The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.

Although the spliceogenic nature of the BRCA2 c.68-7T>A variant has been demonstrated, its association with cancer risk remains ontroversial. In this study, we accurately quantified by real-time PCR and digital PCR the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T>A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 x 10-115. There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24), nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the non-pathogenicity of the BRCA2 c.68-7T>A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Incidence, characteristics, and survival following cardiopulmonary resuscitation in the quaternary neonatal intensive care unit

BACKGROUND: The contemporary characteristics and outcomes of cardiopulmonary resuscitation (CPR) in the neonatal intensive care unit (NICU) are poorly described. The objectives of this study were to determine the incidence, interventions, and outcomes of CPR in a quaternary referral NICU. METHODS: Retrospective observational study of infants who received chest compressions for resuscitation in the Children’s Hospital of Philadelphia NICU between April 1, 2011 and June 30, 2015. Patient, event, and survival characteristics were abstracted from the medical record and the hospital-wide resuscitation database. The primary outcome was survival to hospital discharge. Univariable and multivariable analyses were performed to identify patient and event factors associated with survival to discharge. RESULTS: There were 1.2 CPR events per 1,000 patient days. CPR was performed in 113 of 5,046 (2.2%) infants admitted to the NICU during the study period. The median duration of chest compressions was 2 minutes (interquartile range 1, 6 minutes). Adrenaline was administered in 34 (30%) CPR events. Of 113 infants with at least one CPR event, 69 (61%) survived to hospital discharge. Factors independently associated with decreased survival to hospital discharge were inotrope treatment prior to CPR (adjusted Odds Ratio [aOR] 0.14, 95% Confidence Interval [CI] 0.04, 0.54), and adrenaline administration during CPR (aOR 0.14, 95% CI 0.04, 0.50). CONCLUSIONS: Although it was not uncommon, the incidence of CPR was low (<3%) among infants hospitalized in a quaternary referral NICU. Infants receiving inotropic therapy prior to CPR and adrenaline administration during CPR were less likely to survive to hospital discharge