Hospital admissions among people who inject opioids following syringe services program implementation.

BACKGROUND: Syringe services programs (SSPs) are an evidence-based harm reduction strategy that reduces dangerous sequelae of injection drug use among people who inject drugs (PWID) such as overdose. SSP services include safer injection education and community-based naloxone distribution programs. This study evaluates differences in overdose-associated hospital admissions following the implementation of the first legal SSP in Florida, based in Miami-Dade County. METHODS: We performed a retrospective analysis of hospitalizations for injection drug-related sequelae at a county hospital before and after the implementation of the SSP. An algorithm utilizing ICD-10 codes for opioid use and sequelae was used to identify people who inject opioids (PWIO). Florida Department of Law Enforcement Medical Examiners Commission Report data was used to analyze concurrent overdose death trends in Florida counties. RESULTS: Over the 25-month study period, 302 PWIO admissions were identified: 146 in the pre-index period vs. 156 in the post-index period. A total of 26 admissions with PWIO overdose were found: 20 pre-index and 6 post-index (p = 0.0034). CONCLUSIONS: Declining overdose-associated admissions among PWIO suggests early impacts following SSP implementation. These results indicate a potential early benefit of SSP that should be further explored for its effects on future hospital admission and mortality.

Mosaic-activating FGFR2 mutation in two fetuses with papillomatous pedunculated sebaceous naevus.

Papillomatous pedunculated sebaceous naevus (PPSN) has been described as a subtype of sebaceous naevus (SN), typically affecting the scalp and face. In contrast with Schimmelpenning syndrome, no cerebral, ocular or skeletal anomalies have hitherto been reported. We report two unrelated fetuses with PPSN, one with large pink exophytic tumours, the other with minor features but similar microscopic findings. We performed whole-exome sequencing in affected skin tissue from fetus 1, which identified a postzygotic de novo FGFR2 c.1144T>C (p.Cys382Arg) mutation in 34·6% of reads which was absent in the parents' blood. Targeted deep sequencing of FGFR2 confirmed its mosaic status in additional affected skin from fetus 1, and identified the same substitution in 26% of reads in affected skin from fetus 2. FGFR2 p.Cys382Arg is a known somatic driver mutation in human cancer, previously reported to result in activation of RAS signalling. A similar paralogous missense mutation in the transmembrane domain of FGFR3 (p.Gly380Arg) has been reported in keratinocytic epidermal naevi. Our findings define a distinct clinical and molecular subgroup of SN, beside HRAS or KRAS-related SN, and expand the spectrum of mosaic skin conditions associated with receptor tyrosine kinase mutations.

Autosomal recessive variations of TBX6, from congenital scoliosis to spondylocostal dysostosis.

Proximal 16p11.2 microdeletions are recurrent microdeletions with an overall prevalence of 0.03%. In patients with segmentation defects of the vertebra (SDV), a burden of this microdeletion was observed with TBX6 as a candidate gene for SDV. In a published cohort of patients with congenital scoliosis (CS), TBX6 haploinsufficiency was compound heterozygous with a common haplotype. Besides, a single three-generation family with spondylocostal dysostosis (SCD) was reported with a heterozygous stop-loss of TBX6. These observations questioned both on the inheritance mode and on the variable expressivity associated with TBX6-associated SDV. Based on a national recruitment of 56 patients with SDV, we describe four patients with variable SDV ranging from CS to SCD associated with biallelic variations of TBX6. Two patients with CS were carrying a proximal 16p11.2 microdeletion associated with the previously reported haplotype. One patient with extensive SDV was carrying a proximal 16p11.2 microdeletion associated with a TBX6 rare missense change. One patient with a clinical diagnosis of SCD was compound heterozygous for two TBX6 rare missense changes. The three rare variants were affecting the chromatin-binding domain. Our data illustrate the variable expressivity of recessive TBX6 ranging from CS to SCD.

