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BACKGROUND: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2-25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing =20 kg) or 0·25 mg/kg (for individuals weighing

Background: Diabetes mellitus (DM) is more common in people living with HIV (PLWH) than in HIV-negative patients. Here we aimed to describe the response of PLWH with DM to glucose-lowering therapies in a reference hospital of northern Italy.Setting: 200 PLWH and DM were identified from the database of our clinic.Methods: Good control of DM was defined as having fasting glucose Results: Mean total fasting glucose and HbA1C were 143 ± 50 mg/dl (51% exceeding the 130 mg/dl cutoff) and 51 ± 16 mmol/mol (30% exceeding the 53 mmol/mol cutoff), respectively. PLWH were less treated with dipeptidyl peptidase-4 inhibitors (1.7% versus 9.6%, p < 0.01) and sulfonylureas (3.3% versus 13.2%, p < 0.01), being conversely more frequently treated with metformin (53.8% versus 37.7%, p < 0.01), glifozins plus metformin (7.1% versus 2.0%, p < 0.05) or insulin plus other glucose-lowering agents (5.5% versus 0.5%, p < 0.01).Conclusion: An underuse of dipeptidyl peptidase-4 inhibitors was found which was, however, counterbalanced by a higher use of combination of drugs (including glifozins). A rational assessment of drug-drug interactions would contribute to a better selection of the best glucose lowering agent for each antiretroviral therapy.

Introduction: Asthma and hypereosinophilia have been treated with different therapeutics in the past. Some of them appear to be more effective in symptoms resolution and decreasing eosinophilic count. Case Presentation: We report here an unusual case of asthma with hypereosinophilia secondary to Chronic Myeloid Leukemia (CML) with high prevalence of eosinophilic infiltrate, treated simultaneously with an anti-IL-5 antibody (Mepolizumab) and Tyrosine-kinase Inhibitors (TKI: Imatinib and Bosutinib) for three years. The patient showed a promising reduction of pulmonary exacerbations and good control of CML without developing side effects. Conclusion: We hope that this finding could inspire further studies on the efficacy and safety of the concomitant use of anti-IL-5 and TKI.

ObjectiveThe present paper describes the design, development, and implementation of the AutoInflammatory Disease Alliance (AIDA) International Registry specifically dedicated to patients with Schnitzler's syndrome.MethodsThis is a clinical physician-driven, population- and electronic-based registry implemented for the retrospective and prospective collection of real-life data from patients with Schnitzler's syndrome; the registry is based on the Research Electronic Data Capture (REDCap) tool, which is designed to collect standardized information for clinical research, and has been realized to change over time according to future scientific acquisitions and potentially communicate with other existing or future similar registries.ResultsSince its launch, 113 centers from 23 countries in 4 continents have been involved. Fifty-seven have already obtained the approval from their local Ethics Committees. The platform counts 324 users (114 Principal Investigators, 205 Site Investigators, 2 Lead Investigators, and 3 data managers) at current (April 28th, 2022). The registry collects baseline and follow-up data using 3,924 fields organized into 25 instruments, including patient's demographics, history, clinical manifestations and symptoms, trigger/risk factors, laboratory, instrumental exams, therapies, socioeconomic information, and healthcare access.ConclusionsThis International Registry for patients with Schnitzler's syndrome facilitates standardized data collection, enabling international collaborative projects through data sharing and dissemination of knowledge; in turn, it will shed light into many blind spots characterizing this complex autoinflammatory disorder.

The small sample sizes inherent in rare and pediatric disease settings offer significant challenges for clinical trial design. In such settings, Bayesian adaptive trial methods can often pay dividends, allowing the sensible incorporation of auxiliary data and other relevant information to bolster that collected by the trial itself. Previous work has also included the use of one-arm trials augmented by the participants’ own natural history data, from which the future course of the disease in the absence of intervention can be predicted. Patient response can then be defined by the degree to which post-intervention observations are inconsistent with the predicted “natural” trajectory. While such trials offer obvious advantages in efficiency and ethical hazard (since they expose no new patients to a placebo, anathema to patients or their parents and caregivers), they can offer no protection against bias arising from the presence of any “placebo effect,” the tendency of patients to improve merely by being in the trial. In this paper, we investigate the impact of both static and transient placebo effects on one-arm responder studies of this type, as well as two-arm versions that incorporate a small concurrent placebo group but still borrow strength from the natural history data. We also propose more traditional Bayesian changepoint models that specify a parametric functional form for the patient’s post-intervention trajectory, which in turn allow quantification of the treatment benefit in terms of the model parameters, rather than semi-parametrically in terms of a response relative to some “null” model. We compare the operating characteristics of our designs in the context of an ongoing investigation of centronuclear myopathies (CNMs), a group of congenital neuromuscular diseases whose most common and severe form is X-linked, affecting approximately 1 in 50,000 newborn boys. Our results indicate our two-arm responder and changepoint methods can offer protection against placebo effects, improving power while protecting the trial’s Type I error rate. However, further research into innovative trial designs as well as ongoing dialog with regulatory authorities remain critically important in rare disease research.

Splenic marginal zone lymphoma (SMZL) is a rare lymphoproliferative disease involving B-cells and affecting elderly patients. SMZL plague peripheral blood and bone marrow, spleen. Lymph nodes are generally spared. SMZL is due to a protracted antigen stimulation of B lymphocytes and of microenvironment leading B-cell to polyclonal and then oligoclonal/monoclonal growth, promoting lymphoproliferation. Integration of the NOTCH2 and NFk-B signaling has been recently identified as the primary mechanism of neoplastic proliferation in SMZL. In total 20% of cases carry mutations in NOTCH2. Although SMZL has an indolent course, progression to diffuse large B-cell lymphoma occurs in about 10-15% of patients. Establishing the prognosis is a key step in disease management, depending on both individual risk and patients' health status. This review discusses tailored treatment of SMZL patients. Progression risk factors include nodal and extra-nodal involvement, peripheral lymphocytosis, anemia and thrombocytopenia. Patients with two or more score points have a median survival of

