Prospective cohort study to characterize the clinical features and course of spinal muscular atrophy type I (SMA-I).
Patients were enrolled at 3 study sites and followed for up to 36 months with ...serial clinical, motor function, laboratory, and electrophysiologic outcome assessments. Intervention was determined by published standard of care guidelines. Palliative care options were offered.
Thirty-four of 54 eligible subjects with SMA-I (63%) enrolled and 50% of these completed at least 12 months of follow-up. The median age at reaching the combined endpoint of death or requiring at least 16 hours/day of ventilation support was 13.5 months (interquartile range 8.1-22.0 months). Requirement for nutritional support preceded that for ventilation support. The distribution of age at reaching the combined endpoint was similar for subjects with SMA-I who had symptom onset before 3 months and after 3 months of age (p=0.58). Having 2 SMN2 copies was associated with greater morbidity and mortality than having 3 copies. Baseline electrophysiologic measures indicated substantial motor neuron loss. By comparison, subjects with SMA-II who lost sitting ability (n=10) had higher motor function, motor unit number estimate and compound motor action potential, longer survival, and later age when feeding or ventilation support was required. The mean rate of decline in The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders motor function scale was 1.27 points/year (95% confidence interval 0.21-2.33, p=0.02).
Infants with SMA-I can be effectively enrolled and retained in a 12-month natural history study until a majority reach the combined endpoint. These outcome data can be used for clinical trial design.
In pregnant individuals with risk factors for preeclampsia, prophylactic low-dose aspirin is recommended to reduce the risk of developing preeclampsia. Fifteen distinct risk factors are recognized, ...including elements of current and past medical and obstetrical history, family history, and examination findings. We present checklists intended to reduce the chance that risk factors might be inadvertently overlooked and to improve the probability of aspirin being recommended for all appropriate candidates. We also suggest how such a checklist can be implemented into practice.
Amniotic fluid embolism is a rare syndrome characterized by sudden cardiorespiratory collapse during labor or soon after delivery. Because of its rarity, many obstetrical providers have no experience ...in managing amniotic fluid embolism and may therefore benefit from a cognitive aid such as a checklist. We present a sample checklist for the initial management of amniotic fluid embolism based on standard management guidelines. We also suggest steps that each facility can take to implement the checklist effectively.
Early research on the impact of COVID-19 on academic scientists suggests that disruptions to research, teaching, and daily work life are not experienced equally. However, this work has overwhelmingly ...focused on experiences of women and parents, with limited attention to the disproportionate impact on academic work by race, disability status, sexual identity, first-generation status, and academic career stage. Using a stratified random survey sample of early-career academics in four science disciplines (N = 3,277), we investigated socio-demographic and career stage differences in the effect of the COVID-19 pandemic along seven work outcomes: changes in four work areas (research progress, workload, concern about career advancement, support from mentors) and work disruptions due to three COVID-19 related life challenges (physical health, mental health, and caretaking). Our analyses examined patterns across career stages as well as separately for doctoral students and for postdocs/assistant professors. Overall, our results indicate that scientists from marginalized (i.e., devalued) and minoritized (i.e., underrepresented) groups across early career stages reported more negative work outcomes as a result of COVID-19. However, there were notable patterns of differences depending on the socio-demographic identities examined. Those with a physical or mental disability were negatively impacted on all seven work outcomes. Women, primary caregivers, underrepresented racial minorities, sexual minorities, and first-generation scholars reported more negative experiences across several outcomes such as increased disruptions due to physical health symptoms and additional caretaking compared to more privileged counterparts. Doctoral students reported more work disruptions from life challenges than other early-career scholars, especially those related to health problems, while assistant professors reported more negative changes in areas such as decreased research progress and increased workload. These findings suggest that the COVID-19 pandemic has disproportionately harmed work outcomes for minoritized and marginalized early-career scholars. Institutional interventions are required to address these inequalities in an effort to retain diverse cohorts in academic science.
Accurate prediction of the functional effect of genetic variation is critical for clinical genome interpretation. We systematically characterized the transcriptome effects of protein-truncating ...variants, a class of variants expected to have profound effects on gene function, using data from the Genotype-Tissue Expression (GTEx) and Geuvadis projects. We quantitated tissue-specific and positional effects on nonsense-mediated transcript decay and present an improved predictive model for this decay. We directly measured the effect of variants both proximal and distal to splice junctions. Furthermore, we found that robustness to heterozygous gene inactivation is not due to dosage compensation. Our results illustrate the value of transcriptome data in the functional interpretation of genetic variants.
To characterize the natural history of spinal muscular atrophy type 2 and type 3 (SMA 2/3) beyond 1 year and to report data on clinical and biological outcomes for use in trial planning.
We conducted ...a prospective observational cohort study of 79 children and young adults with SMA 2/3 who participated in evaluations for up to 48 months. Clinically, we evaluated motor and pulmonary function, quality of life, and muscle strength. We also measured SMN2 copy number, hematologic and biochemical profiles, muscle mass by dual x-ray absorptiometry (DXA), and the compound motor action potential (CMAP) in a hand muscle. Data were analyzed for associations between clinical and biological/laboratory characteristics cross-sectionally, and for change over time in outcomes using all available data.
