Easing the way to achieving target serum urate in people with gout: protocol for a non-inferiority randomised strategy trial using an allopurinol dosing model in Aotearoa/New Zealand (the Easy-Allo Study).

INTRODUCTION: Gout is one of the most common forms of arthritis worldwide. Gout is particularly prevalent in Aotearoa/New Zealand and is estimated to affect 13.1% of Maori men, 22.9% of Pacific men and 7.4% of New Zealand European men. Effective long-term treatment requires lowering serum urate to <0.36 mmol/L. Allopurinol is the most commonly used urate-lowering medication worldwide. Despite its efficacy and safety, the allopurinol dose escalation treat-to-target serum urate strategy is difficult to implement and there are important inequities in allopurinol prescribing in Aotearoa. The escalation strategy is labour intensive, time consuming and costly for people with gout and the healthcare system. An easy and effective way to dose-escalate allopurinol is required, especially as gout disproportionately affects working-age Maori men and Pacific men, who frequently do not receive optimal care. METHODS AND ANALYSIS: A 12-month non-inferiority randomised controlled trial in people with gout who have a serum urate ≥ 0.36 mmol/l will be undertaken. 380 participants recruited from primary and secondary care will be randomised to one of the two allopurinol dosing strategies: intensive nurse-led treat-to-target serum urate dosing (intensive treat-to-target) or protocol-driven dose escalation based on dose predicted by an allopurinol dosing model (Easy-Allo). The primary endpoint will be the proportion of participants who achieve target serum urate (<0.36 mmol/L) at 12 months. ETHICS AND DISSEMINATION: The New Zealand Northern B Health and Disability Ethics Committee approved the study (2022 FULL 13478). Results will be disseminated in peer-reviewed journals and to participants. TRIAL REGISTRATION NUMBER: ACTRN12622001279718p.

Sequencing-based functional assays for classification of BRCA2 variants in mouse ESCs.

Sequencing of genes, such as BRCA1 and BRCA2, is recommended for individuals with a personal or family history of early onset and/or bilateral breast and/or ovarian cancer or a history of male breast cancer. Such sequencing efforts have resulted in the identification of more than 17,000 BRCA2 variants. The functional significance of most variants remains unknown; consequently, they are called variants of uncertain clinical significance (VUSs). We have previously developed mouse embryonic stem cell (mESC)-based assays for functional classification of BRCA2 variants. We now developed a next-generation sequencing (NGS)-based approach for functional evaluation of BRCA2 variants using pools of mESCs expressing 10-25 BRCA2 variants from a given exon. We use this approach for functional evaluation of 223 variants listed in ClinVar. Our functional classification of BRCA2 variants is concordant with the classification reported in ClinVar or those reported by other orthogonal assays.

Developmental outcomes for survivors of placental laser photocoagulation for the management of twin-to-twin transfusion syndrome.