Background: Erythropoiesis-stimulating agents (ESAs) are used to treat refractory anemia (RA). Guidelines suggest iron supplementation for unresponsive patients, regardless of iron deficiency. The primary aim of this study was to evaluate the effect of iron supplementation with ferric carboxymaltose (FCM) on the reduction of red blood cell transfusion (RBCT) rate in transfusion-dependent RA patients. Methods: This was a prospective quasi-randomized study, wherein patients were randomly assigned into three groups: (A) ESAs alone, (B) ferric gluconate (FG) and ESAs, and (C) FCM and ESAs. Hemoglobin and ferritin levels, as well as the number of RBCTs at 4 and 28 weeks were compared. Economic evaluation was also performed. Results: A total of 113 RA patients were enrolled. In total, 43 were treated with intravenous FG and ESAs, 38 with FCM and ESAs, and 32 with ESAs alone. At both follow-ups, erythropoietic response was increased in those receiving iron as compared with those with ESAs alone (p = 0.001), regardless of the type of iron. At one month, ferritin levels were higher in the FCM and ESA groups (p = 0.001). RBCTs were lower in both iron groups. The less costly treatment strategy was FCM, followed by FG, and lastly ESAs. Conclusions: Addition of iron to ESAs in RA reduced RBCT requirement and improved hemoglobin values.

The elderly population represents a high percentage of patients hospitalized for COVID-19 pneumonia and severe respiratory failure, for whom CPAP may be a treatment option. The aim of this study was to describe the CPAP support modalities and to explore factors associated with CPAP failure. In this retrospective study, 110 consecutive patients aged ≥ 75 years were enrolled. Median frailty score, baseline partial arterial pressure of oxygen to fraction of inspired oxygen ratio (P/F), and respiratory rate (RR) were 5, 108, and 30 cycles/min, respectively. Of the 110 patients that began CPAP treatment, 17 patients died within 72 h from baseline, while in 2 patients, CPAP was withdrawn for clinical improvement. Thus, of the 91 patients still on CPAP at day 3, 67% of them needed continuous CPAP delivery. Patients with RR ≥ 30 and with frailty score ≥ 5 had an odds ratio of continuous CPAP needing of 3 and 4, respectively. Patients unable to tolerate CPAP-free periods demonstrated higher mortality risk as compared to those able to tolerate intermittent CPAP (OR: 6.04, 95% CI 2.38-16.46

Background: The tunneling technique is currently widely used for placement of CVC. Recently, some clinicians have used this technique for peripherally inserted central catheters (PICC), or Midline catheters (MCs). Objective: To describe a safe antegrade tunneling technique for PICCs and MCs insertion with a blunt tunneler. Methods: This retrospective monocentric survey collected ASST Lodi hospital data from January 1st to December 31st, 2019. The indication for PICCs and MCs tunneled implant was to respect the correct vein/catheter ratio or special clinical situation (children, burns, wounds, and wider catheter 5/6 fr). Contraindications included the operator’s low skills and severe risk of bleeding (INR > 3; Platelet count Results: About 390 PICCs (327 4 fr and 63 5 fr) and 183 MCs were placed. One hundred and sixty-five PICCs (42%) and 110 MCs (60%) were tunneled. Five fr PICCs were more present among tunneled catheters (54/165 [32.7%] vs 9/225 [4%] p Conclusions: The antegrade tunneling technique with blunt tunneler of PICCs and MCs is simple, rapid and is regarded as a safe maneuver. More in-depth and future prospective studies are needed to evaluate the impact of tunneling on early and late complications.

Aging of the vascular system is associated with deep changes of the structural proprieties of the arterial wall. Arterial hypertension, diabetes mellitus, and chronic kidney disease are the major determinants for the loss of elasticity and reduced compliance of vascular wall. Arterial stiffness is a key parameter for assessing the elasticity of the arterial wall and can be easily evaluated with non-invasive methods, such as pulse wave velocity. Early assessment of vessel stiffness is critical because its alteration can precede clinical manifestation of cardiovascular disease. Although there is no specific pharmacological target for arterial stiffness, the treatment of its risk factors helps to improve the elasticity of the arterial wall.

Background During the course of COVID-19, the disease caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), thrombotic phenomena and/or diffuse vascular damage are frequent, and viral elements have been observed within endothelial cells. Objectives CD146 + circulating endothelial cells (CD146 + CECs) and their progenitors (CEPs) are increased in cardiovascular, thrombotic, infectious, and cancer diseases. The present study was designed to investigate their kinetics in novel coronavirus (COVID-19) patients. Methods We used a validated flow cytometry procedure to enumerate viable and apoptotic CD146 + CECs and CEPs in COVID-19 patients during the course of the disease and in patients who recovered. Results Viable CEPs per milliliter were significantly increased in COVID-19 patients compared with healthy controls. This increase was observed in patients with mild symptoms and not further augmented in patients with severe symptoms. In patients who recovered, CEPs decreased, but were in a range still significantly higher than normal controls. Regarding mature CD146 + CECs, in COVID-19 patients, their absolute number was similar to those observed in healthy controls, but the viable/apoptotic CD146 + CEC ratio was significantly different. Both mild and severe COVID-19 patients had significantly less apoptotic CD146 + CECs compared with healthy controls. Patients who recovered had significantly less CD146 + CECs per milliliter when compared with controls as well as to mild and severe COVID-19 patients. A positive correlation was found between the copies of SARS-CoV-2 RNA in the cellular fraction and apoptotic CEPs per milliliter in severe COVID-19 patients. Conclusions CD146 + CECs and CEPs might be investigated as candidate biomarkers of endothelial damage in COVID-19 patients.

