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Risdiplam is an oral, survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier approved for the treatment of spinal muscular atrophy (SMA). SUNFISH (NCT02908685) Part 2, a Phase 3, randomized, double-blind, placebo-controlled study, investigated the efficacy and safety of risdiplam in type 2 and non‑ambulant type 3 SMA. The primary endpoint was met: a significantly greater change from baseline in 32-item Motor Function Measure (MFM32) total score was observed with risdiplam compared with placebo at month 12. After 12 months, all participants received risdiplam while preserving initial treatment blinding. We report 24-month efficacy and safety results in this population. Month 24 exploratory endpoints included change from baseline in MFM32 and safety. MFM‑derived results were compared with an external comparator. At month 24 of risdiplam treatment, 32% of patients demonstrated improvement (a change of ≥ 3) from baseline in MFM32 total score; 58% showed stabilization (a change of ≥ 0). Compared with an external comparator, a treatment difference of 3.12 (95% confidence interval [CI] 1.67-4.57) in favor of risdiplam was observed in MFM-derived scores. Overall, gains in motor function at month 12 were maintained or improved upon at month 24. In patients initially receiving placebo, MFM32 remained stable compared with baseline (0.31 [95% CI - 0.65 to 1.28]) after 12 months of risdiplam; 16% of patients improved their score and 59% exhibited stabilization. The safety profile after 24 months was consistent with that observed after 12 months. Risdiplam over 24 months resulted in further improvement or stabilization in motor function, confirming the benefit of longer-term treatment. ispartof: JOURNAL OF NEUROLOGY vol:270 issue:5 pages:2531-2546 ispartof: location:Germany status: published

Atrial cardiomyopathy refers to structural and electrical remodelling of the atria, which can lead to impaired mechanical function. While historical studies have implicated atrial fibrillation as the leading cause of cardioembolic stroke, atrial cardiomyopathy may be an important, underestimated contributor. To date, the relationship between atrial cardiomyopathy, atrial fibrillation, and cardioembolic stroke remains obscure. This review summarizes the pathogenesis of atrial cardiomyopathy, with a special focus on neurohormonal and inflammatory mechanisms, as well as the role of adipose tissue, especially epicardial fat in atrial remodelling. It reviews the current evidence implicating atrial cardiomyopathy as a cause of embolic stroke, with atrial fibrillation as a lagging marker of an increased thrombogenic atrial substrate. Finally, it discusses the potential of antithrombotic therapy in embolic stroke with undetermined source and appraises the available diagnostic techniques for atrial cardiomyopathy, including imaging techniques such as echocardiography, computed tomography, and magnetic resonance imaging as well as electroanatomic mapping, electrocardiogram, biomarkers, and genetic testing. More prospective studies are needed to define the relationship between atrial cardiomyopathy, atrial fibrillation, and embolic stroke and to establish a prompt diagnosis and specific treatment strategies in these patients with atrial cardiomyopathy for the secondary and even primary prevention of embolic stroke.

BackgroundCancer and ischemic heart disease are the leading causes of mortality. The optimal management for patients with concomitant acute myocardial infarction (AMI) and cancer remains challenging.ObjectiveTo evaluate in-hospital and 1-year adverse outcomes in cancer patients receiving percutaneous coronary intervention (PCI) to treat AMI.MethodsThis was a single-center, retrospective cohort study, patients with cancer admitted to The First Affiliated Hospital of Xi’an Jiaotong University for AMI and discharged between January 2015 and June 2020 were analyzed. The outcomes were all-cause mortality at 1-year follow up and incidence of in-hospital adverse events, including arrhythmias, heart failure, major bleeding, stroke, and all-cause death.ResultsA total of 119 patients were included, of these, 68 (57.1%) received PCI (PCI group) and 51 (42.9%) did not (non-PCI group). Patients in the PCI group had a lower incidence of in-hospital arrhythmias (22.1 vs. 39.2%; p = 0.042), major bleeding (2.9 vs. 15.7%; p = 0.013), and all-cause mortality (1.5 vs. 11.8%; p = 0.018) than those in non-PCI group. On 1-year follow-up, the PCI group had a lower all-cause mortality than the non-PCI group (log-rank test = 14.65; p < 0.001). Multivariable Cox regression showed that PCI is an independent protective factor (adjusted HR = 0.503 [0.243–0.947], p = 0.045) for cancer patients who have concomitant AMI.ConclusionCancer patients receiving PCI for AMI had a lower risk of in-hospital adverse events and mortality as well as 1-year all-cause mortality compared to those who refused PCI. Our study therefore supports the use of PCI to improve prognosis of this selected group of patients.