BACKGROUND: Fetoscopic laser coagulation of placental anastomoses reverses the pathological process in twin-to-twin transfusion syndrome, thereby increasing survival, but there are a paucity of studies addressing long-term neurodevelopmental outcome of survivors. This study aimed to ascertain the presence of neurodevelopmental disabilities in child survivors of monochorionic pregnancies managed by placental laser photocoagulation in the Australian state of Victoria. METHODS: All pregnancies undergoing placental laser photocoagulation with the Victorian Fetal Therapy Service between 2006-2017 were included. Information on each surviving child, including demographics, perinatal course, and developmental progress was collected from parents, and consent was sought to complete the Child Behaviour Checklist. Interviewers evaluated whether this information was consistent with a diagnosis of any of 14 neurodevelopmental conditions. A three-tiered outcome measure was allocated for each child: (1) unimpaired or developmentally normal, (2) mild or moderate neurological impairment, or (3) severe neurological impairment. Clinical predictors for adverse outcome were identified. RESULTS: Of 116 pregnancies (113 twin, 3 triplet), 96 (83%) resulted in 1 + surviving fetuses. 57/113 (50%) twin pregnancies resulted in 2 survivors, 36 (32%) in 1 survivor, and 20 (18%) in no survivors. Of the 235 fetuses, 154 (65.5%) survived to follow-up. Survival increased from 59% in 2006-2008 to 73% in 2015-2017. 90/154 (58%) survivors were followed up at a mean age of 7.5 [SD 3.0] years. Based on parental interview and Child Behaviour Checklist data, 28/90 (31%) participants were assessed as having neurodevelopmental impairment, 27 of mild-moderate severity and 1 severe. Speech/language disorders, attention deficit (hyperactivity) disorders, and fine motor impairment were most common. Neonatal length of stay conferred the highest risk of impairment. CONCLUSION: Substantial variation exists between fetal therapy services in the type and length of neonatal follow-up following fetoscopic laser coagulation, contributing to a lack of data on long-term outcomes. The findings from this study support increasingly urgent calls to undertake systematic and sustained follow-up of fetoscopic laser coagulation survivors until school age. Information from this study may assist parents in their decision-making when offered fetal surgery. Importantly, it highlights a group for targeted surveillance and early intervention.

Rare germline variants in PALB2 and BRCA2 in familial and sporadic chordoma.

Chordoma is a rare bone tumor with genetic risk factors largely unknown. We conducted a whole-exome sequencing (WES) analysis of germline DNA from 19 familial chordoma cases in five pedigrees and 137 sporadic chordoma patients and identified 17 rare germline variants in PALB2 and BRCA2, whose products play essential roles in homologous recombination (HR) and tumor suppression. One PALB2 variant showed disease cosegregation in a family with four affected people or obligate gene carrier. Chordoma cases had a significantly increased burden of rare variants in both genes when compared to population-based controls. Four of the six PALB2 variants identified from chordoma patients modestly affected HR function and three of the 11 BRCA2 variants caused loss of function in experimental assays. These results, together with previous reports of abnormal morphology and Brachyury expression of the notochord in Palb2 knockout mouse embryos and genomic signatures associated with HR defect and HR gene mutations in advanced chordomas, suggest that germline mutations in PALB2 and BRCA2 may increase chordoma susceptibility. Our data shed light on the etiology of chordoma and support the previous finding that PARP-1 inhibitors may be a potential therapy for some chordoma patients.

BRCA2-DSS1 interaction is dispensable for RAD51 recruitment at replication-induced and meiotic DNA double strand breaks.

The interaction between tumor suppressor BRCA2 and DSS1 is essential for RAD51 recruitment and repair of DNA double stand breaks (DSBs) by homologous recombination (HR). We have generated mice with a leucine to proline substitution at position 2431 of BRCA2, which disrupts this interaction. Although a significant number of mutant mice die during embryogenesis, some homozygous and hemizygous mutant mice undergo normal postnatal development. Despite lack of radiation induced RAD51 foci formation and a severe HR defect in somatic cells, mutant mice are fertile and exhibit normal RAD51 recruitment during meiosis. We hypothesize that the presence of homologous chromosomes in close proximity during early prophase I may compensate for the defect in BRCA2-DSS1 interaction. We show the restoration of RAD51 foci in mutant cells when Topoisomerase I inhibitor-induced single strand breaks are converted into DSBs during DNA replication. We also partially rescue the HR defect by tethering the donor DNA to the site of DSBs using streptavidin-fused Cas9. Our findings demonstrate that the BRCA2-DSS1 complex is dispensable for RAD51 loading when the homologous DNA is close to the DSB.

Human Papillomavirus (HPV) Self-Sampling among Never-and Under-Screened Indigenous Maori, Pacific and Asian Women in Aotearoa New Zealand: A Feasibility Study.

