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Introduction Comprehensive genetic testing for dystrophinopathy can detect ∼95% of pathogenic variants in the dystrophin gene (DMD) and is often the preferred diagnostic approach. Methods We reviewed pathology reports for muscle biopsies evaluated at the University of Iowa with a pathological diagnosis of dystrophinopathy based on dystrophic histopathology and abnormal immunofluorescence staining: reduced to absent dystrophin, expression of utrophin, and loss of neuronal nitric oxide synthase. Results The percentage of muscle biopsies with dystrophinopathy has been stable since 1997. Among 2,298 biopsies evaluated between 2011 and 2016, 72 (3.1%) had pathologic features of dystrophinopathy. Median age at biopsy was 8 years (range, 0.66-84). Half had undergone DMD genetic testing prior to biopsy. Clinical phenotypes recorded on requisitions were typical of muscular dystrophy for 57 (79%) biopsies. Discussion Muscle biopsy continues to play an important role in the diagnosis of dystrophinopathy, particularly in patients with later symptom onset, comorbidities, or normal DMD genetic testing results. Muscle Nerve, 2018.

Tobacco use, hypertension, hyperglycemia, overweight, and inactivity are leading causes of overall and cardiovascular disease (CVD) mortality worldwide, yet the relevant metabolic alterations responsible are largely unknown. We conducted a serum metabolomic analysis of 620 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (1985–2013). During 28 years of follow-up, there were 435 deaths (197 CVD and 107 cancer). The analysis included 406 known metabolites measured with ultra-high-performance liquid chromatography/mass spectrometry–gas chromatography/mass spectrometry. We used Cox regression to estimate mortality hazard ratios for a 1-standard-deviation difference in metabolite signals. The strongest associations with overall mortality were N-acetylvaline (hazard ratio (HR) = 1.28; P < 4.1 × 10(−5), below Bonferroni statistical threshold) and dimethylglycine, 7-methylguanine, C-glycosyltryptophan, taurocholate, and N-acetyltryptophan (1.23 ≤ HR ≤ 1.32; 5 × 10(−5) ≤ P ≤ 1 × 10(−4)). C-Glycosyltryptophan, 7-methylguanine, and 4-androsten-3β,17β-diol disulfate were statistically significantly associated with CVD mortality (1.49 ≤ HR ≤ 1.62, P < 4.1 × 10(−5)). No metabolite was associated with cancer mortality, at a false discovery rate of

Background: Alcohol consumption is associated with an increased risk of several cancers. Potential mechanisms include altered oestrogen metabolism. Parent oestrogens metabolise into alternate pathways of oestrogen metabolites that may have variable effects on cancer pathogenesis. We examined associations of alcohol consumption with circulating oestrogen/oestrogen metabolites in postmenopausal women in the Women’s Health Initiative (WHI)-Observational Study (OS). Methods: We conducted a cross-sectional analysis of prediagnosis ovarian/endometrial cancer case-control data within WHI-OS (N=1864). Alcohol consumption was measured by validated food frequency questionnaire. Fasting serum parent oestrogens/oestrogen metabolites were assayed using liquid chromatography tandem mass-spectrometry. Geometric mean analyte concentrations (GM, pmol l−1) were calculated by alcohol category using inverse-probability weighted linear regression, adjusting for venepuncture age/year, race, smoking, body mass index, years since menopause, oral contraceptive duration, caffeine intake, and physical activity. Results: There was evidence for a positive association between alcohol consumption and oestrone, oestradiol and 2-hydroxylation oestrogen metabolite concentrations among menopausal hormone therapy (MHT) users. We observed an association between liquor consumption and parent oestrogens among non-MHT users, who consumed larger doses of liquor than MHT users. Conclusions: Among postmenopausal women, the association between alcohol intake and parent oestrogen, but not oestrogen metabolite concentrations, may be influenced by MHT and type of alcohol.

What has been the trajectory of architectural research in the UK (as reflected in arq: Architectural Research Quarterly) as compared to the United States (as reflected in the Journal of Architectural Education, or JAE) over the past two decades? To answer this question several quantitative methods were used to construct a frame analysis of the various grammars associated with each journal. First we quantify the grammars employed by arq according to the editors’ own categories. Second, we provide a word frequency analysis of arq's article titles and abstracts. Third, we assess the similarities and differences of the content in arq and JAE using the grammars reconstructed in the latter. Fourth, we use these data to reconstruct the trajectory of architectural research in arq. As a final analysis we place arq within the context of the historic emergence of journals recognised by the Avery Index of Architectural Periodicals from 1837 to the present. Our findings reveal numerous conflicts and similarities of content as a representation of the field as a whole and we conclude that these data provide at least three salient patterns worth considering as a foundation for the next two decades: (1) accelerated alienation of research from practice; (2) movement away from literary grammars toward ecological ones; and (3) the explosion of new publication venues and specialised grammars.

Background: The epidemiologic evidence for associations between dietary factors and breast cancer is weak and etiologic mechanisms are often unclear. Exploring the role of dietary biomarkers with metabolomics can potentially facilitate objective dietary characterization, mitigate errors related to self-reported diet, agnostically test metabolic pathways, and identify mechanistic mediators.Objective: The aim of this study was to evaluate associations of diet-related metabolites with the risk of breast cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.Design: We examined prediagnostic serum concentrations of diet-related metabolites in a nested case-control study in 621 postmenopausal invasive breast cancer cases and 621 matched controls in the multicenter PLCO cohort. We calculated partial Pearson correlations between 617 metabolites and 55 foods, food groups, and vitamin supplements on the basis of the 2015 Dietary Guidelines for Americans and derived from a 137-item self-administered food-frequency questionnaire. Diet-related metabolites (P-correlation < 1.47 × 10-6) were evaluated in breast cancer analyses. ORs for the 90th compared with the 10th percentile were calculated by using conditional logistic regression, with body mass index, physical inactivity, other breast cancer risk factors, and caloric intake controlled for (false discovery rate

