Histones and their posttranslational modifications influence the regulation of many DNA-dependent processes. Although an essential role for histone-modifying enzymes in these processes is well ...established, defining the specific contribution of individual histone residues remains a challenge because many histone-modifying enzymes have nonhistone targets. This challenge is exacerbated by the paucity of suitable approaches to genetically engineer histone genes in metazoans. Here, we describe a platform in Drosophila for generating and analyzing any desired histone genotype, and we use it to test the in vivo function of three histone residues. We demonstrate that H4K20 is neither essential for DNA replication nor for completion of development, unlike inferences drawn from analyses of H4K20 methyltransferases. We also show that H3K36 is required for viability and H3K27 is essential for maintenance of cellular identity but not for gene activation. These findings highlight the power of engineering histones to interrogate genome structure and function in animals.
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•Specific histone genotypes can be engineered in Drosophila using BAC transgenes•Histone gene expression is controlled by an active dosage compensation mechanism•Posttranslational modification of H4K20 is not required to complete development•H3K27 is required for Polycomb target gene repression but not for gene activation
McKay et al. describe a platform for histone gene engineering in Drosophila that allows direct genetic assessment of histone residue function in vivo. Using the system, they demonstrate that, contrary to inferences based on analysis of H4K20 methyltransferases, H4K20 is not essential for DNA replication or completion of development.
Unstable Ankle Injury With Normal Radiographs Sherman, Scott C.; Cooper, Stephen W.
The Journal of emergency medicine,
July 2019, 2019-Jul, 2019-07-00, 20190701, Volume:
57, Issue:
1
Journal Article
Subarachnoid hemorrhage (SAH) results frequently from traumatic brain injury (TBI). The standard management for these patients includes brief admission by the acute care surgery (trauma) service with ...neurological checks, neurosurgical consultation and repeat head CT within 24 hours to identify any progression or resolution. Recent studies have questioned the need for repeat CT imaging and specialty consultation in mild TBI. We reviewed patients with mild TBI specifically with isolated SAH to determine progression of the pathology and need for neurosurgical involvement. All patients with SAH secondary to mild TBI (Glasgow Coma Score (GCS) of 13–15) who presented over a 5-year period (January 2010 to December 2014) to a level I trauma center were identified from the trauma registry. Demographic data, initial CT findings, neurosurgical consultation, follow-up CT findings, Injury Severity Score (ISS), admission GCS and length of stay (LOS) were all obtained from the patient’s charts. Patients with other traumatic brain lesions on the initial CT were excluded. There were 299 patients (male, 48.5%), mean age 60.9 and mean ISS 8. Average time between the first and second CT was 11.3 hours. In all, 267 (89.2%) patients had either no change or an improvement/resolution on follow-up CT scan. Only 26 patients (8.7%) had either worsening or new findings on CT. Eight patients did not have a second scan completed (2.6%). All patients had neurosurgical consultation. Patients with mild TBI with isolated SAH generally have low morbidity, short LOS and negligible mortality. Less than 10% of this population had worsening of their head injury on repeat CT scanning. Given the low acuity of these patients with SAH and tendency towards resolution without intervention, acute care surgeons can manage this specific group of patients with TBI without routine neurosurgical consultation. Repeat CT scanning continues to have utility as it may identify new lesions, deterioration or need for further management.
Although opioid pain relievers are commonly prescribed in pregnancy, their association with neonatal outcomes is poorly described. Our objectives were to identify neonatal complications associated ...with antenatal opioid pain reliever exposure and to establish predictors of neonatal abstinence syndrome (NAS).
We used prescription and administrative data linked to vital statistics for mothers and infants enrolled in the Tennessee Medicaid program between 2009 and 2011. A random sample of NAS cases was validated by medical record review. The association of antenatal exposures with NAS was evaluated by using multivariable logistic regression, controlling for maternal and infant characteristics.