Summary Immune thrombocytopenic purpura (ITP) is an autoimmune thrombocytopenia with shortened platelet survival and relative bone marrow failure. The pathogenesis involves antibody production, cytokine release, T cell impairment, complement activation and clearance of platelets. We measured plasma levels of C3, C4, C1q and sC5b-9 in 80 ITP patients in acute phase, 50 ITP patients in complete (CR) or partial (PR) remission and 50 age- and sex-matched healthy volunteers. Statistical analyses showed that acute ITP patients had higher plasma levels of sC5b-9 and C1q than CR or PR patients (median = sC5b-9: 200 versus 98 mg/dl, P-value

Background Quantitative nuclear magnetic resonance imaging (NMRI) is an objective and precise outcome measure for evaluating disease progression in neuromuscular disorders. We aimed to investigate predictive 'disease activity' NMR indices, including water T2 and 31P NMR spectroscopy (NMRS), and its relation to NMR markers of 'disease progression', such as the changes in fat fraction (ΔFat%) and contractile cross-sectional area (ΔcCSA), in GNE myopathy (GNEM) patients. Methods NMR was performed on a 3T clinical scanner, at baseline and at a 1-year interval, in 10 GNEM patients and 29 age-matched controls. Dixon-based fat-water imaging and water T2 mapping were acquired in legs and thighs, and in the dominant forearm. 31P NMRS was performed at the level of quadriceps and hamstring. Water T2 and 31P NMRS indices were determined for all muscle groups and visits. Correlations were performed with 'disease progression' indices ΔFat%, ΔcCSA and the muscle fat transformation rate (Rmuscle_transf). Results In quadriceps, known to be relatively preserved in GNEM, water T2 at baseline was significantly higher compared to controls, and correlated strongly with the one-year evolution of Fat% and cCSA and Rmuscle_transf. Various 31P NMRS indices showed significant differences in quadriceps and hamstring compared to controls and correlations existed between these indices and ΔFat%, ΔcCSA and Rmuscle_transf. Conclusions This study demonstrates that disease activity indices such as water T2 and 31P NMRS may predict disease progression in skeletal muscles of GNEM patients, and suggests that these measures may be considered to be valuable surrogate endpoints in the assessment of GNEM disease progression.

International audience; Background: Fibrosis is defined as an excessive accumulation of extracellular matrix (ECM) components. Many organs are subjected to fibrosis including the lung, liver, heart, skin, kidney, and muscle. Muscle fibrosis occurs in response to trauma, aging, or dystrophies and impairs muscle function. Fibrosis represents a hurdle for the treatment of human muscular dystrophies. While data on the mechanisms of fibrosis have mostly been investigated in mice, dystrophic mouse models often do not recapitulate fibrosis as observed in human patients. Consequently, the cellular and molecular mechanisms that lead to fibrosis in human muscle still need to be identified.Methods: Combining mass cytometry, transcriptome profiling, in vitro co-culture experiments, and in vivo transplantation in immunodeficient mice, we investigated the role and nature of nonmyogenic cells (fibroadipogenic progenitors, FAPs) from human fibrotic muscles of healthy individuals (FibMCT) and individuals with oculopharyngeal muscular dystrophy (OPMD; FibMOP), as compared with nonmyogenic cells from human nonfibrotic muscle (MCT).Results: We found that the proliferation rate of FAPs from fibrotic muscle is 3–4 times higher than those of FAPs from nonfibrotic muscle (population doubling per day: MCT 0.2 ± 0.1, FibMCT 0.7 ± 0.1, and FibMOP 0.8 ± 0.3). When cocultured with muscle cells, FAPs from fibrotic muscle impair the fusion index unlike MCT FAPs (myoblasts alone 57.3 ± 11.1%, coculture with MCT 43.1 ± 8.9%, with FibMCT 31.7 ± 8.2%, and with FibMOP 36.06 ± 10.29%). We also observed an increased proliferation of FAPs from fibrotic muscles in these co-cultures in differentiation conditions (FibMCT +17.4%, P < 0.01 and FibMOP +15.1%, P < 0.01). This effect is likely linked to the increased activation of the canonical TGFβ-SMAD pathway in FAPs from fibrotic muscles evidenced by pSMAD3 immunostaining (P < 0.05). In addition to the profibrogenic TGFβ pathway, we identified endothelin as a new actor implicated in the altered cross-talk between muscle cells and fibrotic FAPs, confirmed by an improvement of the fusion index in the presence of bosentan, an endothelin receptor antagonist (from 33.8 ± 10.9% to 52.9 ± 10.1%, P < 0.05).Conclusions: Our data demonstrate the key role of FAPs and their cross-talk with muscle cells through a paracrine signalling pathway in fibrosis of human skeletal muscle and identify endothelin as a new druggable target to counteract human muscle fibrosis

Introduction: Kidney Disease Outcomes Quality Initiative clinical practice guidelines recommend avoiding placement of peripherally inserted vascular access devices in patients with an estimated glomerular filtration rate (eGFR) Methods: We analyzed data on patients with PICCs or Midlines inserted from October 2018 to November 2019. CCI, Beclap score, and eGFR were calculated for each patient at the time of the catheter insertion. We then followed patients for 2 years to assess 2-year mortality for each. Results: One hundred and thirty-one patients were enrolled, 49 (37.4%) had eGFRConclusion: CCI and Beclap score are good predictors of mortality at 2 years. Physicians and nurses can use these tools in the evaluation of patients at risk for future dialysis, instead of relying exclusively on renal function to decide whether implanting PICCs, Midlines, or other vascular access devices.

