Virtual Bioequivalence Assessment of Ritlecitinib Capsules with Incorporation of Observed Clinical Variability Using a Physiologically Based Pharmacokinetic Model.

Ritlecitinib, an orally available Janus kinase 3 and tyrosine kinase inhibitor being developed for the treatment of alopecia areata (AA), is highly soluble across the physiological pH range at the therapeutic dose. As such, it is expected to dissolve rapidly in any in vitro dissolution conditions. However, in vitro dissolution data showed slower dissolution for 100-mg capsules, used for the clinical bioequivalence (BE) study, compared with proposed commercial 50-mg capsules. Hence, a biowaiver for the lower 50-mg strength using comparable multimedia dissolution based on the f2 similarity factor was not possible. The in vivo relevance of this observed in vitro dissolution profile was evaluated with a physiologically based pharmacokinetic (PBPK) model. This report describes the development, verification, and application of the ritlecitinib PBPK model to translate observed in vitro dissolution data to an in vivo PK profile for ritlecitinib capsule formulations. Virtual BE (VBE) trials were conducted using the Simcyp VBE module, including the model-predicted within-subject variability or intra-subject coefficient of variation (ICV). The results showed the predicted ICV was predicted to be smaller than observed clinical ICV, resulting in a more optimistic BE risk assessment. Additional VBE assessment was conducted by incorporating clinically observed ICV. The VBE trial results including clinically observed ICV demonstrated that proposed commercial 50-mg capsules vs clinical 100-mg capsules were bioequivalent, with > 90% probability of success. This study demonstrates a PBPK model-based biowaiver for a clinical BE study while introducing a novel method to integrate clinically observed ICV into VBE trials with PBPK models. Trial registration: NCT02309827, NCT02684760, NCT04004663, NCT04390776, NCT05040295, NCT05128058.

[Gerstmann-Sträussler disease: a familial case with common PRNP mutation and atypical features]. / Bolezn' Gerstmana­Shtrosslera: semeinyi sluchai s chastoi mutatsiei gena PRNP i atipichnymi proyavleniyami.

Gerstmann-Sträussler disease (GSD) is a very rare autosomal dominant late-onset neurodegenerative disorder related to prion protein gene PRNP. Mutation p.Pro102Leu produces about 80% of cases, which are often named GSD-102. DNA testing provides exact diagnosis. In the presented Russian family there were 3 patients: a female index case, age 32 years, her brother, age 37 years (age of onset in both is 27 years) and their deceased father (onset in 35 years, death in 44 years). GSD was not suspected until whole exome sequencing in the female detected PRNP mutation p.Pro102Leu confirmed in her and in the brother by Sanger sequencing. Atypical features of the case are: early onset in siblings, absence of mental and behavioral problems in the female and in the father and mild disturbances in the brother; epilepsy in the brother; atypical onset with transient signs in the brother. Other intrafamilial differences are prevailing spastic paraparesis in the female in contrast to predominant ataxia in the brother and dysarthria absence in the female. The case illustrates GSD-102 variability, complicating clinical diagnostics.

Prediction of Regulatory SNPs in Putative Minor Genes of the Neuro-Cardiovascular Variant in Fabry Reveals Insights into Autophagy/Apoptosis and Fibrosis.

