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Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US. STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes [vg]/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov, NCT03461289 (completed). From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p<0·0001). 31 (97%, 95% CI 91–100) of 32 patients in the ITT population survived free from permanent ventilatory support at 14 months compared with six (26%, 8–44) of 23 patients in the PNCR natural history cohort (p<0·0001). 32 (97%) of 33 patients had at least one adverse event and six (18%) had adverse events that were considered serious and related to onasemnogene abeparvovec. The most common adverse events were pyrexia (22 [67%] of 33), upper respiratory infection (11 [33%]), and increased alanine aminotransferase (nine [27%]). One death, unrelated to the study drug, occurred from hypoxic-ischaemic brain damage because of a respiratory tract infection during the study. STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline. Novartis Gene Therapies.

Depression is the leading cause of disability worldwide(1). The microbiota-gut-brain axis may play a role in the aetiology of depression, and probiotics show promise for improving mood and depressive state(2). Further evidence is required to support mechanisms and in high-risk populations, such as those with sub-threshold depression (which may be 2-3 times more prevalent than diagnosed depression)(3). The aims were to assess the efficacy of a probiotic compared with placebo in reducing the severity of depressive symptoms in participants with subthreshold depression, and to investigate potential mechanistic markers of inflammatory, antioxidant status and stress response. A double-blind, randomised, placebo-controlled trial was conducted in participants meeting diagnosis of subthreshold depression (DSM-5); aged 18-65 years; ≥18.5 kg/m2 body mass index; not taking antidepressants, centrally acting medications, probiotics nor antibiotics for at least 6 weeks. The probiotic (4 × 109 AFU/CFU, 2.5 g freeze-dried powder containing Lactobacillus fermentum LF16 (DSM26956), L. rhamnosus LR06 (DSM21981), L. plantarum LP01 (LMG P-21021), Bifidobacterium longum BL04 (DSM 23233)) or placebo was taken daily for 3-months. Data was collected at 3 study visits (pre-, mid- (6 weeks), post-intervention). Self-reported questionnaires measured psychological symptoms (Beck Depression Inventory, BDI; Hospital Anxiety Depression Scale, HADS) and quality of life. Blood and salivary samples were collected for biomarkers including cortisol awakening response (CAR). General linear models examined within-group and between-group differences across all time points. Thirty-nine participants completed the study (n = 19 probiotic; n = 20 placebo) using intention-to-treat analysis. The probiotic group decreased in BDI score by −6.5 (95% CI −12.3; −0.7) and −7.6 (95% CI −13.4; −1.8) at 6 and 12 weeks, respectively. The HADS-A score decreased in the probiotic group by −2.8 (95% CI −5.2; −0.4) and −2.7 (95% CI −5.1; −0.3) at 6 and 12, respectively. The HADS-D score decreased in the probiotic group by −3.0 (95% CI −5.4; −0.7) and −2.5 (−4.9; −0.2) at 6 and 12 weeks of intervention, respectively. No between group differences were found. There were no changes in perceived stress or quality of life scores. The probiotic group had reduced hs-CRP levels (7286.2 ± 1205.8 ng/dL vs. 5976.4 ± 1408.3; P = 0.003) and increased total glutathione (14.2 ± 8.9 ng/dL vs. 9.3 ± 4.7; P = 0.049) compared to placebo, post intervention. Lower levels of CAR were found in the probiotic compared to placebo (−0.04 ± 0.17 μg/dL vs. 0.16 ± 0.25; P = 0.009). A significant reduction in depressive symptoms and anxiety was observed within the probiotic group only. These results were supported by improvements observed in biomarkers, suggesting probiotics may improve psychological wellbeing in adults experiencing sub-threshold depression, by potential pathways involved in central nervous system homeostasis and inflammation. Future analyses are required to understand changes within the intestinal microbiota and to clarify how their metabolites facilitate emotional processing.

Background Myosin heavy chain 7 ( MYH7 )-related myopathies are emerging as an important group of muscle diseases of childhood and adulthood, with variable clinical and histopathological expression depending on the type and location of the mutation. Mutations in the head and neck domains are a well-established cause of hypertrophic cardiomyopathy whereas mutation in the distal regions have been associated with a range of skeletal myopathies with or without cardiac involvement, including Laing distal myopathy and Myosin storage myopathy. Recently the spectrum of clinical phenotypes associated with mutations in MYH7 has increased, blurring this scheme and adding further phenotypes to the list. A broader disease spectrum could lead to misdiagnosis of different congenital myopathies, neurogenic atrophy and other neuromuscular conditions. Results As a result of a multicenter Italian study we collected clinical, histopathological and imaging data from a population of 21 cases from 15 families, carrying reported or novel mutations in MYH7 . Patients displayed a variable phenotype including atypical pictures, as dropped head and bent spine, which cannot be classified in previously described groups. Half of the patients showed congenital or early infantile weakness with predominant distal weakness. Conversely, patients with later onset present prevalent proximal weakness. Seven patients were also affected by cardiomyopathy mostly in the form of non-compacted left ventricle. Muscle biopsy was consistent with minicores myopathy in numerous cases. Muscle MRI was meaningful in delineating a shared pattern of selective involvement of tibialis anterior muscles, with relative sparing of quadriceps. Conclusion This work adds to the genotype-phenotype correlation of MYH7 -relatedmyopathies confirming the complexity of the disorder.