In Aotearoa, New Zealand, the majority of cervical cancer cases occur in women who have never been screened or are under-screened. Wahine Maori, Pacific and Asian women have the lowest rate of cervical screening. Self-sampling for human papillomavirus (HPV-SS) has been shown to increase participation in cervical cancer screening. A whole-of-system approach, driven by evidence in the most effective delivery of HPV-SS, is required to mitigate further widening of the avoidable gap in cervical screening access and outcomes between groups of women in Aotearoa. This single-arm feasibility and acceptability study of HPV self-sampling invited never- and under-screened (≥5 years overdue) 30-69-year-old women from general practices in Auckland, Aotearoa. Eligible women were identified by data matching between the National Cervical Programme (NCSP) Register and practice data. Focus groups were additionally held with eligible wahine Maori, Asian and Pacific women to co-design new patient information materials. Questionnaires on HPV knowledge and post-test experience were offered to women. Our follow-up protocols included shared decision-making principles, and we committed to follow-up ≥90% of women who tested positive for HPV. Data matching identified 366 eligible never- and under-screened wahine Maori, Pacific and Asian women in participating practices. We were only able to contact 114 women, and 17, during the discussion, were found to be ineligible. Identifying and contacting women overdue for a cervical screen was resource-intensive, with a high rate of un-contactability despite multiple attempts. We found the best uptake of self-sampling was at focus groups. Of the total 84 HPV-SS tests, there were five positive results (6%), including one participant with HPV18 who was found to have a cervical Adenocarcinoma at colposcopy. In our feasibility study, self-sampling was acceptable and effective at detecting HPV and preventing cervical cancer in under-screened urban wahine Maori, Pacific and Asian women in Aotearoa. This is the first report of cervical Adenocarcinoma (Grade 1B) as a result of an HPV-18 positive self-sample in Aotearoa. We co-designed new patient information materials taking a health literacy and ethnicity-specific approach. This work provides policy-relevant information to the NCSP on the resources required to implement an effective HPV self-sampling programme to improve equity in national cervical cancer screening.

A novel mouse model of PMS2 founder mutation that causes mismatch repair defect due to aberrant splicing.

Hereditary non-polyposis colorectal cancer, now known as Lynch syndrome (LS) is one of the most common cancer predisposition syndromes and is caused by germline pathogenic variants (GPVs) in DNA mismatch repair (MMR) genes. A common founder GPV in PMS2 in the Canadian Inuit population, NM_000535.5: c.2002A>G, leads to a benign missense (p.I668V) but also acts as a de novo splice site that creates a 5 bp deletion resulting in a truncated protein (p.I668*). Individuals homozygous for this GPV are predisposed to atypical constitutional MMR deficiency with a delayed onset of first primary malignancy. We have generated mice with an equivalent germline mutation (Pms2c.1993A>G) and demonstrate that it results in a splicing defect similar to those observed in humans. Homozygous mutant mice are viable like the Pms2 null mice. However, unlike the Pms2 null mice, these mutant mice are fertile, like humans homozygous for this variant. Furthermore, these mice exhibit a significant increase in microsatellite instability and intestinal adenomas on an Apc mutant background. Rectification of the splicing defect in human and murine fibroblasts using antisense morpholinos suggests that this novel mouse model can be valuable in evaluating the efficacy aimed at targeting the splicing defect in PMS2 that is highly prevalent among the Canadian Inuits.

Influence of undergraduate medical education exposure to cadaveric dissection on choice of surgical specialty: a national survey of Canadian surgical residents.