Mutations in ACTA1 cause a group of myopathies with expanding clinical and histopathological heterogeneity. We describe three patients with severe ACTA1-related myopathy who have muscle fiber cytoplasmic bodies but no classic nemaline rods. Patient 1 is a five-year-old boy who presented at birth with severe weakness and respiratory failure, requiring mechanical ventilation. Whole exome sequencing identified a heterozygous c.282C>A (p.Asn94Lys) ACTA1 mutation. Patients 2 and 3 were twin boys with hypotonia, severe weakness, and respiratory insufficiency at birth requiring mechanical ventilation. Both died at 6 months of age. The same heterozygous c.282C>A (p.Asn94Lys) ACTA1 mutation was identified by whole exome sequencing. We conclude that clinically severe ACTA1-related myopathy can present with muscle morphological findings suggestive of cytoplasmic body myopathy in the absence of definite nemaline rods. The Asn94Lys mutation in skeletal muscle sarcomeric α-actin may be linked to this histological appearance. These novel ACTA1 cases also illustrate the successful application of whole exome sequencing in directly arriving at a candidate genetic diagnosis in patients with unexpected phenotypic and histologic features for a known neuromuscular gene.

Background: Obesity has been associated with substantially higher risk of inflammatory breast cancer (IBC) than other breast cancer. Here, we assess whether comorbidities of obesity, namely diabetes, abnormal glucose, dyslipidemia, and hypertension, are differentially related to risk of IBC and other breast cancers by tumor stage at diagnosis (localized/regional/distant/unstaged). Methods: We used linked SEER-Medicare data, with female breast cancer cases ages 66+ years identified by SEER registries (years 1992–2011). We divided first breast cancers into IBC (N = 2,306), locally advanced non-IBC (LABC; N = 10,347), and other (N = 197,276). We selected female controls (N = 200,000) from a stratified 5% random sample of Medicare recipients alive and breast cancer free. We assessed exposures until 12 months before diagnosis/selection using Medicare claims data. We estimated odds ratios (OR) and 99.9% confidence intervals (CI) using unconditional logistic regression. Results: Diabetes was associated with increased risk of distant IBC (98.5% of IBC cases; OR 1.44; 99.9% CI 1.21–1.71), distant (OR 1.24; 99.9% CI, 1.09–1.40) and regional (OR 1.29 (99.9% CI, 1.14–1.45) LABC, and distant (OR 1.23; 99.9% CI, 1.10–1.39) and unstaged (OR 1.32; 99.9% CI, 1.18–1.47) other breast cancers. Dyslipidemia was associated with reduced risk of IBC (OR 0.80; 95% CI, 0.67–0.94) and other breast cancers except localized disease. Results were similar by tumor estrogen receptor status. Abnormal glucose levels and hypertension had little association with risk of any tumor type. Conclusions: Associations with diabetes and dyslipidemia were similar for distant stage IBC and other advanced tumors. Impact: If confirmed, such findings could suggest avenues for prevention. Cancer Epidemiol Biomarkers Prev; 26(6); 862–8. ©2017 AACR.

The experimental characterisation of a set of microcantilevers targeted at use in multi-frequency atomic force microscope is presented. The aim of this work is to design a cantilever that naturally amplifies its harmonic oscillations which are introduced by nonlinear probe-sample interaction forces. This is performed by placing the modal frequencies of the cantilever at integer multiples of the first modal frequency. The developed routine demonstrates the placement of the frequency of the second to fifth mode. The characterisation shows a trend that lower-order modes are more accurately placed than higher-order modes. With two fabricated designs, the error in the second mode is at most 2.26% while the greatest error in the fifth mode is at 10.5%.

We describe a 70 year-old independently ambulatory man with a 10-year history of progressive axial and limb-girdle weakness, hyperCKemia, and a 5-year history of dyspnea requiring nocturnal ventilatory support due to a known c.1309C>T (p.Arg437Cys) variant and a novel in-frame deletion of exons 17–19 in the calpain-3 encoding gene (CAPN3). Pulmonary function tests revealed neuromuscular respiratory weakness. Biceps femoris biopsy showed chronic myopathic changes, numerous lobulated fibers, and reduced calpain-3 immunoreactivity. Muscle immunoblot showed markedly reduced calpain-3 expression. Respiratory insufficiency is uncommon in autosomal recessive calpainopathy, and generally develops in the advanced stages of the disease when individuals become wheelchair-dependent. Our patient broadens the phenotypic spectrum of recessive calpainopathy to include early respiratory insufficiency and also further expands its molecular spectrum.

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype–phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease. Electronic supplementary material The online version of this article (10.1007/s00401-019-02059-z) contains supplementary material, which is available to authorized users.

The causative agent of anthrax, Bacillus anthracis, evades the host immune response and establishes infection through the production of binary exotoxins composed of Protective Antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). The majority of vaccination strategies have focused upon the antibody response to the PA subunit. We have used a panel of humanised HLA class II transgenic mouse strains to define HLA-DR-restricted and HLA-DQ-restricted CD4+ T cell responses to the immunodominant epitopes of PA. This was correlated with the binding affinities of epitopes to HLA class II molecules, as well as the responses of two human cohorts: individuals vaccinated with the Anthrax Vaccine Precipitated (AVP) vaccine (which contains PA and trace amounts of LF), and patients recovering from cutaneous anthrax infections. The infected and vaccinated cohorts expressing different HLA types were found to make CD4+ T cell responses to multiple and diverse epitopes of PA. The effects of HLA polymorphism were explored using transgenic mouse lines, which demonstrated differential susceptibility, indicating that HLA-DR1 and HLA-DQ8 alleles conferred protective immunity relative to HLA-DR15, HLA-DR4 and HLA-DQ6. The HLA transgenics enabled a reductionist approach, allowing us to better define CD4+ T cell epitopes. Appreciating the effects of HLA polymorphism on the variability of responses to natural infection and vaccination will be vital in planning protective strategies against anthrax.Author SummaryThe bacterium responsible for causing the disease anthrax, Bacillus anthracis, produces a binary toxin composed of Protective Antigen (PA) and either Lethal Factor (LF) or Edema Factor (EF). Previous vaccination strategies have focused upon the antibody response to the PA subunit. However, within the field of bacterial immunity, there is a growing appreciation of the importance of the adaptive immune response, specifically led by CD4+ T cells. We identified long-term CD4+ T cell responses to PA epitopes following cutaneous human anthrax infection and vaccination, indicating that this toxin component is a principle B. anthracis antigen. To characterise the impact of polymorphism in HLA class II alleles at DR and DQ loci, we used transgenic mice to map the immunodominant epitopes from PA. This was correlated with survival in the transgenic lines following live anthrax challenge. We were able to demonstrate the differential impact of HLA class II alleles upon the CD4+ T cell immunodominant epitopes which shaped the immune hierarchy and therefore susceptibility to anthrax infection.