Expansion microscopy (ExM) involves the physical, isotropic expansion of specimens enabling nanoscale imaging using a standard confocal microscope. ExM is widely employed to image proteins, nucleic acids, and lipid membranes in single cells at nanoscale; however, current methods are low throughput which limits the number of samples that can be processed simultaneously. We developed High-throughput Expansion Microscopy (HiExM), a robust platform that enables expansion microscopy of cells cultured in a standard 96-well plate. Our method enables consistent ∼4.2x expansion across individual wells and entire plates in parallel. We also demonstrate that samples expanded using HiExM can be imaged and analyzed using standard high-throughput confocal imaging platforms. Our method broadens the application of ExM as a tool for scalable super-resolution imaging of specimens for pharmaceutical and research applications including drug and cell phenotype screening.

The main objective of this chapter is to present an overview of the different areas of key technologies that will be needed to fly the technically most challenging of the representative missions identified in chapter 4 (the Pillar 2 Horizon 2061 report). It starts with a description of the future scientific instruments which will address the key questions of Horizon 2061 described in chapter 3 (the Pillar 1 Horizon 2061 report) and the new technologies that the next generations of space instruments will require (section 2). From there, the chapter follows the line of logical development and implementation of a planetary mission: section 3 describes some of the novel mission architectures that will be needed and how they will articulate interplanetary spacecraft and science platforms; section 4 summarizes the system-level technologies needed: power, propulsion, navigation, communication, advanced autonomy on board planetary spacecraft; section 5 describes the diversity of specialized science platforms that will be needed to survive, operate and return scientific data from the extreme environments that future missions will target; section 6 describes the new technology developments that will be needed for long-duration missions and semi-permanent settlements; finally, section 7 attempts to anticipate on the disruptive technologies that should emerge and progressively prevail in the decades to come to meet the long-term needs of future planetary missions., Comment: 100 pages, 23 figures, Horizon 2061 is a science-driven, foresight exercise, for future scientific investigations

The main goal of ARCFIRE is to bring RINA from the labs into the realworld. RINA, the Recursive InterNetwork Architecture, is an innovative “back-to-basics” network architecture that solves current limitations and facilitates full integration between distributed computing and networking. RINA addresses the challenges that drive the communications industry in moving from dedicated hardware to almost completely virtualised infrastructure. New technologies such as 5G will change the communication industry even more significantly before 2020. Here,ARCFIRE contributes by providing experimental evidence of RINA’s benefits, at large scale, in compelling and realistic business cases. This will motivate RINA adoption. ARCFIRE demonstrates – experimentally – RINA’s key benefits integrating current European investment in advanced networks (IRATI, PRISTINE) and Future Internet testbeds (FIRE+).