Background: The number of Canadian Residency Matching Service (CaRMS) applicants ranking surgical specialties as their first choice has declined over the past 20 years; concurrently, there has been a reduction in the number of hours spent teaching undergraduate medical education (UGME) anatomy, particularly with cadaveric dissection. The aim of this study was to determine the factors that most influence selection of a surgical specialty, with specific focus on the impact of UGME anatomy training. Methods: A 36-item cross-sectional survey was designed by experts in medical education and distributed to all current surgical residents in Canada in October 2018. Responses were recorded on a 5-point Likert scale or by means of list ranking. We analyzed univariable outcomes with a t test for continuous outcomes and the χ2 test for dichotomous outcomes. Results: Of 1493 surgical residents, 228 responded to the survey (response rate 15.3%). Respondents reported experiences on core rotations and elective rotations, and access to a mentor as the most important factors in deciding to pursue a surgical residency. Anatomy training with or without cadaveric dissection was moderately influential in respondents' first-choice CaRMS discipline (mean Likert scale score 2.97 [standard deviation (SD) 1.34] and 2.87 [SD 1.26], respectively). General surgery residents' CaRMS applications were more likely to have been influenced by UGME anatomy training than the applications by residents in other surgical specialties (p < 0.001). The impact of UGME anatomy training did not vary between postgraduate years or between male and female residents. Conclusion: Canadian surgical residents' decision to apply to a surgical specialty did not seem to be strongly influenced by their UGME anatomy training, with or without cadaveric dissection, but, rather, by factors such as clinical experience and surgical mentorship. Further evaluation of groups that were more positively affected by their UGME anatomy training is warranted.

Contexte: Le nombre de candidats inscrits au Service de jumelage canadien des résidents (SJCR) qui classent les spécialités chirurgicales parmi leurs premiers choix a diminué ces 20 dernières années. Simultanément, dans les programmes d'études médicales prédoctorales, on a noté une baisse du nombre d'heures consacrées à l'enseignement de l'anatomie, particulièrement à la dissection de cadavres. Le but de cette étude était d'identifier les principaux facteurs qui influent sur le choix d'une spécialité chirurgicale, en portant une attention particulière à l'impact de la formation prédoctorale en anatomie. Méthodes: Des experts en formation médicale ont préparé un sondage de 36 questions qui a été distribué à tous les résidents en chirurgie au Canada en date d'octobre 2018. Les réponses ont été reportées sur une échelle de Likert en 5 points ou sous forme de liste de classement. Nous avons analysé les résultats univariés au moyen d'un test t pour les résultats continus et d'un test du χ2 pour les variables dichotomiques. Résultats: Sur 1493 résidents en chirurgie, 228 ont répondu au sondage (taux de réponse, 15,3 %). Parmi les plus importants facteurs pour décider de poursuivre leur résidence, les répondants ont mentionné leurs expériences de stages obligatoires et électifs et l'accès à un mentor. La formation en anatomie, avec ou sans dissection de cadavres, a eu une influence modérée sur le premier choix d'une discipline du SJCR (score moyen à l'échelle de Likert 2,97 [écart-type (É.-T.) 1,34] et 2,87 [É.-T. 1,26], respectivement). Les demandes d'admission des résidents en chirurgie générale étaient plus susceptibles de dépendre de la formation prédoctorale en anatomie que les demandes d'admission dans d'autres spécialités chirurgicales (p < 0.001). L'impact de la formation prédoctorale en anatomie n'a pas varié en fonction de l'année de résidence ni selon le sexe des résidents. Conclusion: La décision des résidents de chirurgie canadiens de s'inscrire dans une spécialité chirurgicale n'a pas semblé fortement influencée par la formation prédoctorale en anatomie, avec ou sans dissection de cadavres, mais plutôt par des facteurs tels que l'expérience clinique et le mentorat en chirurgie. Il faudrait étudier plus en profondeur les groupes pour qui la formation prédoctorale en anatomie a été positive.

Blood transfusion following major orthopaedic surgery in cerebral palsy: a retrospective analysis.

