Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites.

Dysfunction in sodium channels and their ankyrin scaffolding partners have both been implicated in neurodevelopmental disorders, including autism spectrum disorder (ASD). In particular, the genes SCN2A, which encodes the sodium channel NaV1.2, and ANK2, which encodes ankyrin-B, have strong ASD association. Recent studies indicate that ASD-associated haploinsufficiency in Scn2a impairs dendritic excitability and synaptic function in neocortical pyramidal cells, but how NaV1.2 is anchored within dendritic regions is unknown. Here, we show that ankyrin-B is essential for scaffolding NaV1.2 to the dendritic membrane of mouse neocortical neurons and that haploinsufficiency of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits observed in Scn2a+/- conditions. These results establish a direct, convergent link between two major ASD risk genes and reinforce an emerging framework suggesting that neocortical pyramidal cell dendritic dysfunction can contribute to neurodevelopmental disorder pathophysiology.

Prematriculation Predictors of Academic Difficulties During the First Year of a Doctor of Physical Therapy Program.

PURPOSE: To analyze the ability of pre-matriculation metrics to predict difficulties during the first year of a Doctor of Physical Therapy (DPT) program with a pass-fail grading system. METHODS: Undergraduate cumulative, science, and pre-requisite grade point averages (GPAs) and verbal and quantitative Graduate Record Examination (GRE) percentiles were collected during the admissions process of 190 students in an accredited DPT program at a southeastern US private university between 2019-2021. Students were dichotomized to groups with and without academic difficulties in coursework and a first-year comprehensive assessment (CA). Independent t-tests identified differences between groups, and logistic regression analyses identified predictors of academic difficulties. Receiver operating characteristic (ROC) curve analyses were performed to identify cut-off scores and risk ratios were calculated. RESULTS: Students with coursework difficulties had lower verbal (d=0.36, p=0.009) and quantitative (d=0.31, p=0.02) GRE scores. Verbal GRE scores were also lower in students who failed the CA (p=0.049). Students who scored less than the 47th percentile on the verbal GRE were 53% more likely to have academic difficulties and 4.2 times more likely to fail the CA than those who scored in the 70th percentile or higher. CONCLUSION: Verbal GRE percentile best predicted academic difficulty in the first year of a DPT program.

Effects of chronic lithium treatment on neuronal excitability and GABAergic transmission in an Ank3 mutant mouse model.

Bipolar disorder (BD) is a common psychiatric disease that can lead to psychosocial disability, decreased quality of life, and high risk for suicide. Genome-wide association studies have shown that the ANK3 gene is a significant risk factor for BD, but the mechanisms involved in BD pathophysiology are not yet fully understood. Previous work has shown that ankyrin-G, the protein encoded by ANK3, stabilizes inhibitory synapses in vivo through its interaction with the GABAA receptor-associated protein (GABARAP). We generated a mouse model with a missense p.W1989R mutation in Ank3, that abolishes the interaction between ankyrin-G and GABARAP, which leads to reduced inhibitory signaling in the somatosensory cortex and increased pyramidal cell excitability. Humans with the same mutation exhibit BD symptoms, which can be attenuated with lithium therapy. In this study, we describe that chronic treatment of Ank3 p.W1989R mice with lithium normalizes neuronal excitability in cortical pyramidal neurons and increases inhibitory GABAergic postsynaptic currents. The same outcome in inhibitory transmission was observed when mice were treated with the GSK-3ß inhibitor Tideglusib. These results suggest that lithium treatment modulates the excitability of pyramidal neurons in the cerebral cortex by increasing GABAergic neurotransmission, likely via GSK-3 inhibition. In addition to the importance of these findings regarding ANK3 variants as a risk factor for BD development, this study may have significant implications for treating other psychiatric disorders associated with alterations in inhibitory signaling, such as schizophrenia, autism spectrum disorder, and major depressive disorder.

Tolerability, safety and pharmacodynamics of oral, small-molecule glucagon-like peptide-1 receptor agonist danuglipron for type 2 diabetes: A 12-week, randomized, placebo-controlled, Phase 2 study comparing different dose-escalation schemes.

