The mitochondrial (mt) DNA depletion syndromes (MDDS) are genetic disorders characterized by a severe, tissue-specific decrease of mtDNA copy number, leading to organ failure. There are two main ...clinical presentations: myopathic (OMIM 609560) and hepatocerebral (OMIM 251880). Known mutant genes, including TK2 (ref. 2), SUCLA2 (ref. 3), DGUOK (ref. 4) and POLG, account for only a fraction of MDDS cases. We found a new locus for hepatocerebral MDDS on chromosome 2p21-23 and prioritized the genes on this locus using a new integrative genomics strategy. One of the top-scoring candidates was the human ortholog of the mouse kidney disease gene Mpv17 (ref. 8). We found disease-segregating mutations in three families with hepatocerebral MDDS and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product, MPV17 is a mitochondrial inner membrane protein, and its absence or malfunction causes oxidative phosphorylation (OXPHOS) failure and mtDNA depletion, not only in affected individuals but also in Mpv17−/− mice.
To compare intensivist-diagnosed ventilator-associated pneumonia (iVAP) with four established definitions, assessing their agreement in detecting new episodes.
A multi-centric prospective study on ...pulmonary microbiota was carried out in patients requiring mechanical ventilation (MV). Data collected were used to compare hypothetical VAP onset according to iVAP with the study consensus criteria, the European Centre for Disease Control and Prevention definition, and two versions of the latter adjusted for leukocyte count and fever.
In our cohort of 186 adult patients, iVAPs were 36.6% (68/186, 95% confidence interval 30.0–44.0%), with an incidence rate of 4.64/100 patient-MV-days, and median MV-day at diagnosis of 6. Forty-seven percent of patients (87/186) were identified as VAP by at least one criterion, with a median MV-day at diagnosis of 5. Agreement between intensivist judgement (iVAP/no-iVAP) and the criteria was highest for the study consensus criteria (50/87, 57.4%), but still one-third of iVAP were not identified and 9% of patients were identified as VAP contrary to intensivist diagnosis. VAP proportion differed between criteria (25.2–30.1%).
Caution is needed when evaluating studies describing VAP incidence. Pre-agreed criteria and definitions that capture VAP's evolving nature provide greater consistency, but new clinically driven definitions are needed to align surveillance and diagnostic criteria with clinical practice.
Intraocular pressure increase (IOPi) after intravitreal injections of vascular endothelial growth factor inhibitors (VEGFis) might be different among different VEGFis (bevacizumab, aflibercept, ...ranibizumab). The purpose of this study was to evaluate the risk of IOPi among new users of bevacizumab, ranibizumab, and aflibercept in nondiabetic patients in Tuscany, Italy.
Retrospective cohort study.
Tuscan regional administrative database was used to identify subjects with a first VEGFi intravitreal injection between 2011 and 2020, followed to first incidence of IOPi. Diabetic subjects, those with pre-existing IOPi, or previous use of dexamethasone implants were excluded. Multivariable Cox regression analyses (intention-to-treat and as treated) were conducted to evaluate risk of IOPi among aflibercept, bevacizumab, and ranibizumab, adjusting for potential confounding variables. IOPi was defined as the first record of International Classification of Diseases, Ninth Revision (ICD-9-CM) code 365 or use of 2 glaucoma drugs dispensations within 180 days of each other.
We identified 6585 new users of VEGFis: 1749 aflibercept, 1112 bevacizumab, and 3724 ranibizumab. Women made up 60% of the cohort, with a mean age of 73.6 years. In the intention-to-treat analysis, the adjusted hazard ratio (HR) for incident IOPi, compared with aflibercept, was higher for bevacizumab (HR = 2.20, 95% CI = 1.64-2.95) and ranibizumab users (HR = 1.88, 95% CI = 1.46-2.42), respectively. The HRs remained robust after exclusion of patients with proxy of retinal vascular occlusion. As treated analysis confirmed such results (bevacizumab: HR = 3.76, 95% CI = 2.30-6.17; ranibizumab: HR = 2.49, 95% CI = 1.62-3.82).
This study found an increased risk of IOPi among nondiabetic patients with ranibizumab and bevacizumab compared with aflibercept. Future studies are needed to validate these findings.
Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity and is frequently associated with obesity and metabolic syndrome. The recently discovered hormone adiponectin is ...produced by adipose tissue, and low plasma adiponectin is considered a key factor in the development of the insulin resistance underlying metabolic syndrome. Animal studies suggest that adiponectin may protect against non-alcoholic steatohepatitis, but direct evidence in humans is lacking. We therefore conducted this study to assess the relationship between plasma adiponectin and nonalcoholic fatty liver disease to explore its role in the pathogenesis of this disease.
We measured plasma adiponectin and anthropometric, biochemical, hormonal and metabolic correlates in a group of 17 NAFLD patients with diagnosis confirmed by biopsy, and 20 controls with comparable age, body-mass index and sex. Furthermore we compared plasma adiponectin in patients with simple steatosis and steatohepatitis.