BACKGROUND: Progressive musculoskeletal pathology is ubiquitous among children with cerebral palsy (CP). Corrective surgery places them at risk of major blood loss and red blood cell (RBC) transfusion. Significant variability exists in uptake of perioperative patient blood management (PBM) strategies. This study aimed to examine factors contributing to RBC transfusion and assist in future development of care pathways. METHODS: A retrospective review at a tertiary paediatric hospital was undertaken to identify patients with CP undergoing either primary spinal fusion or single event, multilevel surgery (SEMLS) between 2010 and 2015. Solely soft tissue procedures were excluded. Data collected included demographics, Gross Motor Function Classification System level, surgical details, perioperative PBM and transfusion rates. Univariable analysis was performed to assess contributing factors to RBC transfusion. RESULTS: A total of 36 spinal fusion and 98 SEMLS patients were included. Preoperatively, 12% were anaemic, but only 19% had a ferritin checked. Overall, 49 patients (37%) received RBC transfusions. Intraoperative usage of tranexamic acid and cell salvage was 89% and 81%, respectively, for the spine cohort, and 22% and 3% for the SEMLS cohort. Successively higher Gross Motor Function Classification System levels, sodium valproate usage, longer surgical times, spinal fusion, pelvis instrumentation and more osteotomies were associated with RBC transfusion. CONCLUSION: More than one-third of CP patients who underwent major orthopaedic surgery received RBC transfusion. As expected, the more severely affected patients undergoing longer procedures were at highest risk. Significant improvements can be made in PBM to help optimize patients for surgery and minimize the need for transfusion.

Epidemiological and ES cell-based functional evaluation of BRCA2 variants identified in families with breast cancer.

The discovery of high-risk breast cancer susceptibility genes, such as Breast cancer associated gene 1 (BRCA1) and Breast cancer associated gene 2 (BRCA2) has led to accurate identification of individuals for risk management and targeted therapy. The rapid decline in sequencing costs has tremendously increased the number of individuals who are undergoing genetic testing world-wide. However, given the significant differences in population-specific variants, interpreting the results of these tests can be challenging especially for novel genetic variants in understudied populations. Here we report the characterization of novel variants in the Malaysian and Singaporean population that consist of different ethnic groups (Malays, Chinese, Indian, and other indigenous groups). We have evaluated the functional significance of 14 BRCA2 variants of uncertain clinical significance by using multiple in silico prediction tools and examined their frequency in a cohort of 7840 breast cancer cases and 7928 healthy controls. In addition, we have used a mouse embryonic stem cell (mESC)-based functional assay to assess the impact of these variants on BRCA2 function. We found these variants to be functionally indistinguishable from wild-type BRCA2. These variants could fully rescue the lethality of Brca2-null mESCs and exhibited no sensitivity to six different DNA damaging agents including a poly ADP ribose polymerase inhibitor. Our findings strongly suggest that all 14 evaluated variants are functionally neutral. Our findings should be valuable in risk assessment of individuals carrying these variants.

First-trimester maternal serum biomarkers and the risk of cerebral palsy.

AIM: To investigate whether combined first-trimester screening (cFTS) biomarkers are associated with cerebral palsy (CP) and to identify CP characteristics associated with abnormal biomarker levels. METHOD: In this retrospective case-control data linkage study, we matched mothers of 435 singletons with CP from a population register to their cFTS records and selected 10 singleton pregnancy controls per case. We compared mean and abnormal levels (expressed as multiples of the median [MoMs]) of pregnancy-associated plasma protein-A (PAPP-A), beta subunit of human chorionic gonadotrophin (ß-hCG), and nuchal translucency between cases and controls and between CP subgroups. RESULTS: Compared with control pregnancies, CP pregnancies had lower mean levels of PAPP-A (0.95 vs 1.01 MoM, p=0.02) and ß-hCG (0.93 vs 0.99 MoM, p=0.02). Biomarker levels in CP pregnancies were 1.8 times more likely to be associated with abnormally low levels of PAPP-A (p<0.01), 1.4 times for ß-hCG (p=0.12), and 2.6 times for low PAPP-A and ß-hCG together (p=0.04). In cases with CP, an abnormally low PAPP-A level was associated with moderate preterm birth, low Apgar scores, and Gross Motor Function Classification System level V. Low ß-hCG was associated with very low birthweight. INTERPRETATION: Low first-trimester biomarker levels suggest a role for early pregnancy factors in some causal pathways to CP. WHAT THIS PAPER ADDS: Low first-trimester levels of biomarkers in maternal serum are associated with later cerebral palsy (CP). Early pregnancy factors have potential importance in causal pathways to CP. Causal pathways involving preterm birth, term neonatal encephalopathy, and genetic syndromes may be implicated.

