Chronic UCN2 treatment desensitizes CRHR2 and improves insulin sensitivity.

Urocortin 2 (UCN2) acts as a ligand for the G protein-coupled receptor corticotropin-releasing hormone receptor 2 (CRHR2). UCN2 has been reported to improve or worsen insulin sensitivity and glucose tolerance in vivo. Here we show that acute dosing of UCN2 induces systemic insulin resistance in male mice and skeletal muscle. Inversely, chronic elevation of UCN2 by injection with adenovirus encoding UCN2 resolves metabolic complications, improving glucose tolerance. CRHR2 recruits Gs in response to low concentrations of UCN2, as well as Gi and ß-Arrestin at high concentrations of UCN2. Pre-treating cells and skeletal muscle ex vivo with UCN2 leads to internalization of CRHR2, dampened ligand-dependent increases in cAMP, and blunted reductions in insulin signaling. These results provide mechanistic insights into how UCN2 regulates insulin sensitivity and glucose metabolism in skeletal muscle and in vivo. Importantly, a working model was derived from these results that unifies the contradictory metabolic effects of UCN2.

Findings on Repeat Posttraumatic Brain Computed Tomography Scans in Older Patients With Minimal Head Trauma and the Impact of Existing Antithrombotic Use.

STUDY OBJECTIVE: Evaluate the utility of routine rescanning of older, mild head trauma patients with an initial negative brain computed tomography (CT), who is on a preinjury antithrombotic (AT) agent by assessing the rate of delayed intracranial hemorrhage (dICH), need for surgery, and attributable mortality. METHODS: Participating centers were trained and provided data collection instruments per institutional review board-approved protocols. Data were obtained from manual chart review and electronic medical record download. Adults ≥55 years seen at Level I/II Trauma Centers, between 2017 and 2019 with suspected head trauma, Glasgow Coma Scale 14 to 15, negative initial brain CT, and no other Abbreviated Injury Scale injuries >2 were identified, grouped by preinjury AT therapy (AT- or AT+) and compared on dICH rate, need for operative neurosurgical intervention, and attributable mortality using univariate analysis (α=.05). RESULTS: A total of 2,950 patients from 24 centers were enrolled; 280 (9.5%) had a repeat brain CT. In those rescanned, the dICH rate was 15/126 (11.9%) for AT- and 6/154 (3.9%) in AT+. Assuming nonrescanned patients did not suffer clinically meaningful dICH, the dICH rate would be 15/2001 (0.7%) for AT- and 6/949 (0.6%) for AT+. No surgical operations were done for dICH. All-cause mortality was 9/2950 (0.3%) and attributable mortality was 1/2950 (0.03%). The attributable death was an AT+, dICH patient whose family declined intervention. CONCLUSION: In older patients with an initial Glasgow Coma Scale of 14 to 15 and a negative initial brain CT scan, the dICH rate is low (<1%) and of minimal clinical consequence, regardless of AT use. In addition, no patient had operative neurosurgical intervention. Therefore, routine rescanning is not supported based on the results of this study.

Hepatic Activin E mediates liver-adipose inter-organ communication, suppressing adipose lipolysis in response to elevated serum fatty acids.

