Publications by authors named "Susan Hamilton"

103 Publications

Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation.

FASEB J 2021 May;35(5):e21349

Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.

Mice with a mutation (D244G, DG) in calsequestrin 1 (CASQ1), analogous to a human mutation in CASQ1 associated with a delayed onset human myopathy (vacuolar aggregate myopathy), display a progressive myopathy characterized by decreased activity, decreased ability of fast twitch muscles to generate force and low body weight after one year of age. The DG mutation causes CASQ1 to partially dissociate from the junctional sarcoplasmic reticulum (SR) and accumulate in the endoplasmic reticulum (ER). Decreased junctional CASQ1 reduces SR Ca release. Muscles from older DG mice display ER stress, ER expansion, increased mTOR signaling, inadequate clearance of aggregated proteins by the proteasomes, and elevation of protein aggregates and lysosomes. This study suggests that the myopathy associated with the D244G mutation in CASQ1 is driven by CASQ1 mislocalization, reduced SR Ca release, CASQ1 misfolding/aggregation and ER stress. The subsequent maladaptive increase in protein synthesis and decreased protein aggregate clearance are likely to contribute to disease progression.
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http://dx.doi.org/10.1096/fj.202001653RRDOI Listing
May 2021

The Diagnostic Yield of Prenatal Genetic Technologies in Congenital Heart Disease: A Prospective Cohort Study.

Fetal Diagn Ther 2021 Feb 5:1-8. Epub 2021 Feb 5.

West Midlands Fetal Medicine Centre, Birmingham Women's and Children's National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom.

Introduction: The objective was to evaluate: (i) the proportion of prenatally diagnosed congenital heart disease (CHD) associated with an abnormal quantitative fluorescence-PCR (QF-PCR), chromosome microarray (CMA), and exome sequencing (ES) result; and (ii) the diagnostic yield of these technologies based on CHD category and presence of extra-cardiac anomalies (ECAs).

Methods: This prospective cohort study was set across 12 UK foetal medicine centres. All cases underwent QF-PCR, CMA, and ES, and the diagnostic yield in n = 147 cases of prenatally diagnosed CHD was assessed.

Results: In 34.7% (n = 51/147), a genetic diagnosis was obtained. Using a stepwise testing strategy, the diagnostic yield for QF-PCR, CMA, and ES was 15.6% (n = 23/147), 13.7% (n = 17/124), and 10.2% (n = 11/107), respectively. Abnormal QF-PCR/shunt (septal) defects 31.4% (n = 11/35), p = 0.046, and abnormal CMA/conotruncal anomalies 22.7% (n = 10/44), p = 0.04, had significant associations. Monogenic variants were commonest in complex CHD 36.4% (n = 4/11). Multisystem CHD had a greater diagnostic yield overall compared to isolated OR 2.41 (95% CI, 1.1-5.1), particularly in association with brain and gastrointestinal tract anomalies. The proportion of variants of uncertain significance was 4.7% (n = 5/107) with ES, with none in the CMA group.

Conclusion: In the era of prenatal ES, there remains an important role for QF-PCR and CMA. Identification of monogenic pathologic variants further allows delineation of prognosis in CHD.
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http://dx.doi.org/10.1159/000512488DOI Listing
February 2021

Untargeted metabolomics profiling of skeletal muscle samples from malignant hyperthermia susceptible patients.

Can J Anaesth 2021 Jan 6. Epub 2021 Jan 6.

Department of Chemistry, University of Waterloo, Waterloo, ON, Canada.

Purpose: Malignant hyperthermia (MH) is a potentially fatal hypermetabolic condition triggered by certain anesthetics and caused by defective calcium homeostasis in skeletal muscle cells. Recent evidence has revealed impairment of various biochemical pathways in MH-susceptible patients in the absence of anesthetics. We hypothesized that clinical differences between MH-susceptible and control individuals are reflected in measurable differences in myoplasmic metabolites.

Methods: We performed metabolomic profiling of skeletal muscle samples from MH-negative (control) individuals and MH-susceptible patients undergoing muscle biopsy for diagnosis of MH susceptibility. Cellular metabolites were extracted from 33 fresh and 87 frozen human muscle samples using solid phase microextraction and Metabolon® untargeted biochemical profiling platforms, respectively. Ultra-performance liquid chromatography-high resolution mass spectrometry was used for metabolite identification and validation, followed by analysis of differences in metabolites between the MH-susceptible and MH-negative groups.

Results: Significant fold-change differences between the MH-susceptible and control groups in metabolites from various pathways were found (P value range: 0.009 to < 0.001). These included accumulation of long chain acylcarnitines, diacylglycerols, phosphoenolpyruvate, histidine pathway metabolites, lysophosphatidylcholine, oxidative stress markers, and phosphoinositols, as well as decreased levels of monoacylglycerols. The results from both analytical platforms were in agreement.

Conclusion: This metabolomics study indicates a shift from utilization of carbohydrates towards lipids for energy production in MH-susceptible individuals. This shift may result in inefficiency of beta-oxidation, and increased muscle protein turnover, oxidative stress, and/or lysophosphatidylcholine levels.
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http://dx.doi.org/10.1007/s12630-020-01895-yDOI Listing
January 2021

MyoSight-semi-automated image analysis of skeletal muscle cross sections.

Skelet Muscle 2020 11 16;10(1):33. Epub 2020 Nov 16.

Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.

Background: Manual analysis of cross-sectional area, fiber-type distribution, and total and centralized nuclei in skeletal muscle cross sections is tedious and time consuming, necessitating an accurate, automated method of analysis. While several excellent programs are available, our analyses of skeletal muscle disease models suggest the need for additional features and flexibility to adequately describe disease pathology. We introduce a new semi-automated analysis program, MyoSight, which is designed to facilitate image analysis of skeletal muscle cross sections and provide additional flexibility in the analyses.