A computational model for classification of BRCA2 variants using mouse embryonic stem cell-based functional assays.

Sequencing-based genetic tests to identify individuals at increased risk of hereditary breast and ovarian cancers have resulted in the identification of more than 40,000 sequence variants of BRCA1 and BRCA2. A majority of these variants are considered to be variants of uncertain significance (VUS) because their impact on disease risk remains unknown, largely due to lack of sufficient familial linkage and epidemiological data. Several assays have been developed to examine the effect of VUS on protein function, which can be used to assess their impact on cancer susceptibility. In this study, we report the functional characterization of 88 BRCA2 variants, including several previously uncharacterized variants, using a well-established mouse embryonic stem cell (mESC)-based assay. We have examined their ability to rescue the lethality of Brca2 null mESC as well as sensitivity to six DNA damaging agents including ionizing radiation and a PARP inhibitor. We have also examined the impact of BRCA2 variants on splicing. In addition, we have developed a computational model to determine the probability of impact on function of the variants that can be used for risk assessment. In contrast to the previous VarCall models that are based on a single functional assay, we have developed a new platform to analyze the data from multiple functional assays separately and in combination. We have validated our VarCall models using 12 known pathogenic and 10 neutral variants and demonstrated their usefulness in determining the pathogenicity of BRCA2 variants that are listed as VUS or as variants with conflicting functional interpretation.

The role of gender in the decision to pursue a surgical career: A qualitative, interview-based study.

BACKGROUND: Previous literature has explored the underrepresentation of women in surgery. However, this research has often been quantitative or limited by considering only the perspectives and experiences of women at more advanced career stages. Here, we use a qualitative methodology and a sample of women and men across the career continuum to identify the role that gender plays in the decision to pursue a surgical career. METHODS: We audio-recorded and transcribed semi-structured interviews conducted with 12 women and 12 men ranging in their level of medical training from medical students to residents to staff surgeons. We used Braun and Clarke's six-step approach to thematic analysis to analyze the data, maintaining trustworthiness and credibility by employing strategies including reflexivity and participant input. RESULTS: Our findings suggested that the characteristics of surgery and early exposure to the profession served as important factors in participants' decisions to pursue a surgical career. Although not explicitly mentioned by participants, each of these areas may implicitly be gendered. Gender-based factors explicitly mentioned by participants included the surgical lifestyle and experiences with gender discrimination, including sexual harassment. These factors were perceived as challenges that disproportionately affected women and needed to be overcome when pursuing a surgical career. CONCLUSIONS: Our findings suggest that gender is more likely to act as a barrier to a career in surgery than as a motivator, especially among women. This suggests a need for early experiences in the operating room and mentorship. Policy change promoting work-life integration and education to target gender discrimination is also recommended.

