predictors of lower odds of discharge were age > 65 years, antiviral treatment and for severe disease, lactate dehydrogenase > 300 mg/dL.

Bedside wireless lung ultrasound for the evaluation of COVID-19 lung injury in senior nursing home residents.

Lung Ultrasound (LUS) is regarded to be potentially useful to diagnose lung injury in older adults living in nursing homes with suspected COVID-19 pneumonia. We aimed at evaluating presence lung injury among senior nursing home residents by LUS performed with portable wireless scanner echography. The study population consisted of 150 residents with a mean age of 88 years (85% female) residing in 12 nursing homes in Northern Italy. Subjects had to have a history of recent onset of symptoms compatible with COVID-19 pneumonia or have been exposed to the contagion of patients carrying the disease. COVID-19 testing was performed with SARS-CoV-2 nasal-pharyngeal (NP) swabs. Positive subjects to LUS scanning were considered those with non-coascelent B-lines in >3 zones, coalescent B-lines in >3 zones and with iperdensed patchy non-consolidated lungs. Sixty-three percent had positive NP testing and 65% had LUS signs of pulmonary injury. LUS had a sensitivity of 79% in predicting positive NP testing. Sixteen percent of residents tested negative for SARSCoV-2 carried the signs of COVID-19 lung injury at LUS. There were 92 patients (61%) with current or recent symptoms.Positivity to LUS scanning was reported in 73% of residents with symptoms, while it was 53% in those without (P=0.016). A positive NP testing was observed in 66% of residents with symptoms and in 57% of those without (P=0.27). We conclude that assessment of LUS by portable wireless scanner echography can be profitability utilized to diagnose lung injury among senior nursing home residents with or without symptoms compatible with COVID-19 pneumonia.

A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis.

Immunomodulatory drugs are active agents in light-chain (AL) amyloidosis. However, previous studies could not show a survival advantage for patients with AL amyloidosis responding to salvage treatment with pomalidomide. In this phase 2 trial, we assessed the safety and efficacy of pomalidomide and dexamethasone (PDex) in patients with AL amyloidosis who were previously exposed to bortezomib, alkylators, and other immunomodulatory drugs. Twenty-eight patients were enrolled. Three patients received pomalidomide 2 mg/d with no dose-limiting toxicity. The remaining patients received 4 mg/d. Pomalidomide was administered continuously and dexamethasone was given once per week at a dose of 20 or 40 mg. Fifteen patients experienced grade 3 to 4 adverse events; the most common were fluid retention and infection. Hematologic response was observed in 68% of patients (very good partial response or complete response in 29%), as well as improved survival. Median time to response was 1 month. PDex is a rapidly active regimen and improves survival in responding, heavily pretreated patients with AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT01510613.

Novel mitochondrial protein interactors of immunoglobulin light chains causing heart amyloidosis.

In immunoglobulin (Ig) light-chain (LC) (AL) amyloidosis, AL deposition translates into life-threatening cardiomyopathy. Clinical and experimental evidence indicates that soluble cardiotoxic LCs are themselves harmful for cells, by which they are internalized. Hypothesizing that interaction of soluble cardiotoxic LCs with cellular proteins contributes to damage, we characterized their interactome in cardiac cells. LCs were purified from patients with AL amyloidosis cardiomyopathy or multiple myeloma without amyloidosis (the nonamyloidogenic/noncardiotoxic LCs served as controls) and employed at concentrations in the range observed in AL patients' sera. A functional proteomic approach, based on direct and inverse coimmunoprecipitation and mass spectrometry, allowed identifying LC-protein complexes. Findings were validated by colocalization, fluorescence lifetime imaging microscopy (FLIM)-fluorescence resonance energy transfer (FRET), and ultrastructural studies, using human primary cardiac fibroblasts (hCFs) and stem cell-derived cardiomyocytes. Amyloidogenic cardiotoxic LCs interact in vitro with specific intracellular proteins involved in viability and metabolism. Imaging confirmed that, especially in hCFs, cardiotoxic LCs (not controls) colocalize with mitochondria and spatially associate with selected interactors: mitochondrial optic atrophy 1-like protein and peroxisomal acyl-coenzyme A oxidase 1 (FLIM-FRET efficiencies 11 and 6%, respectively). Cardiotoxic LC-treated hCFs display mitochondrial ultrastructural changes, supporting mitochondrial involvement. We show that cardiotoxic LCs establish nonphysiologic protein-protein contacts in human cardiac cells, offering new clues on the pathogenesis of AL cardiomyopathy.

New and Evolving Concepts Regarding the Prognosis and Treatment of Cardiac Amyloidosis.

Systemic amyloidoses are rare and proteiform diseases, caused by extracellular accumulation of insoluble misfolded fibrillar proteins. Prognosis is dictated by cardiac involvement, which is especially frequent in light chain (AL) and in transthyretin variants (ATTR, both mutated, (ATTRm), and wild-type, (ATTRwt)). Recently, ATTRwt has emerged as a potentially relevant cause of a heart failure with preserved ejection fraction (HFpEF). Cardiac amyloidosis is an archetypal example of restrictive cardiomyopathy, with signs and symptoms of global heart failure and diastolic dysfunction. Independent of the aetiology, cardiac amyloidosis is associated with left ventricular concentric "hypertrophy" (i.e. increased wall thickness), preserved (or mildly depressed) ejection fraction, reduced midwall fractional shortening and global longitudinal function, as well as evident diastolic dysfunction, up to an overly restrictive pattern of the left ventricular filling. Cardiac biomarkers such as troponins and natriuretic peptides are very robust and widely accepted diagnostic as well as prognostic tools. Owing to its dismal prognosis, accurate and early diagnosis is mandatory and potentially life-saving. Although pathogenesis is still not completely understood, direct cardiomyocyte toxicity of the amyloidogenic precursor proteins and/or oligomer aggregates adds on tissue architecture disruption caused by amyloid deposition. The clarification of mechanisms of cardiac damage is offering new potential therapeutic targets, and several treatment options with a relevant impact on prognosis are now available.