Results: We describe staining and imaging methods that generate high-quality images of immunofluorescent-labelled cross sections from mouse skeletal muscle. Using these methods, we can analyze up to 5 different fluorophores in a single image, allowing simultaneous analyses of perinuclei, central nuclei, fiber size, and fiber-type distribution. MyoSight displays high reproducibility among users, and the data generated are in close agreement with data obtained from manual analyses of cross-sectional area (CSA), fiber number, fiber-type distribution, and number and localization of myonuclei. Furthermore, MyoSight clearly delineates changes in these parameters in muscle sections from a mouse model of Duchenne muscular dystrophy (mdx).

Conclusions: MyoSight is a new program based on an algorithm that can be optimized by the user to obtain highly accurate fiber size, fiber-type identification, and perinuclei and central nuclei per fiber measurements. MyoSight combines features available separately in other programs, is user friendly, and provides visual outputs that allow the user to confirm the accuracy of the analyses and correct any inaccuracies. We present MyoSight as a new program to facilitate the analyses of fiber type and CSA changes arising from injury, disease, exercise, and therapeutic interventions.
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http://dx.doi.org/10.1186/s13395-020-00250-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667765PMC
November 2020

Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature.

Skelet Muscle 2020 11 16;10(1):32. Epub 2020 Nov 16.

Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA.

The RYR1 gene, which encodes the sarcoplasmic reticulum calcium release channel or type 1 ryanodine receptor (RyR1) of skeletal muscle, was sequenced in 1988 and RYR1 variations that impair calcium homeostasis and increase susceptibility to malignant hyperthermia were first identified in 1991. Since then, RYR1-related myopathies (RYR1-RM) have been described as rare, histopathologically and clinically heterogeneous, and slowly progressive neuromuscular disorders. RYR1 variants can lead to dysfunctional RyR1-mediated calcium release, malignant hyperthermia susceptibility, elevated oxidative stress, deleterious post-translational modifications, and decreased RyR1 expression. RYR1-RM-affected individuals can present with delayed motor milestones, contractures, scoliosis, ophthalmoplegia, and respiratory insufficiency.Historically, RYR1-RM-affected individuals were diagnosed based on morphologic features observed in muscle biopsies including central cores, cores and rods, central nuclei, fiber type disproportion, and multi-minicores. However, these histopathologic features are not always specific to RYR1-RM and often change over time. As additional phenotypes were associated with RYR1 variations (including King-Denborough syndrome, exercise-induced rhabdomyolysis, lethal multiple pterygium syndrome, adult-onset distal myopathy, atypical periodic paralysis with or without myalgia, mild calf-predominant myopathy, and dusty core disease) the overlap among diagnostic categories is ever increasing. With the continuing emergence of new clinical subtypes along the RYR1 disease spectrum and reports of adult-onset phenotypes, nuanced nomenclatures have been reported (RYR1- [related, related congenital, congenital] myopathies). In this narrative review, we provide historical highlights of RYR1 research, accounts of the main diagnostic disease subtypes and propose RYR1-related disorders (RYR1-RD) as a unified nomenclature to describe this complex and evolving disease spectrum.
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http://dx.doi.org/10.1186/s13395-020-00243-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667763PMC
November 2020

Diagnostic and perinatal outcomes in consanguineous couples with a structural fetal anomaly: A cohort study.

Acta Obstet Gynecol Scand 2021 03 27;100(3):418-424. Epub 2020 Nov 27.

Fetal Medicine Centre, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.

Introduction: Consanguineous unions occur when a couple are related outside marriage and is associated with adverse genetic and perinatal outcomes for affected offspring. The objectives of this study were to evaluate: (i) background characteristics, (ii) uptake of prenatal and postnatal investigation and (iii) diagnostic outcomes of UK consanguineous couples presenting with a fetal structural anomaly.

Material And Methods: This was a retrospective and partly prospective cohort study comparing consanguineous (n = 62) and non-consanguineous (n = 218) pregnancies with current or previous fetal structural anomalies reviewed in a UK prenatal genetic clinic from 2008 to 2019. Outcomes were compared using odds ratios (OR).

Results: Most consanguineous couples were of Pakistani ethnicity (odds ratio [OR] 29, 95% confidence interval [95% CI] 13-62) and required use of an interpreter [OR 9, 95% CI 4-20). In the consanguineous group, the uptake of prenatal invasive testing was lower (OR 0.4, 95% CI 0.2-0.7) and the number declining follow up was greater (OR 10, 95% CI 3-34) than in the non-consanguineous group. This likely explained the lower proportion of consanguineous couples where a final definitive unifying diagnosis to explain the fetal structural anomalies was reached (OR 0.3, 95% CI 0.2-0.6). When a diagnosis was obtained in this group, it was always postnatal and most often using genomic sequencing technologies (OR 6, 95% CI 1-27). The risk of perinatal death was greater (OR 3, 95% CI 1-6) in the consanguineous group, as was the risk of fetal structural anomaly recurrence in a subsequent pregnancy (OR 4, 95% CI 1-13). There was no difference in the uptake of perinatal autopsy or termination of pregnancy between groups.

Conclusions: Consanguineous couples are a vulnerable group in the prenatal setting. Although adverse perinatal outcomes in this group are more common secondary to congenital anomalies, despite the evolution of genomic sequencing technologies, due to a lower uptake of prenatal testing it is less likely that a unifying diagnosis is obtained and recurrence can occur. There is a need for proactive genetic counseling and education from the multidisciplinary team, addressing language barriers as well as religious and cultural beliefs in an attempt to optimize reproductive options.
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http://dx.doi.org/10.1111/aogs.14036DOI Listing
March 2021

Cell-Free DNA in the Investigation of Miscarriage.

J Clin Med 2020 Oct 26;9(11). Epub 2020 Oct 26.

West Midlands Regional Genetics Laboratory, Birmingham Women's and Children's Hospital, Birmingham B15 2TG, UK.