Objective: Recently, the ASC-1 complex has been identified as a mechanistic link between amyotrophic lateral sclerosis and spinal muscular atrophy (SMA), and 3 mutations of the ASC-1 gene TRIP4 have been associated with SMA or congenital myopathy. Our goal was to define ASC-1 neuromuscular function and the phenotypical spectrum associated with TRIP4 mutations. Methods: Clinical, molecular, histological, and magnetic resonance imaging studies were made in 5 families with 7 novel TRIP4 mutations. Fluorescence activated cell sorting and Western blot were performed in patient-derived fibroblasts and muscles and in Trip4 knocked-down C2C12 cells. Results: All mutations caused ASC-1 protein depletion. The clinical phenotype was purely myopathic, ranging from lethal neonatal to mild ambulatory adult patients. It included early onset axial and proximal weakness, scoliosis, rigid spine, dysmorphic facies, cutaneous involvement, respiratory failure, and in the older cases, dilated cardiomyopathy. Muscle biopsies showed multiminicores, nemaline rods, cytoplasmic bodies, caps, central nuclei, rimmed fibers, and/or mild endomysial fibrosis. ASC-1 depletion in C2C12 and in patient-derived fibroblasts and muscles caused accelerated proliferation, altered expression of cell cycle proteins, and/or shortening of the G0/G1 cell cycle phase leading to cell size reduction. Interpretation: Our results expand the phenotypical and molecular spectrum of TRIP4-associated disease to include mild adult forms with or without cardiomyopathy, associate ASC-1 depletion with isolated primary muscle involvement, and establish TRIP4 as a causative gene for several congenital muscle diseases, including nemaline, core, centronuclear, and cytoplasmic-body myopathies. They also identify ASC-1 as a novel cell cycle regulator with a key role in cell proliferation, and underline transcriptional coregulation defects as a novel pathophysiological mechanism. ANN NEUROL 2020;87:217–232., SCOPUS: ar.j, info:eu-repo/semantics/published

In the last twelve years the clinical management of patients with atrial fibrillation has been revolutionised by the introduction of direct oral anticoagulants. Despite the large amount of evidence produced, some populations remain relatively poorly explored regarding the effectiveness and safety of direct oral anticoagulants, such as the oldest and/or frailest individuals. Frailty is clinical syndrome characterized by a reduction of functions and physiological reserves which results in individuals having higher vulnerability. While current evidence underlines a relationship between atrial fibrillation and frailty, particularly in determining a higher risk of adverse outcomes, data regarding effectiveness and safety of direct oral anticoagulants in frailty atrial fibrillation patients are still lacking, leaving uncertainty about how to guide prescription in this specific subgroup. On these premises, this multidisciplinary consensus document explains why it would be useful to integrate the clinical evaluation performed through comprehensive geriatric assessment to gather further elements to guide prescription of direct oral anticoagulants in such a high-risk group of patients.

Aim: We investigated the effect of ataluren plus standard of care (SoC) on age at loss of ambulation (LoA) and respiratory decline in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) versus patients with DMD on SoC alone. Patients & methods: Study 019 was a long-term Phase III study of ataluren safety in nmDMD patients with a history of ataluren exposure. Propensity score matching identified Study 019 and CINRG DNHS patients similar in disease progression predictors. Results & conclusion: Ataluren plus SoC was associated with a 2.2-year delay in age at LoA (p = 0.0006), and a 3.0-year delay in decline of predicted forced vital capacity to ClinicalTrials.gov registration : NCT01557400 .

INTRODUCTION/AIMS Limb girdle muscular dystrophy type 2B (LGMDR2) and facioscapulohumeral muscular dystrophy (FSHD) are genetic muscular dystrophies with an increasing number of potential therapeutic approaches. The aim of this study is to report the data of exploratory digital outcomes extracted from wearable magneto-inertial sensors used in a non-controlled environment for ambulant patients with FSHD and LGMDR2 in a short-term, multicenter clinical study. METHODS Digital outcomes (stride length, stride speed, and walk parameters in a non-controlled environment) were used as exploratory outcomes in the open-label study ATYR1940-C-004 in ambulant patients during the 3 mo of ATYR1940 treatment and 1 mo of follow-up. Activity and gait variables were calculated from the data recorded in 30-day sub-periods using the sensors. For each sub-period, activity and gait parameters were compared between FSHD and LGMDR2 patients. Change from baseline over the 4-mo study period was assessed. RESULTS Ten patients (5 FSHD, 5 LGMDR2) were ambulant and compliant for analysis. Gait parameters, but not activity variables, were significantly lower in LGMDR2 compared to FSHD patients at baseline. Longitudinal analyses showed a slight but significant decrease in stride speed at month 4 for all subjects. Activity variables such as total number of strides per day were highly variable from month to month in individual patients, and no visit effects were found for this variable. DISCUSSION The present study suggests that home-recorded stride speed constitutes a precise and sensitive outcome in ambulant patients with FSHD and LGMDR2.

The Senhance Surgical System is a novel robotic system. We report of our experience using this system for robotic radical prostatectomy (RRP).

Acquired hemophilia A (AHA) is a rare bleeding disorder caused by the development of specific autoantibodies against factor VIII (FVIII). Immunotherapy is a recent therapeutic option that targets the patient’s self-tolerance against tumor cells. Because therapeutic effects of the immune checkpoint inhibitors (ICIs) are mediated by enhancing the immune response to restore antitumor immunity, autoimmune-related adverse effects can be seen in up to 80% of patients during treatment and after treatment. A rare hematologic ICIs-related adverse event is AHA. Hereafter we report two cases of AHA developed during anti-PD-1 immunotherapy for advanced melanoma: one secondary to treatment with nivolumab and one secondary to pembrolizumab. Both patients were treated with activated FVII (Novoseven®, Novo Nordisk, Bagsværd, Denmark) as hemostatic treatment combined with the eradication of antibodies anti-FVIII obtained with rituximab. In the last few years these drugs have significantly improved the therapeutic armamentarium for the management of AHA. Indeed, while FVIIa has proven to be an effective and safe tool for the treatment of acute bleeding related to FVIII autoantibodies, rituximab is a promising alternative for the autoantibodies’ elimination and the restoration of normal hemostasis. Our finding supports the use of this combination even in AHA secondary to ICIs treatment.