Even though a mutation in monogenic diseases leads to a "classic" manifestation, many disorders exhibit great clinical variability that could be due to modifying genes also called minor genes. Fabry disease (FD) is an X-linked inborn error resulting from the deficient or absent activity of alpha-galactosidase A (α-GAL) enzyme, that leads to deposits of globotriaosylceramide. With our proprietary software SNPclinic v.1.0, we analyzed 110 single nucleotide polymorphisms (SNPs) in the proximal promoter of 14 genes that could modify the FD phenotype FD. We found seven regulatory-SNP (rSNPs) in three genes (IL10, TGFB1 and EDN1) in five cell lines relevant to FD (Cardiac myocytes and fibroblasts, Astrocytes-cerebellar, endothelial cells and T helper cells 1-TH1). Each SNP was confirmed as a true rSNP in public eQTL databases, and additional software suggested the prediction of variants. The two proposed rSNPs in IL10, could explain components for the regulation of active B cells that influence the fibrosis process. The three predicted rSNPs in TGFB1, could act in apoptosis-autophagy regulation. The two putative rSNPs in EDN1, putatively regulate chronic inflammation. The seven rSNPs described here could act to modulate Fabry's clinical phenotype so we propose that IL10, TGFB1 and EDN1 be considered minor genes in FD.

Variabilidad clínica del síndrome de ovario poliquístico / Clinical variability in polycystic ovary syndrome

Introducción: El síndrome de ovario poliquístico es la forma más común de anovulación crónica relacionada con exceso de andrógenos. La prevalencia oscila según el criterio diagnóstico utilizado entre 4-21 pòr ciento. Objetivo: Describir las características clínicas de las pacientes con síndrome de ovario poliquístico. Métodos: Se seleccionaron los consensos hasta ahora realizados y artículos originales de los último 10 años, disponibles en los siguientes buscadores: Pubmed, Medscape, Scielo, Bireme. Se consideraron otras publicaciones que por su importancia clínica no han sido replicados. Conclusiones: La variedad de fenotipos presentes en el SOP hace que las manifestaciones clínicas y factores de riesgo para otras morbilidades sean heterogéneas. La influencia que ejerce además su etiopatogenia, no completamente dilucidada, hace que el diagnóstico y por consiguiente el manejo actual de estas pacientes tenga un enfoque multidisciplinario, individualizado y enfocado a las prioridades e inconformidades que puedan afectar su calidad de vida(AU)

Introduction: Polycystic ovary syndrome (PCOS) is the most common form of chronic anovulation related to androgen excess. The prevalence ranges according to the diagnostic criteria used between 4-21 percent. Objective: To describe the clinical characteristics of patients with polycystic ovary syndrome. Methods: The consensuses and original articles of the last 10 years were selected, which were available in the following search engines: Pubmed, Medscape, Scielo, and Bireme. Other publications that due to their clinical importance have not been replicated were considered. Conclusions: The variety of phenotypes present in the polycystic ovary syndrome makes the clinical manifestations and risk factors for other morbidities heterogeneous. The influence exerted also by its etiopathogenesis, not completely elucidated, causes the diagnosis and therefore the current management of these patients to have a multidisciplinary approach which is individualized and focused on the priorities and nonconformities that may affect the patients' quality of life(AU)

A novel phenotype in an Italian family with a rare progranulin mutation.

INTRODUCTION: Progranulin (PGRN) is a secreted glycoprotein encoded in humans by the GRN gene, located on chromosome 17q21. Several nonsense and missense pathogenetic GRN mutations have been described. OBJECTIVE: We herein describe two sisters carrying a rare GRN mutation with extremely different clinical features and family history of dementia and behavioral disorders, with a novel presentation with stridor and dysphonia. METHODS: Patients underwent a multidimensional assessment including neurological and neuropsychological evaluation, structural and functional imaging, and genetic screening. RESULTS: The younger sister presented at the age of 64 with inspiratory stridor, dysphonia and exercise-induced dyspnea. Transnasal fiberoptic laryngoscopy showed bilateral adduction of the vocal cords at rest and paradoxical further adduction of the vocal cords during forced inspiration, suggesting the hypothesis of an adductor laryngeal dystonia. The older sister presented at the age of 63 with a rapidly progressive corticobasal syndrome. The only clinical feature common to both sisters was a dysexecutive syndrome. The c.893G > A mutation in exon 9 of GRN was found in heterozygosis in both sisters, causing a missense Arginine to Histidine substitution in position 298 of the protein (p.R298H). CONCLUSIONS: Our report supports the pathogenicity of the GRN p.R298H mutation, which is first detected in two members from the same family, showing an extremely different phenotypes. Moreover, we report the first case of an FTD-associated mutation presenting with inspiratory stridor and dysphonia linked to adductor laryngeal dystonia, thus expanding the clinical spectrum of GRN-related disorders.

