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Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS). In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019). We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient. RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a’s than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex. This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes.

The Mississippi River Delta (MRD) is a global natural and economic asset and socio-economic hub with an extensive fishery, major petrochemical complexes, and the largest global commodity port. During the twentieth century, >25% of MRD coastal wetlands were lost. Climate forcings threatening the MRD include extreme precipitation, increasing river discharge, tropical cyclones, and sea-level rise exacerbated by subsidence. We outline adaptation strategies to enhance the sustainability of the MRD. These include defining defensive baselines, diverting river water into the deltaic plain, protecting the crucial river corridor between Baton Rouge and New Orleans, strengthening protection for New Orleans, and sustaining the fishing industry. These strategies highlight potential challenges of existing “restoration” plans, which sometimes fail to address ongoing climate challenges. Management plans must be more adaptation focused. We offer suggestions for current restoration initiatives and put our findings into the context of global delta restoration.

Long-term, real-world effectiveness and safety data of disease-modifying treatments for spinal muscular atrophy (SMA) are important for assessing outcomes and providing information for a larger number and broader range of SMA patients than included in clinical trials. We sought to describe patients with SMA treated with onasemnogene abeparvovec monotherapy in the real-world setting. RESTORE is a prospective, multicenter, multinational, observational registry that captures data from a variety of sources. Recruitment started in September 2018. As of May 23, 2022, data were available for 168 patients treated with onasemnogene abeparvovec monotherapy. Median (IQR) age at initial SMA diagnosis was 1 (0–6) month and at onasemnogene abeparvovec infusion was 3 (1–10) months. Eighty patients (47.6%) had two and 70 (41.7%) had three copies of SMN2, and 98 (58.3%) were identified by newborn screening. Infants identified by newborn screening had a lower age at final assessment (mean age 11.5 months) and greater mean final (SD) CHOP INTEND score (57.0 [10.0] points) compared with clinically diagnosed patients (23.1 months; 52.1 [8.0] points). All patients maintained/achieved motor milestones. 48.5% (n = 81/167) experienced at least one treatment-emergent adverse event (AE), and 31/167 patients (18.6%) experienced at least one serious AE, of which 8/31 were considered treatment-related. These real-world outcomes support findings from the interventional trial program and demonstrate effectiveness of onasemnogene abeparvovec over a large patient population, which was consistent with initial clinical data and published 5-year follow-up data. Observed AEs were consistent with the established safety profile of onasemnogene abeparvovec.

Spinal muscular atrophy (SMA) is a neuromuscular disorder arising from biallelic non-functional survival motor neuron 1(SMN1) genes with variable copies of partially functional SMN2gene. Intrathecal onasemnogene abeparvovec administration, at fixed, low doses, may enable treatment of heavier patients ineligible for weight-based intravenous dosing. STRONG (NCT03381729) assessed the safety/tolerability and efficacy of intrathecal onasemnogene abeparvovec for sitting, nonambulatory SMA patients. Sitting, nonambulatory SMA patients (biallelic SMN1loss, three SMN2copies, aged 6–<60 months) received a single dose of intrathecal onasemnogene abeparvovec. Patients were enrolled sequentially into one of three (low, medium, and high) dose cohorts and stratified into two groups by age at dosing: younger (6–<24 months) and older (24–<60 months). Primary endpoints included safety/tolerability, independent standing ≥3 seconds (younger group), and change in Hammersmith Functional Motor Scale Expanded (HFMSE) from baseline (older group) compared with historic controls. Thirty-two patients were enrolled and completed the study (medium dose, n = 25). All patients had one or more treatment-emergent adverse events, with one serious and related to treatment (transaminase elevations). No deaths were reported. One of 13 patients (7.7%) in the younger group treated with the medium dose achieved independent standing. At Month 12 for the older group receiving the medium dose, change from baseline in HFMSE was significantly improved compared with the SMA historic control population (P < 0.01). Intrathecal onasemnogene abeparvovec was safe and well-tolerated. Older patients treated with the medium dose demonstrated increases in HFMSE score greater than commonly observed in natural history.