Background: Contrast enhanced ultrasound (CEUS) through MicroBubbles Time (MBT) (time from infusion of saline with addition of micro-bubbles of air to visualization of first bubbles in right atrium (RA), visualized by subxiphoid or apical echocardiography) is an alternative to Intracavitary ECG and chest X-ray in evaluation of tip location in central venous catheters. Objective: To evaluate feasibility and variability of CEUS in peripheral catheters (Midline-MC) in a cohort of patients and in a subgroup where tip location was also performed through chest X-ray. Secondary outcomes were verifying the correlation between MBT and distance between tip of MC and RA (anthropometric and radiological measures), body mass index (BMI), vein diameter at point of insertion. Methods: Patients with insertion of MC were enrolled in this prospective cohort. After catheter insertion, CEUS was performed recording MBT. Results: One hundred thirty-two MCs were inserted, 45 performed Chest X-ray. MBT wasn’t feasible in 7 (5%) because of low quality echocardiographic images. Subcostal view was available in 114 patients (91.2%), while 11 patients (8.8%) were examined through apical four-chamber view. Mean MBT in the whole population was 2.3 ± 0.8 s. Significant correlation between anthropometric and radiological measures, BMI and MBT was found. 32.8% of MC had a MBT ⩽2 s. Conclusions: CEUS could be useful to estimate tip position. Our study showed how 2 s is not a suitable cutoff to confirm central catheter’s tip.

BACKGROUND AND OBJECTIVE: To identify the most responsive and sensitive clinical outcome measures in GNE myopathy. METHODS: ClinBio-GNE is a natural history study in GNE myopathy. Patients were assessed prospectively by clinical, functional and quantitative nuclear magnetic resonance imaging (qNMRI) evaluations. Strength and functional tests included Myogrip, Myopinch, MoviPlate and Brooke assessments for upper limb and the 6-min walk distance for lower limb. qNMRI was performed for determining the degree of fatty infiltration and trophicity in leg, thigh, forearm and hand skeletal muscles. Ten GNE myopathy patients were included. Three patients were non-ambulant. Age and gender-matched healthy subjects were used as controls. RESULTS: Fatty infiltration and contractile cross-sectional area changed inversely and significantly in lower distal limbs and in proximal lower and distal upper limbs over 1 year. qNMRI indices and functional assessment results were strongly correlated. CONCLUSIONS: Even in a limited number of patients, qNMRI could detect a significant change over a 1-year period in GNE myopathy, which suggests that qNMRI could constitute a surrogate endpoint in this slowly progressive disease. Quantitative NMRI outcome measures can monitor intramuscular fat accumulation with high responsiveness. Longer follow-up should improve our understanding of GNE myopathy evolution and also lead to the identification of non-invasive outcome measures with the highest discriminant power for upcoming clinical trials.

Item does not contain fulltext No data exists concerning the application of a new robotic system with 3-mm instruments (Senhance™, Transenterix, Milano, Italy) in small cavities. Therefore, the aim of this study was to test the system for its performance of intracorporal suturing in small boxes simulating small body cavities. Translucent plastic boxes of decreasing volumes (2519-90 ml) were used. The procedures (two single stitches, each with two consecutive surgical square knots) were performed by a system-experienced and three system-inexperienced surgeons in each box, starting within the largest box, consecutively exchanging the boxes into smaller ones. With this approach, the total amount of procedures performed by each surgeon increased with decreasing volume of boxes being operated in. Outcomes included port placement, time, task completion, internal and external instrument/instrument collisions and instrument/box collisions. The procedures could be performed in all boxes. The operating time decreased gradually in the first three boxes (2519-853 ml), demonstrating a learning curve. The increase of operating time from boxes of 599 ml and lower may be attributed to the increased complexity of the procedure in small cavities as in the smallest box with the dimensions of 2.9 × 6.3 × 4.9 cm. This is also reflected by the parallel increase of internal instrument-instrument collisions. With the introduction of 3-mm instruments in a new robotic surgical system, we were able to perform intracorporal suturing and knot tying in cavities as small as 90 ml. Whether this system is comparable to conventional three-port 3-mm laparoscopic surgery in small cavities-such as in pediatric surgery-has to be evaluated in further studies.

Background: MicroBubbles Time test (MBT), consisting in the rapid infusion of saline with addition of air microbubbles, visualized by B-mode echocardiography, represents a potential alternative to Intracavitary ECG (IC-ECG) and chest X-ray for central venous catheters (CVCs) tip location. Even if promising, this technique lacks of standardization: a clear time cut-off between bubble infusion and their detection in heart’s right chambers hasn’t been yet established. At these regard, microbubbles could be also detected as microembolic signals (MES) with an alternative ultrasound technique: the pulse wave Doppler (PW). Objective and methods: The first aim of this pilot study is to establish agreement of MBT with PW test (MBT-PW) compared with reference standard IC-ECG and normal MBT for tip location on CVCs. Corrected tip’s position was established through reference standard IC-ECG, afterward MBT-PW was performed, with the sample volume placed at tricuspid valve to detect MES simultaneously with micro-bubbles injection in CVCs. The second aim was to evaluate inter-observer variability for MES detection and grading. Results: Eight patients were enrolled; we obtained three records for each patients (24 with MBT and 24 with MBT-PW, the two techniques were acquired simultaneously). Inter-methods agreement through reference standard IC-ECG versus MBT-PW and MBT versus MBT-PW methodic was satisfying (Cohen’s kappa value = 1). MBT-PW and MBT signals were recorded within the first heart beat after microbubble infusion in all patients. Mean time delay thorough MBT-PW and MBT was 0.76 ±0.07 and 0.78 ± 0.07 s respectively; Intraclass correlation coefficient was 0.992 (95% CI: 0.981–0.996) suggesting excellent correlation. Inter-observer variability for positive MBT-PW evaluation was optimal (Cohen’s kappa value was 1), while indicated substantial agreement for MES grade evaluation (Fleiss’ Kappa value was 0.704; 95% CI: 0.328–1.000). Conclusions: Our study supports agreement between MBT-PW and reference standard IC-ECG for tip location. Satisfactory agreement was observed also for MBT-PW and MBT.

