ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes.

Cerebral creatine deficiency syndromes (CCDS) are inherited metabolic phenotypes of creatine synthesis and transport. There are two enzyme deficiencies, guanidinoacetate methyltransferase (GAMT), encoded by GAMT and arginine-glycine amidinotransferase (AGAT), encoded by GATM, which are involved in the synthesis of creatine. After synthesis, creatine is taken up by a sodium-dependent membrane bound creatine transporter (CRTR), encoded by SLC6A8, into all organs. Creatine uptake is very important especially in high energy demanding organs such as the brain, and muscle. To classify the pathogenicity of variants in GAMT, GATM, and SLC6A8, we developed the CCDS Variant Curation Expert Panel (VCEP) in 2018, supported by The Clinical Genome Resource (ClinGen), a National Institutes of Health (NIH)-funded resource. We developed disease-specific variant classification guidelines for GAMT-, GATM-, and SLC6A8-related CCDS, adapted from the American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant interpretation guidelines. We applied specific variant classification guidelines to 30 pilot variants in each of the three genes that have variants associated with CCDS. Our CCDS VCEP was approved by the ClinGen Sequence Variant Interpretation Working Group (SVI WG) and Clinical Domain Oversight Committee in July 2022. We curated 181 variants including 72 variants in GAMT, 45 variants in GATM, and 64 variants in SLC6A8 and submitted these classifications to ClinVar, a public variant database supported by the National Center for Biotechnology Information. Missense variants were the most common variant type in all three genes. We submitted 32 new variants and reclassified 34 variants with conflicting interpretations. We report specific phenotype (PP4) using a points system based on the urine and plasma guanidinoacetate and creatine levels, brain magnetic resonance spectroscopy (MRS) creatine level, and enzyme activity or creatine uptake in fibroblasts ranging from PP4, PP4_Moderate and PP4_Strong. Our CCDS VCEP is one of the first panels applying disease specific variant classification algorithms for an X-linked disease. The availability of these guidelines and classifications can guide molecular genetics and genomic laboratories and health care providers to assess the molecular diagnosis of individuals with a CCDS phenotype.

A randomized controlled clinical trial of prazosin for alcohol use disorder in active duty soldiers: Predictive effects of elevated cardiovascular parameters.

BACKGROUND: Excessive noradrenergic signaling contributes to aversive symptoms of alcohol withdrawal that interfere with abstinence or reductions in harmful use. METHODS: To address this aspect of alcohol use disorder, 102 active-duty soldiers participating in command-mandated Army outpatient alcohol treatment were randomized to also receive the brain-penetrant alpha-1 adrenergic receptor antagonist prazosin or placebo for 13 weeks. Primary outcomes were scores on the Penn Alcohol Craving Scale (PACS), standard drink units (SDUs) per day averaged over each week, % days of any drinking per week, and % days of heavy drinking per week. RESULTS: PACS declines did not differ significantly between the prazosin and placebo groups in the overall sample. In the subgroup with comorbid PTSD (n = 48), PACS declines were significantly greater in the prazosin than in the placebo condition (p < 0.05). Baseline alcohol consumption was markedly reduced by the pre-randomization outpatient alcohol treatment program, but the addition of prazosin treatment produced a greater slope of decline in SDUs per day compared to placebo (p = 0.01). Preplanned subgroup analyses were performed in soldiers with elevated baseline cardiovascular measures consistent with increased noradrenergic signaling. In soldiers with elevated standing heart rate (n = 15), prazosin reduced SDUs per day (p = 0.01), % days drinking (p = 0.03), and % days heavy drinking (p = 0.001) relative to placebo. In soldiers with elevated standing systolic blood pressure (n = 27), prazosin reduced SDUs per day (p = 0.04) and tended to reduce % days drinking (p = 0.056). Prazosin also reduced depressive symptoms and the incidence of emergent depressed mood more than placebo (p = 0.05 and p = 0.01, respectively). During the final 4 weeks of prazosin vs. placebo treatment that followed completion of Army outpatient AUD treatment, alcohol consumption in soldiers with elevated baseline cardiovascular measures increased in those receiving placebo but remained suppressed in those receiving prazosin. CONCLUSIONS: These results extend reports that higher pretreatment cardiovascular measures predict beneficial effects of prazosin, which may be useful for relapse prevention in patients with AUD.