Ventilación mecánica en España, 1998-2016: cambios en la desconexión de la ventilación mecánica / Mechanical ventilation in Spain, 1998-2016: changes in the disconnection of mechanical ventilation

Objetivo Evaluar los cambios en la desconexión de la ventilación mecánica en España desde 1998 hasta 2016. Diseño Análisis post-hoc de 4 estudios de cohorte. Ámbito Un total de 138 UCI. Enfermos Un total de 2.141 enfermos extubados de forma programada. Intervenciones Ninguna. Variables de interés principales Demográficas, motivo de ventilación mecánica, complicaciones, métodos para la desconexión, fracaso del primer intento de desconexión, duración de la desconexión, reintubación, traqueotomía post-reintubación, estancia y mortalidad en la UCI. Resultados Se observa un aumento significativo (p<0,001) en la presión de soporte como técnica de desconexión. Ha aumentado, a lo largo del tiempo, la probabilidad ajustada de utilizar la presión de soporte progresivamente decreciente frente a una prueba de ventilación espontánea, tanto para el primer intento de desconexión (referencia estudio de 1998: odds ratio 0,99 en 2004, 0,57 en 2010 y 2,43 en 2016) como para la desconexión difícil/prolongada (referencia estudio de 1998: odds ratio 2,29 en 2004, 1,23 en 2010 y 2,54 en 2016). La proporción de extubación tras el primer intento de desconexión ha aumentado con el tiempo. Hay una disminución del tiempo dedicado a la desconexión (desde un 45% en 1998 hasta un 36% en 2016). Sin embargo, no ha disminuido la duración en la desconexión difícil/prolongada (mediana 3 días en todos los estudios, p=0,435). Conclusiones Ha habido cambios significativos en el modo de desconexión de la ventilación mecánica, con un aumento progresivo del uso de la presión de soporte. Se han observado mínimos cambios en los desenlaces (AU)

Purpose To evaluate changes in the disconnection of mechanical ventilation in Spain from 1998 to 2016. Design Post-hoc analysis of four cohort studies. Ambit 138 Spanish ICUs. Patients 2141 patients scheduled extubated. Interventions None. Variables of interest Demographics, reason for mechanical ventilation, complications, methods for disconnection, failure on the first attempt at disconnection, duration of weaning, reintubation, post-reintubation tracheotomy, ICU stay and mortality. Results There was a significant increase (p<0.001) in the use of gradual reduction of support pressure. The adjusted probability of using the gradual reduction in pressure support versus a spontaneous breathing trial has increased over time, both for the first attempt at disconnection (taking the 1998 study as a reference: odds ratio 0.99 in 2004, 0.57 in 2010 and 2.43 in 2016) and for difficult/prolonged disconnection (taking the 1998 study as a reference: odds ratio 2.29 in 2004, 1.23 in 2010 and 2.54 in 2016). The proportion of patients extubated after the first attempt at disconnection has increased over time. There is a decrease in the ventilation time dedicated to weaning (from 45% in 1998 to 36% in 2016). However, the duration in difficult/prolonged weaning has not decreased (median 3 days in all studies, p=0.435). Conclusions There have been significant changes in the mode of disconnection of mechanical ventilation, with a progressive increase in the use of gradual reduction of pressure support. No relevant changes in outcomes have been observed (AU)

Mechanical ventilation in Spain, 1998-2016: Changes in the disconnection of mechanical ventilation.