OBJECTIVE: The liver is a central regulator of energy metabolism exerting its influence both through intrinsic processing of substrates such as glucose and fatty acid as well as by secreting endocrine factors, known as hepatokines, which influence metabolism in peripheral tissues. Human genome wide association studies indicate that a predicted loss-of-function variant in the Inhibin ßE gene (INHBE), encoding the putative hepatokine Activin E, is associated with reduced abdominal fat mass and cardiometabolic disease risk. However, the regulation of hepatic Activin E and the influence of Activin E on adiposity and metabolic disease are not well understood. Here, we examine the relationship between hepatic Activin E and adipose metabolism, testing the hypothesis that Activin E functions as part of a liver-adipose, inter-organ feedback loop to suppress adipose tissue lipolysis in response to elevated serum fatty acids and hepatic fatty acid exposure. METHODS: The relationship between hepatic Activin E and non-esterified fatty acids (NEFA) released from adipose lipolysis was assessed in vivo using fasted CL 316,243 treated mice and in vitro using Huh7 hepatocytes treated with fatty acids. The influence of Activin E on adipose lipolysis was examined using a combination of Inhbe knockout mice, a mouse model of hepatocyte-specific overexpression of Activin E, and mouse brown adipocytes treated with Activin E enriched media. RESULTS: Increasing hepatocyte NEFA exposure in vivo by inducing adipose lipolysis through fasting or CL 316,243 treatment increased hepatic Inhbe expression. Similarly, incubation of Huh7 human hepatocytes with fatty acids increased expression of INHBE. Genetic ablation of Inhbe in mice increased fasting circulating NEFA and hepatic triglyceride accumulation. Treatment of mouse brown adipocytes with Activin E conditioned media and overexpression of Activin E in mice suppressed adipose lipolysis and reduced serum FFA levels, respectively. The suppressive effects of Activin E on lipolysis were lost in CRISPR-mediated ALK7 deficient cells and ALK7 kinase deficient mice. Disruption of the Activin E-ALK7 signaling axis in Inhbe KO mice reduced adiposity upon HFD feeding, but caused hepatic steatosis and insulin resistance. CONCLUSIONS: Taken together, our data suggest that Activin E functions as part of a liver-adipose feedback loop, such that in response to increased serum free fatty acids and elevated hepatic triglyceride, Activin E is released from hepatocytes and signals in adipose through ALK7 to suppress lipolysis, thereby reducing free fatty acid efflux to the liver and preventing excessive hepatic lipid accumulation. We find that disrupting this Activin E-ALK7 inter-organ communication network by ablation of Inhbe in mice increases lipolysis and reduces adiposity, but results in elevated hepatic triglyceride and impaired insulin sensitivity. These results highlight the liver-adipose, Activin E-ALK7 signaling axis as a critical regulator of metabolic homeostasis.

Timing and Type of Venous Thromboembolic Chemoprophylaxis Is Associated with Acute Traumatic Brain Injury Outcomes.

Venous thromboembolic (VTE) prophylaxis in acute traumatic brain injury (TBI) is a controversial topic with wide practice variations. This study examined the association of VTE chemoprophylaxis with inpatient mortality and VTE events among isolated TBI patients. This was a retrospective cohort study of 87 trauma centers within a large hospital system in the United States analyzing 23,548 patients with isolated TBI, 7977 of whom had moderate-to-severe TBI. Primary outcomes were inpatient mortality and VTE events. The control group received no chemoprophylaxis. Other groups received low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), and combined LMWH and UFH chemoprophylaxis. Multi-variable regression accounted for confounders. Outcomes were stratified by timing of administration, body mass index (BMI), and TBI type. Patients without VTE prophylaxis had the least VTE events. LMWH had the lowest mortality for both all-isolated and moderate-to-severe isolated TBI populations at adjusted odds ratio (aOR) 0.24 (95% confidence interval [CI], 0.14-0.43) and aOR 0.25 (95% CI, 0.14-0.44), respectively. Clinically significant progression of TBI was lowest among the LMWH group (0.1%; p value, 0.001). After stratifying by timing of VTE chemoprophylaxis, only patients with subdural hematoma and LMWH between 6 and 24 h (N = 62), as well as patients with ≥35 BMI and LMWH between 6 and 24 h (N = 65) or >24-48 h (N = 54), had no VTE events. VTE chemoprophylaxis timing may have prevented VTE in certain subgroups of isolated TBI patients. Though VTE chemoprophylaxis did not prevent VTE for most TBI patients, LMWH VTE chemoprophylaxis was associated with reduced mortality.

Updating and Integrating Core Outcome Sets for Localised, Locally Advanced, Metastatic, and Nonmetastatic Castration-resistant Prostate Cancer: An Update from the PIONEER Consortium.

