FNIP1 (folliculin interacting protein 1)

Review on FNIP1 (folliculin interacting protein 1), with data on DNA, on the protein encoded, and where the gene is implicated

Frameshift mutation hotspot identified in Smith-Magenis syndrome: case report and review of literature

Smith-Magenis syndrome (SMS) is a complex syndrome involving intellectual disabilities, sleep disturbance, behavioural problems, and a variety of craniofacial, skeletal, and visceral anomalies. While the majority of SMS cases harbor an ~3.5 Mb common deletion on 17p11.2 that encompasses the retinoic acid induced-1 (RAI1) gene, some patients carry small intragenic deletions or point mutations in RAI1. We present data on two cases of Smith-Magenis syndrome with mutation of RAI1. Both cases are phenotypically consistent with SMS and RAI1 mutation but also have other anomalies not previously reported in SMS, including spontaneous pneumothoraces. These cases also illustrate variability in the SMS phenotype not previously shown for RAI1 mutation cases, including hearing loss, absence of self-abusive behaviours, and mild global delays. Sequencing of RAI1 revealed mutation of the same heptameric C-tract (CCCCCCC) in exon 3 in both cases (c.3103delC one case and and c.3103insC in the other), resulting in frameshift mutations. Of the seven reported frameshift mutations occurring in poly C-tracts in RAI1, four cases (~57%) occur at this heptameric C-tract. Collectively, these results indicate that this heptameric C-tract is a preferential hotspot for single nucleotide insertion/deletions (SNindels) and therefore, should be considered a primary target for analysis in patients suspected for mutations in RAI1. We expect that as more patients are sequenced for mutations in RAI1, the incidence of frameshift mutations in this hotspot will become more evident

Modal Analysis of Fluid Flows: An Overview

Simple aerodynamic configurations under even modest conditions can exhibit complex flows with a wide range of temporal and spatial features. It has become common practice in the analysis of these flows to look for and extract physically important features, or modes, as a first step in the analysis. This step typically starts with a modal decomposition of an experimental or numerical dataset of the flow field, or of an operator relevant to the system. We describe herein some of the dominant techniques for accomplishing these modal decompositions and analyses that have seen a surge of activity in recent decades. For a non-expert, keeping track of recent developments can be daunting, and the intent of this document is to provide an introduction to modal analysis in a presentation that is accessible to the larger fluid dynamics community. In particular, we present a brief overview of several of the well-established techniques and clearly lay the framework of these methods using familiar linear algebra. The modal analysis techniques covered in this paper include the proper orthogonal decomposition (POD), balanced proper orthogonal decomposition (Balanced POD), dynamic mode decomposition (DMD), Koopman analysis, global linear stability analysis, and resolvent analysis

Cochrane corner: PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease

In this synopsis we describe findings from a recent Cochrane review on PCSK9 inhibitors for cardiovascular disease prevention. Compared against placebo, PCSK9 inhibitors show a substantial reduction in atherogenic lipid particles (LDL-C, Apo-B and Lp(a)), and protective effects on: CVD, MI, stroke, and elevated creatinine. There is however only limited, and lower quality, evidence comparing PCSK9 inhibitors against active treatments such as statins or ezetimibe. Furthermore, the current evidence is limited by the relatively short follow-up (at most a median follow-up of 26 months) which likely also relates to the observed beneficial safety profile, showing no clear signals on adverse events such as influenza, myalgia, T2DM or cancers

UK survey of occupational therapist’s and physiotherapist’s experiences and attitudes towards hip replacement precautions and equipment

Background: Total hip replacement (THR) is one of the most common orthopaedic procedures in the United Kingdom (UK). Historically, people following THR have been provided with hip precautions and equipment such as: raised toilet seats and furniture rises, in order to reduce the risks of dislocation post-operation. The purpose of this study was to determine current practices in the provision of these interventions in the UK for people following primary THR. Methods: A 27-question, self-administered online survey was developed and distributed to UK physiotherapists and occupational therapists involved in the management of people following primary THR (target respondents). The survey included questions regarding the current practices in the provision of equipment and hip precautions for THR patients, and physiotherapist’s and occupational therapist’s attitudes towards these practices. The survey was disseminated through print and web-based/social media channels. Results: 170 health professionals (87 physiotherapists and 83 occupational therapists), responded to the survey. Commonly prescribed equipment in respondent’s health trusts were raised toilet seats (95%), toilet frames and rails (88%), furniture raises (79%), helping hands/grabbers (77%), perching stools (75%) and long-handled shoe horns (75%). Hip precautions were routinely prescribed by 97% of respondents. Hip precautions were most frequently taught in a pre-operative group (52% of respondents). Similarly equipment was most frequently provided pre-operatively (61% respondents), and most commonly by occupational therapists (74% respondents). There was variability in the advice provided on the duration of hip precautions and equipment from up to six weeks post-operatively to life-time usage. Conclusions: Current practice on hip precautions and provision of equipment is not full representative of clinician’s perceptions of best care after THR. Future research is warranted to determine whether and to whom hip precautions and equipment should be prescribed post-THR as opposed to the current ‘blanket’ provision of equipment and movement restriction provided in UK practice

PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease

Background Despite the availability of effective drug therapies that reduce low-density lipoprotein (LDL)-cholesterol (LDL-C), cardiovascular disease (CVD) remains an important cause of mortality and morbidity. Therefore, additional LDL-C reduction may be warranted, especially for patients who are unresponsive to, or unable to take, existing LDL-C-reducing therapies. By inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, monoclonal antibodies (PCSK9 inhibitors) may further reduce LDL-C, potentially reducing CVD risk as well. Objectives Primary To quantify short-term (24 weeks), medium-term (one year), and long-term (five years) effects of PCSK9 inhibitors on lipid parameters and on the incidence of CVD. Secondary To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of type 2 diabetes, cognitive function, and cancer. Additionally, to determine if specific patient subgroups were more or less likely to benefit from the use of PCSK9 inhibitors. Search methods We identified studies by systematically searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and Web of Science. We also searched Clinicaltrials.gov and the International Clinical Trials Registry Platform and screened the reference lists of included studies. We identified the studies included in this review through electronic literature searches conducted up to May 2016, and added three large trials published in March 2017. Selection criteria All parallel-group and factorial randomised controlled trials (RCTs) with a follow-up time of at least 24 weeks were eligible. Data collection and analysis Two review authors independently reviewed and extracted data. When data were available, we calculated pooled effect estimates. Main results We included 20 studies with data on 67,237 participants (median age 61 years; range 52 to 64 years). Twelve trials randomised participants to alirocumab, three trials to bococizumab, one to RG7652, and four to evolocumab. Owing to the small number of trials using agents other than alirocumab, we did not differentiate between types of PCSK9 inhibitors used. We compared PCSK9 inhibitors with placebo (thirteen RCTs), ezetimibe (two RCTs) or ezetimibe and statins (five RCTs). Compared with placebo, PCSK9 inhibitors decreased LDL-C by 53.86% (95% confidence interval (CI) 58.64 to 49.08; eight studies; 4782 participants; GRADE: moderate) at 24 weeks; compared with ezetimibe, PCSK9 inhibitors decreased LDL-C by 30.20% (95% CI 34.18 to 26.23; two studies; 823 participants; GRADE: moderate), and compared with ezetimibe and statins, PCSK9 inhibitors decreased LDL-C by 39.20% (95% CI 56.15 to 22.26; five studies; 5376 participants; GRADE: moderate). Compared with placebo, PCSK9 inhibitors decreased the risk of CVD events, with a risk difference (RD) of 0.91% (odds ratio (OR) of 0.86, 95% CI 0.80 to 0.92; eight studies; 59,294 participants; GRADE: moderate). Compared with ezetimibe and statins, PCSK9 inhibitors appeared to have a stronger protective effect on CVD risk, although with considerable uncertainty (RD 1.06%, OR 0.45, 95% CI 0.27 to 0.75; three studies; 4770 participants; GRADE: very low). No data were available for the ezetimibe only comparison. Compared with placebo, PCSK9 probably had little or no effect on mortality (RD 0.03%, OR 1.02, 95% CI 0.91 to 1.14; 12 studies; 60,684 participants; GRADE: moderate). Compared with placebo, PCSK9 inhibitors increased the risk of any adverse events (RD 1.54%, OR 1.08, 95% CI 1.04 to 1.12; 13 studies; 54,204 participants; GRADE: low). Similar effects were observed for the comparison of ezetimibe and statins: RD 3.70%, OR 1.18, 95% CI 1.05 to 1.34; four studies; 5376 participants; GRADE: low. Clinical event data were unavailable for the ezetimibe only comparison. Authors' conclusions Over short-term to medium-term follow-up, PCSK9 inhibitors reduced LDL-C. Studies with medium-term follow-up time (longest median follow-up recorded was 26 months) reported that PCSK9 inhibitors (compared with placebo) decreased CVD risk but may have increased the risk of any adverse events (driven by SPIRE-1 and -2 trials). Available evidence suggests that PCSK9 inhibitor use probably leads to little or no difference in mortality. Evidence on relative efficacy and safety when PCSK9 inhibitors were compared with active treatments was of low to very low quality (GRADE); follow-up times were short and events were few. Large trials with longer follow-up are needed to evaluate PCSK9 inhibitors versus active treatments as well as placebo. Owing to the predominant inclusion of high-risk patients in these studies, applicability of results to primary prevention is limited. Finally, estimated risk differences indicate that PCSK9 inhibitors only modestly change absolute risks (often to less than 1%)

Síntomas de pacientes antes de la primera hospitalización por Síndrome Coronario Agudo