BACKGROUND Risdiplam is an orally administered therapy that modifies pre-mRNA splicing of the survival of motor neuron 2 (SMN2) gene and is approved for the treatment of spinal muscular atrophy. The FIREFISH study is investigating the safety and efficacy of risdiplam in treated infants with type 1 spinal muscular atrophy versus historical controls. The primary endpoint of part 2 of the FIREFISH study showed that infants with type 1 spinal muscular atrophy attained the ability to sit without support for at least 5 s after 12 months of treatment. Here, we report on the safety and efficacy of risdiplam in FIREFISH part 2 over 24 months of treatment. METHODS FIREFISH is an ongoing, multicentre, open-label, two-part study. In FIREFISH part 2, eligible infants (aged 1-7 months at enrolment, with a genetically confirmed diagnosis of spinal muscular atrophy, and two SMN2 gene copies) were enrolled in 14 hospitals in ten countries across Europe, North America, South America, and Asia. Risdiplam was orally administered once daily at 0·2 mg/kg for infants between 5 months and 2 years of age; once an infant reached 2 years of age, the dose was increased to 0·25 mg/kg. Infants younger than 5 months started at 0·04 mg/kg (infants between 1 month and 3 months old) or 0·08 mg/kg (infants between 3 months and 5 months old), and this starting dose was adjusted to 0·2 mg/kg once pharmacokinetic data were available for each infant. The primary and secondary endpoints included in the statistical hierarchy and assessed at month 12 have been reported previously. Here we present the remainder of the secondary efficacy endpoints that were included in the statistical hierarchy at month 24: the ability to sit without support for at least 30 s, to stand alone, and to walk alone, as assessed by the Bayley Scales of Infant and Toddler Development, third edition gross motor subscale. These three endpoints were compared with a performance criterion of 5% that was defined based on the natural history of type 1 spinal muscular atrophy; the results were considered statistically significant if the lower limit of the two-sided 90% CI was above the 5% threshold. FIREFISH is registered with ClinicalTrials.gov, NCT02913482. Recruitment is closed; the 36-month extension period of the study is ongoing. FINDINGS Between March 13 and Nov 19, 2018, 41 infants were enrolled in FIREFISH part 2. After 24 months of treatment, 38 infants were ongoing in the study and 18 infants (44% [90% CI 31-58]) were able to sit without support for at least 30 s (p

The Jain COS Consortium., [Objective] Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD., [Methods] We collected a longitudinal series of functional assessments from 187 patients with dysferlinopathy over 3 years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and nonambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories., [Results] The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3 to 8 years post symptom onset at baseline., [Interpretation] The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinical practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short-term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy. ANN NEUROL 2021;89:967–978, The estimated US $4 million needed to fund this study was provided by the Jain Foundation. (www.jain-foundation.org) The Jain COS consortium would like to thank the study participants and their families for their invaluable contribution. The John Walton Centre Muscular Dystrophy Research Centre is part of the MRC Centre for Neuromuscular Diseases (Grant number MR/K000608/1).

Pipis et al. describe the characteristics and longitudinal follow-up of 225 patients with Charcot-Marie-Tooth disease type 2A, caused by mutations in MFN2. They describe how different mutations affect disease onset and rate of progression and identify sensitive clinical assessments that can be used for disease monitoring., Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1–2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84 ± 2.42; two-tailed paired t-test P = 0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97 ± 1.77; two-tailed paired t-test P = 0.003) and the CMTESv2-R (mean change 1.21 ± 2.52; two-tailed paired t-test P = 0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24 ± 3.09; two-tailed paired t-test P = 0.009) and over 2 years (mean change 4.00 ± 3.79; two-tailed paired t-test P = 0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design.