AIM: To evaluate the tolerability, safety and pharmacodynamics of different dose-escalation schemes of the oral small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist danuglipron. MATERIALS AND METHODS: This Phase 2a, double-blind, placebo-controlled, parallel-group study randomly assigned adults with type 2 diabetes (T2D) treated with metformin to placebo or danuglipron (low [5-mg] or high [10-mg] starting dose, with 1- or 2-week dose-escalation steps, to target doses of 80, 120 or 200 mg twice daily [BID]) and adults with obesity without diabetes to placebo or danuglipron 200 mg BID. RESULTS: Participants with T2D (n = 123, mean glycated haemoglobin [HbA1c] 8.19%) or obesity without diabetes (n = 28, mean body mass index 37.3 kg/m2 ) were randomly assigned and treated. Discontinuation from study medication occurred in 27.3% to 72.7% of participants across danuglipron groups versus 16.7% to 18.8% for placebo, most often due to adverse events. Nausea (20.0%-47.6% of participants across danuglipron groups vs. 12.5% for placebo) and vomiting (18.2%-40.9% danuglipron vs. 12.5% placebo, respectively) were most commonly reported in participants with T2D. Gastrointestinal adverse events were generally related to danuglipron target dose and were not substantially affected by starting dose. In participants with T2D, least squares mean changes from baseline in HbA1c (-1.04% to -1.57% across danuglipron groups vs. -0.32% for placebo), fasting plasma glucose (-23.34 mg/dL to -53.94 mg/dL danuglipron vs. -13.09 mg/dL placebo) and body weight (-1.93 to -5.38 kg danuglipron vs. -0.42 kg placebo) at Week 12 were generally statistically significant for danuglipron compared with placebo (P < 0.05). CONCLUSIONS: Danuglipron resulted in statistically significant reductions in HbA1c, FPG and body weight over 12 weeks, in the setting of higher discontinuation rates and incidence of gastrointestinal adverse events with higher target doses. CLINICALTRIALS: gov identifier: NCT04617275.

DSCAM gene triplication causes excessive GABAergic synapses in the neocortex in Down syndrome mouse models.

Down syndrome (DS) is caused by the trisomy of human chromosome 21 (HSA21). A major challenge in DS research is to identify the HSA21 genes that cause specific symptoms. Down syndrome cell adhesion molecule (DSCAM) is encoded by a HSA21 gene. Previous studies have shown that the protein level of the Drosophila homolog of DSCAM determines the size of presynaptic terminals. However, whether the triplication of DSCAM contributes to presynaptic development in DS remains unknown. Here, we show that DSCAM levels regulate GABAergic synapses formed on neocortical pyramidal neurons (PyNs). In the Ts65Dn mouse model for DS, where DSCAM is overexpressed due to DSCAM triplication, GABAergic innervation of PyNs by basket and chandelier interneurons is increased. Genetic normalization of DSCAM expression rescues the excessive GABAergic innervations and the increased inhibition of PyNs. Conversely, loss of DSCAM impairs GABAergic synapse development and function. These findings demonstrate excessive GABAergic innervation and synaptic transmission in the neocortex of DS mouse models and identify DSCAM overexpression as the cause. They also implicate dysregulated DSCAM levels as a potential pathogenic driver in related neurological disorders.

Synaptotagmin-7 facilitates acetylcholine release in splanchnic nerve-chromaffin cell synapses during nerve activity.

Disturbances that threaten homeostasis elicit activation of the sympathetic nervous system (SNS) and the adrenal medulla. The effectors discharge as a unit to drive global and immediate changes in whole-body physiology. Descending sympathetic information is conveyed to the adrenal medulla via preganglionic splanchnic fibers. These fibers pass into the gland and synapse onto chromaffin cells, which synthesize, store, and secrete catecholamines and vasoactive peptides. While the importance of the sympatho-adrenal branch of the autonomic nervous system has been appreciated for many decades, the mechanisms underlying transmission between presynaptic splanchnic neurons and postsynaptic chromaffin cells have remained obscure. In contrast to chromaffin cells, which have enjoyed sustained attention as a model system for exocytosis, even the Ca2+ sensors that are expressed within splanchnic terminals have not yet been identified. This study shows that a ubiquitous Ca2+-binding protein, synaptotagmin-7 (Syt7), is expressed within the fibers that innervate the adrenal medulla, and that its absence can alter synaptic transmission in the preganglionic terminals of chromaffin cells. The prevailing impact in synapses that lack Syt7 is a decrease in synaptic strength and neuronal short-term plasticity. Evoked excitatory postsynaptic currents (EPSCs) in Syt7 KO preganglionic terminals are smaller in amplitude than in wild-type synapses stimulated in an identical manner. Splanchnic inputs also display robust short-term presynaptic facilitation, which is compromised in the absence of Syt7. These data reveal, for the first time, a role for any synaptotagmin at the splanchnic-chromaffin cell synapse. They also suggest that Syt7 has actions at synaptic terminals that are conserved across central and peripheral branches of the nervous system.

