Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Signal transduction analysis of the NLRP3-inflammasome pathway after cellular damage and its paracrine regulation

Activation of the NLRP3-inflammasome pathway and production of the inflammatory cytokine IL-1B after cellular damage caused by infarct or infection is a key process in several diseases such as acute myocardial infarction and inflammatory bowel disease. However, while the molecular triggers of the NLRP3-pathway after cellular damage are well known, the mechanisms that sustain or confine its activity are currently under investigation. We present here an Ordinary Differential Equation-based model that investigates the mechanisms of inflammasome activation and regulation in monocytes to predict IL-1β activation kinetics upon a two-step activation by Damage-Associate-Molecular-Particles (DAMP) and extracellular ATP. Assuming both activation signals to be concomitantly present or present with a delay of 12 h, the model predicted a transient IL-1β activation at different concentration levels dependent on signal synchronisation. Introducing a positive feedback loop mediated by active IL-1β resulted in a sustained IL-1β activation, hence arguing for a paracrine signalling between inflammatory cells to guarantee a temporally stable inflammatory response. We then investigate mechanisms that control termination of inflammation using two recently identified molecular intervention points in the inflammasome pathway. We found that a more upstream regulation, by attenuating production of the IL-1β-proform, was more potent in attenuating active IL-1β production than direct inhibition of the NLRP3-inflammasome. Interestingly, ablating this upstream negative feedback led to a high variability of IL-1β production in monocytes from different subjects, consistent with a recent pre-clinical study. We finally discuss the relevance and implications of our findings in disease models of acute myocardial infarction and spontaneous colitis

Implementation of Motivational Interviewing Training in an Undergraduate Nursing Curriculum: Identifying Adolescents at Risk for Substance Use

Motivational interviewing (MI) has been increasingly utilized by health care practitioners for many years. MI has been practiced by social workers, nurses, physicians, psychologists, substance use counselors, and many other health care practitioners. Unfortunately, many health care practitioners do not have adequate training in motivational interviewing, and therefore feel ill equipped to utilize this approach when faced with clients who are in need of assessment and coaching. This paper discusses our experiences with a pilot project to implement MI training within an Adolescent SBIRT (Screening, Brief Intervention, Referral to Treatment) content addition to the undergraduate nursing curriculum. It includes discussion of the evaluation, which measured student attitudes towards substance users with the Substance Use Attitudinal Survey (SAAS), student satisfaction with the newly implemented curriculum, and implications for sustainable inclusion of this content and simulation experiences at the undergraduate level to promote MI use by future health care practitioners. Pre- and post-tests (SAAS) were conducted with 51 nursing students, and 56 students completed the satisfaction survey. Overall, students were very satisfied with the implementation of the curriculum, however, we did not see significant changes in SAAS test scores. This may, however, be a positive indicator of a balanced attitude toward substance users. Continuing evaluation of the curriculum change is needed

Static progressive versus dynamic splinting for posttraumatic elbow stiffness: a systematic review of 232 patients

The elbow is prone to stiffness after trauma. To regain functional elbow motion, several conservative and surgical treatment options are available. Nonoperative treatment includes physical therapy, intra-articular injections with corticosteroids, and a static progressive or dynamic splinting program. The objective of this study was to perform a comprehensive review of the literature to evaluate the best current evidence for nonoperative treatment options for posttraumatic elbow stiffness. We performed a search of all studies on nonoperative treatment for elbow stiffness in human adults. All articles describing nonoperative treatment of elbow stiffness, written in the English, German, French or Dutch language, including human adult patients and with the functional outcome reported were included in this study. Eight studies (including 232 patients) met our eligibility criteria and were included for data analysis and pooling. These studies included one randomized controlled trial and seven retrospective cohort studies. Static progressive splinting was evaluated in 160 patients. The average pre-splinting range of motion of all elbows was 72°, which improved by 36° after splinting to an average post-splinting arc of motion of 108°. Dynamic splinting was evaluated in 72 patients with an average pre-splinting range of motion of 63°. The average improvement was 37° to an average post-splinting arc of motion of 100°. Both dynamic orthoses and static progressive splinting show good results for the treatment of elbow stiffness, regardless of etiology. The choice for one treatment over the other is based on the preference of the surgeon and patient. We recommend to continue nonoperative treatment with dynamic or static bracing for 12 months or until patients stop making progression in range of elbow motio