CONTEXTE: Des publications antérieures ont exploré la sous-représentation des femmes en chirurgie. Toutefois, cette recherche a souvent été quantitative ou limitée en considérant uniquement les perspectives et expériences de femmes à des stades plus avancés de leur carrière. Ici, nous utilisons une méthodologie qualitative et un échantillon de femmes et d'hommes a des stades différents de leur carrière pour établir le rôle que le genre joue dans la décision de poursuivre une carrière en chirurgie. MÉTHODES: Nous avons enregistré et transcrit des entrevues semi-structurées menées avec douze femmes et douze hommes, dont la formation médicale variait d'étudiants en médecine à résidents et à chirurgiens membres du personnel hospitalier. Nous avons utilisé l'analyse thématique en six étapes de Braun et Clarke pour analyser les données, conservant la fiabilité et la crédibilité en utilisant des stratégies qui comprenaient la réflexivité et les commentaires des participants. RÉSULTATS: Nos résultats suggèrent que les caractéristiques de la chirurgie et d'une exposition précoce à la profession constituaient des facteurs importants dans la décision des participants de poursuivre une carrière en chirurgie. Bien que ce n'était pas explicitement mentionné par les participants, chacun de ces domaines peut être implicitement sexospécifique. Les facteurs fondés sur le genre mentionnés explicitement par les participants comprenaient le mode de vie chirurgical et les expériences avec la discrimination fondée sur le sexe, y compris le harcèlement sexuel. Ces facteurs étaient perçus comme des obstacles qui touchaient de manière disproportionnée les femmes et qui devaient être surmontés dans la poursuite d'une carrière en chirurgie. CONCLUSIONS: Nos résultats suggèrent que le genre est plus susceptible d'agir comme un obstacle à une carrière en chirurgie que comme facteur de motivation, plus particulièrement chez les femmes. Cela suggère un besoin pour des expériences précoces dans la salle d'opération et le mentorat. Un changement dans la politique favorisant l'intégration travail-vie et une éducation pour cibler la discrimination fondée sur le genre est également recommandé.

Prevalence and intensity of persistent post-surgical pain following breast cancer surgery: a systematic review and meta-analysis of observational studies.

BACKGROUND: The prevalence and intensity of persistent post-surgical pain (PPSP) after breast cancer surgery are uncertain. We conducted a systematic review and meta-analysis to further elucidate this issue. METHODS: We searched MEDLINE, Embase, CINAHL, and PsycINFO, from inception to November 2018, for observational studies reporting persistent pain (≥3 months) after breast cancer surgery. We used random-effects meta-analysis and the Grading of Recommendations, Assessment, Development and Evaluations approach to rate quality of evidence. RESULTS: We included 187 observational studies with 297 612 breast cancer patients. The prevalence of PPSP ranged from 2% to 78%, median 37% (inter-quartile range: 22-48%); the pooled prevalence was 35% (95% confidence interval [CI]: 32-39%). The pooled pain intensity was 3.9 cm on a 10 cm visual analogue scale (95% CI: 3.6-4.2 cm). Moderate-quality evidence supported the subgroup effects of PPSP prevalence for localized pain vs any pain (29% vs 44%), moderate or greater vs any pain (26% vs 44%), clinician-assessed vs patient-reported pain (23% vs 36%), and whether patients underwent sentinel lymph node biopsy vs axillary lymph node dissection (26% vs 43%). The adjusted analysis found that the prevalence of patient-reported PPSP (any severity/location) was 46% (95% CI: 36-56%), and the prevalence of patient-reported moderate-to-severe PPSP at any location was 27% (95% CI: 10-43%). CONCLUSIONS: Moderate-quality evidence suggests that almost half of all women undergoing breast cancer surgery develop persistent post-surgical pain, and about one in four develop moderate-to-severe persistent post-surgical pain; the higher prevalence was associated with axillary lymph node dissection. Future studies should explore whether nerve sparing for axillary procedures reduces persistent post-surgical pain after breast cancer surgery.

Calibration of Pathogenicity Due to Variant-Induced Leaky Splicing Defects by Using BRCA2 Exon 3 as a Model System.