Approximately one in four pregnancies result in pregnancy loss, and ~50% of these miscarriages are caused by chromosomal abnormalities. Genetic investigations are recommended after three consecutive miscarriages on products of conception (POC) tissue. Cell-free DNA (cfDNA) has been utilised for prenatal screening, but very little work has been carried out in nonviable pregnancies. We investigated the use of cfDNA from maternal blood to identify chromosomal abnormalities in miscarriage. One hundred and two blood samples from women experiencing a first trimester miscarriage were collected and stored. The mean gestational age was 7.1 weeks (range: 5-11 weeks). In this research, samples without a genetic test result from POC were not analysed. CfDNA was extracted and analysed using a modified commercial genome-wide non-invasive prenatal test. No results were provided to the patient. In 57 samples, cytogenetic results from POC analysis were available. Chromosomal abnormalities were identified in 47% (27/57) of POC analyses, and cfDNA analysis correctly identified 59% (16/27) of these. In total, 75% (43/57) of results were correctly identified. The average cfDNA fetal fraction was 6% (2-19%). In conclusion, cfDNA can be used to detect chromosomal abnormalities in miscarriages where the 'fetal fraction' is high enough; however, more studies are required to identify variables that can affect the overall results.
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http://dx.doi.org/10.3390/jcm9113428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693881PMC
October 2020

Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation.

Nat Commun 2020 10 9;11(1):5099. Epub 2020 Oct 9.

Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.

Mutations in the skeletal muscle Ca release channel, the type 1 ryanodine receptor (RYR1), cause malignant hyperthermia susceptibility (MHS) and a life-threatening sensitivity to heat, which is most severe in children. Mice with an MHS-associated mutation in Ryr1 (Y524S, YS) display lethal muscle contractures in response to heat. Here we show that the heat response in the YS mice is exacerbated by brown fat adaptive thermogenesis. In addition, the YS mice have more brown adipose tissue thermogenic capacity than their littermate controls. Blood lactate levels are elevated in both heat-sensitive MHS patients with RYR1 mutations and YS mice due to Ca driven increases in muscle metabolism. Lactate increases brown adipogenesis in both mouse and human brown preadipocytes. This study suggests that simple lifestyle modifications such as avoiding extreme temperatures and maintaining thermoneutrality could decrease the risk of life-threatening responses to heat and exercise in individuals with RYR1 pathogenic variants.
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http://dx.doi.org/10.1038/s41467-020-18865-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547078PMC
October 2020

Evolution of a prenatal genetic clinic-A 10-year cohort study.

Prenat Diagn 2020 04 21;40(5):618-625. Epub 2020 Feb 21.

Fetal Medicine Centre, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.

Objective: To (a) evaluate the proportion of women where a unifying genetic diagnosis was obtained following assessment of an observed pattern of fetal anomalies and (b) assess trends in genetic testing in a joint fetal-medicine genetic clinic.

Method: Retrospective cohort study of all women attending the clinic. Outcomes included (a) indication for referral, (b) genetic test performed and (c) diagnoses obtained.

Results: From 2008 to 2019, 256 patients were referred and reviewed, of which 23% (n = 59) were consanguineous. The main indication for referral was the observed pattern of fetal anomalies. Over 10 years, the number of patients reviewed increased from 11 to 35 per annum. A unifying genetic diagnosis was obtained in 43.2% (n = 79/183), the majority of which were diagnosed prenatally (50.6% [n = 40/79]). The main investigation(s) that was the ultimate diagnostic test was targeted gene panel sequencing 34.2% (n = 27/79), with this and exome sequencing becoming the dominant genetic test by 2019. Pregnancies reviewed due to an abnormal karyotype or microarray decreased as an indication for referral during the study period (21.6% [n = 16/74] 2008-2012 vs 16.5% [n = 30/182] in 2012-2019).

Conclusion: A prenatal genetic clinic with a structured multi-disciplinary team approach may be successful in obtaining a unifying prenatal genetic diagnosis.
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http://dx.doi.org/10.1002/pd.5661DOI Listing
April 2020

Bedside Postpyloric Tube Placement and Enteral Nutrition Delivery in the Pediatric Intensive Care Unit.

Nutr Clin Pract 2020 Apr 28;35(2):299-305. Epub 2020 Jan 28.

Department of Anesthesiology, Critical Care and Pain Medicine, Boston, Massachusetts, USA.

Background: Enteral nutrition (EN) delivery may be more effective via a postpyloric (PP) feeding tube in critically ill children, but tube placement can be challenging. We aimed to describe PP tube placement and EN practices in a multidisciplinary pediatric intensive care unit (PICU) after the implementation of a nurse-led bedside PP tube-placement program.

Methods: In a single-center retrospective study, we identified 100 consecutive patients admitted to the PICU for >48 hours and for whom PP tube placement was attempted. Demographics, clinical characteristics, and details of PP tube placement and EN delivery were examined.

Results: The study cohort had a median age (25th, 75th percentiles) of 3.89 years (0.55, 14.86); 66% were male. Respiratory illness was the primary diagnosis of admission (55%); 92% were on respiratory support. Risk of aspiration was the primary indication for PP tube placement (48%). Bedside placement was the initial technique for PP tube placement in 93% of patients (successful for 84.9%) and was not associated with serious complications. Eighty-seven patients with a PP tube started EN and received a median 73.9% (12.3%, 100%) of prescribed energy goal on day 3 after EN initiation. PP EN allowed 14 of 39 patients receiving parenteral nutrition (PN) to transition off PN 7 days after EN initiation. Thirty-five percent of EN interruptions were due to feeding-tube dysfunction.

Conclusion: Bedside PP tube placement is safe and feasible and allows for effective EN delivery and decreased PN use when applicable. Interruptions in PP EN due to tube malfunction are prevalent.
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http://dx.doi.org/10.1002/ncp.10452DOI Listing
April 2020

Prenatal chromosomal microarray testing of fetuses with ultrasound structural anomalies: A prospective cohort study of over 1000 consecutive cases.

Prenat Diagn 2019 11 22;39(12):1064-1069. Epub 2019 Aug 22.