Plasma adiponectin was significantly lower in NAFLD patients than controls (5.93+/-0.45 vs 15.67+/-1.60ng/ml). Moreover, NAFLD patients were significantly more insulin resistant while having similar serum leptin. Adiponectin was similar in simple steatosis and in steatohepatitis (6.16+/-0.78 vs 5.69+/-0.49ng/ml). An inverse correlation was observed between adiponectin and homeostatic model assessment (HOMA) of insulin resistance (P = 0.008), while adiponectin did not correlate with serum transaminases and lipid values.
These data support a role for low circulating adiponectin in the pathogenesis of NAFLD and confirm the strict association between reduced adiponectin production by adipose tissue, NAFLD and insulin resistance.
Purpose
To describe the use of hydroxychloroquine (HCQ), azithromycin (AZI) and low‐molecular‐weight‐heparins (LMWH) by sex among elderly residents in nursing homes (NHs) of Tuscany region (Italy) ...during the first pandemic peak.
Methods
A population‐based drug utilization study was performed linking the Tuscany Administrative Databases (TAD) to the regional COVID‐19 registry. Among elderly patients (≥ 65 years old) registered in TAD on 1st December 2019, new users of HCQ, AZI and LMWH that started the treatment during NHs stay (i.e., no dispensing of the same drug during the previous 6 months) were respectively identified in each month of observation period (December 2019–May 2020). The percentage of subjects diagnosed with COVID‐19 (COVID‐19+) on, or before, the date of first dispensing of the drug of interest was described. Results were stratified by sex (male = M; female = F).
Results
New users of HCQ, AZI and LMWH were 62, 300, and 1215, respectively. About 95% of HCQ new users received the drug in April (M = 20; F = 40) of which 11 of men (55%) and 25 of women (62%) were COVID‐19+; AZI new users in April (M = 32; F = 83) were two‐fold compared to February, of which 10 of men (31%) and 30 of women (36%) were COVID‐19+; LMWH new users showed a peak in April (M = 74; F = 142), when 31% of men and 34% of women were COVID‐19 + .
Conclusions
New users showed a peak during the first pandemic wave and females were over two‐fold compared to men. HCQ was often prescribed in absence of COVID‐19 diagnosis. During future global emergencies drug prescriptions should better be monitored in frail populations, especially in case of drugs with uncertain efficacy and safety.
In any large device for research on magnetic confinement thermonuclear fusion, the window assemblies are essential to preserve the conditions for successful experiments and to guarantee adequate ...access for inspection and measurement. In ITER, the materials traditionally used for the windows will be exposed to an exceptionally harsh environment. Moreover, the systematic use of tritium as fuel would make any failure of the primary vacuum containment a particularly dangerous accident. It is therefore essential to understand the potential threats to the integrity of the windows assemblies and define a series of tests to ensure their properties and quality before installation. One specific hazard to the windows is the microwave radiation due to either heating schemes or specific diagnostics. A fraction of the stray radiation incident on the window leads to dielectric heating, which causes a thermal load. The potentially harmful consequences of such a thermal load on the window assemblies are: (i) excessively high temperature (risk of bonding melting) and (ii) excessive, heating rate (risk of cracking due to a high temperature gradient at the location of the bonding). In this paper the main causes of degradation, which could lead to failures under microwave loads, have been identified. A series of laboratory tests have been defined, to assess the quality of the materials and the assemblies, including the coatings for the absorption of the microwave radiation in the ducts leading to the windows. Complete testing procedures and an overview of the main facilities, where the assemblies and materials could be qualified, are also provided.
The clinical outcome of primary refractory (PRF) AML patients is poor and only a minor proportion of patients is rescued by allogenic hematopoietic stem cell transplantation (HSCT). The ...identification of pre-HSCT variables may help to determine PRF AML patients who can most likely benefit from HSCT. We analyzed PRF AML patients transplanted between 1999 and 2012 from a sibling, unrelated donor or a cord blood unit. Overall, 227 patients from 26 Gruppo Italiano Trapianto di Midollo Osseo e Terapia cellulare centers were included in the analysis. At 3 years, the overall survival was 14%. By multivariate analysis, the number of chemotherapy cycles, (hazard ratio (HR): 1.87; 95% confidence interval (CI): 1.24-2.85; P=0.0028), the percentage of bone marrow or peripheral blood blasts (HR: 1.75; 95% CI: 1.16-2.64; P=0.0078), the adverse cytogenetic (HR: 1.44; 95% CI: 1.00-2.07; P=0.0508) and the age of patients (HR: 1.77; 95% CI: 1.08-2.88; P=0.0223) remained significantly associated with survival. Thus, we set up a new score predicting at 3 years after transplantation, an overall survival probability of 32% for patients with score 0 (no or 1 prognostic factor), 10% for patients with score 1 (2 prognostic factors) and 3% for patients with score 2 (3 or 4 prognostic factors).