Of 112,029 pregnant women, 31,354 (28%) filled ≥ 1 opioid prescription. Women prescribed opioid pain relievers were more likely than those not prescribed opioids (P < .001) to have depression (5.3% vs 2.7%), anxiety disorder (4.3% vs 1.6%) and to smoke tobacco (41.8% vs 25.8%). Infants with NAS and opioid-exposed infants were more likely than unexposed infants to be born at a low birth weight (21.2% vs 11.8% vs 9.9%; P < .001). In a multivariable model, higher cumulative opioid exposure for short-acting preparations (P < .001), opioid type (P < .001), number of daily cigarettes smoked (P < .001), and selective serotonin reuptake inhibitor use (odds ratio: 2.08 95% confidence interval: 1.67-2.60) were associated with greater risk of developing NAS.
Prescription opioid use in pregnancy is common and strongly associated with neonatal complications. Antenatal cumulative prescription opioid exposure, opioid type, tobacco use, and selective serotonin reuptake inhibitor use increase the risk of NAS.
After increasing for nearly two decades, rates of neonatal abstinence syndrome have recently leveled off, reaching a plateau as early as 2014. These findings may represent successful efforts to ...prevent and treat opioid use before and during pregnancy.
Children and youths who are prescribed antipsychotic medications have multiple, potentially fatal, dose-related cardiovascular, metabolic, and other adverse events, but whether or not these ...medications are associated with an increased risk of death is unknown.
To compare the risk of unexpected death among children and youths who are beginning treatment with antipsychotic or control medications.
This retrospective cohort study was conducted from 1999 through 2014 and included Medicaid enrollees aged 5 to 24 years in Tennessee who had no diagnosis of severe somatic illness, schizophrenia or related psychoses, or Tourette syndrome or chronic tic disorder. Data analysis was performed from January 1, 2017, to August 15, 2018.
Current, new antipsychotic medication use at doses higher than 50 mg (higher-dose group) or 50 mg or lower chlorpromazine equivalents (lower-dose group) as well as control medications (ie, attention-deficit/hyperactivity disorder medications, antidepressants, or mood stabilizers) (control group).
Deaths during study follow-up while out of hospital or within 7 days after hospital admission, classified as either deaths due to injury or suicide or unexpected deaths. Secondary outcomes were unexpected deaths not due to overdose and death due to cardiovascular or metabolic causes.
This study included 189 361 children and youths in the control group (mean SD age, 12.0 5.1 years; 43.4% female), 28 377 in the lower-dose group (mean SD age, 11.7 4.4 years; 32.3% female), and 30 120 in the higher-dose group (mean SD age, 14.5 4.8 years; 39.2% female). The unadjusted incidence of death in the higher-dose group was 146.2 per 100 000 person-years (40 deaths per 27 354 person-years), which was significantly greater than that in the control group (54.5 per 100 000 population; 67 deaths per 123 005 person-years) (P < .001). The difference was primarily attributable to the increased incidence of unexpected deaths in the higher-dose group (21 deaths; 76.8 per 100 000 population) compared with the control group (22 deaths; 17.9 per 100 000 population). The propensity score-adjusted hazard ratios were as follows: all deaths (1.80; 95% CI, 1.06-3.07), deaths due to unintentional injury or suicide (1.03; 95% CI, 0.53-2.01), and unexpected deaths (3.51; 95% CI, 1.54-7.96). The hazard ratio was 3.50 (95% CI, 1.35-9.11) for unexpected deaths not due to overdose and 4.29 (95% CI, 1.33-13.89) for deaths due to cardiovascular or metabolic causes. Neither the unadjusted nor adjusted incidence of death in the lower-dose group differed significantly from that in the control group.
The findings suggest that antipsychotic use is associated with increased risk of unexpected death and appear to reinforce recommendations for careful prescribing and monitoring of antipsychotic treatment for children and youths and to underscore the need for larger antipsychotic treatment safety studies in this population.
Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often co-occur and share genetic risks. The aim of this analysis was to determine more broadly whether ADHD and ASD ...share biological underpinnings.
We compared copy number variant (CNV) data from 727 children with ADHD and 5,081 population controls to data from 996 individuals with ASD and an independent set of 1,287 controls. Using pathway analyses, we investigated whether CNVs observed in individuals with ADHD have an impact on genes in the same biological pathways as on those observed in individuals with ASD.