PURPOSE: To evaluate changes in the disconnection of mechanical ventilation in Spain from 1998 to 2016. DESIGN: Post-hoc analysis of four cohort studies. AMBIT: 138 Spanish ICUs. PATIENTS: 2141 patients scheduled extubated. INTERVENTIONS: None. VARIABLES OF INTEREST: Demographics, reason for mechanical ventilation, complications, methods for disconnection, failure on the first attempt at disconnection, duration of weaning, reintubation, post-reintubation tracheotomy, ICU stay and mortality. RESULTS: There was a significant increase (p < 0.001) in the use of gradual reduction of support pressure. The adjusted probability of using the gradual reduction in pressure support versus a spontaneous breathing trial has increased over time, both for the first attempt at disconnection (taking the 1998 study as a reference: odds ratio 0.99 in 2004, 0.57 in 2010 and 2.43 in 2016) and for difficult/prolonged disconnection (taking the 1998 study as a reference: odds ratio 2.29 in 2004, 1.23 in 2010 and 2.54 in 2016). The proportion of patients extubated after the first attempt at disconnection has increased over time. There is a decrease in the ventilation time dedicated to weaning (from 45% in 1998 to 36% in 2016). However, the duration in difficult/prolonged weaning has not decreased (median 3 days in all studies, p = 0.435). CONCLUSIONS: There have been significant changes in the mode of disconnection of mechanical ventilation, with a progressive increase in the use of gradual reduction of pressure support. No relevant changes in outcomes have been observed.

Effectiveness of an algorithm-based care pathway for patients with non-valvular atrial fibrillation presenting to the emergency department.

OBJECTIVE: Atrial fibrillation (AF) carries substantial morbidity and mortality. Evidence-based guidelines have been synthesized into emergency department (ED) AF care pathways, but the effectiveness and scalability of such approaches are not well established. We thus evaluated the impacts of an algorithmic care pathway for ED management of non-valvular AF (EDAFMP) on hospital use and care process measures. METHODS: We deployed a voluntary-use EDAFMP in 4 EDs (1 tertiary hospital, 1 cardiac hospital, 2 community hospitals) of an integrated delivery organization using a multifaceted implementation approach. We compared outcomes between patients with AF treated using the EDAFMP and historical and contemporaneous "usual care" controls, using a propensity-score adjusted generalized estimating equation. Patients with an index ED encounter for a primary visit reason of non-valvular AF (and no excluding concurrent diagnoses) were eligible for inclusion. RESULTS: Preimplementation (January 1, 2016-December 31, 2016), 628 AF patients were eligible; postimplementation (September 1, 2017-June 30, 2019), 1296, including 271 (20.9%) treated with the EDAFMP, were eligible. EDAFMP patients were less likely to be admitted than both historical (adjusted odds ratio [aOR], 95% confidence interval [CI]: 0.45, 0.29-0.71) and contemporaneous controls (aOR, 95%CI: 0.63, 0.46-0.86). ED visits and hospital readmissions over 90 days subsequent to index ED encounters were similar between postimplementation EDAFMP and usual care groups. EDAFMP patients were more likely to be prescribed anticoagulation (38% v. 5%, P < 0.001) and be referred to a cardiologist (93% vs 29%, P < 0.001) versus the comparator group. CONCLUSION: EDAFMP use is associated with decreased hospital admission during an index ED encounter for non-valvular AF, and improved delivery of AF care processes.

Clinical and genomic findings in brain heterotopia: Report of a pediatric patient cohort from Romania.