PurposeTo characterize clinical characteristics and genotypes of patients in the ADVANCE study of 4000 L-scale alglucosidase alfa (NCT01526785), the largest prospective United States Pompe disease cohort to date.MethodsPatients aged ≥1 year with confirmed Pompe disease previously receiving 160 L alglucosidase alfa were eligible. GAA genotypes were determined before/at enrollment. Baseline assessments included histories/physical exams, Gross Motor Function Measure-88 (GMFM-88), pulmonary function tests, and cardiac assessments.ResultsOf 113 enrollees (60 male/53 female) aged 1-18 years, 87 had infantile-onset Pompe disease (IOPD) and 26 late-onset (LOPD). One hundred eight enrollees with GAA genotypes had 215 pathogenic variants (220 including combinations): 118 missense (4 combinations), 23 splice, 35 nonsense, 34 insertions/deletions, 9 duplications (1 combination), 6 other; c.2560C>T (n = 23), c.-32-13T>G (n = 13), and c.525delT (n = 12) were most common. Four patients had previously unpublished variants, and 14/83 (17%) genotyped IOPD patients were cross-reactive immunological material-negative. All IOPD and 6/26 LOPD patients had cardiac involvement, all without c.-32-13T>G. Thirty-two (26 IOPD, 6 LOPD) were invasively ventilated. GMFM-88 total %scores (mean ± SD, median, range): overall 46.3 ± 33.0% (47.9%, 0.0-100.0%), IOPD 41.6 ± 31.64% (38.9%, 0.0-99.7%), LOPD: 61.8 ± 33.2 (70.9%, 0.0-100.0%).ConclusionADVANCE, a uniformly assessed cohort comprising most US children and adolescents with treated Pompe disease, expands understanding of the phenotype and observed variants in the United States.

Introduction Azathioprine-induced pancreatitis is an idiosyncratic and unpredictable response, occurring in up to 7% of azathioprine-exposed patients with inflammatory bowel disease (IBD). The haplotype HLADQA1-HLADRB1*07:01A>C is strongly associated with azathioprine-induced pancreatitis in IBD. We aimed to evaluate whether pretreatment HLADQA1-HLADRB1*07:01A>C screening will reduce the risk of azathioprine-induced pancreatitis. Methods Participants with IBD were screened for HLADQA1-HLADRB1*07:01A>C, and participants with a variant genotype were excluded from azathioprine treatment. Wild-type participants were started on azathioprine and followed for 3 months. The incidence of pancreatitis was compared with unscreened historical controls. Results HLADQA1-HLADRB1*07:01A>C screening resulted in an 11-fold reduction in the incidence of azathioprine-induced pancreatitis (n = 1/328 or 0.30% vs n = 13/373 or 3.4%). In propensity score-matched cohorts (age and sex), HLA DQA1-HLADRB1*07:01A>C screening was significantly associated with a reduction in the incidence of AZA-induced pancreatitis independent of weight, glucocorticoid exposure, and smoking status (adjusted odds ratio = 0.075, 95% confidence interval = 0.01-0.58, P = 0.01). Up to 45% (n = 271/599) of participants were excluded from azathioprine therapy based on the haplotype in the HLADQA1-HLADRB1*07:01A>C-screened cohort. Discussion HLADQA1-HLADRB1*07:01A>C screening reduced the risk of azathioprine-induced pancreatitis; however, using this strategy to guide the use of azathioprine therapy in IBD may eliminate a large proportion of patients from being eligible for treatment with azathioprine. In regions where there is access to other IBD therapies, and given the short-term and long-term toxicities associated with azathioprine, HLADQA1-HLADRB1*07:01A>C-screening may be a clinically relevant strategy for enhancing the safe use of azathioprine in IBD. In addition, cost-effectiveness analyses are needed to further solidify the utility of HLADQA1-HLADRB1*07:01A>C screening in IBD populations.

Sugar kelp (Saccharina latissima) is an economically important species, and natural populations provide diverse and productive habitats as well as important ecosystem services. For seaweed aquaculture to be successful in newly emerging industry in Europe and other Western countries, it will have to develop sustainable production management strategies. A key feature in this process is the capacity to conserve genetic diversity for breeding programs aimed at developing seed stock for onward cultivation, as well as in the management of wild populations, as potentially interesting genetic resources are predicted to disappear due to climate change. In this study, the cryopreservation of male and female gametophytes (haploid life stage) of S. latissima by different combinations of two-step cooling methods and cryoprotectants was explored. We report here that cryopreservation constitutes an attractive option for the long-term preservation of S. latissima gametophytes, with viable cells in all treatment combinations. The highest viabilities for both male and female gametophytes were found using controlled-rate cooling methods combined with dimethyl sulfoxide 10% (v/v). Morphological normal sporophytes were observed to develop from cryopreserved vegetative gametophytic cells, independent of treatment. This indicates that cryopreservation is a useful preservation method for male and female S. latissima gametophytes.