Systematic review and meta-analysis of within-subject and between-subject biological variation data of coagulation and fibrinolytic measurands.

OBJECTIVES: The diagnosis and monitoring of bleeding and thrombotic disorders depend on correct haemostatic measurements. The availability of high-quality biological variation (BV) data is important in this context. Many studies have reported BV data for these measurands, but results are varied. The present study aims to deliver global within-subject (CVI) and between-subject (CVG) BV estimates for haemostasis measurands by meta-analyses of eligible studies, by assessment with the Biological Variation Data Critical Appraisal Checklist (BIVAC). METHODS: Relevant BV studies were graded by the BIVAC. Weighted estimates for CVI and CVG were obtained via meta-analysis of the BV data derived from BIVAC-compliant studies (graded A-C; whereby A represents optimal study design) performed in healthy adults. RESULTS: In 26 studies BV data were reported for 35 haemostasis measurands. For 9 measurands, only one eligible publication was identified and meta-analysis could not be performed. 74% of the publications were graded as BIVAC C. The CVI and CVG varied extensively between the haemostasis measurands. The highest estimates were observed for PAI-1 antigen (CVI 48.6%; CVG 59.8%) and activity (CVI 34.9%; CVG 90.2%), while the lowest were observed for activated protein C resistance ratio (CVI 1.5%; CVG 4.5%). CONCLUSIONS: This study provides updated BV estimates of CVI and CVG with 95% confidence intervals for a wide range of haemostasis measurands. These estimates can be used to form the basis for analytical performance specifications for haemostasis tests used in the diagnostic work-up required in bleeding- and thrombosis events and for risk assessment.

Family-focused contextual factors associated with lifestyle patterns in young children from two mother-offspring cohorts: GUSTO and EDEN.

BACKGROUND: Integrated patterns of energy balance-related behaviours of preschool children in Asia are sparse, with few comparative analyses. PURPOSE: Using cohorts in Singapore (GUSTO) and France (EDEN), we characterized lifestyle patterns of children and investigated their associations with family-focused contextual factors. METHODS: Ten behavioural variables related to child's diet, walking, outdoor play and screen time were ascertained by parental questionnaires at age 5-6 years. Using principal component analysis, sex-specific lifestyle patterns were derived independently for 630 GUSTO and 989 EDEN children. Contextual variables were organised into distal (family socio-economics, demographics), intermediate (parental health, lifestyle habits) and proximal (parent-child interaction factors) levels of influence and analysed with hierarchical linear regression. RESULTS: Three broadly similar lifestyle patterns were identified in both cohorts: "discretionary consumption and high screen time", "fruit, vegetables, and low screen time" and "high outdoor playtime and walking". The latter two patterns showed small differences between cohorts and sexes. The "discretionary consumption and high screen time" pattern was consistently similar in both cohorts; distal associated factors were lower maternal education (EDEN boys), no younger siblings (GUSTO boys) and Malay/Indian ethnicity (GUSTO), while intermediate and proximal associated factors in both cohorts and sexes were poor maternal diets during pregnancy, parents allowing high child control over food intake, snacking between meals and having television on while eating. CONCLUSIONS: Three similar lifestyle patterns were observed among preschool children in Singapore and France. There were more common associated proximal factors than distal ones. Cohort specific family-focused contextual factors likely reflect differences in social and cultural settings. Findings will aid development of strategies to improve child health.

IDH2 R172 Mutations Across Poorly Differentiated Sinonasal Tract Malignancies: Forty Molecularly Homogenous and Histologically Variable Cases With Favorable Outcome.