Autosomal recessive IFT57 hypomorphic mutation cause ciliary transport defect in unclassified oral-facial-digital syndrome with short stature and brachymesophalangia.

The 13 subtypes of oral-facial-digital syndrome (OFDS) belong to the heterogeneous group of ciliopathies. Disease-causing genes encode for centrosomal proteins, components of the transition zone or proteins implicated in ciliary signaling. A unique consanguineous family presenting with an unclassified OFDS with skeletal dysplasia and brachymesophalangia was explored. Homozygosity mapping and exome sequencing led to the identification of a homozygous mutation in IFT57, which encodes a protein implicated in ciliary transport. The mutation caused splicing anomalies with reduced expression of the wild-type transcript and protein. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects' fibroblasts compared with controls. Sanger sequencing of IFT57 in 13 OFDS subjects and 12 subjects with Ellis-Van Creveld syndrome was negative. This report identifies the implication of IFT57 in human pathology and highlights the first description of a ciliary transport defect in OFDS, extending the genetic heterogeneity of this subgroup of ciliopathies.

Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test.

The current standard of care for diagnosis of severe intellectual disability (ID) and epileptic encephalopathy (EE) results in a diagnostic yield of ∼50%. Affected individuals nonetheless undergo multiple clinical evaluations and low-yield laboratory tests often referred to as a 'diagnostic odyssey'. This study was aimed at assessing the utility of clinical whole-exome sequencing (WES) in individuals with undiagnosed and severe forms of ID and EE, and the feasibility of its implementation in routine practice by a small regional genetic center. We performed WES in a cohort of 43 unrelated individuals with undiagnosed ID and/or EE. All individuals had undergone multiple clinical evaluations and diagnostic tests over the years, with no definitive diagnosis. Sequencing data analysis and interpretation were carried out at the local molecular genetics laboratory. The diagnostic rate of WES reached 32.5% (14 out of 43 individuals). Genetic diagnosis had a direct impact on clinical management in four families, including a prenatal diagnostic test in one family. Our data emphasize the clinical utility and feasibility of WES in individuals with undiagnosed forms of ID and EE and highlight the necessity of close collaborations between ordering physicians, molecular geneticists, bioinformaticians and researchers for accurate data interpretation.

Homozygous FIBP nonsense variant responsible of syndromic overgrowth, with overgrowth, macrocephaly, retinal coloboma and learning disabilities.

The acidic fibroblast growth factor (FGF) intracellular binding protein (FIBP) interacts directly with the fibroblast growth factor FGF1. Although FIBP is known to be implicated in the FGF signaling pathway, its precise function remains unclear. Gain-of-function variants in several FGF receptors (FGFRs) are implicated in a wide spectrum of growth disorders from achondroplasia to overgrowth syndromes. In a unique case from a consanguineous union presenting with overgrowth, macrocephaly, retinal coloboma, large thumbs, severe varicose veins and learning disabilities, exome sequencing identified a homozygous nonsense FIBP variant. The patient's fibroblasts exhibit FIBP cDNA degradation and an increased proliferation capacity compared with controls. The phenotype defines a new multiple congenital abnormalities (MCA) syndrome, overlapping with the heterogeneous group of overgrowth syndromes with macrocephaly. The different clinical features can be explained by the alteration of the FGFR pathway. Taken together, these results suggest the implication of FIBP in a new autosomal recessive MCA.

Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management.

SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had four or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included intrauterine growth restriction (IUGR) <10th percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended.

Validation of a simple index (SIisOGTT) of insulin sensitivity in a population of sedentary men.