Coalition Building and Food Insecurity: How an Equity and Justice Framework Guided a Viable Food Assistance Network.

Food insecurity is widespread in the United States. The COVID-19 pandemic intensified the need for food assistance and created opportunities for collaboration among historically-siloed organizations. Research has demonstrated the importance of coalition building and community organizing in Policy, Systems, and Environmental (PSE) change and its potential to address equitable access to food, ultimately improving population health outcomes. In New Haven, community partners formed a coalition to address systems-level issues in the local food assistance system through the Greater New Haven Coordinated Food Assistance Network (CFAN). Organizing the development of CFAN within the framework of Collaborating for Equity and Justice (CEJ) reveals a new way of collaborating with communities for social change with an explicit focus on equity and justice. A document review exploring the initiation and growth of the network found that 165 individuals, representing 63 organizations, participated in CFAN since its inception and collaborated on 50 actions that promote food access and overall health. Eighty-one percent of these actions advanced equitable resource distribution across the food system, with forty-five percent focused on coordinating food programs to meet the needs of underserved communities. With the goal of improving access to food while addressing overall equity within the system, the authors describe CFAN as a potential community organizing model in food assistance systems.

Pain points in parents' interactions with newborn screening systems: a qualitative study.

BACKGROUND & OBJECTIVES: This study aims to explore and elucidate parents' experience of newborn screening [NBS], with the overarching goal of identifying desiderata for the development of informatics-based educational and health management resources. METHODS: We conducted four focus groups and four one-on-one qualitative interviews with a total of 35 participants between March and September 2020. Participants were grouped into three types: parents who had received true positive newborn screening results; parents who had received false positive results; and soon-to-be parents who had no direct experience of the screening process. Interview data were subjected to analysis using an inductive, constant comparison approach. RESULTS: Results are divided into five sections: (1) experiences related to the process of receiving NBS results and prior knowledge of the NBS program; (2) approaches to the management of a child's medical data; (3) sources of additional informational and emotional support; (4) barriers faced by parents navigating the health system; and (5) recommendations and suggestions for new parents experiencing the NBS process. CONCLUSION: Our analysis revealed a wide range of experiences of, and attitudes towards the newborn screening program and the wider newborn screening system. While parents' view of the screening process was - on the whole - positive, some participants reported experiencing substantial frustration, particularly related to how results are initially communicated and difficulties in accessing reliable, timely information. This frustration with current information management and education resources indicates a role for informatics-based approaches in addressing parents' information needs.

Towards a Newborn Screening Common Data Model: The Utah Newborn Screening Data Model.

As newborn screening programs transition from paper-based data exchange toward automated, electronic methods, significant data exchange challenges must be overcome. This article outlines a data model that maps newborn screening data elements associated with patient demographic information, birthing facilities, laboratories, result reporting, and follow-up care to the LOINC, SNOMED CT, ICD-10-CM, and HL7 healthcare standards. The described framework lays the foundation for the implementation of standardized electronic data exchange across newborn screening programs, leading to greater data interoperability. The use of this model can accelerate the implementation of electronic data exchange between healthcare providers and newborn screening programs, which would ultimately improve health outcomes for all newborns and standardize data exchange across programs.

ResultsMyWay: combining Fast Healthcare Interoperability Resources (FHIR), Clinical Quality Language (CQL), and informational resources to create a newborn screening application.

Newborn screening (NBS) can be life-changing for the families of infants who test positive for a rare condition. While resources exist to support these families, there can be delays in sharing these resources due to communication lag between the laboratory, result interpreting clinician, family of the newborn, and additional care providers. This delay can also be exacerbated when additional health history is required from the mother and infant. ResultsMyWay is a proof-of-concept application that uses Clinical Quality Language (CQL) to automate the search for this additional health history. It also translates the NBS results into Fast Healthcare Interoperability Resources (FHIR), increasing both the ease of exchange and the future utility of these data points. After the families are given the NBS results, ResultsMyWay then acts as a hub for several types of informational resources about the recently diagnosed condition.

Prospective identification by neonatal screening of patients with guanidinoacetate methyltransferase deficiency.