Fetal Medicine Centre, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.

Objective: Evaluate the diagnostic yield of prenatal submicroscopic chromosome anomalies using prenatal array comparative genomic hybridisation (aCGH).

Method: Prospective cohort study conducted between March 2013 and June 2017 including fetuses where an elevated nuchal translucency (NT) or structural anomaly was identified on ultrasound and common aneuploidy testing was negative. aCGH was performed using an 8-plex oligonucleotide platform with a genome wide backbone resolution of greater than 200 kb and interpretation in line with American College of Medical Genetics guidance.

Results: One thousand one hundred twenty-nine fetuses were included; 371 fetuses with an increased NT (32.9%) and 758 with a structural anomaly (67.1%). The rate of pathogenic copy number variants (CNVs) and variant of uncertain significance (VUS) was 5.9% (n = 22) and 0.5% (n = 2) in the elevated NT group and 7.3% (n = 55) and 0.8% (n = 6) in the mid-trimester anomaly group. No pathogenic CNVs were identified in fetuses with an NT less than 4.0 mm. Multisystem and cardiac anomalies had the greatest yield of pathogenic CNV with a 22q11.2 microdeletion present in 40% (12/30).

Conclusion: Prenatal aCGH is a useful diagnostic tool in the investigation of fetuses with a significantly elevated NT or structural anomaly. With time and experience, rates of pathogenic CNVs have increased, and VUS have reduced, supporting the prenatal application of increasingly high resolution aCGH platforms.
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http://dx.doi.org/10.1002/pd.5545DOI Listing
November 2019

Potential genetic causes of miscarriage in euploid pregnancies: a systematic review.

Hum Reprod Update 2019 07;25(4):452-472

Tommy's National Centre for Miscarriage Research, Birmingham Women's and Children's Hospital, Birmingham, UK.

Background: Approximately 50% of pregnancy losses are caused by chromosomal abnormalities, such as aneuploidy. The remainder has an apparent euploid karyotype, but it is plausible that there are cases of pregnancy loss with other genetic aberrations that are not currently routinely detected. Studies investigating the use of exome sequencing and chromosomal microarrays in structurally abnormal pregnancies and developmental disorders have demonstrated their clinical application and/or potential utility in these groups of patients. Similarly, there have been several studies that have sought to identify genes that are potentially causative of, or associated with, spontaneous pregnancy loss, but the evidence has not yet been synthesized.

Objective And Rationale: The objective was to identify studies that have recorded monogenic genetic contributions to pregnancy loss in euploid pregnancies, establish evidence for genetic causes of pregnancy loss, identify the limitations of current evidence, and make recommendations for future studies. This evidence is important in considering additional research into Mendelian causes of pregnancy loss and appropriate genetic investigations for couples experiencing recurrent pregnancy loss.

Search Methods: A systematic review was conducted in MEDLINE (1946 to May 2018) and Embase (1974 to May 2018). The search terms 'spontaneous abortion', 'miscarriage', 'pregnancy loss', or 'lethal' were used to identify pregnancy loss terms. These were combined with search terms to identify the genetic contribution including 'exome', 'human genome', 'sequencing analysis', 'sequencing', 'copy number variation', 'single-nucleotide polymorphism', 'microarray analysis', and 'comparative genomic hybridization'. Studies were limited to pregnancy loss up to 20 weeks in humans and excluded if the genetic content included genes that are not lethal in utero, PGD studies, infertility studies, expression studies, aneuploidy with no recurrence risk, methodologies where there is no clinical relevance, and complex genetic studies. The quality of the studies was assessed using a modified version of the Newcastle-Ottawa scale.

Outcomes: A total of 50 studies were identified and categorized into three themes: whole-exome sequencing studies; copy number variation studies; and other studies related to pregnancy loss including recurrent molar pregnancies, epigenetics, and mitochondrial DNA aberrations. Putatively causative variants were found in a range of genes, including CHRNA1 (cholinergic receptor, nicotinic, alpha polypeptide 1), DYNC2H1 (dynein, cytoplasmic 2, heavy chain 1), and RYR1 (ryanodine receptor 1), which were identified in multiple studies. Copy number variants were also identified to have a causal or associated link with recurrent miscarriage.

Wider Implications: Identification of genes that are causative of or predisposing to pregnancy loss will be of significant individual patient impact with respect to counselling and treatment. In addition, knowledge of specific genes that contribute to pregnancy loss could also be of importance in designing a diagnostic sequencing panel for patients with recurrent pregnancy loss and also in understanding the biological pathways that can cause pregnancy loss.
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http://dx.doi.org/10.1093/humupd/dmz015DOI Listing
July 2019

Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study.

Lancet 2019 02 31;393(10173):747-757. Epub 2019 Jan 31.

Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Department of Medical Genetics, University of Cambridge, Cambridge, UK; Cambridge Biomedical Research Centre, National Institute for Health Research, Cambridge, UK. Electronic address:

Background: Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES).

Methods: In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly.

Findings: The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4-11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three [3·2%] of 93 fetuses).

Interpretation: WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness.

Funding: UK Department of Health and Social Care and The Wellcome Trust.
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http://dx.doi.org/10.1016/S0140-6736(18)31940-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386638PMC
February 2019

Competency-based Professional Advancement Model for Advanced Practice RNs.

J Nurs Adm 2019 Feb;49(2):66-72

Author Affiliations: Nurse Practitioner (Dr Paul), Center for Motility and Functional Gastrointestinal Disorders; Clinical Nurse Specialist (Ms Abecassis), Medical Intensive Care; Clinical Nurse Specialist (Ms Freiberger), Pulmonary/Pediatric Transplant Center; Clinical Nurse Specialist (Ms Hamilton), Medical Surgical Intensive Care; Nurse Practitioner (Ms Kelly), Urology and Urodynamics; Clinical Nurse Specialist (Ms Klements), Asthma and Medicine Patient Services; Nurse Practitioner (Dr LaGrasta), Cardiovascular Surgical Services; Nurse Practitioner (Mss Lemire, O'Donnell, and Phinney), General Surgery; Nurse Practitioner (Ms Patisteas), Orthopedic Surgery; Professional Development Specialist (Ms Conwell), Clinical Education and Informatics; Nurse Practitioner (Dr Saia), Cardiology; Nurse Practitioner (Ms Whelan), Cardiac Intensive Care; Senior VP, Patient Care Operations and Chief Nursing Officer (Dr Wood); and Nurse Practitioner (Ms O'Brien), Cardiology: Boston Children's Hospital, Massachusetts.