AIM: The ongoing obesity epidemic is associated with numerous health problems related to altered metabolic function. Among these is type 2 diabetes, characterized by lowered insulin sensitivity (IS). Consequently, the development of simple indices to assess IS has research and clinical importance. The SI(is)OGTT, a new index of IS, was recently described by Bastard et al. (Diabetes & Metabolism 2007;33:261-8), and validated in sedentary, non-diabetic, overweight and obese postmenopausal women. The aim of the present study was to validate the index in men. METHODS: The data used in this project came from sedentary men (n=36), aged 34-53 years, all of whom underwent a hyperinsulinaemic-euglycaemic clamp and 2-hour oral glucose tolerance test (OGTT). Correlations with M/I (glucose infusion rate [GIR] divided by insulin concentration), GIR and GIR divided by fat-free mass (FFM) were obtained by four well-known indices (HOMA, QUICKI, Cederholm and Matsuda) as well as with the new SI(is)OGTT index. Pearson correlations and Bland-Altman analyses were obtained for every index versus clamp value. RESULTS: The best correlate of IS in the present study was the SI(is)OGTT (r=0.84, P<0.0001). The agreement of this method with the hyperinsulinaemic-euglycaemic clamp, as assessed by Bland-Altman plots, was similar to those of the other indices and to those previously described in postmenopausal women. CONCLUSION: The new index proposed by Bastard et al. is as good a predictor of IS in sedentary men as the other commonly used indices, and appears to be as reliable in this population as it was in the original study of postmenopausal women.

Bloodless cardiac surgery and the pediatric patient: a case study.

Peri-operative transfusion of blood or blood products is associated with increased morbidity and mortality after cardiac surgery. However, excessive hemodilution as a result of avoiding the use of homologous blood products can also lead to decreased oxygen delivery to vital end organs and dilutional coagulopathy. This is particularly challenging in pediatric cardiac surgery where there is a large discrepancy between the patient circulating blood volume and the priming volume of the cardiopulmonary bypass (CPB) circuit. Strategies to avoid the use of homologous blood products during pediatric cardiac surgery must also incorporate miniaturization of the CPB circuit and other bypass techniques in order to avoid problems with excessive hemodilution. We report a 5.9 kg male infant who underwent successful surgical correction of a ventricular septal defect without the use of homologous blood transfusion. Our strategies included the pre-operative administration of erythropoietin and iron to increase red blood cell mass, acute normovolemic hemodilution (ANH) before the institution of CPB, retrograde autologous priming (RAP), cell salvage, continuous ultrafiltration, vacuum-assisted venous drainage to minimize the circuit size and priming volume, and the use of near infrared spectroscopy (NIRS) to monitor the patient during the entire procedure. The utilization of these strategies is now standard for our entire pediatric cardiac surgical population.

Delivery of antegrade cerebral perfusion during descending aortic reconstruction: a case report.

Antegrade cerebral perfusion (ACP) has been demonstrated to be a safe and effective method of providing adequate protection to the brain during hypothermic circulatory arrest. By improving oxygen delivery to the cerebral capillaries, users of this technique have reported fewer temporary neurological deficits in postoperative periods, even after prolonged periods of circulatory arrest. Furthermore, ACP may be delivered with little alteration to the cardiopulmonary bypass (CPB) circuit. Surgical correction of a descending aortic aneurysm can provide a challenge when the left subclavian artery is involved. A period of hypothermic circulatory arrest is required to complete the proximal anastamosis of the graft. Access to the cerebral vessels for selective cerebral perfusion is limited during a left thoracotomy approach. A 54-year-old female presented with a computerized tomography (CT) scan of a descending aortic aneurysm, originating at the base of the left subclavian artery. Surgical intervention using CPB via femoral-femoral cannulation was employed. The patient was systemically cooled to 22 degrees C. Selective antegrade cerebral perfusion was administered via cannulation of the left common carotid artery. Antegrade cerebral perfusion lasted 19 minutes, with improved transcranial oximetry readings. The patient was successfully weaned from CPB. The patient was discharged on postoperative day nine with no evident suquelae. It is believed that the application of ACP in this procedure further improved patient outcome.

A founder haplotype for autosomal dominant sensory ataxia in Eastern Canada.