IDH2 R172 mutations occur in sinonasal undifferentiated carcinoma (SNUC), large-cell neuroendocrine carcinoma (LCNEC), sinonasal adenocarcinomas, and olfactory neuroblastoma (ONB). We performed a clinical, pathologic, and genetic/epigenetic analysis of a large IDH2-mutated sinonasal tumor cohort to explore their distinct features. A total 165 sinonasal/skull base tumors included 40 IDH2 mutants studied by light microscopy, immunohistochemistry, and genome-wide DNA methylation, and 125 IDH2 wild-type tumors used for comparison. Methylation profiles were analyzed by unsupervised hierarchical clustering, t-distributed stochastic neighbor embedding dimensionality reduction and assessed for copy number alterations (CNA). Thirty-nine histologically assessable cases included 25 (64.1%) SNUC, 8 (20.5%) LCNEC, 2 (5.1%) poorly differentiated adenocarcinomas, 1 (2.7%) ONB, and 3 (7.7%) IDH2-mutated tumors with ONB features. All cases were high-grade showing necrosis (82.4%), prominent nucleoli (88.9%), and median 21 mitoses/10 HPFs. AE1/AE3 and/or CAM 5.2 were positive in all and insulinoma-associated protein 1 (INSM1) in 80% cases. All IDH2 mutants formed one distinct group by t-distributed stochastic neighbor embedding dimensionality reduction separating from all IDH2 wild-type tumors. There was no correlation between methylation clusters and histopathologic diagnoses. Recurrent CNA included 1q gain (79.3%), 17p loss (75.9%), and 17q gain (58.6%). No CNA differences were observed between SNUC and LCNEC. IDH2 mutants showed better disease-specific survival than SMARCB1-deficient (P=0.027) and IDH2 wild-type carcinomas overall (P=0.042). IDH2-mutated sinonasal tumors are remarkably homogeneous at the molecular level and distinct from IDH2 wild-type sinonasal malignancies. Biology of IDH2-mutated sinonasal tumors might be primarily defined by their unique molecular fingerprint rather than by their respective histopathologic diagnoses.

Association Between Mood Disorders and Risk of COVID-19 Infection, Hospitalization, and Death: A Systematic Review and Meta-analysis.

Importance: Preexisting noncommunicable diseases (eg, diabetes) increase the risk of COVID-19 infection, hospitalization, and death. Mood disorders are associated with impaired immune function and social determinants that increase the risk of COVID-19. Determining whether preexisting mood disorders represent a risk of COVID-19 would inform public health priorities. Objective: To assess whether preexisting mood disorders are associated with a higher risk of COVID-19 susceptibility, hospitalization, severe complications, and death. Data Sources: Systematic searches were conducted for studies reporting data on COVID-19 outcomes in populations with and without mood disorders on PubMed/MEDLINE, The Cochrane Library, PsycInfo, Embase, Web of Science, Google/Google Scholar, LitCovid, and select reference lists. The search timeline was from database inception to February 1, 2021. Study Selection: Primary research articles that reported quantitative COVID-19 outcome data in persons with mood disorders vs persons without mood disorders of any age, sex, and nationality were selected. Of 1950 articles identified through this search strategy, 21 studies were included in the analysis. Data Extraction and Synthesis: The modified Newcastle-Ottawa Scale was used to assess methodological quality and risk of bias of component studies. Reported adjusted odds ratios (ORs) were pooled with unadjusted ORs calculated from summary data to generate 4 random-effects summary ORs, each corresponding to a primary outcome. Main Outcomes and Measures: The 4 a priori primary outcomes were COVID-19 susceptibility, COVID-19 hospitalization, COVID-19 severe events, and COVID-19 death. The hypothesis was formulated before study search. Outcome measures between individuals with and without mood disorders were compared. Results: This review included 21 studies that involved more than 91 million individuals. Significantly higher odds of COVID-19 hospitalization (OR, 1.31; 95% CI, 1.12-1.53; P = .001; n = 26 554 397) and death (OR, 1.51; 95% CI, 1.34-1.69; P < .001; n = 25 808 660) were found in persons with preexisting mood disorders compared with those without mood disorders. There was no association between mood disorders and COVID-19 susceptibility (OR, 1.27; 95% CI, 0.73-2.19; n = 65 514 469) or severe events (OR, 0.94; 95% CI, 0.87-1.03; n = 83 240). Visual inspection of the composite funnel plot for asymmetry indicated the presence of publication bias; however, the Egger regression intercept test result was not statistically significant. Conclusions and Relevance: The results of this systematic review and meta-analysis examining the association between preexisting mood disorders and COVID-19 outcomes suggest that individuals with preexisting mood disorders are at higher risk of COVID-19 hospitalization and death and should be categorized as an at-risk group on the basis of a preexisting condition.