CONTEXT: Harmonisation of outcome reporting and definitions for clinical trials and routine patient records can enable health care systems to provide more efficient outcome-driven and patient-centred interventions. We report on the work of the PIONEER Consortium in this context for prostate cancer (PCa). OBJECTIVE: To update and integrate existing core outcome sets (COS) for PCa for the different stages of the disease, assess their applicability, and develop standardised definitions of prioritised outcomes. EVIDENCE ACQUISITION: We followed a four-stage process involving: (1) systematic reviews; (2) qualitative interviews; (3) expert group meetings to agree standardised terminologies; and (4) recommendations for the most appropriate definitions of clinician-reported outcomes. EVIDENCE SYNTHESIS: Following four systematic reviews, a multinational interview study, and expert group consensus meetings, we defined the most clinically suitable definitions for (1) COS for localised and locally advanced PCa and (2) COS for metastatic and nonmetastatic castration-resistant PCa. No new outcomes were identified in our COS for localised and locally advanced PCa. For our COS for metastatic and nonmetastatic castration-resistant PCa, nine new core outcomes were identified. CONCLUSIONS: These are the first COS for PCa for which the definitions of prioritised outcomes have been surveyed in a systematic, transparent, and replicable way. This is also the first time that outcome definitions across all prostate cancer COS have been agreed on by a multidisciplinary expert group and recommended for use in research and clinical practice. To limit heterogeneity across research, these COS should be recommended for future effectiveness trials, systematic reviews, guidelines and clinical practice of localised and metastatic PCa. PATIENT SUMMARY: Patient outcomes after treatment for prostate cancer (PCa) are difficult to compare because of variability. To allow better use of data from patients with PCa, the PIONEER Consortium has standardised and recommended outcomes (and their definitions) that should be collected as a minimum in all future studies.

Current Australian clinical practice in use of botulinum toxin-A to manage paediatric hypertonicity.

AIM: To describe current rehabilitation paediatricians' use of intramuscular botulinum toxin-A (BoNT-A) to manage hypertonicity. METHODS: Cross-sectional survey. RESULTS: In late 2019, 32 of the 35 identified Australian rehabilitation paediatricians who use BoNT-A to manage paediatric hypertonicity completed the survey. Annually, they administer just over 3750 courses of BoNT-A to manage hypertonicity with a mean of 11 years of clinical experience. Sedation was used by all but 1 clinician who used a number of other strategies during the procedure. Mean (and median) maximum dose of OnabotulinumtoxinA (Botox) was 400 Units (range 300-450 Units). Only three clinicians indicated that they used AbobotulinumtoxinA (Dysport) - the other BoNT-A preparation approved for children available in Australia; analysis of its use was not performed. Dose modifications were made by clinicians according to a patient's response to a previous course of BoNT-A (88% of respondents); patient experience of a previous adverse event (78%); history of aspiration or dysphagia (65 and 63%, respectively); and the presence of dystonia; and where the patient was GMFCS level V (53% each). Intervals between courses ranged from 3 to 24 months with the variation due to clinical circumstances. CONCLUSION: Clinical practice in BoNT-A management of paediatric hypertonicity was largely consistent in regard to maximum doses of OnabotulinumtoxinA (Botox) used. Dose modification and time between injection courses varied according to individual clinical presentation. Procedural sedation was used extensively.

Hospital Employment Of Physicians In Massachusetts Is Associated With Inappropriate Diagnostic Imaging.

The transition among many US physicians from independent practice to hospital employment has raised concerns about whether employed physicians will be more inclined to refer patients for hospital-based services that are unnecessary or inappropriate. Using claims data for 2009-16, we conducted a difference-in-differences analysis to investigate whether this form of hospital-physician integration is associated with inappropriate referrals for magnetic resonance imaging (MRI), a widely used mode of diagnostic imaging, for three common medical conditions: lower back pain, knee pain, and shoulder pain. Study findings indicate that the odds of a patient receiving an inappropriate MRI referral increased by more than 20 percent after a physician transitioned to hospital employment. Most patients who received an MRI referral by an employed physician obtained the procedure at the hospital where the referring physician was employed. These results point to hospital-physician integration as a potential driver of low-value care.

A multicenter study on definitive surgery for isolated hip fracture within 24 hours.

