Anwer, Lucman A.

Background Much research has been done into finding specific molecular pathways involved in the metastatic and invasive potential of breast cancer cells. One of the major discoveries of this past decade has been microRNAs; which are single‐stranded non‐coding RNA molecules. Interestingly a single microRNA can influence the expression of hundreds of proteins, thereby highlighting their significance as modulators of gene expression. Apart from their role in regulating various intracellular processes, abnormal changes in microRNA expression have been linked to various human cancers. Until recently the nature and impact of most of these changes in breast cancer were unclear. However, some of the microRNA dysregulations have now been correlated with clinic‐pathological features such as Her2, ER and PR status, tumor stage, angiogenesis, metastasis and invasion. Of note to our study, compiling data has shown that microRNAs regulate cancer metastasis by influencing multiple steps in the metastatic cascade. This review will focus on key microRNAs associated with breast cancer invasion and metastasis; recently referred to as ‘metastamirs’. Methods We used the program EndNote X7 to research PubMed published articles regarding microRNAs in Breast Cancer. The terms “miRNAs” and “Breast cancer” were used as search words and the publication years were specified to range from 2005 to 2016. Our preliminary search revealed no articles pertaining to our topic before the year 2005, hence our paper covers nearly the entire literature on the topic. The retrieved records were then reviewed, and all those pertaining to metastasis and invasion in breast cancer were included in our study. Results Our EndNote search retrieved a total of 2820 abstracts, of which more than 280 were pertaining to metastasis and invasion in breast cancer. These abstracts were then read thoroughly, and roughly 130 metastasis/invasion specific microRNAs or clusters of microRNAs were identified. Interestingly, some microRNAs were shown to promote metastasis and invasion when up‐regulated, while others did so when they were down‐regulated. Nonetheless, all the identified microRNAs brought about their effects through various molecular pathways, some at more critical stages in the metastasis cascade than others. presents some of the commonly identified pro‐metastatic & anti‐metastatic microRNAs. Conclusion The last decade has been revelationary with regards to non‐coding RNAs, microRNAs, and their association with various cancers. Our comprehensive review highlights the various microRNAs involved in key pathways within the breast cancer metastatic pathway. Co‐relating these microRNAs to clinically targetable pathophysiological points could revolutionize our fight against breast cancer; by not only serving as diagnostic & prognostic markers, but also being potential therapeutic targets. Carefully designed translational studies seem to be the call of the hour, to finally give us the much‐needed edge over breast cancer. Support or Funding Information The authors report no source of funding or support.

Background Sudden unexpected death in epilepsy ( SUDEP ) is the leading cause of epilepsy‐related death. SUDEP shares many features with sudden cardiac death and sudden unexplained death in the young and may have a similar genetic contribution. We aim to systematically review the literature on the genetics of SUDEP . Methods and Results PubMed, MEDLINE Epub Ahead of Print, Ovid Medline In‐Process & Other Non‐Indexed Citations, MEDLINE , EMBASE , Cochrane Database of Systematic Reviews, and Scopus were searched through April 4, 2017. English language human studies analyzing SUDEP for known sudden death, ion channel and arrhythmia‐related pathogenic variants, novel variant discovery, and copy number variant analyses were included. Aggregate descriptive statistics were generated; data were insufficient for meta‐analysis. A total of 8 studies with 161 unique individuals were included; mean was age 29.0 (± SD 14.2) years; 61% males; ECG data were reported in 7.5% of cases; 50.7% were found prone and 58% of deaths were nocturnal. Cause included all types of epilepsy. Antemortem diagnosis of Dravet syndrome and autism (with duplication of chromosome 15) was associated with 11% and 9% of cases. The most frequently detected known pathogenic variants at postmortem were in Na + and K + ion channel subunits, as were novel potentially pathogenic variants (11%). Overall, the majority of variants were of unknown significance. Analysis of copy number variant was insignificant. Conclusions SUDEP case adjudication and evaluation remains limited largely because of crucial missing data such as ECG s. The most frequent pathogenic/likely pathogenic variants identified by molecular autopsy are in ion channel or arrhythmia‐related genes, with an ≈11% discovery rate. Comprehensive postmortem examination should include examination of the heart and brain by specialized pathologists and blood storage.

Despite the growing acceptance of left ventricular assist device (LVAD) therapy to improve survival and quality of life in heart failure (HF) patients, uncertainties persist regarding the definition of a successful implant. We sought to define an innovative approach to assess success and subsequently compare preoperative variables affecting outcomes. From January 2007 to 2015, 278 patients underwent LVAD implantation. Median age at implant was 62 years and 81% patients were males. Indication for support was bridge-to-transplantation in 36% patients and the etiology of HF was ischemic in 49% patients. Based on clinically relevant and accepted standards, we defined successful LVAD implant as someone who was alive or transplanted at 2 years, had two or less readmissions in the first year, had no major adverse events in the first year, and had a New York Heart Association class of ≤ II at 6 months. Follow-up was obtained for a median of 1.7 years for a total of 605 patient-years-of-support. Based on our criteria, 81/278 (29%) patients were defined as having a successful implant. Univariate predictors of LVAD failure included destination therapy indication (hazard ratio [HR] = 2.11 [1.24, 3.58]), ischemic cardiomyopathy (HR = 1.73 [1.02, 2.94]), and a higher left ventricular ejection fraction (HR = 1.54 [1.07, 2.22]). After multivariable analysis, only destination therapy indication (HR = 2.2 [1.28, 3.78]) was found to be independently predictive of success failure. Despite an overall trend toward improved outcomes on device therapy, our criteria classified only one-third of patients as successful. Continued improvements in adverse event profiles, appropriate patient selection, and optimal time of implantation, together hold the key to improve outcomes after LVAD therapy.