A Curriculum Innovation on Writing Simulated Patient Cases for Communication Skills Education.

Introduction: Facilitated communication practice with simulated patients (SPs) is a highly effective form of communication training. Unfortunately, little guidance exists on writing SP cases. Methods: We created a curriculum composed of a case-development workbook and case-writing session with input from national communication educators. In November 2017, we implemented the curriculum in a Teaching Communication Skills course for medical educators. Educators divided into four groups to write cases. Primary outcome was the number of criteria that cases fulfilled. Secondary outcomes were SP evaluation and educator-reported confidence and satisfaction. Results: Seventeen medical educators (including 15 fellows) completed the curriculum. Four new cases were analyzed against 24 criteria and compared to eight cases written by educators following a previous curriculum. An SP evaluated ease of portrayal for all 12 cases on a 5-point Likert scale (1 = poor, 5 = excellent). Educators completed precurriculum and postcurriculum surveys. Compared to the previous curriculum, cases based on the new curriculum incorporated 26% more case criteria (70% or 16.8 criteria/case vs. 96% or 23.0 criteria/case, p < .01). Ease-of-portrayal rating improved but did not differ statistically (mean: 2.8 vs. 4.5, p = .11). A moderate correlation was found between number of included case criteria and Likert-scale rating (rs = .61, p = .03). Pre- and postcurriculum, educators reported significant increases in confidence (mean: 1.9 vs. 4.0, p < .01) and high curricular satisfaction (mean: 4.8). Discussion: A case-development workbook and case-writing session increased the quality of newly developed SP cases as assessed by prespecified case criteria.

The Role of Angiogenesis-Inducing microRNAs in Vascular Tissue Engineering.

Angiogenesis is an important process in tissue repair and regeneration as blood vessels are integral to supply nutrients to a functioning tissue. In this review, the application of microRNAs (miRNAs) or anti-miRNAs that can induce angiogenesis to aid in blood vessel formation for vascular tissue engineering in ischemic diseases such as peripheral arterial disease and stroke, cardiac diseases, and skin and bone tissue engineering is discussed. Endothelial cells (ECs) form the endothelium of the blood vessel and are recognized as the primary cell type that drives angiogenesis and studied in the applications that were reviewed. Besides ECs, mesenchymal stem cells can also play a pivotal role in these applications, specifically, by secreting growth factors or cytokines for paracrine signaling and/or as constituent cells in the new blood vessel formed. In addition to delivering miRNAs or cells transfected/transduced with miRNAs for angiogenesis and vascular tissue engineering, the utilization of extracellular vesicles (EVs), such as exosomes, microvesicles, and EVs collectively, has been more recently explored. Proangiogenic miRNAs and anti-miRNAs contribute to angiogenesis by targeting the 3'-untranslated region of targets to upregulate proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and hypoxia-inducible factor-1 and increase the transduction of VEGF signaling through the PI3K/AKT and Ras/Raf/MEK/ERK signaling pathways such as phosphatase and tensin homolog or regulating the signaling of other pathways important for angiogenesis such as the Notch signaling pathway and the pathway to produce nitric oxide. In conclusion, angiogenesis-inducing miRNAs and anti-miRNAs are promising tools for vascular tissue engineering for several applications; however, future work should emphasize optimizing the delivery and usage of these therapies as miRNAs can also be associated with the negative implications of cancer.