Pharmacokinetic/pharmacodynamic modeling indicates that the higher dose of nusinersen may be associated with a clinically meaningful increase in efficacy above that seen with the 12-mg approved dose. Here we describe both the design of DEVOTE (NCT04089566), a 3-part clinical study evaluating safety, tolerability, and efficacy of higher dose of nusinersen, and results from the initial Part A. DEVOTE Part A evaluates safety and tolerability of a higher nusinersen dose; Part B assesses efficacy in a randomized, double-blind design; and Part C assesses safety and tolerability of participants transitioning from the 12-mg dose to higher doses. In the completed Part A of DEVOTE, all 6 enrolled participants aged 6.1–12.6 years have completed the study. Four participants experienced treatment-emergent adverse events (TEAEs), the majority of which were mild. Common TEAEs of headache, pain, chills, vomiting, and paresthesia were considered related to the lumbar puncture procedure. There were no safety concerns regarding clinical or laboratory parameters. Nusinersen levels in the cerebrospinal fluid were within the range of modeled predictions for higher dose of nusinersen. While Part A was not designed for assessing efficacy, most participants showed stabilization or improvement in motor function. Parts B and C of DEVOTE are ongoing. The findings from Part A of the DEVOTE study support further development of higher dose of nusinersen.

IMPORTANCE: In the previously reported Comparative Enzyme Replacement Trial With neoGAA Versus rhGAA (COMET) trial, avalglucosidase alfa treatment for 49 weeks showed clinically meaningful improvements in upright forced vital capacity (FVC) percent predicted and 6-minute walk test (6MWT) compared with alglucosidase alfa. OBJECTIVE: To report avalglucosidase alfa treatment outcomes during the COMET trial extension. DESIGN, SETTING, AND PARTICIPANTS: This phase 3 double-blind randomized clinical trial with crossover in the extension period enrolled patients 3 years and older with previously untreated late-onset Pompe disease (LOPD) between November 2, 2016, and February 10, 2021, with primary analysis after 49 weeks. Patients were treated at 55 referral centers in 20 countries. Efficacy outcomes were assessed at 97 weeks and safety outcomes to last follow-up, with data cutoff at February 10, 2021. Data were analyzed from May to June 2021. INTERVENTIONS: Random assignment (1:1) to receive 20 mg/kg of avalglucosidase alfa or alglucosidase alfa by intravenous infusion every other week for 49 weeks; thereafter, all patients received 20 mg/kg of avalglucosidase alfa every other week. MAIN OUTCOMES AND MEASURES: The primary outcome was the least squares (LS) mean change from baseline in FVC percent predicted. Secondary outcomes included the LS mean change from baseline in 6MWT, muscle strength, motor function, quality of life, and disease biomarkers. Safety and tolerability were also assessed. RESULTS: Of 100 participants from the double-blind treatment period, 95 entered the extension period. Of these, 51 (54%) were men, and the mean (range) age was 48.3 (10-79) years. At the start of this study, mean upright FVC percent predicted was similar between treatment arms, and 6MWT distance was greater in the avalglucosidase alfa arm. From baseline to week 97, LS mean (SE) FVC percent predicted increased by 2.65 (1.05) for those who continued avalglucosidase alfa and 0.36 (1.12) for those who switched to avalglucosidase alfa. The LS mean (SE) 6MWT distance increased by 18.60 (12.01) m and 4.56 (12.44) m, respectively. For participants who switched to avalglucosidase alfa, FVC percent predicted remained stable (LS mean [SE] change from week 49 to 97, 0.09 [0.88]) and 6MWT distance improved (LS mean [SE] change from week 49 to 97, 5.33 [10.81] m). Potentially treatment-related adverse events were reported in 29 patients (56.9%) who continued avalglucosidase alfa and in 25 patients (56.8%) who switched. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial extension, maintenance of positive clinical outcomes was demonstrated for patients continuing avalglucosidase alfa treatment and, to a lesser extent, patients who switched from alglucosidase alfa. No new safety concerns were observed. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02782741

THE CANADIAN MILITARY is top heavy and the officer ranks need to be cut down drastically. We need more troops and less Brass. It has always bothered me the amount [...]