C-reactive protein during and after myocardial infarction in relation to cardiac injury and left ventricular function at follow-up

BACKGROUND: Acute myocardial infarction (MI) invokes a large inflammatory response, which contributes to myocardial repair. HYPOTHESIS: We investigated whether C-reactive protein (CRP) measured during MI vs at 1 month follow-up improves the prediction of left ventricular (LV) function. METHODS: We prospectively enrolled 131 consecutive patients with acute MI and without non-cardiovascular causes of inflammation. We correlated admission and peak levels of CRP during hospitalization and high-sensitivity (hs) CRP at 1 month follow-up with markers of cardiac injury. Clinical follow-up and echocardiography for LV function were performed at a mean of 17 months. RESULTS: Median CRP levels were 1.89 mg/L on admission with MI, peaked to 12.10 mg/L during hospitalization and dropped to 1.24 mg/L at 1 month. Although admission CRP levels only weakly correlated with ejection fraction in the acute phase of MI (coefficient -0.164, P = 0.094), peak CRP was significantly related to ejection fraction (coefficient -0.4, P < 0.001), hsTroponin T (0.389, P < 0.001), and white blood cell count (0.389, P < 0.001). hsCRP at 1 month was not related to the extent of acute cardiac injury. These findings were replicated in an independent cohort of 57 patients. Peak CRP predicted LV dysfunction at follow-up (OR 11.0, 3.1-39.5 per log CRP, P < 0.001), persisting after adjustment for infarct size (OR 5.1, 1.1-23.6, P = 0.037), while hsCRP at 1 month was unrelated to LV function at follow-up. CONCLUSIONS: hsCRP 1 month post-MI does not relate to acute cardiac injury or LV function at follow-up, but we confirm that peak CRP is an independent predictor of LV dysfunction at follow-up.status: publishe

Network structure of time-varying depressive symptoms through dynamic time warp analysis in late-life depression

OBJECTIVES: Late‐life major depressive disorder (MDD) can be conceptualized as a complex dynamic system. However, it is not straightforward how to analyze the covarying depressive symptoms over time in case of sparse panel data. Dynamic time warping (DTW) analysis may yield symptom networks and dimensions both at the patient and group level. METHODS: In the Netherlands Study of Depression in Older People (NESDO) depressive symptoms were assessed every 6 months using the 30‐item Inventory of Depressive Symptomatology (IDS) with up to 13 assessments per participant. Our sample consisted of 182 persons, aged ≥ 60 years, with an IDS total score of 26 or higher at baseline. Symptom networks dimensions, and centrality metrics were analyzed using DTW and Distatis analyses. RESULTS: The mean age was 69.8 years (SD 7.1), with 69.0% females, and a mean IDS score of 38.0 (SD = 8.7). DTW enabled visualization of an idiographic symptom network in a single NESDO participant. In the group‐level nomothetic approach, four depressive symptom dimensions were identified: “core symptoms”, “lethargy/somatic”, “sleep”, and “appetite/atypical”. Items of the “internalizing symptoms” dimension had the highest centrality, whose symptom changes over time were most similar to those changes of other symptoms. CONCLUSIONS: DTW revealed symptom networks and dimensions based on the within‐person symptom changes in older MDD patients. Its centrality metrics signal the most influential symptoms, which may aid personalized care

