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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atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data.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

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.

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.

Background: Venous Access Devices (VADs) are the most used devices in COVID-19 patients. Objective: Identify 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). Methods: This multicenter, retrospective cohort study collected data from seven hospitals in Lombardy during the pandemic period from February 21st to May 31st 2020. Results: A total of 2206 VADs were evaluated, 1107 (50.2%) of which 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 (307 vs 334). We recorded 42 (1.9%) CRT; 32 (79.2%) were observed in COVID-19 patients. A total of 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); p Conclusions: CRT, CRBSI, and accidental removal are significantly more frequent in COVID-19 patients. Accidental removals are the principal complication, for this reason, the use of subcutaneously anchored securement is recommended for a shorter period than usual.

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

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, p < 0.001). The overall in-hospital mortality was 63.6%. Delirium occurred in 59.1%, with a mortality rate in this subgroup of 83.1%. In a time-varying Cox model, the hazard ratio of death was 2.9 in patients with baseline RR ≥ 30 cycle/min, 2.4 in those with baseline P/F < 100. In the same model, the hazard ratio of death was 20 in patients with delirium and a frailty score < 5 and 8.8 in those without delirium and with frailty ≥ 5, indicating a competitive effect between these two variables on the death risk. Conclusions: Respiratory impairment, frailty, and delirium predict treatment failure, with the latter two factors demonstrating a competitive effect on mortality risk. CPAP support may represent a feasible therapeutic option in elderly patients, although chances of a therapeutic benefit are markedly reduced in case of severe respiratory impairment, very frail baseline condition or delirium occurrence.

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 Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare disease. Few states in developing countries have an adequate management of HAE, but none of them belongs to the former USSR area. This study analyses data from C1-INH-HAE patients from Belarus. Methods Data about clinical characteristics, genetics, access to diagnosis and treatment were collected from 2010 by the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology in Minsk. A questionnaire about attacks, prophylactic (LTP) and on-demand therapy (ODT) was administered to patients. Results We identified 64 C1-INH-HAE patients belonging to 26 families, 27 (42.2%) of which were diagnosed in the last 3 years. The estimated minimal prevalence was 1:148,000. Median age at diagnosis was 29 years, with diagnostic delay of 19 years. Thirty-eight patients answered a questionnaire about therapy. Eleven patients did not use any treatment to resolve HAE attacks. Twenty-seven patients underwent ODT: 9 with appropriate treatments, and 18 with inappropriate treatments. Nine patients used LTP with attenuated androgens and 1 with tranexamic acid. Thirty-two patients answered a questionnaire about attacks and triggers: 368 angioedema attacks were reported, with an average of 10 attacks per year. We found 24 different SERPING1 variants: 9 missenses, 6 in splice sites, 6 small deletions, 2 nonsense, 1 large deletion; 7 have not been previously described. De novo variants were found in 11 patients. Conclusions C1-INH-HAE diagnosis and management in Belarus is improved as seen from the high number of new diagnosis in the last 3 years. Next steps will be to reduce the diagnostic delay and to promote the LTP and ODT.

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.

OBJECTIVE: To characterize the natural history of spinal muscular atrophy (SMA) over 24 months using innovative measures such as wearable devices, and to provide evidence for the sensitivity of these measures to determine their suitability as endpoints in clinical trials. METHODS: Patients with Type 2 and 3 SMA (N = 81) with varied functional abilities (sitters, nonsitters, nonambulant, and ambulant) who were not receiving disease-modifying treatment were assessed over 24 months: motor function (Motor Function Measure [MFM]), upper limb strength (MyoGrip, MyoPinch), upper limb activity (ActiMyo® ), quantitative magnetic resonance imaging (fat fraction [FFT2 ] mapping and contractile cross-sectional area [C-CSA]), pulmonary function (forced vital capacity [FVC], peak cough flow, maximum expiratory pressure, maximum inspiratory pressure, and sniff nasal inspiratory pressure), and survival of motor neuron (SMN) protein levels. RESULTS: MFM32 scores declined significantly over 24 months, but not 12 months. Changes in upper limb activity could be detected over 6 months and continued to decrease significantly over 12 months, but not 24 months. Upper limb strength decreased significantly over 12 and 24 months. FVC declined significantly over 12 months, but not 24 months. FFT2 increased over 12 and 24 months, although not with statistical significance. A significant increase in C-CSA was observed at 12 but not 24 months. Blood SMN protein levels were stable over 12 and 24 months. INTERPRETATION: These data demonstrate that the MFM32, MyoGrip, MyoPinch, and ActiMyo® enable the detection of a significant decline in patients with Type 2 and 3 SMA over 12 or 24 months. ispartof: ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY vol:8 issue:2 pages:359-373 ispartof: location:United States status: published