Novel Spinal Muscular Atrophy (SMA) treatments have demonstrated improvements on motor measures that are clearly distinct from the natural history of progressive decline. Comparable measures are needed to monitor bulbar function, which is affected in severe SMA. To assess bulbar function with patient-reported outcome measures (PROs) and determine their relationships with clinical characteristics. We recruited 47 non-ambulatory participants (mean (SD) age = 29.8 (13.7) years, range = 10.3–73.2) with SMA. PROs including Voice Handicap Index (VHI) and Eating Assessment Tool-10 (EAT-10) were collected alongside clinical characteristics and standardized motor assessments. Associations were assessed using Spearman correlation coefficients and group comparisons were performed using Wilcoxon rank sum tests. A majority of the 47 participants were SMA type 2 (70.2%), non-sitters (78.7%), 3 copies of SMN2(77.5%), and using respiratory support (66.0%). A majority (94%) reported voice issues primarily in 8/30 VHI questions. Problems included: difficulty understanding me in a noisy room (87.2%); difficult for people to hear me (74.5%); and people ask me to repeat when speaking face-to-face (72.3%). A majority (85.1%) reported swallowing issues primarily in 3/10 EAT-10 questions: swallowing pills (68.1%); food sticks to my throat (66.0%); and swallowing solids (61.7%). The two PROs were moderately associated (rs = 0.66). Weaker individuals with SMA experience bulbar problems including difficulties with voice and swallowing. Further refinement and assessment of functional bulbar scales will help determine their relevance and responsiveness to changes in SMA. Additional study is needed to quantify bulbar changes caused by SMA and their response to disease-modifying treatments.

Change is a part of any industry, driven by innovators who recognize the need to grow. This philosophy was elegantly underscored in a Wall Street Journal article titled 'The Genius [...]

Water T2 (T2H2O) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2H2Oto identify changes in muscle function over time in limb girdle muscular dystrophies. Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3‐tesla magnetic resonance imaging (MRI) systems from the same vendor. T2H2Ovalue was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3 years was assessed in a linear model against covariates of high or low T2H2Oat baseline, age, disease duration, and baseline function. A higher T2H2Oat baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2H2Oin adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2H2O(>40.6 ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86 m on the 6‐min walk than those with a lower T2H2O(<40.6 ms). Optimum sensitivity and specificity thresholds for predicting decline were 39.0 ms in adductor magnus and vastus intermedius, 40.0 ms in vastus medialis, and 40.5 ms in vastus lateralis from different sites equipped with different MRI systems. In dysferlinopathy, T2H2Odid not correlate with current functional ability. However, T2H2Oat baseline was higher in patients who worsened more rapidly on functional tests. This suggests that inter‐patient differences in functional decline over time may be, in part, explained by different severities of the active muscle damage, assessed by T2H2Omeasure at baseline. Significant challenges remain in standardizing T2H2Ovalues across sites to allow determining globally applicable thresholds. The results from the present work are encouraging and suggest that T2H2Ocould be used to improve prognostication, patient selection, and disease modelling for clinical trials.

ADVANCE (NCT01526785) presented an opportunity to obtain a more nuanced understanding of motor function changes in treatment-experienced children with Pompe disease receiving 4000L-production-scale alglucosidase alfa for 52 weeks. To estimate minimal detectable change (MDC) and effect size on Gross Motor Function Measure-88 (GMFM-88) after 52 weeks of 4000L alglucosidase alfa (complete data N =  90). The GMFM-88 mean total % score changes, MDC, and effect size were analyzed post hocby Pompe Motor Function Level at enrollment, age groups at enrollment, and fraction of life on pre-study 160L-production-scale alglucosidase alfa. Overall, participants aged < 2 years surpassed MDC at Week 52 (change [mean±standard deviation] 21.1±14.1, MDC range 5.7–13.3, effect size 1.1), whereas participants aged≥2 years did not attain this (change –0.9±15.3, MDC range 10.8–25.2, effect size –0.03). In participants aged < 2 years, improvements surpassed the MDC for walkers (change 17.1±13.3, MDC range 3.0–6.9, effect size 1.7), supported standers (change 35.2±18.0, MDC range 5.9–13.7, effect size 1.8) and sitters (change 24.1±12.1, MDC range 2.6–6.2, effect size 2.7). Age-independent MDC ranges were only attained by walkers (change 7.7±12.3, MDC range 6.4–15.0, effect size 0.4) and sitters (change 9.9±17.2, MDC range 3.3–7.7, effect size 0.9). These first GMFM-88 minimal-detectable-change estimates for alglucosidase alfa-treated Pompe disease offer utility for monitoring motor skills. ClinicalTrials.gov; NCT01526785; Registered 6 February 2012; https://clinicaltrials.gov/ct2/show/NCT01526785