INTRODUCTION: Isolated hip fractures (IHFs) in the elderly are high-frequency, life-altering events. Definitive surgery ≤24 hours of admission is associated with improved outcomes. An IHF process management guideline (IHF-PMG) to expedite definitive surgery ≤24 hours was developed for a multihospital network. We report on its feasibility and subsequent patient outcomes. METHODS: This is a prospective multicenter cohort study, involving 85 levels 1, 2, 3, and 4 trauma centers. Patients with an IHF between 65 and 100 years old were studied. Four cohorts were examined: (1) hospitals that did not implement any PMG, (2) hospitals that used their own PMG, (3) hospitals that partially used the network IHF-PMG, and (4) hospitals that used the network's IHF-PMG. Multivariable logistic regression with reliability adjustment was used to calculate the expected value of observed to expected (O/E) mortality. Statistical significance was defined as p < 0.05. RESULTS: Data on 24,457 IHF were prospectively collected. Following implementation of the IHF-PMG, overall IHF O/E mortality ratios decreased within the hospital network, from 1.13 in 2017 to 0.87 in 2018 and 0.86 in 2019. Hospitals that developed their own IHF-PMG or used the enterprise-wide IHF-PMG had the lowest inpatient O/E mortality at 0.59 and 0.65, respectively. CONCLUSION: Goal-directed IHF-PMG for definitive surgery ≤24 hours was implemented across a large hospital network. The IHF-PMG was associated with lower inpatient mortality. LEVEL OF EVIDENCE: Therapeutic/ Care management, Level III.

Correction to: Effects of Physician Experience, Specialty Training, and Self-referral on Inappropriate Diagnostic Imaging.

There were some errors in the variables in this paper.

Effects of Physician Experience, Specialty Training, and Self-referral on Inappropriate Diagnostic Imaging.

BACKGROUND: Although previous research has demonstrated high rates of inappropriate diagnostic imaging, the potential influence of several physician-level characteristics is not well established. OBJECTIVE: To examine the influence of three types of physician characteristics on inappropriate imaging: experience, specialty training, and self-referral. DESIGN: A retrospective analysis of over 70,000 MRI claims submitted for commercially insured individuals. Physician characteristics were identified through a combination of administrative records and primary data collection. Multi-level modeling was used to assess relationships between physician characteristics and inappropriate MRIs. SETTING: Massachusetts PARTICIPANTS: Commercially insured individuals who received an MRI between 2010 and 2013 for one of three conditions: low back pain, knee pain, and shoulder pain. MEASUREMENTS: Guidelines from the American College of Radiology were used to classify MRI referrals as appropriate/inappropriate. Experience was measured from the date of medical school graduation. Specialty training comprised three principal groups: general internal medicine, family medicine, and orthopedics. Two forms of self-referral were examined: (a) the same physician who ordered the procedure also performed it, and (b) the physicians who ordered and performed the procedure were members of the same group practice and the procedure was performed outside the hospital setting. RESULTS: Approximately 23% of claims were classified as inappropriate. Physicians with 10 or less years of experience had significantly higher odds of ordering inappropriate MRIs. Primary care physicians were almost twice as likely to order an inappropriate MRI as orthopedists. Self-referral was not associated with higher rates of inappropriate MRIs. LIMITATIONS: Classification of MRIs was conducted with claims data. Not all self-referred MRIs could be detected. CONCLUSIONS: Inappropriate imaging continues to be a driver of wasteful health care spending. Both physician experience and specialty training were highly associated with inappropriate imaging.

Conditional deletion of melanin-concentrating hormone receptor 1 from GABAergic neurons increases locomotor activity.