The objective of this study is to determine the relationship between short-term temperature variability on neighboring days and mortality. The change in maximum temperature in Northern Virginia, Richmond, Roanoke, and Norfolk, Virginia, on neighboring days was calculated from airport observations and associated with total mortality over a multi-county area surrounding each weather station. The association between day-to-day temperature change and mortality, lagged over a 28-day period, was analyzed using distributed lag non-linear models that controlled for air quality, temporal trends, and other factors. Days following large temperature declines were associated with an increased risk of mortality in three of the four locations, and temperature increases were linked to higher mortality risk in two cities. For example, the relative risk of mortality for a 12°C daily temperature decline (1 st percentile) was 1.74 [0.92, 3.27] in Roanoke and 1.16 [0.70, 1.92] in Richmond. The net effect of short-term temperature increases was smaller, with the largest relative risk of 1.03 [0.58, 1.83] for a 12°C increase (99 th percentile) in maximum temperature in Norfolk. In Richmond and Roanoke, there was an observed lagged effect of increased mortality (maximum relative risks varying from 1.08 to 1.10) that extended from 5 to 25 days associated with large temperature declines of 15°C or more. In contrast, there was a strong and immediate (lag 0–3 day) increase in the risk of mortality (1.10 to 1.15) in northern Virginia and Norfolk when the temperature increase exceeded 10°C (short-term warming). In general, consecutive day warming had a more immediate mortality impact than short-term cooling, when the peak mortality is lagged by one week or more. However, cooling of at least 10°C after a hot (summer) day reduced mortality relative to comparable cooling following a cold (winter) day, which is associated with high mortality. This differential mortality response as a function of temperature suggests that there is some relationship between average temperature, temperature variability, and season. The findings of this study may be useful to public health officials in developing mitigation strategies to reduce the adverse health risks associated with short-term temperature variability.

Background Counselling has been shown to improve adherence to medication in people living with HIV (PLHIV). The aim of this study was to investigate factors associated with regular counselling attendance of patients taking antiretroviral therapy (ART). Methods We conducted a cross-sectional, paper-based survey among 880 PLHIV patients on ART attending outpatient clinics of a referral hospital in Jakarta. Patients on ART, above 18 years old, providing written consent were included. The primary outcome was regular counselling attendance (i.e., having attended at least 3 sessions in the previous 3 months) using records from counsellors. Factors associated with regular counselling attendance were assessed using logistic regression analysis. Results The majority of patients were male (71.1%) and had regular counselling (78.4%). Being 31 to 40 years old (odds ratio (OR) = 0.55, 95% confidence interval (CI) = 0.32–0.93, > 40 years (OR = 0.30, 95% CI = 0.16–0.55) vs < 30 years, hepatitis B/C co-infection (OR = 0.42, 95% CI = 0.24–0.75), living > 20 km from the hospital (OR = 0.55, 95% CI = 0.33–0.93), transmission male-to-male (OR = 0.13, 95% CI = 0.04–0.44), unemployment (OR = 1.88, 95% CI = 1.02–3.44), part-time employment (OR = 10.71, 95% CI = 4.09–28.02), household member with HIV (OR = 3.31, 95% CI = 1.70–6.44), and Christianity (OR = 1.82, 95% CI = 1.12–2.94) were associated with regular counselling attendance. Conclusion This study suggests that counselling services should be reviewed to ensure that they are near home and fit the needs of older patients or patients with co-morbidities and minorities. Tailoring counselling may improve attendance.

Technological developments on energy savings are caused by increasing demand for energy use from year to year. This is done to avoid an energy crisis. The energy crisis is a problem that is being faced because of the depletion of fossil energy. To restore fossil energy can require natural processes in a long time. With the limited availability of fossil energy, it is very necessary to develop alternative energy sources that are friendly to the environment, one of which is wind energy. Indonesia is an archipelago, so the wind speed in Indonesia is relatively low, then in this study can be overcome using a vertical axis wind turbine (VAWT). This research was conducted to find out power of Coefficient, type speed ratio in the variation of wind speed in the turbine. This study uses a wind power design with a vertical axis. Blades are used from modified NACA 0018 airfoil. Research result taken at the time of testing is with wind speeds ranging from 3 m / s to 6,1 m/s which measures the capacity of electric power produced by turbines with a load of 10 watts. The results of this study are the minimum actual power of the turbine 2.881 Watt with TSR 0.4 and Cp 0.18 at wind speed 3 m/s, and the maximum power obtained at a speed of 6,1m/s that is equal to 14.62 Watt with a TSR of 0.25 and Cp of 0.29.