A substantial body of literature has investigated many issues surrounding police encounters with persons with mental illness. This paper focuses on a specific type of encounter - individuals with mental illness charged with assaulting officers because of their behavior during a psychiatric crisis - and uses administrative data to examine its prevalence in one state. Results suggest that individuals with mental health histories comprise a small but meaningful percentage (c. 9%) of assault on law enforcement charges, and c. 10% of these charges have an offense date within 14 days of an emergency mental health custody order, increasing the likelihood that psychiatric symptoms influenced their behavior at the time of the offense. Further results describe different categories of relevant charges, charge classifications, final dispositions, and sentences. Results are discussed in the context of outcomes for persons with mental illness and law enforcement as well as the role and limitations of forensic mental health assessment in these cases. The paper concludes with a call for similar data collection across jurisdictions.

Background Frailty is more prevalent among black versus white older Americans. We previously identified 37 metabolites associated with the vigor to frailty spectrum using the Scale of Aging Vigor in Epidemiology (SAVE) among older black men from the Health, Aging, and Body Composition (Health ABC) study. Here, we sought to develop a metabolite composite score based on the 37 SAVE-associated metabolites and determine whether the composite score predicts mortality and whether it attenuates the association between frailty and mortality among older black men. Methods Plasma metabolites were measured using liquid chromatography–mass spectrometry. Most of the 37 metabolites were organic acids/derivatives or lipids. Metabolites were ranked into tertiles: tertiles associated with more vigorous SAVE scores were scored 0, mid-tertiles were scored 1, and tertiles associated with frailer SAVE scores were scored 2. Composite scores were the sum of metabolite tertile scores. We examined mortality associations using Cox regression. Percent attenuation estimated the extent to which metabolites attenuated the association between frailty and mortality. Results One standard deviation frailer SAVE was associated with 30% higher mortality, adjusting for age and site (p = .0002); this association was attenuated by 56% after additionally adjusting for the metabolite composite score. In this model, one standard deviation higher metabolite composite score was associated with 46% higher mortality (p < .0001). Metabolite composite scores also predicted mortality (p = .045) in a validation sample of 120 older adults (40% men, 90% white). Conclusion These metabolites may provide a deeper characterization of the higher mortality that is associated with frailty among older adults.

Key Points Question What is the association of metabolomic biomarkers with lung cancer in women who have never smoked? Findings In this case-control study of 275 never-smoking women with lung cancer and 289 never-smoking cancer-free women in China, the metabolite 5-methyl-2-furoic acid was correlated with dietary soy consumption and pathways including 1-carbon metabolism, oxidative stress, nucleotide metabolism, and inflammation and was significantly associated with lower lung cancer risk. Meaning These findings suggest that certain metabolites and pathways are associated with lower lung cancer risk in never-smoking women and biological processes linked to air pollution may be associated with higher lung cancer risk in this population., This case-control study investigates the association between urinary metabolomic biomarkers and lung cancer risk among never-smoking women in China., Importance Chinese women have the highest rate of lung cancer among female never-smokers in the world, and the etiology is poorly understood. Objective To assess the association between metabolomics and lung cancer risk among never-smoking women. Design, Setting, and Participants This nested case-control study included 275 never-smoking female patients with lung cancer and 289 never-smoking cancer-free control participants from the prospective Shanghai Women’s Health Study recruited from December 28, 1996, to May 23, 2000. Validated food frequency questionnaires were used for the collection of dietary information. Metabolomic analysis was conducted from November 13, 2015, to January 6, 2016. Data analysis was conducted from January 6, 2016, to November 29, 2018. Exposures Untargeted ultra-high-performance liquid chromatography–tandem mass spectrometry and nuclear magnetic resonance metabolomic profiles were characterized using prediagnosis urine samples. A total of 39 416 metabolites were measured. Main Outcomes and Measures Incident lung cancer. Results Among the 564 women, those who developed lung cancer (275 participants; median [interquartile range] age, 61.0 [52-65] years) and those who did not develop lung cancer (289 participants; median [interquartile range] age, 62.0 [53-66] years) at follow-up (median [interquartile range] follow-up, 10.9 [9.0-11.7] years) were similar in terms of their secondhand smoke exposure, history of respiratory diseases, and body mass index. A peak metabolite, identified as 5-methyl-2-furoic acid, was significantly associated with lower lung cancer risk (odds ratio, 0.57 [95% CI, 0.46-0.72]; P

Introduction Ample data support that leisure time aerobic moderate to vigorous physical activity (MVPA) is associated with lower risk of at least seven types of cancer. However, the link between muscle-strengthening activities and cancer etiology is not well understood. Our objective was to determine the association of weight lifting with incidence of 10 common cancer types. Methods We used multivariable Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for association of weight lifting with incidence of 10 cancer types in the National Institutes of Health-American Association of Retired Persons Diet and Health Study follow-up. Weight lifting was modeled continuously and categorically. Dose-response relationships were evaluated using cubic restricted spline models. We explored whether associations varied by subgroups defined by sex, age, and body mass index using the Wald test for homogeneity. We examined joint categories of MVPA and weight lifting in relation to cancer risk for significant associations. Results After adjusting for all covariates including MVPA, we observed a statistically significant lower risk of colon cancer (Ptrend = 0.003) in individuals who weight lifted; the HR and 95% CI associated with low and high weight lifting as compared with no weight lifting were 0.75 (95% CI, 0.66-0.87) and 0.78 (95% CI, 0.61-0.98), respectively. The weight lifting-colon cancer relationship differed between men and women (any weight lifting vs no weight lifting: HRmen = 0.91; 95% CI, 0.84-0.98; HRwomen = 1.00; 95% CI, 0.93-1.08; Pinteraction = 0.008). A lower risk of kidney cancer among weight lifters was observed but became nonsignificant after adjusting for MVPA (Ptrend = 0.06), resulting in an HR of 0.94 (95% CI, 0.78-1.12) for low weight lifting and 0.80 (95% CI, 0.59-1.11) for high weight lifting. Conclusions Participants who engaged in weight lifting had a significantly lower risk of colon cancer and a trend toward a lower risk of kidney cancer than participants who did not weight lift.