Síndrome de pseudo-Foster Kennedy por hipertensión intracraneal idiopática / Pseudo-Foster Kennedy syndrome due to idiopathic intracranial hypertension

El síndrome de Foster-Kennedy se ha descrito por una compresión directa, debida a un proceso expansivo, del nervio óptico ipsilateral que lleva a su atrofia. En el ojo contralateral existe un papiledema debido a la hipertensión intracraneal secundaria al efecto masa del tumor. Presentamos un caso de un niño de 12 años con sobrepeso (IMC 26) y hallazgo casual en revisión oftalmológica de edema de papila en ojo derecho con atrofia del nervio óptico izquierdo. Ninguna otra sintomatología asociada ni antecedentes de interés. Exploración neurológica normal. Tomografía axial computarizada craneal urgente sin identificar masas. Se realiza punción lumbar con una presión de apertura de líquido cefalorraquídeo de 28 cm H2O. Resto de estudios normales. Hasta la aparición de la neuroimagen, se creía que el síndrome de Foster Kennedy era patognomónico de lesión ocupante de espacio en zona frontal. Existen pocas publicaciones en las que el factor causante del síndrome se atribuya a hipertensión intracraneal benigna y hasta un 25% de ellos se encuentran asintomáticos

Foster-Kennedy syndrome has been diagnosed as a direct compression of the optic nerve due to an expansive process that leads to atrophy. In the contralateral eye there is papillary oedema due to intracranial hypertension secondary to the tumour mass effect. The case is presented of a 12-year-old boy with overweight (BMI 26) with right eye papillary oedema and left optic nerve atrophy, that was casually found in an ophthalmological examination. He had no other symptomatology or personal medical history. The neurological examination was normal, and the urgent cranial computed tomography showed no masses. Lumbar puncture was performed with increased cerebrospinal fluid outflow resistance (28 cm H2O). The rest of studies were normal. Until the appearance of neuroimaging, it was believed that Foster-Kennedy syndrome was pathognomonic of intracranial mass in the frontal area. Pseudo-Foster Kennedy syndrome due to idiopathic intracranial hypertension is very rare, and in the few cases that have been reported in the literature, up to 25% of them are asymptomatic

Pseudo-Foster Kennedy syndrome due to idiopathic intracranial hypertension. / Síndrome de pseudo-Foster Kennedy por hipertensión intracraneal idiopática.

Foster-Kennedy syndrome has been diagnosed as a direct compression of the optic nerve due to an expansive process that leads to atrophy. In the contralateral eye there is papillary oedema due to intracranial hypertension secondary to the tumour mass effect. The case is presented of a 12-year-old boy with overweight (BMI 26) with right eye papillary oedema and left optic nerve atrophy, that was casually found in an ophthalmological examination. He had no other symptomatology or personal medical history. The neurological examination was normal, and the urgent cranial computed tomography showed no masses. Lumbar puncture was performed with increased cerebrospinal fluid outflow resistance (28 cm H2O). The rest of studies were normal. Until the appearance of neuroimaging, it was believed that Foster-Kennedy syndrome was pathognomonic of intracranial mass in the frontal area. Pseudo-Foster Kennedy syndrome due to idiopathic intracranial hypertension is very rare, and in the few cases that have been reported in the literature, up to 25% of them are asymptomatic.

A Proof-of-Concept Study Evaluating the Phosphodiesterase 10A Inhibitor PF-02545920 in the Adjunctive Treatment of Suboptimally Controlled Symptoms of Schizophrenia.

BACKGROUND: Effective treatments for managing suboptimal clinical responses to current therapy for schizophrenia remain a critical unmet need. Phosphodiesterase 10A (PDE10A) inhibition represents a mechanistically novel approach to the treatment of schizophrenia, with preclinical studies suggesting improvements in partially responsive symptoms could be achieved via adjunctive use of the PDE10A inhibitor PF-02545920. Therefore, the adjunctive safety, tolerability, pharmacokinetics, and efficacy of multiple repeat doses of PF-02545920 were investigated in a phase 1b study and subsequent phase 2 study. METHODS: The phase 1b study randomized 37 adult patients with stable symptomatology and stable antipsychotic regimens within 3 cohorts. Study participants received ascending doses of PF-02545920 or placebo for 10 to 18 days. The phase 2 study randomized 240 outpatients with stable symptomatology but suboptimal response to current antipsychotic regimens 1:1:1 to PF-02545920 5 mg, PF-02545920 15 mg, or placebo every 12 hours for 12 weeks. The primary efficacy end point of the phase 2 study was change in the Positive and Negative Syndrome Scale total score from baseline to week 12, with changes in other clinical assessments as secondary end points. RESULTS: Treatment was well tolerated, and observed PF-02545920 exposures were within the range predicted to be adequate for demonstrating efficacy. However, no significant differences in the prespecified efficacy end points between the 2 PF-02545920 treatment arms and placebo were observed. CONCLUSIONS: Current data and results of a prior monotherapy study in which PF-02545920 failed to differentiate from placebo refute the hypothesis that PDE10A inhibitors have use as antipsychotic agents for schizophrenia.