The process of developing a 3-tiered advanced practice RN (APRN) competency-based professional advancement model at Boston Children's Hospital is described. The model recognizes the contributions of entry-level and expert APRNs to advanced clinical practice and outcomes, impact, and leadership, while incorporating the tenets of Patricia Benner's Novice to Expert Model and the American Association of Critical- Care Nurses Synergy Model of Care.
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http://dx.doi.org/10.1097/NNA.0000000000000719DOI Listing
February 2019

Standardized Tracheostomy Education Across the Enterprise.

J Pediatr Nurs 2018 Nov - Dec;43:120-126. Epub 2018 Jun 30.

Boston Children's Hospital, USA.

Purpose: The purpose of this quality improvement project was to create a Tracheostomy Subject Matter Expert (Trach SME) Committee to standardize tracheostomy care, education, and the discharge process across Boston Children's Hospital.

Design And Methods: Boston Children's Hospital (BCH) is a free-standing urban tertiary pediatric hospital with 15 inpatient units. The newly formed Trach SME Committee evaluated the discharge process across the enterprise including hospital satellites and intra-hospital practice. Education materials were centralized, and policies were reviewed, revised and standardized to reflect current best practice. The Trach SME provided education to Trach Champions from each area that became resources for their respective units. The Trach SME also developed measurement outcomes to assess the effectiveness of the education process.

Results: In the implementation year of 2104, our 7-day unplanned readmission rate for tracheostomy patients was 18.18%. This rate decreased to 6.67% in 2015 and to 0% in 2016. In 2015, we began to monitor 30-day unplanned readmissions and the rate was 6.67% in 2015 and decreased to 0% in 2016.

Conclusions And Practice Implications: Standardization of policies, procedures and caregiver educational materials for the management of patients with a tracheostomy tube improved tracheostomy care across the enterprise and reduced tracheostomy readmission rates.
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http://dx.doi.org/10.1016/j.pedn.2018.06.004DOI Listing
April 2019

TRPV1 variants impair intracellular Ca signaling and may confer susceptibility to malignant hyperthermia.

Genet Med 2019 02 21;21(2):441-450. Epub 2018 Jun 21.

Inserm U1003, Laboratory of Excellence, Ion Channels Science and Therapeutics, Equipe Labélisée par la Ligue Nationale Contre le Cancer, SIRIC ONCOLille, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq, 59656, France.

Purpose: Malignant hyperthermia (MH) is a pharmacogenetic disorder arising from uncontrolled muscle calcium release due to an abnormality in the sarcoplasmic reticulum (SR) calcium-release mechanism triggered by halogenated inhalational anesthetics. However, the molecular mechanisms involved are still incomplete.

Methods: We aimed to identify transient receptor potential vanilloid 1 (TRPV1) variants within the entire coding sequence in patients who developed sensitivity to MH of unknown etiology. In vitro and in vivo functional studies were performed in heterologous expression system, trpv1 mice, and a murine model of human MH.

Results: We identified TRPV1 variants in two patients and their heterologous expression in muscles of trpv1 mice strongly enhanced calcium release from SR upon halogenated anesthetic stimulation, suggesting they could be responsible for the MH phenotype. We confirmed the in vivo significance by using mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (Ryr1), a mutation analogous to the Y522S mutation associated with MH in humans. We showed that the TRPV1 antagonist capsazepine slows the heat-induced hypermetabolic response in this model.

Conclusion: We propose that TRPV1 contributes to MH and could represent an actionable therapeutic target for prevention of the pathology and also be responsible for MH sensitivity when mutated.
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http://dx.doi.org/10.1038/s41436-018-0066-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752298PMC
February 2019

A chemical chaperone improves muscle function in mice with a RyR1 mutation.

Nat Commun 2017 03 24;8:14659. Epub 2017 Mar 24.

Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

Mutations in the RYR1 gene cause severe myopathies. Mice with an I4895T mutation in the type 1 ryanodine receptor/Ca release channel (RyR1) display muscle weakness and atrophy, but the underlying mechanisms are unclear. Here we show that the I4895T mutation in RyR1 decreases the amplitude of the sarcoplasmic reticulum (SR) Ca transient, resting cytosolic Ca levels, muscle triadin content and calsequestrin (CSQ) localization to the junctional SR, and increases endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and mitochondrial ROS production. Treatment of mice carrying the I4895T mutation with a chemical chaperone, sodium 4-phenylbutyrate (4PBA), reduces ER stress/UPR and improves muscle function, but does not restore SR Ca transients in I4895T fibres to wild type levels, suggesting that decreased SR Ca release is not the major driver of the myopathy. These findings suggest that 4PBA, an FDA-approved drug, has potential as a therapeutic intervention for RyR1 myopathies that are associated with ER stress.
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http://dx.doi.org/10.1038/ncomms14659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376670PMC
March 2017

Vitamin D levels and perinatal depressive symptoms in women at risk: a secondary analysis of the mothers, omega-3, and mental health study.

BMC Pregnancy Childbirth 2016 08 3;16(1):203. Epub 2016 Aug 3.

Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA.

Background: Vitamin D insufficiency may be associated with depressive symptoms in non-pregnant adults. We performed this study to evaluate whether low maternal vitamin D levels are associated with depressive symptoms in pregnancy.