The paper describes design, modeling and control of a five-axis monolithic nanopositioning stage constructed from a bimorph piezoelectric sheet. In this design, actuators are created by removing parts of the sheet using ultrasonic machining. The constructed nanopositioner is ultra-compact with a thickness of 1 mm. It has a X and Y travel range of 15.5 µm and 13.2 µm respectively; a Z travel range of 26 µm; and a rotational motion about the X- and Y-axis of 600 µrad and 884 µrad respectively. The first resonance frequency occurs at 883 Hz in the Z-axis, and the second and third resonance frequency appears at 1850 Hz, rotating about the X- and Y-axis. A decentralized control strategy is implemented to track Z, θx and θ y motions. The controller provides good tracking and significantly reduces cross-coupling motions among the three degrees-of-freedom.

The application of metabolomics technology to epidemiological studies is emerging as a new approach to elucidate disease etiology and for biomarker discovery. However, analysis of metabolomics data is complex and there is an urgent need for the standardization of analysis workflow and reporting of study findings. To inform the development of such guidelines, we conducted a survey of 47 cohort representatives from the Consortium of Metabolomics Studies (COMETS) to gain insights into the current strategies and procedures used for analyzing metabolomics data in epidemiological studies worldwide. The results indicated a variety of applied analytical strategies, from biospecimen and data pre-processing and quality control to statistical analysis and reporting of study findings. These strategies included methods commonly used within the metabolomics community and applied in epidemiological research, as well as novel approaches to pre-processing pipelines and data analysis. To help with these discrepancies, we propose use of open-source initiatives such as the online web-based tool COMETS Analytics, which includes helpful tools to guide analytical workflow and the standardized reporting of findings from metabolomics analyses within epidemiological studies. Ultimately, this will improve the quality of statistical analyses, research findings, and study reproducibility.

OBJECTIVES: Recent metabolomics studies have identified metabolic correlates of body mass index (BMI), but the degree to which correlations are driven by fat mass as opposed to lean mass has not been established. Our objectives were to 1) replicate findings of BMI-metabolite correlations, and 2) to describe the contributions of FM and LM to the BMI-metabolite associations. METHODS: The Alberta Physical Activity and Breast Cancer Prevention Trial was a two-center randomized trial of healthy but inactive, postmenopausal women (N = 304). BMI (kg/m(2)) was calculated using measured weight and height, while whole body dual X-ray absorptiometry estimated fat mass and lean mass. Serum metabolite levels were measured by ultra-performance liquid chromatography and high-resolution/accurate mass spectrometer. We estimated partial Pearson correlations between 1053 metabolites and BMI, adjusting for age, smoking, and study site. Fat mass/m(2) and lean mass/m(2) correlations were estimated similarly, with mutual adjustment for one another to evaluate independent effects after accounting for their positive intercorrelation. RESULTS: Using a Bonferroni-corrected alpha-level 0.20), and five had virtually no fat mass/m(2) correlation (|r

The Consortium of Metabolomics Studies (COMETS) was established in 2014 to facilitate large-scale collaborative research on the human metabolome and its relationship with disease etiology, diagnosis, and prognosis. COMETS comprises 47 cohorts from Asia, Europe, North America, and South America that together include more than 136,000 participants with blood metabolomics data on samples collected from 1985 to 2017. Metabolomics data were provided by 17 different platforms, with the most frequently used labs being Metabolon, Inc. (14 cohorts), the Broad Institute (15 cohorts), and Nightingale Health (11 cohorts). Participants have been followed for a median of 23 years for health outcomes including death, cancer, cardiovascular disease, diabetes, and others; many of the studies are ongoing. Available exposure-related data include common clinical measurements and behavioral factors, as well as genome-wide genotype data. Two feasibility studies were conducted to evaluate the comparability of metabolomics platforms used by COMETS cohorts. The first study showed that the overlap between any 2 different laboratories ranged from 6 to 121 metabolites at 5 leading laboratories. The second study showed that the median Spearman correlation comparing 111 overlapping metabolites captured by Metabolon and the Broad Institute was 0.79 (interquartile range, 0.56-0.89).

Objective Description of a new variant of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) gene causing congenital myasthenic syndrome (CMS) in 3 children from 2 unrelated families. Methods Muscle biopsies, EMG, and whole-exome sequencing were performed. Results All 3 patients presented with congenital hypotonia, muscle weakness, respiratory insufficiency, head lag, areflexia, and gastrointestinal dysfunction. Genetic analysis identified a homozygous frameshift insertion in the GFPT1 gene (NM_001244710.1: c.686dupC; p.Arg230Ter) that was shared by all 3 patients. In one of the patients, inheritance of the variant was through uniparental disomy (UPD) with maternal origin. Repetitive nerve stimulation and single-fiber EMG was consistent with the clinical diagnosis of CMS with a postjunctional defect. Ultrastructural evaluation of the muscle biopsy from one of the patients showed extremely attenuated postsynaptic folds at neuromuscular junctions and extensive autophagic vacuolar pathology. Conclusions These results expand on the spectrum of known loss-of-function GFPT1 mutations in CMS12 and in one family demonstrate a novel mode of inheritance due to UPD.