Schuerch et al. (2018) [1] deserve credit for compiling a wide range of disparate, global datasets that will be instrumental in predicting future coastal wetland change. However, we challenge their projections that range from modest losses to substantial gains worldwide by the end of this century. Their modeling does not adequately capture the role of sediment supply which must be treated volumetrically, with profound implications for their projections. We anticipate that an appropriate modification will result in substantially different projections, with rates of coastal wetland loss that generally increase as a function of relative sea-level rise (RSLR), regardless of the human adaptation scenario. This is also in line with the findings from a precursor study [2] by a subset of the Schuerch et al. group.

Objective: Genetic modifiers in rare disease have long been suspected to contribute to the considerable variance in disease expression, including Charcot–Marie–Tooth disease type 1A (CMT1A). To address this question, the Inherited Neuropathy Consortium collected a large standardized sample of such rare CMT1A patients over a period of 8 years. CMT1A is caused in most patients by a uniformly sized 1.5 Mb duplication event involving the gene PMP22. Methods: We genotyped DNA samples from 971 CMT1A patients on Illumina BeadChips. Genome-wide analysis was performed in a subset of 330 of these patients, who expressed the extremes of a hallmark symptom: mild and severe foot dorsiflexion strength impairment. SIPA1L2 (signal-induced proliferation-associated 1 like 2), the top identified candidate modifier gene, was expressed in the peripheral nerve, and our functional studies identified and confirmed interacting proteins using coimmunoprecipitation analysis, mass spectrometry, and immunocytochemistry. Chromatin immunoprecipitation and in vitro siRNA experiments were used to analyze gene regulation. Results: We identified significant association of 4 single nucleotide polymorphisms (rs10910527, rs7536385, rs4649265, rs1547740) in SIPA1L2 with foot dorsiflexion strength (p < 1 × 10 −7 ). Coimmunoprecipitation and mass spectroscopy studies identified β-actin and MYH9 as SIPA1L2 binding partners. Furthermore, we show that SIPA1L2 is part of a myelination-associated coexpressed network regulated by the master transcription factor SOX10. Importantly, in vitro knockdown of SIPA1L2 in Schwannoma cells led to a significant reduction of PMP22 expression, hinting at a potential strategy for drug development. Interpretation: SIPA1L2 is a potential genetic modifier of CMT1A phenotypic expressions and offers a new pathway to therapeutic interventions. ANN NEUROL 2019;85:316–330.

OBJECTIVE: To extend the phenotypic description of Charcot-Marie-Tooth disease (CMTX1) and to draw new genotype-phenotype relationships. METHODS: Mutations in GJB1 cause the main X-linked form of CMTX (CMTX1). We report cross-sectional data from 160 patients (from 120 different families, with 89 different mutations) seen at the Inherited Neuropathies Consortium centers. RESULTS: We evaluated 87 males who had a mean age of 41 years (range 10-78 years) and 73 females who had a mean age of 46 years (range 15-84 years). Sensory-motor polyneuropathy affects both sexes, more severely in males than in females, and there was a strong correlation between age and disease burden in males but not in females. Compared with females, males had more severe reduction in motor and sensory neurophysiology parameters. In contrast to females, the radial nerve sensory response in older males tended to be more severely affected compared with younger males. Median and ulnar nerve motor amplitudes were also more severely affected in older males, whereas ulnar nerve motor potentials tended to be more affected in older females. Conversely, there were no statistical differences between the sexes in other features of the disease, such as problems with balance and hand dexterity. CONCLUSIONS: In the absence of a phenotypic correlation with specific GJB1 mutations, sex-specific distinctions and clinically relevant attributes need to be incorporated into the measurements for clinical trials in people with CMTX1. CLINICALTRIALSGOV IDENTIFIER: NCT01193075.