Brain heterotopia is a group of rare malformations with a heterogeneous phenotype, ranging from asymptomatic to a severe clinical picture (drug-resistant epilepsy, severe developmental delay). The etiology is multifactorial, including both genetic and environmental factors. In the present study, a cohort of 15 pediatric patients with brain heterotopia were investigated by clinical examination, electroencephalographic studies, brain imaging, and genomic tests. Most of the patients had epileptic seizures, often difficult to control with one antiepileptic drug; another frequent characteristic in the cohort was developmental delay or intellectual disability, in some cases associated with behavioral problems. The genomic studies revealed an interstitial 22q11.2 microduplication, an anomaly not reported previously in heterotopia patients. Comparing the cohort of the present study with that of a previous series of heterotopia patients, both adult and pediatric, similar aspects, such as the high frequency of drug-resistant epilepsy were observed as well as some differences, such as no systemic malformations and no cases with fatal evolution. The current findings add new data to existing knowledge on a rare heterogeneous disorder. The detailed clinical description, including the epilepsy phenotypes, and genomic profiles bring new insights into a group of disorders, yet to be fully understood.

MLPA analysis of 32 foetuses with a congenital heart defect and 1 foetus with renal defects - pilot study. The significant frequency rate of presented pathological CNV.

AIMS: The aim of this retrospective study was to determine the detection rate of the pathogenic copy number variants (CNVs) in a cohort of 33 foetuses - 32 with CHD (congenital heart defects) and 1 with kidney defect, after exclusion of common aneuploidies (trisomy 13, 18, 21, and monosomy X) by karyotyping, Multiplex ligation - dependent probe amplification (MLPA) and chromosomal microarray analysis (CMA). We also assess the effectivity of MLPA as a method of the first tier for quick and inexpensive detection of mutations, causing congenital malformations in foetuses. METHODS: MLPA with probe mixes P070, P036 - Telomere 3 and 5, P245 - microdeletions, P250 - DiGeorge syndrome, and P311 - CHD (Congenital heart defects) was performed in 33 samples of amniotic fluid and chorionic villi. CMA was performed in 10 relevant cases. RESULTS: Pathogenic CNVs were found in 5 samples: microdeletions in region 22q11.2 (≈2 Mb) in two foetuses, one distal microdeletion of the 22q11.2 region containing genes LZTR1, CRKL, AIFM3 and SNAP29 (≈416 kb) in the foetus with bilateral renal agenesis, 8p23.1 (3.8 Mb) microdeletion syndrome and microdeletion in area 9q34.3 (1.7 Mb, Kleefstra syndrome). MLPA as an initial screening method revealed unambiguously pathogenic CNVs in 15.2 % of samples. CONCLUSION: Our study suggests that MLPA and CMA are a reliable and high-resolution technology and should be used as the first-tier test for prenatal diagnosis of congenital heart disease. Determination of the cause of the abnormality is crucial for genetic counselling and further management of the pregnancy.

Impacts of NF1 Gene Mutations and Genetic Modifiers in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a tumor predisposition genetic disorder that directly affects more than 1 in 3,000 individuals worldwide. It results from mutations of the NF1 gene and shows almost complete penetrance. NF1 patients show high phenotypic variabilities, including cafe-au-lait macules, freckling, or other neoplastic or non-neoplastic features. Understanding the underlying mechanisms of the diversities of clinical symptoms might contribute to the development of personalized healthcare for NF1 patients. Currently, studies have shown that the different types of mutations in the NF1 gene might correlate with this phenomenon. In addition, genetic modifiers are responsible for the different clinical features. In this review, we summarize different genetic mutations of the NF1 gene and related genetic modifiers. More importantly, we focus on the genotype-phenotype correlation. This review suggests a novel aspect to explain the underlying mechanisms of phenotypic heterogeneity of NF1 and provides suggestions for possible novel therapeutic targets to prevent or delay the onset and development of different manifestations of NF1.

Artificial Intelligence-Based Application Provides Accurate Medical Triage Advice When Compared to Consensus Decisions of Healthcare Providers.

Accurate medical triage is essential for improving patient outcomes and efficient healthcare delivery. Patients increasingly rely on artificial intelligence (AI)-based applications to access healthcare information, including medical triage advice. We assessed the accuracy of triage decisions provided by an AI-based application. We presented 50 clinical vignettes to the AI-based application, seven emergency medicine providers, and five internal medicine physicians. We compared the triage decisions of the AI-based application to those of the individual providers as well as their consensus decisions. When compared to the human clinicians' consensus triage decisions, the AI-based application performed equal or better than individual human clinicians.