The results suggest that the biological pathways affected by CNVs in ADHD overlap with those affected by CNVs in ASD more than would be expected by chance. Moreover, this was true even when specific CNV regions common to both disorders were excluded from the analysis. After correction for multiple testing, genes involved in 3 biological processes (nicotinic acetylcholine receptor signalling pathway, cell division, and response to drug) showed significant enrichment for case CNV hits in the combined ADHD and ASD sample.
The results of this study indicate the presence of significant overlap of shared biological processes disrupted by large rare CNVs in children with these 2 neurodevelopmental conditions.
Neonatal abstinence syndrome (NAS) is a postnatal withdrawal syndrome experienced by some infants with opioid exposure. Hospital administrative data are commonly used for research and surveillance ...but have not been validated for NAS. Our objectives for this study were to validate the diagnostic codes for NAS and to develop an algorithm to optimize identification.
Tennessee Medicaid claims from 2009 to 2011 (primary sample) and 2016 (secondary sample; post-
) were obtained. Cases of NAS were identified by using
code (2009-2011) 779.5 and ICD-10-CM code (2016) P96.1. Medical record review cases were then conducted by 2 physicians using a standardized algorithm, and positive predictive value (PPV) was calculated. Algorithms were developed for optimizing the identification of NAS in administrative data.
In our primary sample of 112 029 mother-infant dyads, 950 potential NAS cases were identified from Medicaid claims data and reviewed. Among reviewed records, 863 were confirmed as having NAS (including 628 66.1% cases identified as NAS requiring pharmacotherapy, 224 23.5% as NAS not requiring pharmacotherapy, and 11 1.2% as iatrogenic NAS), and 87 (9.2%) did not meet clinical criteria for NAS. The PPV of the
code for NAS in clinically confirmed NAS was 91% (95% confidence interval: 88.8%-92.5%). Similarly, the PPV for the ICD-10-CM code in the secondary sample was 98.2% (95% confidence interval: 95.4%-99.2%). Algorithms using elements from the Medicaid claims and from length of stay improved PPV.
In a large population-based cohort of Medicaid participants, hospital administrative data had a high PPV in identifying cases of clinically diagnosed NAS.
: Opioid agonist therapies (OATs) are highly effective treatments for opioid use disorders (OUDs), especially for pregnant women; thus, improving access to OAT is an urgent public policy goal. Our ...objective was to determine if insurance and pregnancy status were barriers to obtaining access to OAT in 4 Appalachian states disproportionately impacted by the opioid epidemic.
Between April and May 2017, we conducted phone surveys of OAT providers, opioid treatment programs (OTPs), and outpatient buprenorphine providers, in Kentucky, North Carolina, Tennessee, and West Virginia. Survey response rates were 59%. Logistic models for dichotomous outcomes (e.g., patient acceptance) and negative binomial models were created for count variables (e.g., wait time), overall and for pregnant women.
The majority of OAT providers were accepting new patients; however, providers were less likely to treat pregnant women (91% vs. 75%;
< .01). OTPs were more likely to accept new patients than waivered buprenorphine providers (97% vs. 83%;
= .01); rates of accepting pregnant patients were lower in both (91% and 53%;
< .01). OTPs and buprenorphine providers accepted cash payments for services at high rates (OTP: 100%; buprenorphine: 89.4%;
< .01); Medicaid and private insurance were accepted at lower rates. In adjusted models, providers were less likely to accept pregnant women if they took any insurance (adjusted odds ratio aOR = 0.15, 95% confidence interval CI: 0.03-0.68) or were a buprenorphine provider (aOR = 0.09, 95% CI: 0.02-0.37).
We found that OAT providers frequently did not accept any insurance and frequently did not treat pregnant women in an area of the country disproportionately affected by the opioid epidemic. Policymakers could prioritize improvements in provider training (e.g., training of obstetricians to become buprenorphine prescribers) as a means to enhance access to pregnant women or enhancing reimbursement rates as a means of improving insurance acceptance for OAT.
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