We present phenotypic and genotypic data for an additional family with autosomal dominant sensory ataxia, a disease characterized by gait difficulties associated with diminished sensation in the limbs and areflexia. The same disease haplotype spanning the entire SNAX1 locus is observed in affected members of this second family, enabling the locus to be reduced to a 7.3-cM interval.

A novel autosomal dominant restless legs syndrome locus maps to chromosome 20p13.

The authors investigated genetic factors contributing to restless legs syndrome (RLS) by performing a 10-cM genome-wide scan in a large French-Canadian pedigree. They detected an autosomal-dominant locus mapping to chromosome 20p13, with a maximum multipoint lod score of 3.86 at marker D20S849. This is the third reported autosomal-dominant locus for RLS and the first autosomal-dominant RLS locus in the French-Canadian population.

A new locus for autosomal dominant intracranial aneurysm, ANIB4, maps to chromosome 5p15.2-14.3.

BACKGROUND: Intracranial aneurysms (IA) are dilatations of intracranial arteries that occur most commonly at arterial bifurcations. Unruptured IA are present in approximately 1-2% of the population aged over 30 years of age. Aneurysms are only rarely symptomatic unless they rupture, which typically results in a subarachnoid haemorrhage associated with high morbidity and mortality. METHODS: A large French Canadian (FC) family (Aneu60) was identified which contained 12 affected individuals with intracranial aneurysms. Nine of the affected patients and three unaffected individuals were sent for an 8 cM genome-wide scan. Multipoint and two-point methods were used to analyse the scan data by using a dominant parametric model. RESULTS: We identified an IA susceptibility locus (ANIB4) located on chromosome 5p15.2-14.3. The locus was found by genome-wide linkage analysis and follow up analyses provided a maximum multipoint LOD score of 3.57 over the region. An identical haplotype segment of 7.2 Mb was found in a second FC pedigree and contributes to the refinement of the candidate gene interval. CONCLUSIONS: Our results indicate that there is a major gene locus on chromosome 5p.

Autism spectrum disorders associated with X chromosome markers in French-Canadian males.

It is now well established that genetic factors play an important role in the pathogenesis of autism disorder and converging lines of evidence suggest the implication of the X chromosome. Using a sample of subjects diagnosed with autism spectrum disorders, exclusively composed of males from French-Canadian (FC) origin, we tested markers covering the entire X chromosome using a family-based association study. Our initial analysis revealed the presence of association at two loci: DXS6789 (P=0.026) and DXS8043 (P=0.0101). In a second step, we added support to the association at DXS8043 using additional markers, additional subjects and a haplotype-based analysis (best obtained P-value=0.00001). These results provide support for the existence of a locus on the X chromosome that predisposes the FC to autism spectrum disorders.

The stimulation-induced increase in skeletal muscle glycogen synthase content is impaired in carriers of the glycogen synthase XbaI gene polymorphism.

Associations between glycogen synthase gene (GYS1) polymorphism and states of insulin resistance and type 2 diabetes have been reported. The purpose of this study was to establish if the GYS1 genotype impacts on the content of glycogen synthase (GS) protein in muscle measured under basal and stimulated conditions. To examine this, GYS1 XbaI and Met416Val polymorphisms and thigh muscle GYS1 protein content were determined at rest, both before and after several weeks of neuromuscular electrical stimulation in carriers and noncarriers of the mutations. The allelic frequency was 0.086 for the XbaI mutation (A2) and 0.006 for the Met416Val in our cohort of French-Canadian subjects. When measured at rest, the GS protein content in muscle was similar among carriers and noncarriers of the XbaI variant. However, the stimulation-induced increase (23%) in the amount of GS muscle protein normally seen in wildtype individuals was impaired in those carrying the XbaI mutation. These data demonstrate that some individuals, because of their genetic background, are unable to stimulate the process of GS protein accumulation in skeletal muscle. These results could explain why some individuals appear to be genetically predisposed to developing skeletal muscle insulin resistance when exposed to unfavorable metabolic environments.