BackgroundVariants in the Structural Maintenance of Chromosomes flexible Hinge Domain-containing protein 1 (SMCHD1) can cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) and the unrelated Bosma arhinia microphthalmia syndrome (BAMS). In FSHD2, pathogenic variants are found anywhere in SMCHD1 while in BAMS, pathogenic variants are restricted to the extended ATPase domain. Irrespective of the phenotypic outcome, both FSHD2-associated and BAMS-associated SMCHD1 variants result in quantifiable local DNA hypomethylation. We compared FSHD2, BAMS and non-pathogenic SMCHD1 variants to derive genotype–phenotype relationships.MethodsExamination of SMCHD1 variants and methylation of the SMCHD1-sensitive FSHD locus DUX4 in 187 FSHD2 families, 41 patients with BAMS and in control individuals. Analysis of variants in a three-dimensional model of the ATPase domain of SMCHD1.ResultsDUX4 methylation analysis is essential to establish pathogenicity of SMCHD1 variants. Although the FSHD2 mutation spectrum includes all types of variants covering the entire SMCHD1 locus, missense variants are significantly enriched in the extended ATPase domain. Identification of recurrent variants suggests disease-specific residues for FSHD2 and in BAMS, consistent with a largely disease-specific localisation of variants in SMCHD1.ConclusionsThe localisation of missense variants within the ATPase domain of SMCHD1 may contribute to the differences in phenotypic outcome.

Mutations in the LMNA gene, which encodes the nuclear envelope (NE) proteins lamins A/C, cause Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy and other diseases collectively known as laminopathies. The mechanisms responsible for these diseases remain incompletely understood. Using three mouse models of muscle laminopathies and muscle biopsies from individuals with LMNA-related muscular dystrophy, we found that Lmna mutations reduced nuclear stability and caused transient rupture of the NE in skeletal muscle cells, resulting in DNA damage, DNA damage response activation and reduced cell viability. NE and DNA damage resulted from nuclear migration during skeletal muscle maturation and correlated with disease severity in the mouse models. Reduction of cytoskeletal forces on the myonuclei prevented NE damage and rescued myofibre function and viability in Lmna mutant myofibres, indicating that myofibre dysfunction is the result of mechanically induced NE damage. Taken together, these findings implicate mechanically induced DNA damage as a pathogenic contributor to LMNA skeletal muscle diseases.

Actinopathy is a group of clinically and pathologically heterogeneous myopathies due to mutations in the skeletal muscle sarcomeric α-actin 1-encoding gene (ACTA1). Disease-onset spans from prenatal life to adulthood and weakness can preferentially affect proximal or distal muscles. Myopathological findings include a spectrum of structural abnormalities with nemaline rods being the most common. We report a daughter and father with prominent finger flexors and/or quadriceps involvement. Muscle biopsies revealed rimmed vacuoles in both patients, associated with type 1 fiber atrophy in the daughter, and nemaline rods in the father. Next generation sequencing identified a novel dominant ACTA1 variant, c.149G > A (p.Gly50Asp) in both individuals and no abnormal variants in vacuolar myopathy-associated genes. Our findings expand the clinico-pathological spectrum of actinopathy.

Background: Lipid metabolism pathways have been implicated in type 2 diabetes and inflammatory conditions and may be relevant to pancreatic ductal adenocarcinoma (PDA) etiology. Methods: We conducted an untargeted analysis of 903 lipid species metabolites within 15 lipid classes measured in pre-diagnostic serum (up to 24 years) to determine their association with incident PDA in a nested-case control study of 582 matched case-control sets from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC) and Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Controls were matched to cases by age, sex, race, date of blood draw and follow-up time. We used conditional logistic regressions to calculate odd ratios (OR) and 95% confidence intervals (CI) per 1-standard deviation increase in the log-transformed and normalized lipid concentrations within each cohort and then combined ORs using a fixed-effect meta-analysis. Potential effect modification of the associations by overweight (BMI >25kg.m-2), diabetes status, smoking intensity and time until diagnosis (10 years) was also evaluated. Results: Five lipid species from 4 different lipid classes were significantly associated with PDA risk at a false discovery rate (FDR) Conclusion: This untargeted lipidomics analysis showed evidence for associations between lipid metabolites from 6 different lipid classes and the risk of PDA. These findings support the role of prediagnostic lipid metabolites in PDA etiology. Citation Format: Sabine Naudin, Joshua N. Sampson, Steven C. Moore, Demetrius Albanes, Stephanie Weinstein, Rachael Stolzenberg-Solomon. Lipid metabolites and the risk of pancreatic cancer in two nested case-control studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 755.

This article describes a monolithic nanopositioner constructed from in-plane bending actuators which provide greater deflection than previously reported extension actuators, at the expense of stiffness and resonance frequency. The proposed actuators are demonstrated by constructing an XY nanopositioning stage with a serial kinematic design. Analytical modeling and finite-element-analysis accurately predicts the experimental performance of the nanopositioner. A 10 μ m range is achieved in the X and Y axes with an applied voltage of +/-200 V. The first resonance mode occurs at 250 Hz in the Z axis. The stage is demonstrated for atomic force microscopy imaging.

PURPOSE: This study sought to describe the physical activity-endometrial cancer association and potential mediation of this relationship by obesity in midlife. METHODS: Participants were 67,705 women (aged 50–71 years) enrolled in the NIH-AARP cohort who reported their historical leisure-time physical activity patterns starting at age 15–18 years. We identified five long-term physical activity patterns between adolescence and cohort entry (i.e., inactive, maintained-low, maintained-high, increasers, decreasers). We used Cox regression (Hazard ratio - HR [95% CI]) to assess the relationship between these patterns and midlife obesity and endometrial cancer, adjusting for covariates. Mediation analysis was used to decompose the physical activity patterns-endometrial cancer association to estimate the proportion of the physical activity-endometrial cancer association mediated by midlife obesity. RESULTS: During an average 12.3 years of follow-up 1,468 endometrial cancers occurred. Long-term physical activity patterns were inactive, maintained-low, maintained-high, increasers, and decreasers. Compared to long- term inactive women, women who maintained-high or increased activity levels had a 19–26% lower risk for endometrial cancer (maintained-high: HR = 0.81 [0.67, 0.98]; increasers: HR = 0.74 [0.61, 0.91]). They also had a 45–77% lower risk for obesity in midlife (e.g., maintained-high, BMI 30–39.9: HR = 0.50 [0.46, 0.55]; maintained- high, BMI 40+: HR = 0.32 [0.26, 0.39]). Obesity was a significant mediator and appeared to account for 55–63% of the physical activity-endometrial cancer associations observed. CONCLUSIONS: Both initiating and maintaining physical activity throughout adulthood can play a role in preventing obesity and in turn, lowering the risk for endometrial cancer.