Purpose: This paper aims to discuss how over the past 180 years, a succession of largely unrelated entrepreneurs of differing capabilities have either created or recognised and exploited opportunities offered by this enduring company, their heritage and brand. Design/methodology/approach: Primary data was provided from discussions with Fabergé experts and the new owners of the brand. Extensive secondary data was also used and analysed. Findings: The original Fabergé creations numbered some 200,000, but their creator is remembered best for 65 unique Imperial (and other) Eggs. Many pieces have survived, although the business disappeared in 1917. Since then, dealers and collectors have intervened symbiotically to protect the brand equity – supported by serendipitous popular cultural interventions – although a series of parallel entrepreneurial but parasitic interventions meant the brand and the original products became separated. This changed in 2007 with new owners acquiring the brand and resurrecting high-end jewellery production with a new business model. Their contemporary journey is both informed and shaped by Fabergé’s tumultuous past. Research limitations/implications: Reinforces that while a universal theory of entrepreneurship eludes us that these three key elements – opportunity, uncertainty and resources – help explain the related behaviour of a series of different intervening entrepreneurs. This framework is offered for wider use and testing. Practical implications: Advances the understanding of how entrepreneurs spot and enact opportunity. Originality/value: Develops a model embracing parasitic and symbiotic interventions in the history of a brand, and a conceptual entrepreneurial model capturing three key elements that explain entrepreneurial behaviour. These being: opportunity seeking and exploitation, addressing uncertainty and deploying appropriate resources.

Combine sophistication and simplicity to achieve elegance. Such is the primary goal for today's developers of home-entertainment/ automation control devices. How come? Simply put, the high end is driving the […]

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Three trends are expected to emerge as the dominant themes of computing technology in the next millennium. These include spontaneous computing, ever-greater customer service and central hosting. Technologies such as Internet-linked appliances and speech recognition are also expected to become workplace realities in the 21st century. Technology experts agree that one of the greatest challenge of the future will be to separate tools from toys., Let these experts guide you toward the future, where you'll talk to your PC, see in 3-D and maybe even wear your computer. From wearable PCs to web-enabled alarm clocks, [...]

Kolbe Corp of Phoenix, AZ, offers Warewithal Online, an Internet-based application that helps human resource and line managers select team members, predict productivity and resolve workplace conflicts. The software is based on the concept of 'conate' testing, which identifies the instinctive behaviors that govern job satisfaction. The product measures these behaviors, puts them in a database and manages these databases. Hardware requirements are an IBM-compatible PC or a Macintosh with a standard Web browser., What would it be worth for a manager to know that he had assembled a work team capable of completing a project on time and within budget? Some teams do [...]

Nusinersen showed a favourable benefit–risk profile in participants with infantile-onset spinal muscular atrophy at the interim analysis of a phase 2 clinical study. We present the study's final analysis, assessing the efficacy and safety of nusinersen over 3 years.

The main, but not the only reason a tunnel needs to be refurbished is its age. The structure will need to be repaired or even replaced and the equipment, particularly [...]

It's an often-times very frustrating reality for do-it-yourselfers that everything is easier the second time around, and easier still if you have the right tools for the job at hand. […]

Removal of the anterior clinoid process (ACP) can expand anterior skull base surgical corridors. ACP development and anatomical variations are poorly defined in children.

Congenital muscular dystrophy type 1A (MDC1A) is caused by recessive variants in laminin α2(LAMA2). Patients have been found to have white matter signal abnormalities on magnetic resonance imaging (MRI) but rarely structural brain abnormalities. We describe the autopsy neuropathology in a 17-year-old with white matter signal abnormalities on brain MRI. Dystrophic pathology was observed in skeletal muscle, and the sural nerve manifested a mild degree of segmental demyelination and remyelination. A diffuse, bilateral cobblestone appearance, and numerous points of fusion between adjacent gyri were apparent on gross examination of the cerebrum. Brain histopathology included focal disruptions of the glia limitans associated with abnormal cerebral cortical lamination or arrested cerebellar granule cell migration. Subcortical nodular heterotopia was present within the cerebellar hemispheres. Sampling of the centrum semiovale revealed no light microscopic evidence of leukoencephalopathy. Three additional MDC1A patients were diagnosed with cobblestone malformation on brain MRI. Unlike the autopsied patient whose brain had a symmetric distribution of cobblestone pathology, the latter patients had asymmetric involvement, most severe in the occipital lobes. These cases demonstrate that cobblestone malformation may be an important manifestation of the brain pathology in MDC1A and can be present even when patients have a structurally normal brain MRI.