Continuous-flow left ventricular assist devices (CF-LVADs) have revolutionized the management of patients with advanced heart failure. Alternative implant strategies are increasingly used for device placement. We reviewed our experience from the Mechanical Circulatory Support Research Network registry with the HeartWare centrifugal CF-LVAD (HVAD). From May 2004 to August 2015, 1,150 patients underwent primary CF-LVAD implantation at our institutions. Within this group, a total of 283 patients (25%) were implanted with the HVAD. A minimally invasive left lateral thoracotomy (MILT) implant strategy was used in 53 patients (20%), of which 22 (42%) were implanted off-pump. Median age at implant was 59 years and 183 patients (65%) were implanted as bridge-to-transplantation. Follow-up was 100% complete for a total of 302 patient-years of support. In-hospital mortality was 4.9% (14 patients), and was comparable between the conventional sternotomy (CS) and MILT cohorts (p = 0.15). Patients in the MILT cohort had a shorter median length of stay (p < 0.01) and had a lower incidence of postimplant pump thrombus (p = 0.02). Cumulative survival at the end of follow-up reached 84%, and was comparable between the two groups (p = 0.298). Multivariate analysis identified preoperative bilirubin level as the only independent predictor of survival. Surgical technique had no impact on survival. In this large, multicenter experience, data demonstrate excellent survival and adverse event profiles for patients supported with the HVAD technology, regardless of surgical implant technique. With constant advancements in device technology along with our increasing clinical experience with the newer techniques, minimally invasive LVAD implantation continues to evolve as a valuable alternative to CS in selected patients.

Atrial fibrillation (AF) and tricuspid regurgitation (TR) are common in patients undergoing left ventricular assist device (LVAD) implantation. TR progression is associated with the presence of AF, and questions remain as to who benefits from tricuspid valve procedures (TVPs). We examined the impact of preoperative AF on TR progression after LVAD implantation. From February 2007 to May 2014, 250 patients underwent LVAD implantation at our institution. Patients with concomitant TVP were excluded from this analysis (113 patients). The indication for LVAD was destination therapy in 80 patients (58%) and the etiology of heart failure was ischemic in 73 (53%). Follow-up was available in all early survivors for a total of 393 patient-years of support. Of the 137 non-TVP patients, 52 (38%) had AF preoperatively. Observed overall survival at 1, 3, and 5 years was 82%, 67%, and 55%, respectively. Median grade of TR increased from 2 preoperatively to 3 (p = 0.04) in the AF group and 2.2 (p = 0.75) in the non-AF group at 5 years of follow-up. We also observed a significant difference in the degree of TR between groups at 3 months (p = 0.03) and 12 months (p = 0.01) postimplantation, and a trend toward significance at 18 (p = 0.06) and 24 (p = 0.07) months. The presence of AF is associated with early progression of TR after LVAD implantation. Addition of concomitant TVP in patients with preoperative AF may be considered in patients with less than severe TR. The impact of these findings on right ventricular failure/remodeling remains to be evaluated.

Objectives The qualitative subjective assessment has been exercised either by self-reflection (self-assessment (SA)) or by an observer (peer assessment (PA)) and is considered to play an important role in students’ development. The objectivity of PA and SA by students as well as those by faculty examiners has remained debated. This matters most when it comes to a high-stakes examination. We explored the degree of objectivity in PA, SA, as well as the global rating by examiners being Examiners’ Subjective Assessment (ESA) compared with Objective Structured Clinical Examinations (OSCE). Design Prospective cohort study. Setting Undergraduate medical students at Alfaisal University, Riyadh. Participants All second-year medical students (n=164) of genders, taking a course to learn clinical history taking and general physical examination. Main outcome measures A Likert scale questionnaire was distributed among the participants during selected clinical skills sessions. Each student was evaluated randomly by peers (PA) as well as by himself/herself (SA). Two OSCEs were conducted where students were assessed by an examiner objectively as well as subjectively (ESA) for a global rating of confidence and well-preparedness. OSCE-1 had fewer topics and stations, whereas OSCE-2 was terminal and full scale. Results OSCE-1 (B=0.10) and ESA (B=8.16) predicted OSCE-2 scores. ‘No nervousness’ in PA (r=0.185, p=0.018) and ‘confidence’ in SA (r=0.207, p=0.008) correlated with ‘confidence’ in ESA. In ‘well-preparedness’, SA correlated with ESA (r=0.234, p=0.003). Conclusions OSCE-1 and ESA predicted students’ performance in the OSCE-2, a high-stakes evaluation, indicating practical ‘objectivity’ in ESA, whereas SA and PA had minimal predictive role. Certain components of SA and PA correlated with ESA, suggesting partial objectivity given the limited objectiveness of ESA. Such difference in ‘qualitative’ objectivity probably reflects experience. Thus, subjective assessment can be used with some degree of objectivity for continuous assessment.