OBJECTIVE: Melanin-concentrating hormone (MCH) plays a key role in regulating energy balance. MCH acts via its receptor MCHR1, and MCHR1 deletion increases energy expenditure and locomotor activity, which is associated with a hyperdopaminergic state. Since MCHR1 expression is widespread, the neurons supporting the effects of MCH on energy expenditure are not clearly defined. There is a high density of MCHR1 neurons in the striatum, and these neurons are known to be GABAergic. We thus determined if MCH acts via this GABAergic neurocircuit to mediate energy balance. METHODS: We generated a Mchr1-flox mouse and crossed it with the Vgat-cre mouse to assess if MCHR1 deletion from GABAergic neurons expressing the vesicular GABA transporter (vGAT) in female Vgat-Mchr1-KO mice resulted in lower body weights or increased energy expenditure. Additionally, we determined if MCHR1-expressing neurons within the accumbens form part of the neural circuit underlying MCH-mediated energy balance by delivering an adeno-associated virus expressing Cre recombinase to the accumbens nucleus of Mchr1-flox mice. To evaluate if a dysregulated dopaminergic tone leads to their hyperactivity, we determined if the dopamine reuptake blocker GBR12909 prolonged the drug-induced locomotor activity in Vgat-Mchr1-KO mice. Furthermore, we also performed amperometry recordings to test whether MCHR1 deletion increases dopamine output within the accumbens and whether MCH can suppress dopamine release. RESULTS: Vgat-Mchr1-KO mice have lower body weight, increased energy expenditure, and increased locomotor activity. Similarly, restricting MCHR1 deletion to the accumbens nucleus also increased locomotor activity. Vgat-Mchr1-KO mice show increased and prolonged sensitivity to GBR12909-induced locomotor activity, and amperometry recordings revealed that GBR12909 elevated accumbens dopamine levels to twice that of controls, thus MCHR1 deletion may lead to a hyperdopaminergic state that mediates their observed hyperactivity. Consistent with the inhibitory effect of MCH, we found that MCH acutely suppresses dopamine release within the accumbens. CONCLUSIONS: As with established models of systemic MCH or MCHR1 deletion, we found that MCHR1 deletion from GABAergic neurons, specifically those within the accumbens nucleus, also led to increased locomotor activity. A hyperdopaminergic state underlies this increased locomotor activity, and is consistent with our finding that MCH signaling within the accumbens nucleus suppresses dopamine release. In effect, MCHR1 deletion may disinhibit dopamine release leading to the observed hyperactivity.

Impact of ACA Medicaid Expansion on Hospitals' Financial Status.

EXECUTIVE SUMMARY: The Patient Protection and Affordable Care Act's insurance reforms were expected to have significant and positive implications for hospital finances. In particular, state expansion of Medicaid programs held the promise of reducing hospitals' uncompensated care costs as a result of expanding health insurance to many previously uninsured individuals. Recent research indicates that in the early phases of Medicaid expansion, many hospitals did experience a substantial decline in uncompensated care costs. However, studies to date have not considered whether Medicaid expansion resulted in payment shortfalls that offset some of what hospitals saved from lower uncompensated care costs. We examined filings submitted by hospitals to the Internal Revenue Service (IRS)-one of the few publicly available sources of national data on both uncompensated care costs and Medicaid payment shortfalls. We also compared changes in uncompensated care costs and Medicaid payment shortfalls for hospitals in expansion states with those in nonexpansion states. Our findings indicate that state expansion of Medicaid led to substantial reductions in hospitals' uncompensated care costs, but the savings were offset somewhat by increased Medicaid payment shortfalls. Therefore, studies that focus only on reductions in uncompensated care costs can overstate the benefits of Medicaid expansion on hospitals finances.

A lipase-independent pathway of lipid release and immune modulation by adipocytes.

To meet systemic metabolic needs, adipocytes release fatty acids and glycerol through the action of neutral lipases. Here, we describe a secondary pathway of lipid release from adipocytes that is independent of canonical lipolysis. We found that adipocytes release exosome-sized, lipid-filled vesicles (AdExos) that become a source of lipid for local macrophages. Adipose tissue from lean mice released ~1% of its lipid content per day via exosomes ex vivo, a rate that more than doubles in obese animals. AdExos and associated factors were sufficient to induce in vitro differentiation of bone marrow precursors into adipose tissue macrophage-like cells. Thus, AdExos are both an alternative pathway of local lipid release and a mechanism by which parenchymal cells can modulate tissue macrophage differentiation and function.

Magnitude and financial implications of inappropriate diagnostic imaging for three common clinical conditions.