Methods: This study was a secondary analysis of a randomized trial designed to assess whether prenatal omega-3 fatty acid supplementation would prevent depressive symptoms. Pregnant women from Michigan who were at risk for depression based on Edinburgh Postnatal Depression Scale Score or history of depression were enrolled. Participants completed the Beck Depression Inventory (BDI) and Mini International Neuropsychiatric Interview at 12-20 weeks, 26-28 weeks, 34-36 weeks, and 6-8 weeks postpartum. Vitamin D levels were measured at 12-20 weeks (N = 117) and 34-36 weeks (N = 112). Complete datasets were available on 105 subjects. Using regression analyses, we evaluated the relationship between vitamin D levels with BDI scores as well as with MINI diagnoses of major depressive disorder and generalized anxiety disorder. Our primary outcome measure was the association of maternal vitamin D levels with BDI scores during early and late pregnancy and postpartum.

Results: We found that vitamin D levels at 12-20 weeks were inversely associated with BDI scores both at 12-20 and at 34-36 weeks' gestation (P < 0.05, both). For every one unit increase in vitamin D in early pregnancy, the average decrease in the mean BDI score was .14 units. Vitamin D levels were not associated with diagnoses of major depressive disorder or generalized anxiety disorder.

Conclusions: In women at risk for depression, early pregnancy low vitamin D levels are associated with higher depressive symptom scores in early and late pregnancy. Future investigations should study whether vitamin D supplementation in early pregnancy may prevent perinatal depressive symptoms.

Trial Registration: https://clinicaltrials.gov/

Registration Number: NCT00711971.
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http://dx.doi.org/10.1186/s12884-016-0988-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971719PMC
August 2016

Use of Antidepressants During Pregnancy?: What to Consider when Weighing Treatment with Antidepressants Against Untreated Depression.

Matern Child Health J 2016 11;20(11):2268-2279

Department of Psychiatry, University of Michigan, Rachel Upjohn Building, 4250 Plymouth Road, Ann Arbor, MI, 48109, USA.

Introduction Mood disorders impact many pregnant women, particularly those who have experienced symptoms prior to conception, and there are significant barriers, including stigma and access, to seeking and receiving appropriate treatments. Antidepressants are a helpful option in treating perinatal depression, but research on risks and benefits of antidepressant use in pregnancy is difficult given lack of "gold standard" comparative trials. Methods This paper summarizes current state of knowledge on the safety of antidepressants during pregnancy by providing a summary of the literature published in the past 3 years (January 2013-October 2015). We identified 21 reviews and meta-analyses that were included in this summary report. This report is meant to provide a user-friendly, yet comprehensive guide summarizing the abundant, and in part contradicting, literature on risks and benefits of antidepressants during pregnancy, in order to assist busy primary care prescribers in educating their patients. Our goal is also to contrast the risks/benefits of untreated depression in pregnancy versus treatment with antidepressant medication in pregnancy, and in such support prescribers in their decision-making. Results The past 3 years have yielded an abundance of publications on the topic, in part, with conflicting findings adding to confusion and concern among providers, patients, and their families. Many reported studies have methodological problems limiting their impact. Data on adverse effects of medications on pregnancy and fetal outcomes have to be weighed against the impact of untreated illness and poor health habits associated with untreated illness on the same outcomes. Discussion Medical-decision making is often complex and seldom free of risks. Obviously, as providers we cannot guarantee that fetal exposure to antidepressants is totally free of risk, yet this is true for any medicine taken in pregnancy. However, to date, perinatal psychiatry has collected enough evidence to suggest that, if the clinical picture warrants it, the use of many antidepressants, especially the SSRIs, is favorable compared to exposing mother and child to untreated depressive illness.
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http://dx.doi.org/10.1007/s10995-016-2038-5DOI Listing
November 2016

Ca2+ Binding/Permeation via Calcium Channel, CaV1.1, Regulates the Intracellular Distribution of the Fatty Acid Transport Protein, CD36, and Fatty Acid Metabolism.

J Biol Chem 2015 Sep 5;290(39):23751-65. Epub 2015 Aug 5.

From the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030 and

Ca(2+) permeation and/or binding to the skeletal muscle L-type Ca(2+) channel (CaV1.1) facilitates activation of Ca(2+)/calmodulin kinase type II (CaMKII) and Ca(2+) store refilling to reduce muscle fatigue and atrophy (Lee, C. S., Dagnino-Acosta, A., Yarotskyy, V., Hanna, A., Lyfenko, A., Knoblauch, M., Georgiou, D. K., Poché, R. A., Swank, M. W., Long, C., Ismailov, I. I., Lanner, J., Tran, T., Dong, K., Rodney, G. G., Dickinson, M. E., Beeton, C., Zhang, P., Dirksen, R. T., and Hamilton, S. L. (2015) Skelet. Muscle 5, 4). Mice with a mutation (E1014K) in the Cacna1s (α1 subunit of CaV1.1) gene that abolishes Ca(2+) binding within the CaV1.1 pore gain more body weight and fat on a chow diet than control mice, without changes in food intake or activity, suggesting that CaV1.1-mediated CaMKII activation impacts muscle energy expenditure. We delineate a pathway (Cav1.1→ CaMKII→ NOS) in normal skeletal muscle that regulates the intracellular distribution of the fatty acid transport protein, CD36, altering fatty acid metabolism. The consequences of blocking this pathway are decreased mitochondrial β-oxidation and decreased energy expenditure. This study delineates a previously uncharacterized CaV1.1-mediated pathway that regulates energy utilization in skeletal muscle.
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http://dx.doi.org/10.1074/jbc.M115.643544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583036PMC
September 2015

Pediatric Withdrawal Identification and Management.

J Pediatr Intensive Care 2015 Jun;4(2):73-78

Department of Cardiovascular/Critical Care Nursing, Medical Surgical Intensive Care Unit, Boston Children's Hospital, Boston, Massachusetts, United States.