Background A connection between amyotrophic lateral sclerosis (ALS) and altered gut microbiota composition has previously been reported in animal models. This work is the first prospective longitudinal study addressing the microbiota composition in ALS patients and the impact of a probiotic supplementation on the gut microbiota and disease progression. Methods Fifty patients and 50 matched controls were enrolled. The microbial profile of stool samples from patients and controls was analyzed via PCR-Denaturing Gradient Gel Electrophoresis, and the main microbial groups quantified via qPCR. The whole microbiota was then analyzed via next generation sequencing after amplification of the V3–V4 region of 16S rDNA. Patients were then randomized to receive probiotic treatment or placebo and followed up for 6 months with ALSFRS-R, BMI, and FVC%. Results The results demonstrate that the gut microbiota of ALS patients is characterized by some differences with respect to controls, regardless of the disability degree. Moreover, the gut microbiota composition changes during the course of the disease as demonstrated by the significant decrease in the number of observed operational taxonomic unit during the follow-up. Interestingly, an unbalance between potentially protective microbial groups, such as Bacteroidetes, and other with potential neurotoxic or pro-inflammatory activity, such as Cyanobacteria, has been shown. The 6-month probiotic treatment influenced the gut microbial composition; however, it did not bring the biodiversity of intestinal microbiota of patients closer to that of control subjects and no influence on the progression of the disease measured by ALSFRS-R was demonstrated. Conclusions Our study poses the bases for larger clinical studies to characterize the microbiota changes as a novel ALS biomarker and to test new microbial strategy to ameliorate the health status of the gut. Trial registration CE 107/14, approved by the Ethics Committee of the “Maggiore della Carità” University Hospital, Italy.

Background. Type-2 inflammation commonly marks asthma in childhood. Also, gut and lung dysbiosis is detectable in patients with asthma. Strain-related probiotic supplementation may restore a physiological immune response, dampen airway inflammation, and repair dysbiosis. Therefore, the probiotics in pediatric asthma management (PROPAM) study is aimed at demonstrating that Ligilactobacillus salivarius LS01 (DSM 22775) and Bifidobacterium breve B632 (DSM 24706) mixture could reduce asthma exacerbations in children, followed in a primary care setting. Methods. The study was randomized, placebo-controlled, and double-blind. It involved 11 Italian primary care pediatricians. The probiotic mixture (containing Ligilactobacillus salivarius LS01 1×109 live cells and Bifidobacterium breve B632 1×109 live cells) or placebo was taken twice daily (1 sachet in the morning and 1 in the evening) for eight weeks and subsequently once daily for a further eight weeks. Outcomes included number, severity, and duration of asthma exacerbations, intensity of maintenance and as need treatments, and safety. Results. The per-protocol population included 422 children (mean age seven years, 240 males and 182 females). The probiotic mixture significantly reduced the number of asthmatic exacerbations (OR=3.17). In addition, the number of children with two exacerbations was less than a third in the active group (OR=3.65). Conclusions. This PROPAM study demonstrated that probiotic strains Ligilactobacillus salivarius LS01 (DSM 22775) and Bifidobacterium breve B632 (DSM 24706) were safe and significantly reduced by more than a third the frequency of asthma exacerbations. At present, the first-line treatment of asthma is still drug-based, but specific strains of probiotics may be auxiliary remedies.

The probiotics-supplemented low-protein diet in chronic kidney disease (ProLowCKD) was a single-centre, double-blind, placebo-controlled, randomised trial that was conducted to investigate whether the association between a low protein diet (LPD) and a new formulation of probiotics (Bifidobacterium longum and Lactobacillus reuteri) was effective at reducing traditional uremic, microbiota-derived, and proatherogenic toxins in sixty patients affected by advanced CKD. After 2 months of a LPD—a reduction in blood urea nitrogen (52 ± 17 vs. 46 ± 15 mg/dL, p = 0.003), total cholesterol (185 ± 41 vs. 171 ± 34 mg/dL, p = 0.001), and triglycerides (194 ± 148 vs. 161 ± 70 mg/dL, p = 0.03) was observed; 57 subjects were then randomized to receive probiotics or a placebo for the subsequent 3 months. A total of 27 patients in the placebo group showed increased serum values of total cholesterol (169 ± 36 vs. 185 ± 40 mg/dL, p = 0.01), LDL cholesterol (169 ± 36 vs. 185 ± 40 mg/dL, p = 0.02), lipoprotein-associated phospholipase A2 (155.4 ± 39.3 vs. 167.5 ± 51.4 nmol/mL/min, p = 0.006), and indoxyl-sulphate (30.1 ± 17.6 vs. 34.5 ± 20.2 μM, p = 0.026), while the 24 subjects in the probiotics group showed a trend in the reduction of microbiota toxins. A reduction of antihypertensive and diuretic medications was possible in the probiotics group. This study shows that associating probiotics to LPD may have an additional beneficial effect on the control and modulation of microbiota-derived and proatherogenic toxins in CKD patients.