Mechanical ventilation in Spain, 1998-2016: changes in the disconnection of mechanical ventilation. / Ventilación mecánica en España, 1998-2016: cambios en la desconexión de la ventilación mecánica.

PURPOSE: To evaluate changes in the disconnection of mechanical ventilation in Spain from 1998 to 2016. DESIGN: Post-hoc analysis of four cohort studies. AMBIT: 138 Spanish ICUs. PATIENTS: 2141 patients scheduled extubated. INTERVENTIONS: None. VARIABLES OF INTEREST: Demographics, reason for mechanical ventilation, complications, methods for disconnection, failure on the first attempt at disconnection, duration of weaning, reintubation, post-reintubation tracheotomy, ICU stay and mortality. RESULTS: There was a significant increase (p<0.001) in the use of gradual reduction of support pressure. The adjusted probability of using the gradual reduction in pressure support versus a spontaneous breathing trial has increased over time, both for the first attempt at disconnection (taking the 1998 study as a reference: odds ratio 0.99 in 2004, 0.57 in 2010 and 2.43 in 2016) and for difficult/prolonged disconnection (taking the 1998 study as a reference: odds ratio 2.29 in 2004, 1.23 in 2010 and 2.54 in 2016). The proportion of patients extubated after the first attempt at disconnection has increased over time. There is a decrease in the ventilation time dedicated to weaning (from 45% in 1998 to 36% in 2016). However, the duration in difficult/prolonged weaning has not decreased (median 3 days in all studies, p=0.435). CONCLUSIONS: There have been significant changes in the mode of disconnection of mechanical ventilation, with a progressive increase in the use of gradual reduction of pressure support. No relevant changes in outcomes have been observed.

Interfamilial clinical variability in four Polish families with cranioectodermal dysplasia and identical compound heterozygous variants in WDR35.

Cranioectodermal dysplasia (CED) is a rare autosomal recessive disorder primarily characterized by craniofacial, skeletal, and ectodermal abnormalities. CED is a chondrodysplasia, which is part of a spectrum of clinically and genetically heterogeneous diseases that result from disruptions in cilia. Pathogenic variants in genes encoding components of the ciliary transport machinery are known to cause CED. Intra- and interfamilial clinical variability has been reported in a few CED studies and the findings of this study align with these observations. Here, we report on five CED patients from four Polish families with identical compound heterozygous variants [c.1922T>G p.(Leu641Ter) and c.2522A>T; p.(Asp841Val)] in WDR35. The frequent occurrence of both identified changes in Polish CED families suggests that these variants may be founder mutations. Clinical evaluation of the CED patients revealed interfamilial clinical variability among the patients. This includes differences in skeletal and ectodermal features as well as variability in development, progression, and severity of renal and liver insufficiency. This is the first report showing significant interfamilial clinical variability in a series of CED patients from unrelated families with identical compound heterozygous variants in WDR35. Our findings strongly indicate that other genetic and non-genetic factors may modulate the progression and expression of the patients' phenotypes.

Simulating the Effects of Common Comedications and Genotypes on Alzheimer's Cognitive Trajectory Using a Quantitative Systems Pharmacology Approach.