BACKGROUND: Healthy dietary patterns that conform to national dietary guidelines are related to lower chronic disease incidence and longer life span. However, the precise mechanisms involved are unclear. Identifying biomarkers of dietary patterns may provide tools to validate diet quality measurement and determine underlying metabolic pathways influenced by diet quality. OBJECTIVE: The objective of this study was to examine the correlation of 4 diet quality indexes [the Healthy Eating Index (HEI) 2010, the Alternate Mediterranean Diet Score (aMED), the WHO Healthy Diet Indicator (HDI), and the Baltic Sea Diet (BSD)] with serum metabolites. DESIGN: We evaluated dietary patterns and metabolites in male Finnish smokers (n = 1336) from 5 nested case-control studies within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Participants completed a validated food-frequency questionnaire and provided a fasting serum sample before study randomization (1985-1988). Metabolites were measured with the use of mass spectrometry. We analyzed cross-sectional partial correlations of 1316 metabolites with 4 diet quality indexes, adjusting for age, body mass index, smoking, energy intake, education, and physical activity. We pooled estimates across studies with the use of fixed-effects meta-analysis with Bonferroni correction for multiple comparisons, and conducted metabolic pathway analyses. RESULTS: The HEI-2010, aMED, HDI, and BSD were associated with 23, 46, 23, and 33 metabolites, respectively (17, 21, 11, and 10 metabolites, respectively, were chemically identified; r-range: -0.30 to 0.20; P = 6 × 10(-15) to 8 × 10(-6)). Food-based diet indexes (HEI-2010, aMED, and BSD) were associated with metabolites correlated with most components used to score adherence (e.g., fruit, vegetables, whole grains, fish, and unsaturated fat). HDI correlated with metabolites related to polyunsaturated fat and fiber components, but not other macro- or micronutrients (e.g., percentages of protein and cholesterol). The lysolipid and food and plant xenobiotic pathways were most strongly associated with diet quality. CONCLUSIONS: Diet quality, measured by healthy diet indexes, is associated with serum metabolites, with the specific metabolite profile of each diet index related to the diet components used to score adherence. This trial was registered at clinicaltrials.gov as NCT00342992.

A 30-year-old man who recently immigrated from Liberia was admitted to the neurology service for diffuse weakness. He reported 7 years of painless progressive weakness and atrophy. He noted that his legs began to get weak first, which manifested as difficulty keeping up with his peers while playing soccer. This progressively worsened until he had great difficulty walking and arising from a seated position. A few years after the onset of leg weakness, he developed arm weakness. He denied sensory loss. He had some back pain but no limb pain. He denied fasciculations, cramping, or constitutional symptoms. He was not on medications and denied any toxic exposures. His parents were physically normal but were first cousins. He had 2 children, ages 2 and 4 years, who were physically normal. The authors acknowledge Terese Nelson for performing the muscle biopsy immunostaining and Mary Cox for performing the Western blotting.

The articles focuses on the author's testing of the triangular ideogram constructed by scholar S. D. Campbell in his 1996 article "Green Cities, Growing Cities, Just Cities: Urban Planning and the Contradiction of Sustainable Development." It considers some weaknesses which emerged as conditions changed since 1996 including civic environmentalism, resilience and smart city.

Background: Diet plays an important role in chronic disease etiology, but some diet-disease associations remain inconclusive because of methodologic limitations in dietary assessment. Metabolomics is a novel method for identifying objective dietary biomarkers, although it is unclear what dietary information is captured from metabolites found in serum compared with urine. Objective: We compared metabolite profiles of habitual diet measured from serum with those measured from urine. Design: We first estimated correlations between consumption of 56 foods, beverages, and supplements assessed by a food-frequency questionnaire, with 676 serum and 848 urine metabolites identified by untargeted liquid chromatography mass spectrometry, ultra-high performance liquid chromatography tandem mass spectrometry, and gas chromatography mass spectrometry in a colon adenoma case–control study (n = 125 cases and 128 controls) while adjusting for age, sex, smoking, fasting, case-control status, body mass index, physical activity, education, and caloric intake. We controlled for multiple comparisons with the use of a false discovery rate of

Autonomic dysfunction is common in Chagas disease and diabetes. Patients with either condition complicated by cardiac autonomic dysfunction face increased mortality, but no clinical predictors of autonomic dysfunction exist. Pupillary light reflexes (PLRs) may identify such patients early, allowing for intensified treatment. To evaluate the significance of PLRs, adults were recruited from the outpatient endocrine, cardiology, and surgical clinics at a Bolivian teaching hospital. After testing for Chagas disease and diabetes, participants completed conventional autonomic testing (CAT) evaluating their cardiovascular responses to Valsalva, deep breathing, and orthostatic changes. PLRs were measured using specially designed goggles, then CAT and PLRs were compared as measures of autonomic dysfunction. This study analyzed 163 adults, including 96 with Chagas disease, 35 patients with diabetes, and 32 controls. PLRs were not significantly different between Chagas disease patients and controls. Patients with diabetes had longer latency to onset of pupil constriction, slower maximum constriction velocities, and smaller orthostatic ratios than nonpatients with diabetes. PLRs correlated poorly with CAT results. A PLR-based clinical risk score demonstrated a 2.27-fold increased likelihood of diabetes complicated by autonomic dysfunction compared with the combination of blood tests, CAT, and PLRs (sensitivity 87.9%, specificity 61.3%). PLRs represent a promising tool for evaluating subclinical neuropathy in patients with diabetes without symptomatic autonomic dysfunction. Pupillometry does not have a role in the evaluation of Chagas disease patients.