Sedation administered by continuous intravenous infusion is commonly used in the pediatric intensive care unit to facilitate and maintain safe care of children during critical illness. Prolonged use of sedatives, including opioids, benzodiazepines, and potentially other adjunctive agents, is known to cause withdrawal symptoms when they are stopped abruptly or weaned quickly. In this review, the common signs and symptoms of opioid, benzodiazepine, and dexmedetomidine withdrawal will be discussed. Current tools used to measure withdrawal objectively, as well as withdrawal prevention and management strategies, will be discussed.
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http://dx.doi.org/10.1055/s-0035-1556749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513147PMC
June 2015

Ca(2+) permeation and/or binding to CaV1.1 fine-tunes skeletal muscle Ca(2+) signaling to sustain muscle function.

Skelet Muscle 2015 29;5. Epub 2015 Jan 29.

Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA.

Background: Ca(2+) influx through CaV1.1 is not required for skeletal muscle excitation-contraction coupling, but whether Ca(2+) permeation through CaV1.1 during sustained muscle activity plays a functional role in mammalian skeletal muscle has not been assessed.

Methods: We generated a mouse with a Ca(2+) binding and/or permeation defect in the voltage-dependent Ca(2+) channel, CaV1.1, and used Ca(2+) imaging, western blotting, immunohistochemistry, proximity ligation assays, SUnSET analysis of protein synthesis, and Ca(2+) imaging techniques to define pathways modulated by Ca(2+) binding and/or permeation of CaV1.1. We also assessed fiber type distributions, cross-sectional area, and force frequency and fatigue in isolated muscles.

Results: Using mice with a pore mutation in CaV1.1 required for Ca(2+) binding and/or permeation (E1014K, EK), we demonstrate that CaV1.1 opening is coupled to CaMKII activation and refilling of sarcoplasmic reticulum Ca(2+) stores during sustained activity. Decreases in these Ca(2+)-dependent enzyme activities alter downstream signaling pathways (Ras/Erk/mTORC1) that lead to decreased muscle protein synthesis. The physiological consequences of the permeation and/or Ca(2+) binding defect in CaV1.1 are increased fatigue, decreased fiber size, and increased Type IIb fibers.

Conclusions: While not essential for excitation-contraction coupling, Ca(2+) binding and/or permeation via the CaV1.1 pore plays an important modulatory role in muscle performance.
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http://dx.doi.org/10.1186/s13395-014-0027-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340672PMC
February 2015

Fecal microbiota transplantation in patients with cancer undergoing treatment.

Clin J Oncol Nurs 2015 Feb;19(1):111-4

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH.

Fecal microbiota transplantation (FMT) is a technique used to restore the normal body flora to the gut in cases of Clostridium difficile infection (CDI). It involves instillation of the stool of a healthy donor through a nasogastric tube or colonoscopy into the gastrointestinal tract of the patient. More research is needed to determine the parameters of FMT use in patients with cancer.
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http://dx.doi.org/10.1188/15.CJON.111-114DOI Listing
February 2015

Exome analysis identifies Brody myopathy in a family diagnosed with malignant hyperthermia susceptibility.

Mol Genet Genomic Med 2014 Nov 6;2(6):472-83. Epub 2014 Jun 6.

Banting and Best Department of Medical Research, University of Toronto Toronto, Ontario, Canada.

Whole exome sequencing (WES) was used to determine the primary cause of muscle disorder in a family diagnosed with a mild, undetermined myopathy and malignant hyperthermia (MH) susceptibility (MHS). WES revealed the compound heterozygous mutations, p.Ile235Asn and p.Glu982Lys, in ATP2A1, encoding the sarco(endo)plasmic reticulum Ca(2+) ATPase type 1 (SERCA1), a calcium pump, expressed in fast-twitch muscles. Recessive mutations in ATP2A1 are known to cause Brody myopathy, a rare muscle disorder characterized by exercise-induced impairment of muscle relaxation and stiffness. Analyses of affected muscles showed the absence of SERCA1, but SERCA2 upregulation in slow and fast myofibers, suggesting a compensatory mechanism that partially restores the diminished Ca(2+) transport in Brody myopathy. This compensatory adaptation to the lack of SERCA1 Ca(2+) pumping activity within the muscle explains, in part, the mild course of disease in our patient. Diagnosis of MHS in this family was secondary to a loss of SERCA1 due to disease-associated mutations. Although there are obvious differences in clinical expression and molecular mechanisms between MH and Brody myopathy, a feature common to both conditions is elevated myoplasmic Ca(2+) content. Prolonged intracellular Ca(2+) elevation is likely to have led to MHS diagnosis in vitro and postoperative MH-like symptoms in Brody patient.
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http://dx.doi.org/10.1002/mgg3.91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303217PMC
November 2014

Improving awareness of nonanesthesia-related malignant hyperthermia presentations: a tale of two brothers.

A A Case Rep 2014 Jul;3(2):23-6

From the *Department of Anesthesiology, Walter Reed National Military Medical Center, Bethesda; †DVCIPM, Rockville; ‡Department of Anesthesiology, Uniformed Services University of the Health Sciences; Departments of §Neurosurgery and ‖Neurology, Walter Reed National Military Medical Center, Bethesda, Maryland; ¶Department of Military Medicine, Uniformed Services University of the Health Sciences; and **Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas.

A 30-year-old man developed unexplained rhabdomyolysis, persistently increased creatine kinase and severe debilitating muscle cramps. After a nondiagnostic neurologic evaluation, he was referred for a muscle biopsy, to include histology/histochemistry, a myoglobinuria panel, and a caffeine halothane contracture test. Only the caffeine halothane contracture test was positive, and a subsequent ryanodine receptor type 1 gene evaluation revealed a mutation functionally causative for malignant hyperthermia. His identical twin brother, who was suffering from similar complaints, was found to share the same mutation. They each require oral dantrolene therapy to control symptoms, despite difficulty in identifying health care providers familiar with treating this disorder.
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http://dx.doi.org/10.1213/XAA.0000000000000043DOI Listing
July 2014

The RNA-binding protein Rbfox1 regulates splicing required for skeletal muscle structure and function.