OBJECTIVE: To quantify the level of adherence to imaging guidelines for three common clinical indications for a commercially insured population. DESIGN: Retrospective analysis of administrative claims data for commercially insured individuals with diagnostic imaging claims (MRI and X-ray) for either uncomplicated low back pain, non-traumatic knee pain or non-traumatic shoulder pain. SETTING: The State of Massachusetts for 2010 and 2013. PARTICIPANTS: Adults with no chronic conditions and without evidence of prior management in the 12 months preceding to the initial office visit for each of the clinical indications. MAIN OUTCOMES MEASURES: Imaging procedures performed within 30 days of the initial office visit were classified as appropriate or inappropriate according to adherence to imaging guidelines from American College of Radiology. RESULTS: More than 60% of lumbar spine MRI's were deemed inappropriate in 2010 and in 2013. Over 30% of MRI's for shoulder pain and knee pain were inappropriate in 2010 and in 2013. Patients age 18-59 with inappropriate imaging claims had significantly lower rates of surgical procedures within 90 days of imaging than those with appropriate imaging. Inappropriate imaging accounted for over 20% of annual imaging costs for the three clinical indications. CONCLUSIONS: Reducing inappropriate imaging procedures can lead to substantial savings through the elimination of unnecessary and low value procedures. Increased awareness of and adherence to best practice guidelines should be a focus of efforts to cut waste in our healthcare system.

Systemic adverse events after botulinum neurotoxin A injections in children with cerebral palsy.

AIM: To identify factors that increase the likelihood of systemic adverse events after botulinum neurotoxin A (BoNT-A) injections in children with cerebral palsy (CP). METHOD: A prospective observational study of patients attending a BoNT-A clinic at a tertiary paediatric hospital (2010-2014). Occurrences of systemic adverse events, defined as lower respiratory tract illnesses, generalized weakness, dysphagia, and death were determined at follow-up. The relationship between systemic adverse events and eight preinjection variables (age, Gross Motor Function Classification System [GMFCS] level, history of dysphagia, gastrostomy, aspiration pneumonia, recent history of illness, BoNT-A dose, and type of sedation) were examined using univariable and multivariable logistic regression with generalized estimating equations methods. RESULTS: In total 591 children underwent 2219 injection episodes with follow-up in 2158 (97%) cases. Systemic adverse events were reported in 77 (3.6%) injection episodes. Univariable analysis suggested that GMFCS levels IV and V, a history of dysphagia, gastrostomy, aspiration pneumonia, and increasing BoNT-A dose increase the likelihood of systemic adverse events. In multivariable analysis, a history of dysphagia (odds ratio [OR] 3.42) and/or aspiration pneumonia (OR 2.31) remained associated with increased likelihood of systemic adverse events. INTERPRETATION: A history of dysphagia and/or aspiration pneumonia are the factors that most increase the likelihood of systemic adverse events after BoNT-A. WHAT THIS PAPER ADDS: Systemic adverse events occur in 3.6% of botulinum neurotoxin A (BoNT-A) injection episodes. Dysphagia and/or aspiration pneumonia are associated with increased likelihood of systemic adverse events. Multivariable models showed no evidence of association between Gross Motor Function Classification System and systemic adverse events. Multivariable models showed no evidence of association between BoNT-A dose and systemic adverse events.

Utilization Trends in Diagnostic Imaging for a Commercially Insured Population: A Study of Massachusetts Residents 2009 to 2013.

PURPOSE: To report utilization trends in diagnostic imaging among commercially insured Massachusetts residents from 2009 to 2013. MATERIALS AND METHODS: Current Procedural Terminology codes were used to identify diagnostic imaging claims in the Massachusetts All-Payer Claims Database for the years 2009 to 2013. We reported utilization and spending annually by imaging modality using total claims, claims per 1,000 individuals, total expenditures, and average per claim payments. RESULTS: The number of diagnostic imaging claims per insured MA resident increased only 0.6% from 2009 to 2013, whereas nonradiology claims increased by 6% annually. Overall diagnostic imaging expenditures, adjusted for inflation, were 27% lower in 2009 than 2013, compared with an 18% increase in nonimaging expenditures. Average payments per claim were lower in 2013 than 2009 for all modalities except nuclear medicine. Imaging procedure claims per 1,000 MA residents increased from 2009 to 2013 by 13% in MRI, from 147 to 166; by 17% in ultrasound, from 453 to 530; and by 12% in radiography (x-ray), from 985 to 1,100. However, CT claims per 1,000 fell by 37%, from 341 to 213, and nuclear medicine declined 57%, from 89 claims per 1,000 to 38. CONCLUSION: Diagnostic imaging utilization exhibited negligible growth over the study period. Diagnostic imaging expenditures declined, largely the result of falling payments per claim in most imaging modalities, in contrast with increased utilization and spending on nonimaging services. Utilization of MRI, ultrasound, and x-ray increased from 2009 to 2013, whereas CT and nuclear medicine use decreased sharply, although CT was heavily impacted by billing code changes.