It is estimated that almost one-third of patients with COVID-19 develop delirium in the course of disease, actually it may be the only presenting symptom, especially in dementia patients. In COVID-19 patients delirium is associated with higher mortality rate, increased length of stay and a greater rate of admission in Intensive Care Unit and ventilator utilisation. We hypothesized a greater rate of delirium in Helmet CPAP COVID-19 ventilated patients because many known risk factors for delirium co-exist in these kind of patients (i.e. isolation, noise, dehydration). The first aim of our study is to investigate the incidence of delirium occurring during Helmet CPAP therapy in COVID-19 patients. Moreover, we wanted to verify if there are predictable risk factors for delirium and to determine if delirium increases the risk of adverse outcomes (need of endotracheal intubation and death). The cohort of CPAP ventilated COVID-19 patients were composed by 194 patients. Of them, 57 patients (29.3%) developed delirium during CPAP, more than two third in the first 48h. Age over 70 years, previous diagnosis of dementia or psychiatric condition, P/F < 150 after starting CPAP and Gr/Lys >8 resulted risk factors for delirium. Delirium group had a significantly higher mortality rate (47% vs 23%) and lower intubation rate (12% vs 26%) compared to non-delirious ones. Despite many potential predisposing factors are common in CPAP ventilated patients, delirium incidence in our population seems not to differ from what reported by other studies. Moreover, the occurrence of delirium seems not to be related to prolonged CPAP treatment, indeed no correlation between time spent in CPAP and delirium onset was found.

R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) has been considered the standard of care for diffuse large B cell lymphoma (DLBCL) patients, including in the elderlies, and represent the current standard treatment. Ineligibility for R-CHOP-like treatments seems to be associated with shorter survival. Recent studies have shown that bendamustine and rituximab is linked, in elderly patients affected by DLBCL. Here we report our experience with BR in 40 elderly frail patients affected by DLBCL ineligibles for R-CHOP. The OOR was 77.5%, with 22 complete responses and 9 partial responses statistical analysis showed no significant difference in overall survival (OS) between patients aged 80 years and older and patients younger than 80 years (6·4 vs. 10·2 months, respectively, P = 0·43). Complete responders were more likely patients with good performance status, (ECOG 0-1) 13 patients (60%), 9 patients (40%) were ECOG 2; of the 9 patients who achieved partial response, 7 patients had ECOG 0-1 and 2 patients had ECOG 2. Four patients had stable disease. Progression-free survival (PFS) median PFS was 13.5 months. These preliminary results showed that bendamustine and rituximab has been associated with high response rates, acceptable toxicity in frail DLBCL patients and high rate of OSS. In older patients with advanced IPI scores, no significant difference in OS were observed between patients aged 80 years and older and patients younger than 80 years. We conclude that bendamustine and rituximab seems to be a reasonable alternative for frail DLBCL patients.

Additional file 1. Search strategy of electronic database.

Additional file 3. Characteristics of the enrolled investigations, overall clinical characteristics of the populations investigated in the enrolled studies, and list of studies excluded after reading the full text.

Introduction: Multiple myeloma (MM) is characterized by a high prevalence of thrombotic complications. Microvesicles (MVs) are small membrane vesicles released from activated cells, and they may potentially contribute to thrombosis. Methods: We have evaluated the plasma levels of MVs and cytokines (IL-10, IL-17, and TGF-β in MM and Watch and Wait Smoldering MM (WWSMM) from patients and related them to thrombotic complications. The secondary aim was to assess the impact of ongoing therapy on MV and on cytokine levels. Result: 92 MM and 31 WWSMM were enrolled, and 14 (12%) experienced a thrombotic episode. Using univariate analysis, TGF-β and MV were significantly higher in patients with thrombotic events (p = 0.012; p = 0.008, respectively). Utilizing a Cox proportional hazard model, we confirmed this difference (TGF-β p = 0.003; Odds ratio 0.001, 95% CI 0–0.003 and MV p = 0.001; Odds ratio 0.003, 95% CI 0.001–0.005). Active treatment management displayed higher levels of MV (p < 0.001) and lower levels of glomerular filtration-rate (p < 0.001), IL-17 (p < 0.001) as compared to the WWSMM group. The TGF-β values of immunomodulatory derivatives patients were lower in the WWSMM (p < 0.001) and Dexamethasone/Bortezomib subgroup (p < 0.001). Conclusion: The increased levels of MVs in active regimens add insight into the mechanisms of hypercoagulation in MM. In addition, a role for cytokine-related thrombosis is also suggested.

BackgroundVenous Access Devices (VADs) are the most used device in COVID-19 patients.ObjectiveIdentify VADs implanted, catheter related thrombosis (CRT), catheter-related bloodstream infection (CRBSI), and accidental remove of VADs in both COVID-19 positive and COVID-19 free patients. Successive analysis was conducted comparing COVID-19 positive patients with COVID-19 free with inverse probability propensity score weights using simple regression to account for these two confounders (peripheral tip as central/peripheral and hospitalization as no/yes).MethodsThis multicenter, retrospective cohort study was conducted using data from 7 hospitals in Lombardy during the pandemic period from February 21st to May 31st 2020.Results2206 VADs were evaluated, of which 1107 (50.2%) were inserted in COVID-19 patients. In COVID-19 cohort the first choice was Long Peripheral Cannula in 388 patients (35.1%) followed by Midline Catheter in 385 (34.8%). The number of “central tip” VADs inserted in COVID-free inpatients and COVID-19 positive were similar (307vs334). We recorded 42 (1.9%) CRT; 32 (79.2%) were observed in COVID-19 patients. 19 CRBSI were diagnosed; 15 (78.95%) were observed in COVID-19. Accidental removals were the more represented complication with 123 cases, 85 (69.1%) of them were in COVID-19. COVID-19 significantly predicted occurrence of CRT (OR = 2.00(1.85-5.03); PConclusionsCRT, CRBSI, and accidental removal are significantly more frequent in COVID-19 patients. Accidental removals are the principal complication, for this reason use of subcutaneously anchored securement is recommended for shorter period than usual.

