The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease (COVID-19), is a major pandemic challenging health care systems around the world. The optimal ...management of patients infected with COVID-19 is still unclear, although the consensus is moving toward the need of a biphasic approach. During the first phase of the disease (from onset of the symptoms up to 7–10 days) viral-induced effects are prominent, with the opportunity to institute antiviral therapy. In the second inflammatory phase of the disease, immunosuppressive strategies (for example with glucocorticoids or anticytokine drugs) may be considered. This latter stage is characterized by the development of progressive lung involvement with increasing oxygen requirements and occasionally signs of the hemophagocytic syndrome. The management of the disease in patients with kidney disease is even more challenging, especially in those who are immunosuppressed or with severe comorbidities. Here we present the therapeutic approach used in Brescia (Italy) for managing patients infected with COVID-19 who underwent kidney transplantation and are receiving hemodialysis. Furthermore, we provide some clinical and physiopathological background, as well as preliminary outcome data of our cohort, to better clarify the pathogenesis of the disease and clinical management.
The SARS-CoV-2 epidemic is pressuring healthcare systems worldwide. Disease outcomes in certain subgroups of patients are still scarce, and data are needed. Therefore, we describe here the experience ...of four dialysis centers of the Brescia Renal COVID Task Force. During March 2020, within an overall population of 643 hemodialysis patients, SARS-CoV-2 RNA positivity was detected in 94 (15%). At disease diagnosis, 37 of the 94 (39%) patients (group 1) were managed on an outpatient basis, whereas the remaining 57 (61%) (group 2) required hospitalization. Choices regarding management strategy were made based on disease severity. In group 1, 41% received antivirals and 76% hydroxychloroquine. Eight percent died and 5% developed acute respiratory distress syndrome (ARDS). In group 2, 79% received antivirals and 77% hydroxychloroquine. Forty two percent died and 79% developed ARDS. Overall mortality rate for the entire cohort was 29%. History of ischemic cardiac disease, fever, older age (over age 70), and dyspnea at presentation were associated with the risk of developing ARDS, whereas fever, cough and a C-reactive protein higher than 50 mg/l at disease presentation were associated with the risk of death. Thus, in our population of hemodialysis patients with SARS-CoV-2 infection, we documented a wide range of disease severity. The risk of ARDS and death is significant for patients requiring hospital admission at disease diagnosis.
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Background and purpose
Therapy for myasthenia gravis (MG) is undergoing a profound change, with new treatments being tested. These include complement inhibitors and neonatal Fc receptor (FcRn) ...blockers. The aim of this study was to perform a meta‐analysis and network meta‐analysis of randomized and placebo‐controlled trials of innovative therapies in MG with available efficacy data.
Methods
We assessed statistical heterogeneity across trials based on the Cochrane Q test and I2 values, and mean differences were pooled using the random‐effects model. Treatment efficacy was assessed after 26 weeks of eculizumab and ravulizumab, 28 days of efgartigimod, 43 days of rozanolixizumab, 12 weeks of zilucoplan, and 16, 24 or 52 weeks of rituximab treatment.
Results
We observed an overall mean Myasthenia Gravis‐Activities of Daily Living scale (MG‐ADL) score change of −2.17 points (95% confidence interval CI −2.67, −1.67; p < 0.001) as compared to placebo. No significant difference emerged between complement inhibitors and anti‐FcRn treatment (p = 0.16). The change in Quantitative Myasthenia Gravis scale (QMG) score was −3.46 (95% CI −4.53, −2.39; p < 0.001), with a higher reduction with FcRns (−4.78 vs. −2.60; p < 0.001). Rituximab did not significantly improve the MG‐ADL (−0.92 95% CI −2.24, 0.39; p = 0.17) or QMG scores (−1.9 95% CI −3.97, 0.18; p = 0.07). In the network meta‐analysis, efgartigimod had the highest probability of being the best treatment, followed by rozanolixizumab.