Questionnaire provided to the carers. Sample of the questionnaire submitted to the carers. (DOCX 19 kb)

Knowledge of biofouling typical of marine structures is essential for engineers to define appropriate loading criteria in addition to informing other stakeholders about the ecological implications of creating novel artificial environments. There is a lack of information regarding biofouling community composition (including weight and density characteristics) on floating structures associated with future marine renewable energy generation technologies. A network of navigation buoys were identified across a range of geographical areas, environmental conditions (tidal flow speed, temperature and salinity), and deployment durations suitable for future developments. Despite the perceived importance of environmental and temporal factors, geographical location explained the greatest proportion of the observed variation in community composition, emphasising the importance of considering geography when assessing the impact of biofouling on device functioning and associated ecology. The principal taxa associated with variation in biofouling community composition were mussels (Mytilus edulis), which were also important when determining loading criteria.

Darko Bosnakovski1,2, Lynn M. Hartweck1, Abhijit Dandapat1, John Day3, Ramiro Nandez1, Radbod Darabi4, Rita R. Perlingeiro4, Lauren Snider5, Stephen J. Tapscott5, Janet Sowden6, Rabi Tawil6 and Michael Kyba1 1Lillehei Heart Institute and Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455 2Faculty of Technology and Technical Science‐Veles, University St. Kliment Ohridski‐Bitola, Skopje, R. Macedonia 3Paul and Sheila Wellstone Center for Muscular Dystrophy and Department of Neurology, University of Minnesota, Minneapolis, MN 55455 4Lillehei Heart Institute and Department of Medicine, University of Minnesota, Minneapolis, MN 55455 5Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 6Fields Center for FSHD and Neuromuscular Research and Department of Neurology, University of Rochester, Rochester, NY 14642 There is currently no animal model bearing the actual FSHD mutation (D4Z4 contraction), and the lack of a suitable model system to study the effects of this mutation has severely hampered progress in understanding FSHD. We present data from two approaches to model FSHD: the generation of a mouse bearing a doxycycline‐inducible Dux4 gene, and the differentiation of iPS cells derived from myoblasts cultures established from FSHD and control biopsies. We have inserted a construct starting at the MAL initiation of Dux4 and continuing to the end of the EcoRI site, therefore containing the pLAM polyA signal from the FSHD A haplotype, into constitutively open chromatin 5’ of the HPRT gene. Even without induction we observed that males are almost never born and carrier females present several pathologies, although not in muscle. Rare males are severely affected, and do not survive past about 1 month of age. In addition to the phenotypes observed in the females, males also present testis abnormalities, including a defect in spermatogenesis. We are currently investigating vascular pathologies, which are especially evident in embryos, and severely enhanced when doxycycline is applied to induce expression of the transgene. Although muscle is not dystrophic, these are the first animals presenting a phenotype due to the presence of human D4Z4 DNA. In a second strategy, we have derived iPS cells from myoblast cultures taken from FSHD patients and controls. We present preliminary data on the ability of these cells to differentiate into muscle in vitro, and on the chromatin state and transcription of DUX4/D4Z4 at different stages of development.

Torsional oscillator experiments on solid 4He show frequency changes which suggest mass decoupling, but the onset is broad and is accompanied by a dissipation peak. We have measured the elastic shear modulus over a broad frequency range, from 0.5 Hz to 8 kHz, and observe similar behavior - stiffening and a dissipation peak. These features are associated with a dynamical crossover in a thermally activated relaxation process in a disordered system rather than a true phase transition. If there is a transition in the DC response, e.g. to a supersolid state, it must occur below 55 mK.