BACKGROUND: Many Alzheimer's disease patients in clinical practice are on polypharmacy for treatment of comorbidities. OBJECTIVE: While pharmacokinetic interactions between drugs have been relatively well established with corresponding treatment guidelines, many medications and common genotype variants also affect central brain circuits involved in cognitive trajectory, leading to complex pharmacodynamic interactions and a large variability in clinical trials. METHODS: We applied a mechanism-based and ADAS-Cog calibrated Quantitative Systems Pharmacology biophysical model of neuronal circuits relevant for cognition in Alzheimer's disease, to standard-of-care cholinergic therapy with COMTVal158Met, 5-HTTLPR rs25531, and APOE genotypes and with benzodiazepines, antidepressants, and antipsychotics, all together 9,585 combinations. RESULTS: The model predicts a variability of up to 14 points on ADAS-Cog at baseline (COMTVV 5-HTTLPRss APOE 4/4 combination is worst) and a four-fold range for the rate of progression. The progression rate is inversely proportional to baseline ADAS-Cog. Antidepressants, benzodiazepines, first-generation more than second generation, and most antipsychotics with the exception of aripiprazole worsen the outcome when added to standard-of-care in mild cases. Low dose second-generation benzodiazepines revert the negative effects of risperidone and olanzapine, but only in mild stages. Non APOE4 carriers with a COMTMM and 5HTTLPRLL are predicted to have the best cognitive performance at baseline but deteriorate somewhat faster over time. However, this effect is significantly modulated by comedications. CONCLUSION: Once these simulations are validated, the platform can in principle provide optimal treatment guidance in clinical practice at an individual patient level, identify negative pharmacodynamic interactions with novel targets and address protocol amendments in clinical trials.

[Spastic ataxia of Charlevoix-Saguenay: the first Russian case report and literature review]. / Spasticheskaia ataksiia Sharlevua-Sagené: pervoe rossiiskoe nabliudenie i obzor literatury.

Spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare autosomal recessive neurodegenerative disease related to SACS gene and characterized by cerebellar, pyramidal and some other signs. The disease was delineated in Quebec, where it cumulates due to founder effect and has similar phenotype with very early onset. ARSACS in other populations is more variable. The first Russian case of ARSACS in a 37-year-old woman, an only patient in a Lak (one of Dagestan ethnicities) family, is presented. Along with main typical features, she had atypical late disease onset (in 32 years) and moderate cognitive decline. MPS-panel 'hereditary paraplegias' detected an earlier reported homo- or hemizygous mutation c.72276C>T (p.Arg2426Stop) in SACS exon 10.

Variation in Diabetes Management: A National Assessment of Primary Care Providers.

BACKGROUND: Glucose control is monitored primarily through ordering HbA1c levels, which is problematic in patients with glycemic variability. Herein, we report on the management of these patients by board-certified primary care providers (PCPs) in the United States. METHODS: We measured provider practice in a representative sample of 156 PCPs. All providers cared for simulated patients with diabetes presenting with symptoms of glycemic variability. Provider responses were reviewed by trained clinicians against evidence-based care standards and accepted standard of care protocols. RESULTS: Care varied widely-overall quality of care averaged 51.3%±10.6%-with providers performing just over half the evidence-based practices necessary for their cases. More worryingly, provider identified the underlying etiology of the poor glycemic control only 36.3% of the time. HbA1c was routinely ordered in 91.3% of all cases but often (59.5%) inappropriately. Ordering other tests of glycemic control (done in 15% of cases) led to significant increases in identifying the etiology of the hyperglycemia. Correctly modifying their patient's treatment was more likely to occur if doctors first identified the underlying etiology (65.9% vs 49.0%, P<0.001). We conservatively estimated a US $65/patient/visit in unnecessary testing and US $389 annually in additional care costs when the etiology was missed, translating potentially into millions of dollars of wasteful spending. CONCLUSION: Despite established evidence that HbA1c misses short-term changes in diabetes, we found PCPs consistently ordered HbA1c, rarely using other available blood tests. However, if the factors leading to poor glycemic control were recognized, PCPs were more likely to correctly alter their patient's hypoglycemic therapy.

Pharmacological venous thromboembolism prophylaxis in radical prostatectomy. / Profilaxis farmacológica de la tromboembolia venosa en la prostatectomía radical.