Conclusion
Anti‐complement and FcRn treatments both proved to be effective in MG patients, whereas rituximab did not show a significant benefit for patients. Within the limitations of this meta‐analysis, including efficacy time points, FcRn treatments showed a greater effect on QMG score in the short term. Real‐life studies with long‐term measurements are needed to confirm our results.
The spatial organization of replicons into clusters is believed to be of critical importance for genome duplication in higher eukaryotes, but its functional organization still remains to be fully ...clarified. The coordinated activation of origins is insufficient on its own to account for a timely completion of genome duplication when interorigin distances vary significantly and fork velocities are constant. Mechanisms coordinating origin distribution with fork progression are still poorly elucidated, because of technical difficulties of visualizing the process. Taking advantage of a single molecule approach, we delineated and compared the DNA replication kinetics at the genome level in human normal primary and malignant cells. Our results show that replication forks moving from one origin, as well as from neighboring origins, tend to exhibit the same velocity, although the plasticity of the replication program allows for their adaptation to variable interorigin distances. We also found that forks that emanated from closely spaced origins tended to move slower than those associated with long replicons. Taken together, our results indicate a functional role for origin clustering in the dynamic regulation of genome duplication.
The induction of mitochondrial biogenesis could potentially alleviate mitochondrial and muscle disease. We show here that dimethyl fumarate (DMF) dose-dependently induces mitochondrial biogenesis and ...function dosed to cells in vitro, and also dosed in vivo to mice and humans. The induction of mitochondrial gene expression is more dependent on DMF's target Nrf2 than hydroxycarboxylic acid receptor 2 (HCAR2). Thus, DMF induces mitochondrial biogenesis primarily through its action on Nrf2, and is the first drug demonstrated to increase mitochondrial biogenesis with in vivo human dosing. This is the first demonstration that mitochondrial biogenesis is deficient in Multiple Sclerosis patients, which could have implications for MS pathophysiology and therapy. The observation that DMF stimulates mitochondrial biogenesis, gene expression and function suggests that it could be considered for mitochondrial disease therapy and/or therapy in muscle disease in which mitochondrial function is important.
In Italy, medical grade cannabis (MGC) can be prescribed for different medical conditions, including drug-resistant epilepsy (DRE), once standard and approved therapies have failed, or caused ...non-tolerable side effects. Here, we present a retrospective case series report of five patients with DRE who started therapy with MGC. Authorized ISO 9001:2008 pharmacies prepared MGC according to Italian laws. Olive oil extracts (OOEs) were prepared following standard extraction protocols, and cannabinoids were measured on each OOE to check for successful extraction.After treatment with MGC, all patients reported a reduction in seizure frequency and severity, and some reported improved mood, sleep quality, and general well-being without relevant side effects. Despite the small sample size and open-label nature of the data, we show that MGC may be successfully used to treat DRE. This is especially true when considering that no valid therapeutic option exists for these patients and that MGC was extremely well tolerated.
In recent years, the poorly remarkable goals achieved in terms of patients’ important outcomes for ovarian cancer have fueled our interest toward the study of its metabolic roots. Within this ...research pipeline, we assessed the association between the expression of the glucose transporter GLUT1, as expressed at the tumor tissue level, and circulating pre‐surgical levels of fasting glucose in a case series including data from 40 patients with high FIGO stage serous ovarian cancer. Patients who provided data to the current analysis were randomly selected from a larger cohort. To our purposes, the procedures related to serum and tissue collection, storage and biomarker assessment were highly standardized and centralized at the institutional laboratories. The GLUT1 antibody SPM498 SPRING (REF. E13810) was used at a 1:500 dilution in 2 µm slides. Staining for GLUT1 was observed at the cell membrane level in all the cases assessed, but strong staining was described in 29 (72.5%) of them. The agreement between the two independent reviewers was 100%. Strong GLUT1 staining was inversely associated with circulating levels of fasting glucose, with a particularly striking difference for patients in the lowest fasting glucose tertile (p = 0.044). These results support the biological plausibility of the association of interest. If confirmed in larger studies, our findings may help clarify the potentials of biomarkers related to energy metabolism in terms of prognosis definition, treatment assignment, and outcome interpretation for patients with high FIGO stage serous ovarian cancer.