The objective of this preliminary study was to identify genomic regions that may predispose Gordon setters from the United Kingdom to familial protein-losing enteropathy (PLE) at a young age. A total ...of 106 related Gordon setters was used, including 6 affected dogs from an affected
litter, 6 case controls from the same litter, 10 related/affected dogs, and 84 related/unaffected dogs. Genomic DNA was collected from each Gordon setter and extracted from buccal mucosal swabs. Genotyping of affected and unaffected dogs was carried out using the Canine Illumina HD SNP array
and data generated were analyzed with PLINK software, using fixation index (Fst) and runs of homozygosity (ROH) methods. Pairwise Fst analyses between the affected and unaffected Gordon setter dogs identified various regions of differentiation on chromosomes 10, 18, 21, and 23 that contained
several important genes. These regions revealed 5 candidate genes, including RARB, TTC7A, SOCS5, PIGF, and RHOD, that are associated with human inflammatory bowel disease (IBD) and could potentially be associated with PLE in Gordon setters. Run of homozygosity (ROH) analyses
revealed additional unique regions on chromosomes 15 and 17. These regions contained genes SYT1, UCN, and FNDC that could also be potential candidates for PLE in Gordon setters. The biological functions of the identified genes provided initial insights into the pathophysiology
of PLE. Further large-scale studies are warranted to investigate the possible causality of these genomic regions and any possible genetic markers that could be used in predicting susceptibility to PLE syndrome.
Background: Over recent years numerous patients with severe forms of multiple sclerosis (MS) refractory to conventional therapies have been treated with intense immunosuppression followed by ...autologous haematopoietic stem cell transplantation (AHSCT). The clinical outcome and the toxicity of AHSCT can be diverse, depending on the various types of conditioning protocols and on the disease phase.
Objectives: To report the Italian experience on all the consecutive patients with MS treated with AHSCT with an intermediate intensity conditioning regimen, named BEAM/ATG, in the period from 1996 to 2008.
Methods: Clinical and magnetic resonance imaging outcomes of 74 patients were collected after a median follow-up period of 48.3 (range = 0.8–126) months.
Results: Two patients (2.7%) died from transplant-related causes. After 5 years, 66% of patients remained stable or improved. Among patients with a follow-up longer than 1 year, eight out of 25 subjects with a relapsing–remitting course (31%) had a 6–12 months confirmed Expanded Disability Status Scale improvement > 1 point after AHSCT as compared with one out of 36 (3%) patients with a secondary progressive disease course (p = 0.009). Among the 18 cases with a follow-up longer than 7 years, eight (44%) remained stable or had a sustained improvement while 10 (56%), after an initial period of stabilization or improvement with median duration of 3.5 years, showed a slow disability progression.
Conclusions: This study shows that AHSCT with a BEAM/ATG conditioning regimen has a sustained effect in suppressing disease progression in aggressive MS cases unresponsive to conventional therapies. It can also cause a sustained clinical improvement, especially if treated subjects are still in the relapsing–remitting phase of the disease.
•We present the first measurements of soil C6H6 fluxes in a volcanic system.•Methane oxidation rate is controlled by soil gas fluxes.•Benzene oxidation rate is controlled by presence of a SO42--rich ...aquifer.•Fumarolic emissions cause a strong benzene air contamination at a local scale.•Endogenous monoaromatics are detected in air samples from the whole crater.
Measurements of soil fluxes of hydrothermal gases, with special emphasis on C6H6, as well as chemical composition of mono-aromatic compounds in fumaroles and air, were carried out in April 2012 at the Solfatara crater (Campi Flegrei, Southern Italy) to investigate the distribution and behavior of these species as they migrate through the soil from their deep source to the atmosphere. Soil fluxes of CO2, CH4 and C6H6 exhibit good spatial correlation, suggesting that diffuse degassing is mainly controlled by local fractures. The calculated total output of diffuse C6H6 from Solfatara is 0.10kgday−1, whereas fluxes of CO2 and CH4 are 79×103 and 1.04kgday−1, respectively. A comparison between soil gas fluxes and fumarole composition reveals that within the crater soil CH4 is significantly affected by oxidation processes, which are more efficient for low gas fluxes, being dependent on the residence time of the uprising hydrothermal gases at shallow depth. Benzene degradation, mainly proceeding through oxidation via benzoate, seems to be strongly controlled by the presence of a shallow SO42--rich aquifer located in the central and southwestern sectors of the crater, suggesting that the process is particularly efficient when SO42- acts as terminal electron acceptor (SO4 reduction). Relatively high C6H6/C7H8 ratios, typical of hydrothermal fluids, were measured in air close to the main fumarolic field of Solfatara crater. Here, C6H6 concentrations, whose detection limit is ∼0.1μgm−3, are more than one order of magnitude higher than the limit value for ambient air (5μgm−3). This suggests that hydrothermal fluids have a strong impact on air quality in the immediate surroundings of the fumarolic vents. Significant concentrations of endogenous mono-aromatics were also detected in air samples collected from the northern and western sides of the crater, where these gas compounds are mostly fed by diffuse degassing through the crater bottom soil.
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