Radial Head Arthroplasty: A Systematic Review

Despite the expanding body of literature on radial head arthroplasty, the increasing understanding of elbow anatomy, biomechanics, and kinetics, and the evolution of surgical techniques and prosthesis designs, there is currently no evidence to support one type of radial head prosthesis over another. The purposes of the present report were to review the literature and to explore the association between prosthesis design variables and the timing of surgery and the outcome of modern radial head arthroplasty. The literature search was limited to studies involving skeletally mature patients. Major databases were searched from January 1940 to May 2015 to identify studies relating to functional and subjective outcomes and radiographic results after radial head arthroplasty. Thirty articles involving 727 patients were included. Seventy percent of the implants were made of cobalt-chromium, 15% were made of pyrocarbon, 9% were made of titanium, and 6% were made of Vitallium. Seventy percent were monopolar, and 30% were bipolar. Twenty-one percent were cemented in place, 32% were press-fit, 32% were intentionally loose-fit, and 15% were fixed with an expandable stem. The weighted average duration of follow-up was 45 months. The rate of revision ranged from 0% to 29% among studies. The incidence of revision was 8% during 2,714 person-years of follow-up across all 727 patients, yielding a crude overall revision rate of 2.06 per 100 person-years of follow-up. The revision rate was not significantly affected by prosthesis polarity, material, or fixation technique, nor was it significantly affected by the delay of treatment. There was also no significant effect of prosthesis polarity, material, or fixation technique on postoperative range of motion. The Mayo Elbow Performance Score was only reported for half of the overall patient population, but, among those patients, the combined rate of excellent and good results was 85%. Seven percent of the overall patient population underwent secondary surgery about the elbow other than revision surgery. Twenty-three percent were reported to have 1 or more complications. On the basis of our analysis of the peer-reviewed English-language literature on radial head arthroplasty from January 1940 to May 2015, there seems to be no evidence to support one type of radial head prosthesis over another. The only exception is that silicone prostheses have been shown to be biologically and biomechanically insufficient. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidenc

Peripheral Blood RNA Levels of QSOX1 and PLBD1 Are New Independent Predictors of Left Ventricular Dysfunction After Acute Myocardial Infarction

BACKGROUND: The identification of patients with acute myocardial infarction (MI) at risk of subsequent left ventricular (LV) dysfunction remains challenging, but it is important to optimize therapies. The aim of this study was to determine the unbiased RNA profile in peripheral blood of patients with acute MI and to identify and validate new prognostic markers of LV dysfunction. METHODS: We prospectively enrolled a discovery cohort with acute MI (n=143) and performed whole-blood RNA profiling at different time points. We then selected transcripts on admission that related to LV dysfunction at follow-up and validated them by quantitative polymerase chain reaction in the discovery cohort, in an external validation cohort (n=449), and in a representative porcine MI model with cardiac magnetic resonance-based measurements of infarct size and postmortem myocardial pathology (n=33). RESULTS: RNA profiling in the discovery cohort showed upregulation of genes involved in chemotaxis, IL (interleukin)-6, and NF-κB (nuclear factor-κB) signaling in the acute phase of MI. Expression levels of the majority of these transcripts paralleled the rise in cardiac troponin T and decayed at 30 days. RNA levels of QSOX1, PLBD1, and S100A8 on admission with MI correlated with LV dysfunction at follow-up. Using quantitative polymerase chain reaction, we confirmed that QSOX1 and PLBD1 predicted LV dysfunction (odds ratio, 2.6 [95% CI, 1.1-6.1] and 3.2 [95% CI, 1.4-7.4]), whereas S100A8 did not. In the external validation cohort, we confirmed QSOX1 and PLBD1 as new independent markers of LV dysfunction (odds ratio, 1.41 [95% CI, 1.06-1.88] and 1.43 [95% CI, 1.08-1.89]). QSOX1 had an incremental predictive value in a model consisting of clinical variables and cardiac biomarkers (including NT-proBNP [N-terminal pro-B-type natriuretic peptide]). In the porcine MI model, whole-blood levels of QSOX1 and PLBD1 related to neutrophil infiltration in the ischemic myocardium in an infarct size-independent manner. CONCLUSIONS: Peripheral blood QSOX1 and PLBD1 in acute MI are new independent markers of LV dysfunction post-MI.status: publishe