In cross-sectional analyses, certain biological measures (specifically, CMAP, DXA fat-free mass index, and SMN2 copy number) and muscle strength measures were associated with motor function. Motor and pulmonary function declined over time, particularly at time points beyond 12 months of follow-up.
The intermediate and mild phenotypes of SMA show slow functional declines when observation periods exceed 1 year. Whole body muscle mass, hand muscle compound motor action potentials, and muscle strength are associated with clinical measures of motor function. The data from this study will be useful for clinical trial planning and suggest that CMAP and DXA warrant further evaluation as potential biomarkers.
The Centers for Disease Control and Prevention have demonstrated continuous increased risk for maternal mortality and severe morbidity with racial disparities among non-Hispanic black women an ...important contributing factor. More than 50,000 women experienced severe maternal morbidity in 2014, with a mortality rate of 18.0 per 100,000, higher than in many other developed countries. In 2012, the first “Putting the ‘M’ back in Maternal-Fetal Medicine” session was held at the Society for Maternal-Fetal Medicine’s (SMFM) Annual Meeting. With the realization that rising risk for severe maternal morbidity and mortality required action, the “M in MFM” meeting identified the following urgent needs: (i) to enhance education and training in maternal care for maternal-fetal medicine (MFM) fellows; (ii) to improve the medical care and management of pregnant women across the country; and (iii) to address critical research gaps in maternal medicine. Since that first meeting, a broad collaborative effort has made a number of major steps forward, including the proliferation of maternal mortality review committees, advances in research, increasing educational focus on maternal critical care, and development of comprehensive clinical strategies to reduce maternal risk. Five years later, the 2017 M in MFM meeting served as a “report card” looking back at progress made but also looking forward to what needs to be done over the next 5 years, given that too many mothers still experience preventable harm and adverse outcomes.
There is little consensus on how best to manage head and neck cancer with palliative intent. Predicting outcome is difficult and reported survival varies. The present study sought to delineate local ...practice and outcomes in patients treated with palliative intent.
The clinical records of all head and neck cancer patients treated with palliative intent presenting between 2015 and 2016 to our multidisciplinary team were reviewed.
Eighty-four patients (21.5 per cent) were treated with palliative intent. All had squamous cell carcinoma. Mean survival time was 151 days (standard deviation = 121.1; range, 8-536 days). Of the patients, 83.3 per cent had a palliative care referral; 74.1 per cent had a hospice referral. Patients received a variety of interventions, and there was an associated complication in 8.2 per cent. The mean number of days spent in hospital for interventions was 11.9 days (standard deviation = 12.5; range, 0-41 days).
Different interventions are used to manage head and neck cancer patients with palliative intent, and these may be associated with significant morbidity. Survival time is variable, often several months; thus, any treatment must take into account morbidity in conjunction with the patient's wishes.
Identification of risk variants for neuropsychiatric diseases within enhancers underscores the importance of understanding population-level variation in enhancer function in the human brain. Besides ...regulating tissue-specific and cell-type-specific transcription of target genes, enhancers themselves can be transcribed. By jointly analyzing large-scale cell-type-specific transcriptome and regulome data, we cataloged 30,795 neuronal and 23,265 non-neuronal candidate transcribed enhancers. Examination of the transcriptome in 1,382 brain samples identified robust expression of transcribed enhancers. We explored gene-enhancer coordination and found that enhancer-linked genes are strongly implicated in neuropsychiatric disease. We identified expression quantitative trait loci (eQTLs) for both genes and enhancers and found that enhancer eQTLs mediate a substantial fraction of neuropsychiatric trait heritability. Inclusion of enhancer eQTLs in transcriptome-wide association studies enhanced functional interpretation of disease loci. Overall, our study characterizes the gene-enhancer regulome and genetic mechanisms in the human cortex in both healthy and diseased states.
Primary care patients with a suspected head and neck cancer are referred through the urgent suspicion of cancer referral pathway. Rates of cancer detection through this pathway are low. Evidence ...surrounding the pathway of these patients is lacking. This study aimed to determine the outcome of urgent suspicion of cancer referrals for head and neck cancer.
All head and neck cancer urgent suspicion of cancer referrals in NHS Greater Glasgow and Clyde between June 2015 and May 2016 were analysed in regard to their clinical pathway.
There were 2116 urgent suspicion of cancer referrals in the one-year period. The overall cancer rate was 235 (11.8%), compared with 152 (7.6%) that resulted in a primary head and neck cancer diagnosis. Of the total, 851 (42.6%) were reassured and discharged after one clinic appointment; 536 (26.8%) were followed up for suspected benign pathology and 436 (21.8%) were actively investigated for cancer.
A significant proportion of patients attending urgent suspicion of cancer clinic appointments can be seen and discharged in one clinic appointment, provided there is same day imaging available. Cancer identification rates through urgent suspicion of cancer pathways remain low.
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