INTRODUCTION: Guanidinoacetate methyltransferase (GAMT) deficiency is an inherited metabolic disorder that impairs the synthesis of creatine (CRE). Lack of CRE in the brain can cause intellectual disability, autistic-like behavior, seizures, and movement disorders. Identification at birth and immediate therapy can prevent intellectual disability and seizures. Here we report the first two cases of GAMT deficiency identified at birth by newborn screening (NBS) in Utah and New York. METHODS: NBS dried blood spots were analyzed by tandem mass spectrometry (MS/MS) using either derivatized or non-derivatized assays to detect guanidinoacetate (GUAC) and CRE. For any positive samples, a second-tier test using a more selective method, ultra-performance liquid chromatography (UPLC) combined with MS/MS, was performed to separate GUAC from potential isobaric interferences. RESULTS: NBS for GAMT deficiency began in Utah on June 1, 2015 using a derivatized method for the detection of GUAC and CRE. In May 2019, the laboratory and method transitioned to a non-derivatized method. GAMT screening was added to the New York State NBS panel on October 1, 2018 using a derivatized method. In New York, a total of 537,408 babies were screened, 23 infants were referred and one newborn was identified with GAMT deficiency. In Utah, a total of 273,902 infants were screened (195,425 with the derivatized method, 78,477 with the non-derivatized method), three infants referred and one was identified with GAMT deficiency. Mean levels of GUAC and CRE were similar between methods (Utah derivatized: GUAC = 1.20 ± 0.43 µmol/L, CRE = 238 ± 96 µmol/L; Utah non-derivatized: GUAC = 1.23 ± 0.61 µmol/L, CRE = 344 ± 150 µmol/L, New York derivatized: GUAC = 1.34 ± 0.57 µmol/L, CRE = 569 ± 155 µmol/L). With either Utah method, similar concentrations of GUAC are observed in first (collected around 1 day of age) and the second NBS specimens (routinely collected at 7-16 days of age), while CRE concentrations decreased in the second NBS specimens. Both infants identified with GAMT deficiency started therapy by 2 weeks of age and are growing and developing normally at 7 (Utah) and 4 (New York) months of age. CONCLUSIONS: Newborn screening allows for the prospective identification of GAMT deficiency utilizing elevated GUAC concentration as a marker. First-tier screening may be incorporated into existing methods for amino acids and acylcarnitines without the need for new equipment or staff. Newborn screening performed by either derivatized or non-derivatized methods and coupled with second-tier testing, has a very low false positive rate and can prospectively identify affected children. SummaryCerebral creatine deficiency syndromes caused by defects in creatine synthesis can result in intellectual disability, and are preventable if therapy is initiated early in life. This manuscript reports the identification of two infants with GAMT deficiency (one of the cerebral creatine deficiency syndromes) by newborn screening and demonstrates NBS feasibility using a variety of methods.

Methods and feasibility study for exome sequencing as a universal second-tier test in newborn screening.

PURPOSE: Newborn screening disorders increasingly require genetic variant analysis as part of second-tier or confirmatory testing. Sanger sequencing and gene-specific next-generation sequencing (NGS)-based tests, the current methods of choice, are costly and lack scalability when expanding to new conditions. We describe a scalable, exome sequencing-based NGS pipeline with a priori analysis restriction that can be universally applied to any NBS disorder. METHODS: De-identified abnormal newborn screening specimens representing severe combined immune deficiency (SCID), cystic fibrosis (CF), VLCAD deficiency, metachromatic leukodystrophy (MLD), and in silico sequence read data sets were used to validate the pipeline. To support interpretation and clinical decision-making within the bioinformatics pipeline, variants from multiple databases were curated and validated. RESULTS: CFTR variant panel analysis correctly identified all variants. Concordance compared with diagnostic testing results for targeted gene analysis was between 78.6% and 100%. Validation of the bioinformatics pipeline with in silico data sets revealed a 100% detection rate. Varying degrees of overlap were observed between ClinVar and other databases ranging from 3% to 65%. Data normalization revealed that 11% of variants across the databases required manual curation. CONCLUSION: This pipeline allows for restriction of analysis to variants within a single gene or multiple genes, and can be readily expanded to full exome analysis if clinically indicated and parental consent is granted.

Newborn Screening Knowledge and Attitudes Among Midwives and Out-of-Hospital-Birth Parents.