Serous ovarian cystoadenocarcinoma with intense positive staining for glucose transporter protein 1 (GLUT1). A. GLUT1 x20; B. GLUT1x10.
Introduction
Friedreich Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder that causes gait and limb ataxia, dysarthria, and impaired vibratory sense, with cardiomyopathy being the ...predominant cause of death. There is no approved therapy, which results in the use of symptomatic treatments and the chronic support of physiotherapy. Dimethyl fumarate (DMF) is a fumaric acid ester used for the treatment of psoriasis and Multiple Sclerosis (MS). It induces Nrf2
in vitro
and
in vivo
, and it increases frataxin in FRDA patient lymphoblasts, in mouse models, and in MS treated patients.
Methods
The aim of our study is to investigate if DMF can increase the expression of the
FXN
gene and frataxin protein and ameliorate
in-vivo
detectable measures of mitochondrial dysfunction in FRDA. The study is composed of a screening visit and two sequential 12-week phases: a core phase and an extension phase. During the first phase (core), patients will be randomly assigned to either the DMF or a placebo group in a 1:1 ratio. During the first week, patients will receive a total daily dose of 240 mg of DMF or placebo; from the second week of treatment, the dose will be increased to two 120 mg tablets BID for a total daily dose of 480 mg. During the second phase (extension), all patients will be treated with DMF. EudraCT number 2021-006274-23.
Endpoints
The primary endpoint will be a change in
FXN
gene expression level after 12 weeks of treatment. Secondary endpoints will be frataxin protein level,
c
ardiopulmonary exercise test outputs, echocardiographic measures, Nrf2 pathway and mitochondrial biogenesis gene expression, safety, clinical scales, and quality of life scales.
Conclusions
This is the first study aimed at exploring the ability of DMF, an already available treatment for MS and psoriasis, to correct the biological deficits of FRDA and potentially improve mitochondrial respiration
in-vivo
.
Abstract Introduction Eculizumab, a complement active antibody, and efgartigimod, an Fc fragment that blocks neonatal Fc receptor, are both approved to treat generalized myasthenia gravis (gMG) ...patients. The objective of this study is to describe the clinical response to both treatments in a real-life setting. Methods We collected baseline and follow-up clinical data using the Myasthenia Gravis-Activities of Daily Living (MG-ADL), and Quantitative Myasthenia Gravis (QMG). We included 63 patients, 32 treated with eculizumab and 31 with efgartigimod. Of the efgartigimod-treated patients, 22 were anti-acetylcholine receptor antibody-positive (AChR-Ab +) and 9 were AChR-Ab- (3 MuSK-Ab + and 6 seronegative). Results Both treatments showed similar efficacy relative to the MG-ADL scale reduction ( p = 0.237). Efgartigimod had a similar effect on both AChR-Ab + and AChR-Ab- ( p = 0.280). Eculizumab was superior to efgartigimod relative to the QMG score reduction for the entire dataset ( p = 0.003) and was more likely to achieve a clinical response at the QMG compared to efgartigimod (OR 1.373; p = 0.016). Steroid-sparing effect was higher for eculizumab than efgartigimod ( – 16.7 vs – 5.2 mg of the baseline daily dose at follow-up; p = 0.001). Mean speed of prednisone reduction was – 13.1 mg of the daily dose for each month of follow-up for eculizumab-treated patients and – 3.2 for efgartigimod ( p = 0.001). We found three serious events, all not related to treatment in the investigator’s opinion. One eculizumab-treated patient experienced a severe pneumonia and died despite treatment. Conclusions Our study provides evidence that eculizumab and efgartigimod can be used in clinical practice to reduce disability in gMG patients. Eculizumab-treated patients had a higher QMG response and steroid sparing effect. Efgartigimod may offer a more flexible schedule due to its cyclical use, no need for vaccination, and efficacy in AChR-Ab- patients.
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