Este estudo objetivou caracterizar os pacientes quanto ao relato da presença de sintomas de dor torácica, dispneia e limitação das atividades diárias uma semana antes da primeira hospitalização por Síndrome Coronariana Aguda, segundo a forma de apresentação clínica, e compará-las. Estudo transversal, descritivo e correlacional. Utilizou-se um instrumento de avaliação clínica que investigou a presença e a gravidade dos sintomas de dispneia, precordialgia e restrição física decorrentes da isquemia do miocárdio. Com relação à limitação para realização de atividades físicas, pacientes com diagnóstico de angina instável mostraram maior comprometimento na semana que antecedeu a internação, assim como relataram a presença de dispneia e precordialgia com maior frequência do que os pacientes infartados em situações que vão desde realizarem grandes esforços como, por exemplo, caminhar na subida ou muito rápido no plano, até situações de repouso ou de pequenos esforços.The objective of this study was to characterize and compare patients regarding their report of experiencing chest pain, dyspnea and limitation of the daily life activities one week before their first hospitalization due to Acute Coronary Syndrome, according to the clinical presentation form, and compare them. This is a cross-sectional, descriptive and correlational study. A clinical evaluation instrument was used to investigate the presence and severity of dyspnea, chest pain and physical restriction due to myocardial ischemia. Regarding the limitation to carry out physical activities, patients diagnosed with unstable angina showed lower capacity the week before hospitalization, and reported experiencing dyspnea and chest pain more frequently than patients who had an infarction in situations ranging from making strong efforts, such as walking uphill or on a flat surface but very quickly, to resting and in situations of little effort.Estudio que objetivó caracterizar a pacientes en cuanto al relato de presencia de síntomas de dolor torácico, disnea y limitación de actividades diarias una semana antes de la primera hospitalización por Síndrome Coronario Agudo, según la forma de presentación clínica, y compararlas. Estudio transversal, descriptivo y correlacional. Se utilizó un instrumento de evaluación clínica que investigó la presencia y gravedad de síntomas de disnea, precordialgia y restricción física derivadas de isquemia de miocardio. En relación a limitaciones para realización de actividades físicas, pacientes con diagnóstico de angina inestable mostraron mayor compromiso en la semana que antecedió a la internación, así como relataron la presencia de disnea y precordialgia con mayor frecuencia que en los pacientes infartados en situaciones tales como realizar grandes esfuerzos como, por ejemplo, caminar en pendiente ascendiente o muy rápido en el llano, hasta situaciones de reposo o pequeños esfuerzos

New mutations at the imprinted Gnas cluster show gene dosage effects of Gsα in postnatal growth and implicate XLαs in bone and fat metabolism, but not in suckling

The imprinted Gnas cluster is involved in obesity, energy metabolism, feeding behavior, and viability. Relative contribution of paternally expressed proteins XLαs, XLN1, and ALEX or a double dose of maternally expressed Gsα to phenotype has not been established. In this study, we have generated two new mutants (Ex1A-T-CON and Ex1A-T) at the Gnas cluster. Paternal inheritance of Ex1A-T-CON leads to loss of imprinting of Gsα, resulting in preweaning growth retardation followed by catch-up growth. Paternal inheritance of Ex1A-T leads to loss of imprinting of Gsα and loss of expression of XLαs and XLN1. These mice have severe preweaning growth retardation and incomplete catch-up growth. They are fully viable probably because suckling is unimpaired, unlike mutants in which the expression of all the known paternally expressed Gnasxl proteins (XLαs, XLN1 and ALEX) is compromised. We suggest that loss of ALEX is most likely responsible for the suckling defects previously observed. In adults, paternal inheritance of Ex1A-T results in an increased metabolic rate and reductions in fat mass, leptin, and bone mineral density attributable to loss of XLαs. This is, to our knowledge, the first report describing a role for XLαs in bone metabolism. We propose that XLαs is involved in the regulation of bone and adipocyte metabolism

Malignancy risk analysis in patients with inadequate fine needle aspiration cytology (FNAC) of the thyroid

Background Thyroid fine needle aspiration cytology (FNAC) is the standard diagnostic modality for thyroid nodules. However, it has limitations among which is the incidence of non-diagnostic results (Thy1). Management of cases with repeatedly non-diagnostic FNAC ranges from simple observation to surgical intervention. We aim to evaluate the incidence of malignancy in non-diagnostic FNAC, and the success rate of repeated FNAC. We also aim to evaluate risk factors for malignancy in patients with non-diagnostic FNAC. Materials and Methods Retrospective analyses of consecutive cases with thyroid non diagnostic FNAC results were included. Results Out of total 1657 thyroid FNAC done during the study period, there were 264 (15.9%) non-diagnostic FNAC on the first attempt. On repeating those, the rate of a non-diagnostic result on second FNAC was 61.8% and on third FNAC was 47.2%. The overall malignancy rate in Thy1 FNAC was 4.5% (42% papillary, 42% follicular and 8% anaplastic), and the yield of malignancy decreased considerably with successive non-diagnostic FNAC. Ultrasound guidance by an experienced head neck radiologist produced the lowest non-diagnostic rate (38%) on repetition compared to US guidance by a generalist radiologist (65%) and by non US guidance (90%). Conclusions There is a low risk of malignancy in patients with a non-diagnostic FNAC result, commensurate to the risk of any nodule. The yield of malignancy decreased considerably with successive non-diagnostic FNAC