Midwifery and nursing are collaborative partners in both education and practice. Understanding needs and barriers to clinical services such as newborn screening is essential. This study examined knowledge and attitudes of midwives and out-of-hospital-birth parents about newborn blood spot screening (NBS). Descriptive and cross-sectional surveys were distributed to midwives and out-of-hospital-birth parents from birth center registries and the Utah Health Department of Vital Records. Seventeen midwife surveys (response rate: 17%) and 113 parent surveys (response rate: 31%) were returned. Most midwives and out-of-hospital-birth parents reported satisfactory knowledge scores about NBS. Only 5% of parents (n = 6) did not participate in NBS. Most midwives reported that NBS is important and encouraged patients to consider undergoing NBS. Some concerns included the lack of education for both midwives and out-of-hospital patients and the trauma and accuracy of the heel prick soon after birth. Both midwives and out-of-hospital-birth parents expressed a need for improved NBS education. Additional studies are needed to ascertain whether this trend is seen with similar populations throughout the United States, to further elucidate the factors that drive NBS nonparticipation, and to develop educational resources for midwives and their patients.

Rehabilitation Practices in Patients With Moderate and Severe Traumatic Brain Injury.

OBJECTIVE: To characterize the indications, timing, barriers, and perceived value of rehabilitation currently provided for individuals with moderate or severe traumatic brain injury (TBI) admitted to the intensive care unit (ICU) based on the perspectives of providers who work in the ICU setting. PARTICIPANTS: Members (n = 66) of the Neurocritical Care Society and the American Congress of Rehabilitation Medicine. DESIGN: An anonymous electronic survey of the timing of rehabilitation for patients with TBI in the ICU. MAIN MEASURES: Questions asked about type and timing of rehabilitation in the ICU, extent of family involvement, participation of physiatrists in patient care, and barriers to early rehabilitation. RESULTS: Sixty-six respondents who reported caring for patients with TBI in the ICU completed the survey; 98% recommended rehabilitative care while patients were in the ICU. Common reasons to wait for the initiation of physical therapy and occupational therapy were normalization of intracranial pressure (86% and 89%) and hemodynamic stability (66% and 69%). CONCLUSIONS: The majority of providers caring for patients with TBI in the ICU support rehabilitation efforts, typically after a patient is extubated, intracranial pressure has normalized, and the patient is hemodynamically stable. Our findings describe current practice; future studies can be designed to determine optimal timing, intensity, and patient selection for early rehabilitation.

Identification of Primary Congenital Hypothyroidism Based on Two Newborn Screens - Utah, 2010-2016.

Newborn screening for primary congenital hypothyroidism is part of the U.S. Recommended Uniform Screening Panel (1,2). Untreated congenital hypothyroidism can result in cognitive impairment and growth complications (decreased height/length). Initial newborn screening for congenital hypothyroidism is typically performed 24-48 hours after birth. Fourteen states, including Utah, perform a routine second screen at approximately 2 weeks of age.* During 2010-2016, a total of 359,432 infants in Utah were screened for congenital hypothyroidism, and 130 cases were diagnosed; among these, 98 had an abnormal first screen, and 25 had an abnormal second screen (seven infants were excluded because of missing data). A retrospective examination of Utah's screening data indicated that 20% of congenital hypothyroidism cases could not have been efficiently identified by a single screen alone. This study highlights the utility of a two-screen process and demonstrates that differential cutoff values for the first and second screens could optimize both screening sensitivity and specificity.

Impact of a low intensity and broadly inclusive ED care coordination intervention on linkage to primary care and ED utilization.

OBJECTIVE: We aim to evaluate the effectiveness of a broadly inclusive, comparatively low intensity intervention linking ED patients to a primary care home. METHODS: This retrospective cohort study evaluated ED patients referred for primary care linkage in a large, urban, academic ED. A care coordination specialist performed a brief interview to gauge access barriers and provide a clinic referral with optional scheduling assistance. Data were abstracted from program records and the electronic medical record. The primary outcome was the proportion of referred individuals who attended at least one primary care appointment. Secondary outcomes included return ED encounters within one year, and factors associated with linkage outcomes. RESULTS: There were 2142 referrals made for 2064 patients; 1688/2142 accepted assistance. Linkage was successful for 1059/1688 (63%, CI95 60% to 65%). Among patients accepting assistance, those without successful linkage were younger (41 vs 45years, difference 3years, CI95 2 to 3), more often male (62% vs 55%,difference 7%, CI95 2% to 12%), and less likely to have a chronic medical condition (37% vs 45%, difference 8%; CI95 3% to 12%) or to have had an appointment scheduled within two weeks (26% vs 33%, difference 7%, CI95 2% to 12%). Insurance status and self-reported barriers to care were not associated with linkage success. Patterns of subsequent ED use were similar, regardless of referral status or linkage outcome. CONCLUSION: Low intensity, broadly inclusive, ED care coordination linked nearly 50% of patients referred for intervention, and two-thirds of willing participants, with a primary care home.