Hypertrophic cardiomyopathy (HCM) is a genetic disease of the cardiac sarcomere with an autosomal dominant pattern of inheritance. Patients with HCM are at high risk of developing atrial fibrillation (AF) particularly in the setting of advanced diastolic dysfunction and left atrial enlargement. AF is a marker of increased mortality and morbidity and results in a significant reduction in quality of life. Antiarrhythmic medications improve symptoms and reduce AF recurrence, but few are safe and there exists little data to guide their long-term use in HCM. Non-pharmacologic approaches have emerged and have equal or greater efficacy than pharmacologic approaches. Although these approaches are promising, the long-term impact on atrial function needs to be carefully studied as it may impact quality of life in patients that age in the setting of a progressive diastolic disease disorder. Nonetheless, with the significant impact of AF in HCM, rhythm control strategies are often required. The understanding of rhythm control strategies in HCM, an often rapidly progressive diastolic dysfunction disorder, may provide insight in how to treat the much more prevalent AF patient with hypertensive cardiomyopathy. Regardless of treatment strategy (rhythm or rate control) patients are a moderate to high risk of thromboembolism and until data are available to suggest otherwise require long-term warfarin anticoagulation.

Lampyroidea maculata Geisthardt & Day, sp. nov. Male (Figs. 1���11). Length: 7.5���8.0 mm, width: 2.1���2.2 mm. Description Colour: Head and eyes black; pronotum predominantly dark brown with yellow brown sides and the middle of the basis reddish brown; maxillary palpi and antennae brown; scutellum yellow brown; thorax yellow; abdomen brown; legs predominantly yellow. Head (Fig. 1). Base of antennae nearly contiguous. Vertex and frons polished and punctate. Vertex in the middle of the posterior half with defined but very narrow groove. Mouthparts with the exception of the palpi paler; tip of mandible dark, last segment of maxillary palpus enlarged (Fig. 2) with the underside, for the most part, paler. Antennae long, reaching the first third of the elytra (Fig. 3), all antennomeres slender; brownish, the first two antennomeres paler. First antennomere twice as long as second, third nearly as long as first, the remaining antennomeres decreasing in length with the tenth and eleventh nearly equal in length with the eleventh only fractionally longer than the tenth (eleventh antennomere lacking in holotype, present in one paratype; the absence of the eleventh antennomere is indicated in Fig. 3 by a dotted line). Pronotum (Fig. 4). Width much greater than length, nearly twice as wide as long (5.2:3); dark brown with the sides relatively broad and yellow brown, middle of posterior margin reddish brown. Slightly deepened between three��quarters and halfway to posterior margin, with very thin ridge in last third. Sides straight and slightly narrowed or straight towards posterior margin; posterior margin nearly straight, middle of margin slightly pronounced posteriorly, hind angles only a little pronounced, broadly rounded; anterior border depressed, rounded in middle and straighter towards the anterior angles that are rounded. Disk well and deeply punctate (Fig. 5), punctures somewhat enlarged near the middle of the posterior margin. Hairs relatively compact, short, thick, protruding and yellow brown. Scutellum (Fig. 4). Smooth and triangular with sides in second half nearly straight, tip broadly rounded. Scutellum yellow brown in colour. Elytra (Fig. 6). Elongate, parallel, last third broadening slightly; at humeri slightly broader than posterior margin of pronotum; brown, with lateral margins and suture very small and yellow respectively paler. Posterior eighth of elytra distinctly reddish brown and somewhat reflective. Anterior half of the elytra irregularly punctate but punctures small and shallow; posterior half increasingly rough but not polished except for posterior eighth. Elytra with four very plain ridges, n.b. hard to visualise. All ridges do not reach either anterior margin or apex. Hairs thin, yellow brown and relatively sparse. Thorax and Abdomen (Figs. 7���8). Abdomen contains irregular pale regions on first two sternites. Light organs on last two sternites, well developed adult lanterns filling most of sternite. Pygidium and last abdominal sternite as in Figs. 7 & 8. Pygidium white��yellow, margin in the middle brownish, but brownish part covered by penultimate tergite. Legs (Fig. 9). Slender, coxae and femora yellow, tibiae slightly brown, tarsi paler brown. First tarsomere of hind tarsus twice as long as second, third shorter than second and longer than fourth, last tarsomere shorter than first. Aedaeagus see Figs. 10���11. Female unknown. Specimens examined and deposition Holotype male. Northern Iran, Prov. Mazandaran, Amol forest (36��28���N, 52��21���E), ca. 500m asl; July��August 2003 (In the collection of the first author; to be transferred to the Staatliches Museum f��r Naturkunde, Stuttgart, Germany); Paratypes: 2 male, same locality as holotype; in the collection of the Centre for Ecology & Hydrology, CEH Oxford, UK (to be transferred to the Hope Entomological Collections, Oxford University Museum of Natural History, Oxford, UK). Antennae of Paratypes partially missing. Etymology This species is named after the paler and more shining apices of the elytra (patched = maculata). Discussion Lampyroidea maculata sp. nov. is the third Iranian species of this genus. Compared with two other species recorded from Iran, L. antennalis Geisthardt and L. persica Olivier, Lampyroidea maculata sp. nov. is much greater in size, has slender antennae, and the apex of the elytra is paler and somewhat reflective. The most important differences are given in table 1., Published as part of Geisthardt, Michael & Day, John C., 2004, Lampyroidea maculata (Coleoptera: Lampyridae): A new species of lampyrid from Iran, pp. 1-6 in Zootaxa 427 (1) on pages 2-5, DOI: 10.11646/zootaxa.427.1.1, http://zenodo.org/record/5028064