Usability evaluation of the progress note construction set.

OVERVIEW: The Veterans Administration (VA) Computerized Patient Record System (CPRS) is a nationally deployed software product that integrates provider order entry, progress notes, vitals, consults, discharge summaries, problem lists, medications, labs, radiology, transcribed documents, study reports, and clinical reminders. Users rapidly adopted the graphical user interface for data retrieval, but demanded options to typing for data entry. We programmed "point and click" forms that integrate with CPRS individually, but were soon overwhelmed by requests. Subsequently, we developed the Progress Note Construction Set (PNCS); a tool suite that permits subject matter experts without programming skills to create reusable "point and click" forms. In this study, we evaluate the usability of these user-constructed forms. METHODS: An untrained, non-VA subject matter expert used the PNCS to create a graphical form for "skin tear" documentation. Ten VA nurses used the skin tear form to document findings for 7 standardized clinical scenarios. Following each scenario the subjects answered usability questions about the form. RESULTS: The subject matter expert created the skin tear form in 78 minutes. Users found the form to facilitate their data entry (p 0.0265), and to be at least as fast (p 0.0029) and as easy to use as expected (p 0.0166). Average note entry time was 3.4 minutes. CONCLUSION: The PNCS allowed a non-programmer to quickly create a usable, CPRS-integrated point and click form. Users found the subject matter expert s form fast and easy to use. The tool suite is a more scaleable form creation method because capacity is no longer limited by programmer availability.

Preventive practicum training in healthcare organizations. The Meharry model.

BACKGROUND: Practicum training for preventive medicine residents often occurs in agencies whose community is geographically defined and whose governance is closely linked to public election. We were unsure about the financial ability of such departments to support training and are concerned that over-reliance on traditional health departments might not be best for either medically indigent populations or preventive medicine. We, therefore, sought to apply a public health model--based on a strategic partnership between nursing and preventive medicine--to a large health care organization. The result was formation of a mini-health department, suitable for fully accredited preventive medicine practicum training, within the Alvin C. York Veterans Affairs Medical Center, Murfreesboro, TN. This Center serves a defined population of 21,594 patients and about 1600 employees. The theoretical framework for the new department was based on demonstration of a close fit between the competencies expected of preventive medicine physicians by the American College of Preventive Medicine (ACPM) and activities required by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO). Because of JCAHO requirements, many healthcare organizations already pay for preventive medicine services. CONCLUSIONS: By placing preventive medicine training faculty into existing budget slots at our institution, systemwide personnel costs for prevention decreased by about $36,000 per year, even as personnel funding for preventive medicine physicians increased from about $24,000 to $376,000 per year. Moreover, there was dramatic, sustained improvement in 17 indicators of preventive care quality as determined by an external peer review organization. In addition to providing a new venue for training, this model may also improve the quality and reach of preventive services, decreased fixed costs for service delivery, and yield new employment opportunities for preventive medicine physicians.

Medical education must make room for student-specific ethical dilemmas.

Most contemporary undergraduate courses in medical ethics leave a critical gap unfilled because they fail to address student-specific issues, says third-year student Joye St. Onge. In this article, which won third prize in CMAJs 1996 Dr. William Logie Medical Ethics Essay Contest, St. Onge outlines the importance of discussing student-specific ethical dilemmas and suggests ways to introduce such teaching in medical schools.

Self-care styles in military veterans.

Understanding of self-care behaviors in veterans has been hampered by lack of a framework by which to describe styles or patterns of individual self-care. The primary purpose of this study was to identify consciously performed health practices in 69 U.S. military veterans and to categorize these behaviors into styles. Four categories of self-care were described based on the nature and extent of health concerns addressed by individual health regimens and on the types of resources utilized. Membership in the various categories was not related to age, sex, race, or health status of veteran subjects, but was significantly related to scores on Kearney and Fleischer's Exercise of Self-Care Agency Instrument.