Opportunities for earlier HIV diagnosis in a pediatric ED.

OBJECTIVES: Emergency department (ED) HIV screening is recommended but challenging to implement and of uncertain effectiveness in pediatric EDs (PEDs). We sought to determine whether there were opportunities for earlier HIV diagnosis in the PED for a cohort of young adults diagnosed with HIV. METHODS: This retrospective cohort study reviewed PED records of a group of young adults receiving HIV care in an urban hospital setting. Pediatric ED visits were selected for review if they took place after the patient's estimated time of HIV acquisition and before their eventual diagnosis. Charts were reviewed to determine whether HIV infection was suspected and whether testing was offered. RESULTS: Among a cohort of HIV-positive young adults, only 3 (3.6%; 95% confidence interval, 0.9-10.8) of 84 were seen in the PED during the time they were undiagnosed but likely to be infected with HIV. Among these subjects, there was no documentation that HIV testing was offered or refused nor was there documented suspicion of HIV. CONCLUSIONS: There are opportunities for earlier diagnosis of HIV in PEDs, affirming the importance of HIV screening implementation in these settings. However, PEDs are unlikely to have the same frequency of contact with undiagnosed individuals as do adult EDs. Alternative methods of accessing at-risk adolescent populations must be identified.

Repeat neuroimaging of mild traumatic brain-injured patients with acute traumatic intracranial hemorrhage: clinical outcomes and radiographic features.

OBJECTIVES: Emergency department (ED) management of mild traumatic brain injury (TBI) patients with any form of traumatic intracranial hemorrhage (ICH) is variable. Since 2000, our center's standard practice has been to obtain a repeat head computed tomography (CT) at least 6 hours after initial imaging. Patients are eligible for discharge if clinical and CT findings are stable. Whether this practice is safe is unknown. This study characterized clinical outcomes in mild TBI patients with acute traumatic ICH seen on initial ED neuroimaging. METHODS: This retrospective cohort study included patients presenting to the ED with blunt mild TBI with Glasgow Coma Scale (GCS) scores of 14 or 15 and stable vital signs, during the period from January 2001 to January 2010. Patients with any ICH on initial head CT and repeat head CT within 24 hours were eligible. Cases were excluded for initial GCS < 14, injury > 24 hours old, pregnancy, concomitant nonminor injuries, and coagulopathy. A single investigator abstracted data from records using a standardized case report form and data dictionary. Primary endpoints included death, neurosurgical procedures, and for discharged patients, return to the ED within 7 days. Differences in proportions were computed with 95% confidence intervals (CIs). RESULTS: Of 1,011 patients who presented to the ED and had two head CTs within 24 hours, 323 (32%) met inclusion criteria. The median time between CT scans was 6 hours (interquartile range = 5 to 7 hours). A total of 153 (47%) patients had subarachnoid hemorrhage, 132 (41%) patients had subdural hemorrhage, 11 (3%) patients had epidural hemorrhage, 78 (24%) patients had cerebral contusions, and 59 (18%) patients had intraparenchymal hemorrhage. Four of 323 (1.2%, 95% CI = 0.3% to 3.2%) patients died within 2 weeks of injury. Three of the patients who died had been admitted from the ED on their initial visits, and one had been discharged home. There were 206 patients (64%) discharged from the ED, 28 (13.6%) of whom returned to the ED within 1 week. Of the 92 who were hospitalized, three (0.9%, 95% CI = 0.2% to 2.7%) required neurosurgical intervention. CONCLUSION: Discharge after a repeat head CT and brief period of observation in the ED allowed early discharge of a cohort of mild TBI patients with traumatic ICH without delayed adverse outcomes. Whether this justifies the cost and radiation exposure involved with this pattern of practice requires further study.