In order for farmers to accept improved soil and water management practices, new technologies must be appropriate to the specific site conditions found in the farm setting and be consistent with farmers' objectives and available resources. A whole-farm modeling analysis of this problem is described. Preliminary estimates of the benefits of increased soil moisture conservation for representative low-resource farmers in Mali are presented. If farmers could improve rainfall infiltration from currently low rates of about 40% up to 60%, and use small amounts of chemical fertilizers, disposable income could increase two to four times depending on rainfall. Income could be increased another 50% if the infiltration rate was raised to 80%. Food grain production could increase 60 to 90% with improved moisture conservation and fertilizer use.

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Im Bereich des Beckens verbundene weibliche Zwillinge mit drei Beinen (Ischiopagus tripus), die in Middleton Stoney bei Oxford am 3. August 1552 zur Welt kamen, Anonymer Künstler, Einblattdruck auf Unterlagenblatt kaschiert, Text in lateinischer und englischer Sprache, Zierleiste in der Mitte des Blattes und Zierbuchstabe am Anfang des Textes, Fragment: Titel und ein zweiter Holzschnitt mit der Vorderansicht des Zwillingspaars fehlen, Aus der Sammlung von Johann Jakob Wick (herausgelöst aus Ms F 24, 468-469) Exemplar der Zentralbibliothek Zürich, Graphische Sammlung und Fotoarchiv

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Growth in fundamental drivers—energy use, economic productivity and population—can provide quantitative indications of the proposed boundary between the Holocene Epoch and the Anthropocene. Human energy expenditure in the Anthropocene, ~22 zetajoules (ZJ), exceeds that across the prior 11,700 years of the Holocene (~14.6 ZJ), largely through combustion of fossil fuels. The global warming effect during the Anthropocene is more than an order of magnitude greater still. Global human population, their productivity and energy consumption, and most changes impacting the global environment, are highly correlated. This extraordinary outburst of consumption and productivity demonstrates how the Earth System has departed from its Holocene state since ~1950 CE, forcing abrupt physical, chemical and biological changes to the Earth’s stratigraphic record that can be used to justify the proposal for naming a new epoch—the Anthropocene.