Background Acute Hypoxemic Respiratory Failure (AHRF) is a common complication of Covid-19 related pneumonia, for which non-invasive ventilation (NIV) with Helmet Continuous Positive Airway Pressure (CPAP) is widely used. During past epidemics of SARS and MERS pneumomediastinum (PNM) and pneumothorax (PNX) were common complications (respectively 1.7-12% and 16,4%) either spontaneous or associated to ventilation. Methods Aim of our retrospective study was to investigate the incidence of PNX/PNM in COVID-19 pneumonia patients treated with CPAP. Moreover, we examined the correlation between PNX/PNM and Positive end-expiratory pressure (PEEP) values. We collected data from patients admitted to “Luigi Sacco” University Hospital of Milan from 21/02/2020 to 06/05/2020 with COVID-19 pneumonia requiring CPAP. Results One-hundred-fifty-four patients were enrolled. During hospitalization 3 PNX and 2 PNM occurred (3.2%). Out of these five patients 2 needed invasive ventilation after PNX, two died. In the overall population, 42 patients (27%) were treated with High-PEEP (>10 cmH2O), and 112 with Low-PEEP (≤10 cmH2O). All the PNX/PNM occurred in the High-PEEP group (5/37 vs 0/112, p Conclusion The incidence of PNX appears to be lower in COVID-19 than SARS and MERS, but their occurrence is accompanied by high mortality and worsening of clinical conditions. Considering the association of PNX/PNM with high PEEP we suggest using the lower PEEP as possible to prevent these complications. “Key messages” box Section 1: What is already known on this subject Elevated incidence of pneumomediastinum (PNM) and pneumothorax (PNX) occurring during SARS and MERS pneumonia (respectively 1.7-12%9,10 and 16,4%11), either spontaneous or associated to ventilation.Conversely, these complications have not been reported when NIV was used for the treatment of common pneumonia patients6,7. Some cases of PNX and PNM have been recently reported in patients with COVID-19 pneumonia, most of them spontaneous12-14, in some cases related to NIV15,16 or endotracheal intubation (ETI)17,18. Section 2: What this study adds Incidence of PNX/PNM is lower in COVID19 pneumonia patients during CPAP (3,2%) than SARS and MERS. Considering mortality rate and need of ETI, occurrence of PNX/PNM worsens prognosis. All the PNX/PNM occurred in the High-PEEP (>10 cmH2O) group (5/37 vs 0/112, p Considering the association of high PEEP (>10 cmH2O) with PNX/PNM, the use of low PEEP values has to be taken into consideration.

BACKGROUND: Quantitative nuclear magnetic resonance imaging (NMRI) is an objective and precise outcome measure for evaluating disease progression in neuromuscular disorders. We aimed to investigate predictive ‘disease activity’ NMR indices, including water T(2) and (31)P NMR spectroscopy (NMRS), and its relation to NMR markers of ‘disease progression’, such as the changes in fat fraction (ΔFat%) and contractile cross-sectional area (ΔcCSA), in GNE myopathy (GNEM) patients. METHODS: NMR was performed on a 3T clinical scanner, at baseline and at a 1-year interval, in 10 GNEM patients and 29 age-matched controls. Dixon-based fat-water imaging and water T(2) mapping were acquired in legs and thighs, and in the dominant forearm. (31)P NMRS was performed at the level of quadriceps and hamstring. Water T(2) and (31)P NMRS indices were determined for all muscle groups and visits. Correlations were performed with ‘disease progression’ indices ΔFat%, ΔcCSA and the muscle fat transformation rate (R(muscle_transf)). RESULTS: In quadriceps, known to be relatively preserved in GNEM, water T(2) at baseline was significantly higher compared to controls, and correlated strongly with the one-year evolution of Fat% and cCSA and R(muscle_transf). Various (31)P NMRS indices showed significant differences in quadriceps and hamstring compared to controls and correlations existed between these indices and ΔFat%, ΔcCSA and R(muscle_transf). CONCLUSIONS: This study demonstrates that disease activity indices such as water T(2) and (31)P NMRS may predict disease progression in skeletal muscles of GNEM patients, and suggests that these measures may be considered to be valuable surrogate endpoints in the assessment of GNEM disease progression.

Magnetic resonance imaging (MRI) constitutes a powerful outcome measure in neuromuscular disorders, yet there is a broad diversity of approaches in data acquisition and analysis. Since each neuromuscular disease presents a specific pattern of muscle involvement, the recommended analysis is assumed to be the muscle-by-muscle approach. We, therefore, performed a comparative analysis of different segmentation approaches, including global muscle segmentation, to determine the best strategy for evaluating disease progression. In 102 patients (21 immune-mediated necrotizing myopathy/IMNM, 21 inclusion body myositis/IBM, 10 GNE myopathy/GNEM, 19 Duchenne muscular dystrophy/DMD, 12 dysferlinopathy/DYSF, 7 limb-girdle muscular dystrophy/LGMD2I, 7 Pompe disease, 5 spinal muscular atrophy/SMA), two MRI scans were obtained at a 1-year interval in thighs and lower legs. Regions of interest (ROIs) were drawn in individual muscles, muscle groups, and the global muscle segment. Standardized response means (SRMs) were determined to assess sensitivity to change in fat fraction (ΔFat%) in individual muscles, muscle groups, weighted combinations of muscles and muscle groups, and in the global muscle segment. Global muscle segmentation gave high SRMs for ΔFat% in thigh and lower leg for IMNM, DYSF, LGMD2I, DMD, SMA, and Pompe disease, and only in lower leg for GNEM and thigh for IBM. Global muscle segment Fat% showed to be sensitive to change in most investigated neuromuscular disorders. As compared to individual muscle drawing, it is a faster and an easier approach to assess disease progression. The use of individual muscle ROIs, however, is still of interest for exploring selective muscle involvement. • MRI-based evaluation of fatty replacement in muscles is used as an outcome measure in the assessment of 1-year disease progression in 8 different neuromuscular diseases. • Different segmentation approaches, including global muscle segmentation, were evaluated for determining 1-year fat fraction changes in lower limb skeletal muscles. • Global muscle segment fat fraction has shown to be sensitive to change in lower leg and thigh in most of the investigated neuromuscular diseases.