Severity of cerebral palsy and likelihood of adverse events after botulinum toxin A injections.

AIM: To determine the incidence of common adverse events after botulinum toxin A (BoNT-A) injections in children with cerebral palsy (CP) and to identify whether the severity of CP influences the incidence of adverse events. METHOD: This was an observational study of patients attending a BoNT-A clinic at a tertiary paediatric hospital (2010-2014). Data examined included procedural adverse events at the time of injection and at follow-up. Systemic adverse events were defined as lower respiratory tract illnesses, generalized weakness, dysphagia, and death. Severity of CP was categorized by the Gross Motor Function Classification System (GMFCS). The relationships between GMFCS and adverse events were analysed using negative binomial regression models. RESULTS: In total, 591 children underwent 2219 injection episodes. Adverse events were reported during the procedure (130 [6%] injection episodes) and at follow-up (492 [22%] injection episodes). There were significantly increased rates of systemic adverse events in injection episodes involving children in GMFCS level IV (incidence rate ratio [IRR] 3.92 [95% confidence interval] 1.45-10.57]) and GMFCS level V (IRR 7.37 [95% confidence interval 2.90-18.73]; p<0.001). INTERPRETATION: Adverse events after BoNT-A injections are common but mostly mild and self-limiting. Children in GMFCS levels IV and V are at increased risk of systemic adverse events. The relationship between CP severity and BoNT-A adverse events is complex and further research is required to better understand this relationship. WHAT THIS PAPER ADDS: Adverse events reported at the time of botulinum toxin A injection occurred in 6% of injection episodes. Adverse events were reported at follow-up in 22% of injection episodes. Children in Gross Motor Function Classification System (GMFCS) levels IV and V have increased rates of systemic adverse events. Children in GMFCS levels IV and V report less local weakness and pain.

Community Benefit Spending By Tax-Exempt Hospitals Changed Little After ACA.

Provisions of the Affordable Care Act (ACA) encouraged tax-exempt hospitals to invest broadly in community health benefits. Four years after the ACA's enactment, hospitals had increased their average spending for all community benefits by 0.5 percentage point, from 7.6 percent of their operating expenses in 2010 to 8.1 percent in 2014.

Outcome Trends after US Military Concussive Traumatic Brain Injury.

Care for US military personnel with combat-related concussive traumatic brain injury (TBI) has substantially changed in recent years, yet trends in clinical outcomes remain largely unknown. Our prospective longitudinal studies of US military personnel with concussive TBI from 2008-2013 at Landstuhl Regional Medical Center in Germany and twp sites in Afghanistan provided an opportunity to assess for changes in outcomes over time and analyze correlates of overall disability. We enrolled 321 active-duty US military personnel who sustained concussive TBI in theater and 254 military controls. We prospectively assessed clinical outcomes 6-12 months later in 199 with concussive TBI and 148 controls. Global disability, neurobehavioral impairment, depression severity, and post-traumatic stress disorder (PTSD) severity were worse in concussive TBI groups in comparison with controls in all cohorts. Global disability primarily reflected a combination of work-related and nonwork-related disability. There was a modest but statistically significant trend toward less PTSD in later cohorts. Specifically, there was a decrease of 5.9 points of 136 possible on the Clinician Administered PTSD Scale (-4.3%) per year (95% confidence interval, 2.8-9.0 points, p = 0.0037 linear regression, p = 0.03 including covariates in generalized linear model). No other significant trends in outcomes were found. Global disability was more common in those with TBI, those evacuated from theater, and those with more severe depression and PTSD. Disability was not significantly related to neuropsychological performance, age, education, self-reported sleep deprivation, injury mechanism, or date of enrollment. Thus, across multiple cohorts of US military personnel with combat-related concussion, 6-12 month outcomes have improved only modestly and are often poor. Future focus on early depression and PTSD after concussive TBI appears warranted. Adverse outcomes are incompletely explained, however, and additional studies with prospective collection of data on acute injury severity and polytrauma, as well as reduced attrition before follow-up will be required to fully address the root causes of persistent disability after wartime injury.