Determination of sigma score based on biological variation for haemostasis assays: fit-for-purpose for daily practice?

Background Internal quality control (QC) rules for laboratory tests can be derived from analytical performance specifications (APS) using the six-sigma method. We tested the applicability of this paradigm to routine haemostasis measurements. Methods Three laboratories using different instruments and reagents calculated sigma scores for their prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen and antithrombin (AT) measurements. Sigma scores were calculated using biological variation (BV) data from the literature in combination with internal and external QC data. Results Wide ranges in sigma scores for the PT (0.1-6.8), APTT (0.0-4.3), fibrinogen (1.5-8.3) and AT (0.1-2.4) were observed when QC data was combined with the minimum, median and maximum value of BV data, due in particular to a large variation in within-subject and between-subjects coefficients of variation. When the median BV values were applied, most sigma scores were below 3.0, for internal QC data; 75% and for external QC data; 92%. Conclusions Our findings demonstrate that: (1) The sigma scores for common haemostasis parameters are relatively low, and (2) The application of the six-sigma method to BV-derived APS is hampered by the large variation in published BV data. As the six-sigma concept is based on requirements for monitoring, and many haemostasis tests are only designed for diagnostic purposes, a fit-for-purpose APS is needed to achieve clinically relevant quality goals.

La narcolepsia «va a la escuela» / Narcolepsy «goes to school»

Introducción: La narcolepsia es una de las causas más comunes de somnolencia crónica. A pesar de ello, el tiempo entre el inicio de los síntomas y el diagnóstico oscila entre 5 y 15 años, y puede ser un trastorno infradiagnosticado en muchos pacientes. La clínica suele empezar a partir de los 10 años de edad, pero es difícil identificarla si aparece a edades inferiores. Presentamos el caso clínico de un niño con diagnóstico de narcolepsia con sólo 5 años de edad. Caso clínico: Niño de 5 años de edad, con excesiva somnolencia diurna acompañada de episodios de atonía ocasional de 1 mes de evolución. Se planteó un amplio diagnóstico diferencial y se solicitaron pruebas complementarias para su estudio. Ante la sospecha de narcolepsia, se realizó una videopolisomnografía nocturna, seguida de un test de latencias múltiples. En ambas pruebas se obtuvieron resultados compatibles con el diagnóstico de narcolepsia. Se practicó una punción lumbar, en la que se analizaron los valores de hipocretina en el líquido cefalorraquídeo, que resultaron indetectables. Junto con estos resultados, se solicitó la determinación de HLA DQ en sangre, con lo que se concluyó que el paciente era homocigoto por DQ6.2, indicativo de susceptibilidad a sufrir narcolepsia. Ante estos hallazgos se inició tratamiento. Conclusiones: Se presenta un caso de narcolepsia, peculiar por la edad de su inicio, con la finalidad de difundir esta entidad en el medio pediátrico y su forma de presentación, que difiere de la de los adultos. Su diagnóstico precoz permite un tratamiento eficaz y mejorar la calidad de vida de estos pacientes (AU)

Introduction: Narcolepsy is a chronic debilitating sleep disorder. Nevertheless, the time between the symptoms and diagnosis ranges from 5 to 15 years, and may be an underdiagnosed disorder in many patients. Disease onset occurs mainly around 10 years, but is difficult to identify if it appears at lower ages. We present the clinical case of a child diagnosed with narcolepsy at only 5 years of age. Case report: A 5-year-old child, with excessive daytime sleepiness and occasional episodes of sudden loss of muscle tone of 1 month evolution. A large differential diagnosis was proposed and complementary tests were performed for its study. On suspicion of narcolepsy, a nocturnal videopolisomnography was done, followed by a multiple latency test. In both tests, the results were consistent with the diagnosis of narcolepsy. The values of hypocretin in the cerebrospinal fluid were undetectable. The HLA DQ in blood, concluded that the patient was homozygous for DQ6.2, indicative of susceptibility to narcolepsy. Conclusions: A case of narcolepsy is presented, due to the early age of onset, in order to spread this entity in children, which differs from adults. Its early diagnosis allows improve the quality of life of these patients (AU)

Transient cefuroxime/metronidazole treatment induced factor V antibodies.