During the course of Covid-19, the disease caused by the new Coronavirus SARS-CoV-2, thrombotic phenomena and/or diffuse vascular damage are frequent, and viral elements have been observed within endothelial cells. Circulating endothelial cells (CECs) and their progenitors (CEPs) are increased in cardiovascular, thrombotic, infectious and cancer diseases. Using a validated flow cytometry procedure, we found that viable CEPs/mL were significantly increased in Covid-19 patients compared to healthy controls. This increase was observed in patients with mild symptoms and not further augmented in patients with severe symptoms. In patients who recovered, CEPs decreased, but were in a range still significantly higher than normal controls. Regarding mature CECs, in Covid-19 patients their absolute number was similar to those observed in healthy controls, but the viable/apoptotic CEC ratio was significantly different. Both mild and severe Covid-19 patients had significantly more viable CECs compared to healthy controls. Patients who recovered had significantly less CECs/mL when compared to controls as well as to mild and severe Covid-19 patients. A positive correlation was found between the copies of SARS-CoV-2 RNA in the cellular fraction and apoptotic CEPs/mL in severe Covid-19 patients. These findings suggest that CECs and CEPs might be investigated as candidate biomarkers of endothelial damage in Covid-19 patients.

Contains fulltext : 220816.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The main aim was to explore the changes in hand-grip strength in patients with Duchenne muscular dystrophy (DMD) aged 5-29 years. Secondary aims were to test the effect of mutation, ambulatory status and glucocorticoid use on grip strength and its changes over time and to compute the number of subjects needed for a clinical trial to stabilize grip strength. METHODS: The analysis was performed on data collected during five international natural history studies on a cohort of DMD patients. Two hundred and two patients with genetically proven DMD were pooled from five different natural history studies. Excepting 13 patients with only one visit, the mean duration of follow-up was 2.2 +/- 1.6 years. A total of 977 measurement points were collected. Grip strength was measured on the dominant side with a high precision dynamometer. The analysis was performed using absolute values and normalized values expressed in percentage of predicted values for age. RESULTS: For absolute values, grip strength typically increased in ambulatory boys and decreased in non-ambulatory patients. However, when normalized, grip strength was already reduced at age 5 years and thereafter continued to fall away from normal values. The weaker the patients, the less strength they are prone to lose over again. INTERPRETATION: Grip strength constitutes a sensitive and continuous outcome measure that can be used across all stages of DMD. Its measurement is easy to standardized, can be used in ambulatory and non-ambulatory patients and does not present any floor or ceiling effect. It is thus attractive as an outcome measure in therapeutic trials.

Spinal muscular atrophy (SMA) is a recessive disorder caused by a mutation in the survival motor neuron 1 gene (SMN1); it affects 1 in 11 000 newborn infants. The most severe and most common form, type 1 SMA, is associated with early mortality in most cases and severe disability in survivors. Nusinersen, an antisense oligonucleotide, promotes production of full-length protein from the pseudogene SMN2. Nusinersen treatment prolongs survival of patients with type 1 SMA and allows motor milestone acquisition. Patients with type 2 SMA also show progress on different motor scales after nusinersen treatment. Nusinersen was recently approved by the European Medicines Agency and the US Food and Drug Administration; it is now reimbursed in several European countries and in the USA. In Australia, the transition from expanded access programme to commercial availability is coming soon. In New Zealand, an expanded access programme is opened, and in Canada price negotiation for the treatment is in progress. In this review we exemplify the clinical benefit of nusinersen in subgroups of patients with SMA. Nusinersen represents the first efficacious marked approved drug in type 1 and type 2 SMA. Different knowledge gaps, such as results in older patients, in patients with permanent ventilation, in patients with neonatal forms, or in patients after spinal fusion, still need to be addressed. WHAT THIS PAPER ADDS: Identifies gaps in knowledge about the efficacy of nusinersen in broader populations of patients with spinal muscular atrophy. Identifies open questions in populations of patients where proof of efficacy is available.

I cateteri venosi centrali o permanenti sono sempre più utilizzati nei nostri Centri dialisi. Una delle problematiche emergenti, legata alla lunga permanenza dei CVC permanenti, è la difficoltà nel rimuoverli, a causa della formazione di tenaci aderenze tra tali dispositivi e la parete vasale. Attualmente per tali complicanze, non esistono linee guida definite. Riteniamo quindi importante condividere le singole esperienze e le procedure utilizzate per la loro rimozione anche per poter definire la reale incidenza del fenomeno, le eventuali complicanze e le migliori strategie da attuare. In questo articolo, descriviamo due casi clinici di difficile rimozione di un CVCp posizionato in vena giugulare interna sin ed i metodi utilizzati per la sua estrazione.

La nefropatia da mezzo di contrasto (contrast induced nephropathy) (CIN) è una delle cause più frequenti di danno renale acuto nei pazienti ricoverati. L'incidenza di CIN dipende dalla presenza di fattori di rischio legati al paziente (insufficienza renale, diabete, malattie cardiovascolari, età avanzata) e da cause dipendenti dalla procedura (dose elevata di mezzo di contrasto, via di somministrazione intra-arteriosa). L'insufficienza renale rappresenta il maggiore fattore di rischio di CIN, in particolare quando è associata al diabete. L'idratazione pre- e post-somministrazione di MDC rappresenta la sola terapia di prevenzione ad essere strettamente raccomandata dalle Linee Guida nei pazienti a rischio. Gli studi sulla prevenzione della CIN hanno riguardato soprattutto casistiche cardiologiche di pazienti con moderato rischio renale (GFR 60– 40 mL/min) sottoposti a somministrazione intra-arteriosa di mezzo di contrasto. In molti trial clinici è stata valutata l'efficacia dell'idratazione con bicarbonato di sodio e della N-acetilcisteina (NAC) nella prevenzione della CIN. L'infusione con sodio bicarbonato ha dimostrato una maggiore efficacia rispetto alla fisiologica, in modo particolare quando l'idratazione necessita tempi rapidi come nelle procedure in emergenza. La NAC non ha dimostrato una chiara efficacia in quanto i risultati positivi osservati in alcuni studi non sono stati confermati in altri. Il problema aperto rimane la prevenzione della CIN nei soggetti con elevato rischio renale (e-GFR < 30 mL/min) nei quali la presenza di CIN può associarsi all'ingresso in dialisi cronica.