BACKGROUND AND AIM: Pulmonary thromboembolism is one of the most common causes of non-surgical death in patients following urological abdominopelvic surgery. Since the beginning of prophylaxis for venous thromboembolic disease, episodes of deep vein thrombosis and pulmonary thromboembolism have decreased. Our objective is to analyse the prognosis factors of thromboembolic disease, the clinical variability in the use of pharmacological prophylaxis and the results of its application. MATERIAL AND METHODS: Retrospective multicentric study of 610 patients undergoing radical prostatectomy between December 2013 and November 2014, in 7general hospitals in Spain, Italy and Portugal. Patients were classified according to their baseline characteristics into thrombotic risk groups and haemorrhagic risk groups. The venous thromboembolic events that occurred in the different groups were analysed. RESULTS: The average age was 65.22years (48-78). The average body mass index was 26.7 and the average ASA risk 2.1. In all patients, early mobilization began in the first 24hours. In 4.1% intermittent pneumatic compression was used and 84.6% received pharmacological prophylaxis with low molecular weight heparins. Only 3.4% used the combination of mechanical prophylaxis with pharmacological prophylaxis. We observed a decrease in the incidence of thromboembolic events in the patients who received pharmacological prophylaxis, with an absolute risk reduction of 6.8%. There was no increase in the risk of haemorrhage in the patients who received pharmacological prophylaxis. CONCLUSIONS: In this study on patients undergoing radical prostatectomy, there was no difference in haemorrhagic complications derived from the use of pharmacological prophylaxis for venous thromboembolic disease. Pharmacological prophylaxis reduces the risk of presenting a thromboembolic event in patients undergoing radical prostatectomy, although this risk is not associated with the approach technique.

[Hereditary spastic paraplegia type 4 (SPG4) in Russian patients]. / Nasledstvennaia spasticheskaia paraplegiia 4-go tipa u rossiiskikh bol'nykh.

AIM: To investigate molecular, clinical and genealogical characteristics of SPG4 in a first representative Russian group, to estimate SPG4 proportion among all DNA-diagnosed spastic paraplegias. MATERIAL AND METHODS: Fifty unrelated Russian families with SPG4 detected in the course of clinical and molecular studies of spastic paraplegias were studied. Clinical, genealogical and several molecular methods were used, i.e. Sanger sequencing of SPAST, massive parallel sequencing MPS (panel 'hereditary paraplegias') and multiplex ligation-dependent amplification MLPA. RESULTS: SPG4 proportion was 56% among all DNA verified SPG cases (90 families/14 forms) and 68% in subgroup of dominant SPG. In 50 families, 43 different SPAST mutations were detected, of which 21 were novel; percentage of large rearrangements was 30% (13 mutations in 15 families). Four mutations were detected in two families each, nonsense mutation c.1291C>T (p.Arg431*) in 4 unrelated families. Proportion of familial cases was 68%, pedigrees with 'missing' disease in elderly carriers pointed to incomplete penetrance. Age of onset varied from one year to 58 years, middle-age onset was common but the proportion of early-onset cases, particularly in male index cases, was also high. Onset age showed marked intrafamilial differences (more than 10 years in 14 pedigrees, up to 50 year in one) and between families with identical mutations. Insidious onset, slow development with most patients ambulant and 'uncomplicated' phenotype were typical. Cases with additional signs were: a family with ataxia in both patients, two families with epilepsy in one of SPG4 patients; three families with mild mental deficiency in one of SPG4 patients. A case described separately is a 29-year-old male patient with indeterminate myalgia and no SPG signs in whom SPAST previously reported mutation p.Ala430Thr de novo was an unexpected MPS finding. CONCLUSION: SPG4 substantially predomimates in SPG structure in Russian families as practically everywhere else. Half of 43 detected SPAST mutations are novel, the proportion of large rearrangements is 30% higher than in most of studies. Clinical inter- and intrafamilial variability concerns mostly age of onset. SPG4 is not exclusively adult-onset as was thought earlier.