A 29-year-old patient presented with an appendicular infiltrate, initially treated with intravenous antibiotics, but later requiring percutaneous drainage. Both prothrombin time (PT) and activated partial thromboplastin time (aPTT) were prolonged on 3 days of antibiotic treatment and unresponsive to vitamin K or prothrombin complex concentrate. Laboratory investigation ultimately showed reduced factor V activity and factor V antibodies. In contrast to previously described cases of factor V antibodies, PT and aPTT were only mildly prolonged and residual factor V activity was still >20%. Draining of the abscess did not induce significant bleeding. Afterwards, no haemostatic medication was required. The patient was discharged from the hospital without complications. One week after cessation of the antibiotic treatment, PT and aPTT were within normal range again, with a factor V activity level of 36%. In conclusion, we present a patient with transient factor V antibodies, induced by antibiotics, without clinical bleeding tendency.

Communication skills training in surgical residency: a needs assessment and metacognition analysis of a difficult conversation objective structured clinical examination.

BACKGROUND: The objective structured clinical examination (OSCE) can be used to evaluate the Accreditation Council for Graduate Medical Education Core Competencies of Professionalism and Interpersonal and Communication Skills. The aim of this study was to describe general surgery resident performance on a "difficult conversation" OSCE. METHODS: In this prospective study, junior and senior residents participated in a 2-station OSCE. Junior stations involved discussing operative risks and benefits and breaking bad news. Senior stations involved discussing goals of care and discussing transition to comfort measures only status. Residents completed post-OSCE checklist and Likert-based self-evaluations of experience, comfort, and confidence. Trained standardized patients (SPs) evaluated residents using communication skill-based checklists and Likert-based assessments. Pearson correlation coefficients were determined between self-assessment and SP assessment. Mann-Whitney U tests were conducted between junior and senior resident variables, using α = 0.05. RESULTS: There were 27 junior residents (age 28.1 ± 1.9 years [29.6% female]) and 27 senior residents (age 32.1 ± 2.5 years [26.9% female]). The correlation of self-assessment and SP assessment of overall communication skills by junior residents was -0.32 on the risks and benefits case and 0.07 on the breaking bad news case. The correlation of self-assessment and SP assessment of overall communication skills by senior residents was 0.30 on the goals of care case and 0.26 on the comfort measures only case. SP assessments showed that junior residents had higher overall communication skills than senior residents (p = 0.03). Senior residents perceived that having difficult conversations was more level appropriate (p < 0.001), and they were less nervous having difficult conversations (p < 0.01) than junior residents. CONCLUSIONS: We found that residents perform difficult conversations well, that subjective and objective skills are correlated, and that skills-based training is needed across all residency levels. This well-received method may be used to observe, document, and provide resident feedback for these important skills.

Myocardial perfusion imaging with 13N-ammonia PET is a strong predictor for outcome.

BACKGROUND/OBJECTIVES: The aim of the present study was to assess the long-term predictive value of myocardial perfusion imaging (MPI) with (13)N-ammonia positron emission tomography (PET) in patients with suspected myocardial perfusion abnormality. At present, outcome data on the predictive value of MPI in (13)N-ammonia PET exist only for rather small patient populations. METHODS: Cardiac perfusion was assessed in 943 consecutive patients using (13)N-ammonia PET, and follow-up was obtained in 698 (74%). 77 patients who underwent early revascularization (<60 days) were excluded and 621 patients were assigned to normal versus abnormal perfusion for outcome analysis. Hard events (cardiac death and non-fatal myocardial infarction) and major adverse cardiac events (MACE; hard events, hospitalization for cardiac reasons and late revascularization) were investigated using the Kaplan-Meier method. Independent predictors for various cardiac events were identified using Cox proportional hazard regression analysis. RESULTS: During follow-up (5.7 ± 2.5 years), 275 patients had at least 1 cardiac event, including 102 cardiac deaths and 33 non-fatal myocardial infarction. Abnormal perfusion (n=469) was associated with a higher incidence of MACE (P<0.001) and hard events (P<0.001) throughout the 10-year follow-up period. CONCLUSIONS: Cardiac perfusion findings in (13)N-ammonia PET are strong predictors of long-term outcome.