Background Physical activity is associated with a variety of health benefits, but the biological mechanisms that explain these associations remain unclear. Metabolomics is a powerful tool to comprehensively evaluate global metabolic signature associated with physical activity and helps to pinpoint the pathways that mediate the health effects of physical activity. There has been limited research on metabolomics and habitual physical activity, and no metabolomics study has examined sedentary behaviour and physical activity of different intensities. Methods In a group of Chinese adults (N = 277), we used an untargeted approach to examine 328 plasma metabolites in relation to accelerometer-measured physical activity, including overall volume of physical activity (physical activity energy expenditure (PAEE) and duration of physically active time) and sedentary time, and measures related to different intensities of physical activity (moderate-to-vigorous activity (MVPA), light activity, average physical activity intensity). Results We identified 11 metabolites that were associated with total activity, with a false discovery rate of 0.2 or lower. Notably, we observed generally lower levels of amino acids in the valine, leucine and isoleucine metabolism pathway and of carbohydrates in sugar metabolism among participants with higher activity levels. Moreover, we found that PAEE, time spent in light activity and duration of physically active time were associated with a similar metabolic pattern, whereas the metabolic signature associated with sedentary time mirrored this pattern. In contrast, average activity intensity and time spent in MVPA appeared to be associated with somewhat different metabolic patterns. Conclusions Overall, the metabolomics patterns support a beneficial role of higher volume of physical activity in cardiometabolic health. Our findings identified candidate pathways and provide insight into the mechanisms underlying the health effects of physical activity.

ObjectiveDescription of a new variant of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) gene causing congenital myasthenic syndrome (CMS) in 3 children from 2 unrelated families.MethodsMuscle biopsies, EMG, and whole-exome sequencing were performed.ResultsAll 3 patients presented with congenital hypotonia, muscle weakness, respiratory insufficiency, head lag, areflexia, and gastrointestinal dysfunction. Genetic analysis identified a homozygous frameshift insertion in the GFPT1 gene (NM_001244710.1: c.686dupC; p.Arg230Ter) that was shared by all 3 patients. In one of the patients, inheritance of the variant was through uniparental disomy (UPD) with maternal origin. Repetitive nerve stimulation and single-fiber EMG was consistent with the clinical diagnosis of CMS with a postjunctional defect. Ultrastructural evaluation of the muscle biopsy from one of the patients showed extremely attenuated postsynaptic folds at neuromuscular junctions and extensive autophagic vacuolar pathology.ConclusionsThese results expand on the spectrum of known loss-of-function GFPT1 mutations in CMS12 and in one family demonstrate a novel mode of inheritance due to UPD.

Congenital myopathies are early onset, slowly progressive neuromuscular disorders of variable severity. They are genetically and phenotypically heterogeneous and caused by pathogenic variants in several genes. Multi-minicore Disease, one of the more common congenital myopathies, is frequently caused by recessive variants in either SELENON, encoding the endoplasmic reticulum glycoprotein selenoprotein N or RYR1, encoding a protein involved in calcium homeostasis and excitation–contraction coupling. The mechanism by which recessive SELENON variants cause Multi-minicore Disease is unclear. Here, we extensively investigated muscle physiological, biochemical and epigenetic modifications, including DNA methylation, histone modification and non-coding RNA expression, to understand the pathomechanism of Multi-minicore Disease. We identified biochemical changes that are common in patients harbouring recessive RYR1 and SELENON variants, including depletion of transcripts encoding proteins involved in skeletal muscle calcium homeostasis, increased levels of class II HDACs and DNA methyltransferases. CpG methylation analysis of genomic DNA of patients with RYR1 and SELENON variants identified more than 3500 common aberrantly methylated genes, many of which are involved in calcium signalling. These results provide the proof of concept for the potential use of drugs targeting HDACs and DNA methyltransferases to treat patients with specific forms of congenital myopathies.

Performance of astronaut pilots during space shuttle landing was degraded after a few weeks of microgravity exposure, and longer-term exposure has the potential to impact operator proficiency during critical landing and post-landing operations for exploration-class missions. Full-motion simulations of operationally-relevant tasks were utilized to assess the impact of long-duration spaceflight on operator proficiency in a group of 8 astronauts assigned to the International Space Station, as well as a battery of cognitive/sensorimotor tests to determine the underlying cause of any post-flight performance decrements. A ground control group (N = 12) and a sleep restriction cohort (N = 9) were also tested to control for non-spaceflight factors such as lack of practice between pre- and post-flight testing and fatigue. On the day of return after 6 months aboard the space station, astronauts exhibited significant deficits in manual dexterity, dual-tasking and motion perception, and a striking degradation in the ability to operate a vehicle. These deficits were not primarily due to fatigue; performance on the same tasks was unaffected after a 30-h period of sleep restriction. Astronauts experienced a general post-flight malaise in motor function and motion perception, and a lack of cognitive reserve apparent only when faced with dual tasks, which had recovered to baseline by four days after landing.

Maintaining a healthy body weight, eating well and being physically active lowers cancer risk by 30%. However, the biology underlying these relationships is not well understood. We examined cross-sectional associations between metabolites and cancer preventive behaviors as well as the relevance to cancer-related pathways among 120 participants (50% men, mean BMI 26.6 kg/m2, mean age 54 years) with no history of smoking or cancer. Participants completed questionnaires, physical measurements and provided blood samples. Non-targeted nuclear magnetic resonance captured 223 metabolite measures. Factor analysis was performed separately for amino acid, fatty acid and lipoprotein groups. Multivariable-adjusted linear regression was used to evaluate associations between cancer preventive recommendations and metabolite-containing factors (p-value

Objective To characterize the clinical phenotype, genetic origin, and muscle pathology of patients with the FKRP c.1387A>G mutation. Methods Standardized clinical data were collected for all patients known to the authors with c.1387A>G mutations in FKRP. Muscle biopsies were reviewed and used for histopathology, immunostaining, Western blotting, and DNA extraction. Genetic analysis was performed on extracted DNA. Results We report the clinical phenotypes of 6 patients homozygous for the c.1387A>G mutation in FKRP. Onset of symptoms was G patients revealed a 500-kb region of shared homozygosity at 19q13.32, including FKRP. All 4 muscle biopsies available for review showed end-stage dystrophic pathology, near absence of glycosylated α-dystroglycan (α-DG) by immunofluorescence, and reduced molecular weight of α-DG compared with controls and patients with homozygous FKRP c.826C>A limb-girdle muscular dystrophy. Conclusions The clinical features and muscle pathology in these newly reported patients homozygous for FKRP c.1387A>G confirm that this mutation causes congenital muscular dystrophy. The clinical severity might be explained by the greater reduction in α-DG glycosylation compared with that seen with the c.826C>A mutation. The shared region of homozygosity at 19q13.32 indicates that FKRP c.1387A>G is a founder mutation with an estimated age of 60 generations (∼1,200–1,500 years).