Genetic counselor review of genetic test orders in a reference laboratory reduces unnecessary testing.

Genetic tests are routinely ordered by health care providers (HCPs) within a wide range of medical specialties. Many providers have limited knowledge or experience with ordering and interpreting genetic tests; thus, test order errors are common. Rigorous review of genetic test orders by genetic counselors (GCs) can provide a direct financial benefit to medical institutions, patients and insurers. GCs at ARUP (Associated Regional University Pathologists) Laboratories routinely perform a preanalytic assessment of complex molecular genetic test orders that includes reviewing clinical and family history information and considering the clinical utility and cost-effectiveness of ordered tests. GCs contact the ordering institution and/or HCP as needed to collect additional clinical information and confirm the test order or suggest alternative testing based on the provided information. A retrospective review of the GC-facilitated test changes over a 21-month period at ARUP laboratories was performed. Approximately 26% of all requests for complex genetic tests assessing germ line mutations were changed following GC review. Testing fees associated with canceled tests were summed to estimate the cost-savings resulting from GC-facilitated test reviews. The test review process resulted in an average reduction in charges to the referring institutions of $48,000.00 per month. GC review of genetic test orders for appropriateness and clinical utility reduces healthcare costs to hospitals, insurers, and patients.

Neuroimaging, behavioral, and psychological sequelae of repetitive combined blast/impact mild traumatic brain injury in Iraq and Afghanistan war veterans.

Abstract Whether persisting cognitive complaints and postconcussive symptoms (PCS) reported by Iraq and Afghanistan war veterans with blast- and/or combined blast/impact-related mild traumatic brain injuries (mTBIs) are associated with enduring structural and/or functional brain abnormalities versus comorbid depression or posttraumatic stress disorder (PTSD) remains unclear. We sought to characterize relationships among these variables in a convenience sample of Iraq and Afghanistan-deployed veterans with (n=34) and without (n=18) a history of one or more combined blast/impact-related mTBIs. Participants underwent magnetic resonance imaging of fractional anisotropy (FA) and macromolecular proton fraction (MPF) to assess brain white matter (WM) integrity; [(18)F]-fluorodeoxyglucose positron emission tomography imaging of cerebral glucose metabolism (CMRglu); structured clinical assessments of blast exposure, psychiatric diagnoses, and PTSD symptoms; neurologic evaluations; and self-report scales of PCS, combat exposure, depression, sleep quality, and alcohol use. Veterans with versus without blast/impact-mTBIs exhibited reduced FA in the corpus callosum; reduced MPF values in subgyral, longitudinal, and cortical/subcortical WM tracts and gray matter (GM)/WM border regions (with a possible threshold effect beginning at 20 blast-mTBIs); reduced CMRglu in parietal, somatosensory, and visual cortices; and higher scores on measures of PCS, PTSD, combat exposure, depression, sleep disturbance, and alcohol use. Neuroimaging metrics did not differ between participants with versus without PTSD. Iraq and Afghanistan veterans with one or more blast-related mTBIs exhibit abnormalities of brain WM structural integrity and macromolecular organization and CMRglu that are not related to comorbid PTSD. These findings are congruent with recent neuropathological evidence of chronic brain injury in this cohort of veterans.

Factors associated with hospitalization of patients with angiotensin-converting enzyme inhibitor-induced angioedema.

Angiotensin-converting enzyme inhibitor (ACE-I)-induced angioedema can be life-threatening without emergent intervention. The putative mediator is believed to be bradykinin, similar to hereditary angioedema, so these patients respond poorly to corticosteroids and antihistamines. This study was designed to determine characteristics and clinical outcomes of patients presenting to an emergency department (ED) with ACE-I angioedema. This was a retrospective chart review of 100 patients presenting to the ED from 2007 to 2008 with an ICD-9 code of 995.1 (angioedema) or 995.2 (drug-induced angioedema). Two hundred fifty-two patients with these ICD-9 codes were identified and placed in random order, and the first 100 meeting inclusion criteria were included. Statistical analysis was primarily descriptive. All 100 patients had an ICD-9 code of 995.1 (angioedema). Patients presented in every month, with spring months (April-June) having the most presentations (32%). The median age was 59 years, 75% were African American, and 66% were admitted to the hospital. Two patients (2%) required endotracheal intubation. Lisinopril was the most commonly prescribed ACE-I (84%). The most common symptom was moderate lip and tongue swelling (89%) followed by mild difficulty breathing (12%). Tongue swelling was significantly associated with admission. Time from symptom onset to ED presentation was not associated with need for admission. Concomitant medications did not differ between admitted and discharged patients. ACE-I angioedema is associated with significant morbidity and health care use because many patients require hospitalization, suggesting an unmet need for novel therapies targeted to treat this condition.