Hum Mol Genet 2015 Apr 9;24(8):2360-74. Epub 2015 Jan 9.

Department of Pathology and Immunology, Department of Molecular and Cellular Biology, Department of Molecular Physiology and Biophysics,

The Rbfox family of RNA-binding proteins is highly conserved with established roles in alternative splicing (AS) regulation. High-throughput studies aimed at understanding transcriptome remodeling have revealed skeletal muscle as displaying one of the largest number of AS events. This finding is consistent with requirements for tissue-specific protein isoforms needed to sustain muscle-specific functions. Rbfox1 is abundant in vertebrate brain, heart and skeletal muscle. Genome-wide genetic approaches have linked the Rbfox1 gene to autism, and a brain-specific knockout mouse revealed a critical role for this splicing regulator in neuronal function. Moreover, a Caenorhabditis elegans Rbfox1 homolog regulates muscle-specific splicing. To determine the role of Rbfox1 in muscle function, we developed a conditional knockout mouse model to specifically delete Rbfox1 in adult tissue. We show that Rbfox1 is required for muscle function but a >70% loss of Rbfox1 in satellite cells does not disrupt muscle regeneration. Deep sequencing identified aberrant splicing of multiple genes including those encoding myofibrillar and cytoskeletal proteins, and proteins that regulate calcium handling. Ultrastructure analysis of Rbfox1(-/-) muscle by electron microscopy revealed abundant tubular aggregates. Immunostaining showed mislocalization of the sarcoplasmic reticulum proteins Serca1 and Ryr1 in a pattern indicative of colocalization with the tubular aggregates. Consistent with mislocalization of Serca1 and Ryr1, calcium handling was drastically altered in Rbfox1(-/-) muscle. Moreover, muscle function was significantly impaired in Rbfox1(-/-) muscle as indicated by decreased force generation. These results demonstrate that Rbfox1 regulates a network of AS events required to maintain multiple aspects of muscle physiology.
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http://dx.doi.org/10.1093/hmg/ddv003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380076PMC
April 2015

Ligands for FKBP12 increase Ca2+ influx and protein synthesis to improve skeletal muscle function.

J Biol Chem 2014 Sep 22;289(37):25556-70. Epub 2014 Jul 22.

From the Baylor College of Medicine, Houston, Texas 77030,

Rapamycin at high doses (2-10 mg/kg body weight) inhibits mammalian target of rapamycin complex 1 (mTORC1) and protein synthesis in mice. In contrast, low doses of rapamycin (10 μg/kg) increase mTORC1 activity and protein synthesis in skeletal muscle. Similar changes are found with SLF (synthetic ligand for FKBP12, which does not inhibit mTORC1) and in mice with a skeletal muscle-specific FKBP12 deficiency. These interventions also increase Ca(2+) influx to enhance refilling of sarcoplasmic reticulum Ca(2+) stores, slow muscle fatigue, and increase running endurance without negatively impacting cardiac function. FKBP12 deficiency or longer treatments with low dose rapamycin or SLF increase the percentage of type I fibers, further adding to fatigue resistance. We demonstrate that FKBP12 and its ligands impact multiple aspects of muscle function.
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http://dx.doi.org/10.1074/jbc.M114.586289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162161PMC
September 2014

A stepwise enteral nutrition algorithm for critically ill children helps achieve nutrient delivery goals*.

Pediatr Crit Care Med 2014 Sep;15(7):583-9

1Department of Cardiovascular/Critical Care Nursing, Boston Children's Hospital, Boston, MA. 2Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA. 3Critical Care Medicine, Department of Anesthesiology, Pain and Perioperative Medicine, Boston Children's Hospital, Boston, MA.

Objectives: To evaluate the impact of implementing an enteral nutrition algorithm on achieving optimal enteral nutrition delivery in the PICU.

Design: Prospective pre/post implementation audit of enteral nutrition practices.

Setting: One 29-bed medical/surgical PICU in a freestanding, university-affiliated children's hospital.

Patients: Consecutive patients admitted to the PICU over two 4-week periods pre and post implementation, with a stay of more than 24 hours who received enteral nutrition.

Interventions: Based on the results of our previous study, we developed and systematically implemented a stepwise, evidence and consensus-based algorithm for initiating, advancing, and maintaining enteral nutrition in critically ill children. Three months after implementation, we prospectively recorded clinical characteristics, nutrient delivery, enteral nutrition interruptions, parenteral nutrition use, and ability to reach energy goal in eligible children over a 4-week period. Clinical and nutritional variables were compared between the pre and postintervention cohorts. Time to achieving energy goal was analyzed using Kaplan-Meier statistical analysis.

Measurements And Main Results: Eighty patients were eligible for this study and were compared to a cohort of 80 patients in the preimplementation audit. There were no significant differences in median age, gender, need for mechanical ventilation, time to initiating enteral nutrition, or use of postpyloric feeding between the two cohorts. We recorded a significant decrease in the number of avoidable episodes of enteral nutrition interruption (3 vs 51, p < 0.0001) and the prevalence and duration of parenteral nutrition dependence in patients with avoidable enteral nutrition interruptions in the postintervention cohort. Median time to reach energy goal decreased from 4 days to 1 day (p < 0.0001), with a higher proportion of patients reaching this goal (99% vs 61%, p = 0.01).

Conclusions: The implementation of an enteral nutrition algorithm significantly improved enteral nutrition delivery and decreased reliance on parenteral nutrition in critically ill children. Energy intake goal was reached earlier in a higher proportion of patients.
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http://dx.doi.org/10.1097/PCC.0000000000000179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4156550PMC
September 2014

Chromosomal microarray analysis allows prenatal detection of low level mosaic autosomal aneuploidy.

Prenat Diagn 2014 May 14;34(5):505-7. Epub 2014 Feb 14.

West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Edgbaston, Birmingham, UK.

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http://dx.doi.org/10.1002/pd.4333DOI Listing
May 2014