Impaired metabolism may play an important role in the pathogenesis of lethal prostate cancer, yet there is a paucity of evidence regarding the association. We conducted a large prospective serum metabolomic analysis of lethal prostate cancer in 523 cases and 523 matched controls nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Median time from baseline fasting serum collection to prostate cancer death was 18 years (maximum 30 years). We identified 860 known biochemicals through an ultrahigh-performance LC-MS/MS platform. Conditional logistic regression models estimated odds ratios (OR) and 95% confidence intervals of risk associated with 1-standard deviation (s.d.) increases in log-metabolite signals. We identified 34 metabolites associated with lethal prostate cancer with a false discovery rate (FDR) < 0.15. Notably, higher serum thioproline, and thioproline combined with two other cysteine-related amino acids and redox metabolites, cystine and cysteine, were associated with reduced risk (1-s.d. OR = 0.75 and 0.71, respectively; p ≤ 8.2 × 10-5 ). By contrast, the dipeptide leucylglycine (OR = 1.36, p = 8.2 × 10-5 ), and three gamma-glutamyl amino acids (OR = 1.28-1.30, p ≤ 4.6 × 10-4 ) were associated with increased risk of lethal prostate cancer. Cases with metastatic disease at diagnosis (n = 179) showed elevated risk for several lipids, including especially the ketone body 3-hydroxybutyrate (BHBA), acyl carnitines, and dicarboxylic fatty acids (1.37 ≤ OR ≤ 1.49, FDR < 0.15). These findings provide a prospective metabolomic profile of lethal prostate cancer characterized by altered biochemicals in the redox, dipeptide, pyrimidine, and gamma-glutamyl amino acid pathways, whereas ketone bodies and fatty acids were associated specifically with metastatic disease.

Atomic force microscope (AFM) cantilevers with integrated actuation and sensing provide several distinct advantages over conventional cantilever instrumentation. These include clean frequency responses, the possibility of down-scaling and parallelization to cantilever arrays as well as the absence of optical interference. While cantilever microfabrication technology has continuously advanced over the years, the overall design has remained largely unchanged; a passive rectangular shaped cantilever design has been adopted as the industry wide standard. In this article, we demonstrate multimode AFM imaging on higher eigenmodes as well as bimodal AFM imaging with cantilevers using fully integrated piezoelectric actuation and sensing. The cantilever design maximizes the higher eigenmode deflection sensitivity by optimizing the transducer layout according to the strain mode shape. Without the need for feedthrough cancellation, the read-out method achieves close to zero actuator/sensor feedthrough and the sensitivity is sufficient to resolve the cantilever Brownian motion.

Ahstract- This article presents a novel cantilever design approach to place higher mode frequencies within a specific frequency band to alleviate instrumentation and Q control feasibility. This work is motivated by the emerging field of multifrequency atomic force microscopy (AFM) which involves the excitation and/or detection of several cantilever modes at once. Unlike other operating modes, multifrequency AFM allows the tracking of the sample topography on the fundamental mode while simultaneously acquiring complimentary nanomechanical information on a higher mode. However, higher modes of conventional rectangular tapping-mode cantilevers are usually in the MHz regime and therefore impose severe restrictions on the direct controllability of these modes. To overcome this limitation, an optimization technique is employed which is capable of placing the first five modes within a 200 kHz bandwidth.

This article describes the design, modeling and simulation of a serial-kinematic nanopositioner machined from a single sheet of piezoelectric material. In this class of nanopo-sitioners, the flexures, sensors and actuators are completely integrated into a single monolithic structure. A non-trivial electrode topology is etched into the sheet to achieve in-plane bending and displacement of the moving platform. Finite element analysis predicts a sensitivity of 18.6 nmN in the x-axis and 18.1 nm/V in the y-axis with a voltage limit of −250 V to 1000 V. The first resonance frequency is 250 Hz in the Z axis. This design enables high-speed, long-range, lateral positioning in space-limited applications.

Leukodystrophies and genetic leukoencephalopathies are a heterogeneous group of heritable disorders that affect the glial-axonal unit. As more patients with unsolved leukodystrophies and genetic leukoencephalopathies undergo next generation sequencing, causative mutations in genes leading to central hypomyelination are being identified. Two such individuals presented with arthrogryposis multiplex congenita, congenital hypomyelinating neuropathy, and central hypomyelination with early respiratory failure. Whole exome sequencing identified biallelic mutations in the CNTNAP1 gene: homozygous c.1163G>C (p.Arg388Pro) and compound heterozygous c.967T>C (p.Cys323Arg) and c.319C>T (p.Arg107*). Sural nerve and quadriceps muscle biopsies demonstrated progressive, severe onion bulb and axonal pathology. By ultrastructural evaluation, septate axoglial paranodal junctions were absent from nodes of Ranvier. Serial brain magnetic resonance images revealed hypomyelination, progressive atrophy, and reduced diffusion in the globus pallidus in both patients. These 2 families illustrate severe progressive peripheral demyelinating neuropathy due to the absence of septate paranodal junctions and central hypomyelination with neurodegeneration in CNTNAP1-associated arthrogryposis multiplex congenita.

A fundamental component of the z-axis feedback loop in amplitude modulation atomic force microscopy is the demodulator. It dictates both bandwidth and noise in the amplitude and phase estimate of the cantilever deflection signal. In this paper, we derive a linear time-invariant model of a closed-loop demodulator with user definable tracking bandwidth and sensitivity to other frequency components. A direct demodulator design method is proposed based on the reformulation of the Lyapunov filter as a modulated-demodulated controller in closed loop with a unity plant. Simulation and experimental results for a higher order Lyapunov filter as well as Butterworth and Chebyshev type demodulators are presented.