High prevalence of chronic pituitary and target-organ hormone abnormalities after blast-related mild traumatic brain injury.

Studies of traumatic brain injury from all causes have found evidence of chronic hypopituitarism, defined by deficient production of one or more pituitary hormones at least 1 year after injury, in 25-50% of cases. Most studies found the occurrence of posttraumatic hypopituitarism (PTHP) to be unrelated to injury severity. Growth hormone deficiency (GHD) and hypogonadism were reported most frequently. Hypopituitarism, and in particular adult GHD, is associated with symptoms that resemble those of PTSD, including fatigue, anxiety, depression, irritability, insomnia, sexual dysfunction, cognitive deficiencies, and decreased quality of life. However, the prevalence of PTHP after blast-related mild TBI (mTBI), an extremely common injury in modern military operations, has not been characterized. We measured concentrations of 12 pituitary and target-organ hormones in two groups of male US Veterans of combat in Iraq or Afghanistan. One group consisted of participants with blast-related mTBI whose last blast exposure was at least 1 year prior to the study. The other consisted of Veterans with similar military deployment histories but without blast exposure. Eleven of 26, or 42% of participants with blast concussions were found to have abnormal hormone levels in one or more pituitary axes, a prevalence similar to that found in other forms of TBI. Five members of the mTBI group were found with markedly low age-adjusted insulin-like growth factor-I (IGF-I) levels indicative of probable GHD, and three had testosterone and gonadotropin concentrations consistent with hypogonadism. If symptoms characteristic of both PTHP and PTSD can be linked to pituitary dysfunction, they may be amenable to treatment with hormone replacement. Routine screening for chronic hypopituitarism after blast concussion shows promise for appropriately directing diagnostic and therapeutic decisions that otherwise may remain unconsidered and for markedly facilitating recovery and rehabilitation.

Clostridium difficile infection and treatment in the pediatric inflammatory bowel disease population.

OBJECTIVE: Recent changes in the epidemiology of Clostridium difficile infection include an increase in the incidence of C difficile-associated disease (CDAD) and the identification of patients with inflammatory bowel disease (IBD) as a group at risk. In addition, the effectiveness of antimicrobial therapies has been questioned. Our aim was to estimate the incidence of CDAD in a pediatric IBD population and review treatment efficacy. PATIENTS AND METHODS: We identified patients ages 18 years or younger from our center's IBD database who tested positive for C difficile toxin A and/or B between August 1, 2007 and December 31, 2008. Demographic information and treatment details were recorded. Chi-square and Fisher exact tests were used to compare categorical variables and the Student t test was used for continuous variables. RESULTS: From 372 pediatric patients with IBD, we identified 29 patients who experienced a total of 40 cases of CDAD. The annualized incidence rate of CDAD was 7.2%. Initial treatment was successful in 17 cases (43%). Eventual success was documented with metronidazole in 15 cases (41%), with vancomycin in 16 cases (43%), and with other agents or a combination of agents in 6 cases (16%). Age, sex, and IBD type were not associated with initial treatment outcome or recurrence. The choice of initial antimicrobial treatment was not associated with treatment outcome. The type of IBD therapy medication was not associated with the likelihood of CDAD recurrence, although the use of anti-inflammatory therapy was positively associated with initial antimicrobial treatment success. CONCLUSIONS: CDAD occurred frequently in our cohort of pediatric patients with IBD. Antimicrobial treatment success was achieved equally with either metronidazole or vancomycin. Initial treatment failed more than half of the time, regardless of medication choice. Apparent lack of antimicrobial efficacy in resolving symptoms may reflect resistant C difficile infection or increased IBD severity in a subset of patients who are C difficile carriers. Awareness of the potential for a high incidence of CDAD and frequent failure rate of initial therapy is important in the management of children with IBD.