BRCA2 is a clinically actionable gene implicated in breast and ovarian cancer predisposition that has become a high priority target for improving the classification of variants of unknown significance (VUS). Among all BRCA2 VUS, those causing partial/leaky splicing defects are the most challenging to classify because the minimal level of full-length (FL) transcripts required for normal function remains to be established. Here, we explored BRCA2 exon 3 (BRCA2e3) as a model for calibrating variant-induced spliceogenicity and estimating thresholds for BRCA2 haploinsufficiency. In silico predictions, minigene splicing assays, patients' RNA analyses, a mouse embryonic stem cell (mESC) complementation assay and retrieval of patient-related information were combined to determine the minimal requirement of FL BRCA2 transcripts. Of 100 BRCA2e3 variants tested in the minigene assay, 64 were found to be spliceogenic, causing mild to severe RNA defects. Splicing defects were also confirmed in patients' RNA when available. Analysis of a neutral leaky variant (c.231T>G) showed that a reduction of approximately 60% of FL BRCA2 transcripts from a mutant allele does not cause any increase in cancer risk. Moreover, data obtained from mESCs suggest that variants causing a decline in FL BRCA2 with approximately 30% of wild-type are not pathogenic, given that mESCs are fully viable and resistant to DNA-damaging agents in those conditions. In contrast, mESCs producing lower relative amounts of FL BRCA2 exhibited either null or hypomorphic phenotypes. Overall, our findings are likely to have broader implications on the interpretation of BRCA2 variants affecting the splicing pattern of other essential exons. SIGNIFICANCE: These findings demonstrate that BRCA2 tumor suppressor function tolerates substantial reduction in full-length transcripts, helping to determine the pathogenicity of BRCA2 leaky splicing variants, some of which may not increase cancer risk.

Long-term impact of saliva control surgery in children with disability.

Sialorrhea is a common problem in children with disability, often negatively affecting socialization, self-esteem, and burden of care. Saliva control surgery is an available option to manage this problem, particularly when other conservative methods have failed. As little is known about the long-term impact of surgery, we followed up 62 patients who had combined bilateral submandibular duct translocation and bilateral sublingual gland excision at our pediatric hospital between 1994 and 2014. Eligible individuals were identified through a search of ICD procedure codes. When families of patients were contacted successfully, they were invited to complete a 14-item questionnaire designed specifically for this study. The results indicated that long-term outcomes of surgery were very good; 13/62 (21%) individuals no longer had a drooling problem and another 30 (48%) experienced only mild to moderate drooling. Although 84% families reported some or major improvement in drooling, 9 families reported that they would not go through the experience again because of a difficult recovery period, lack of effectiveness of the intervention, changes in saliva consistency that caused coughing and gagging, and dental decay. None of the collected variables were predictive of good or poor outcome. The study indicated that surgical intervention is effective in the long term in the majority of cases and can be recommended to other families who attend our saliva control clinic.

Perioperative Pregabalin and Intraoperative Lidocaine Infusion to Reduce Persistent Neuropathic Pain After Breast Cancer Surgery: A Multicenter, Factorial, Randomized, Controlled Pilot Trial.

Persistent postsurgical pain is defined as pain localized to the area of surgery of a duration of ≥2 months and is, unfortunately, a common complication after breast cancer surgery. Although there is insufficient evidence to support any preventative strategy, prior literature suggests the possible efficacy of intravenous lidocaine and perioperative pregabalin in preventing persistent pain after surgery. To determine feasibility of conducting a larger definitive trial, we conducted a multicenter 2 × 2 factorial, randomized, placebo-controlled pilot trial of 100 female patients undergoing breast cancer surgery. Patients were randomized to receive an intraoperative lidocaine infusion (1.5 mg/kg bolus followed by 2 mg/kg/h) or placebo and perioperative pregabalin (300 mg preoperatively, 75 mg twice daily for 9 days) or placebo. All feasibility criteria were surpassed; recruitment of 100 patients was accomplished within 42 weeks, with a follow-up rate of 100% and study drug compliance of ≥80%. At 3 months, 53% of patients reported persistent neuropathic pain. Although there was no interaction between lidocaine and pregabalin, lidocaine decreased the development of persistent neuropathic pain (43.1% vs 63.3%; relative risk = .68; 95% confidence interval = .47-1.0). Pregabalin did not reduce persistent pain (60% vs 46%; relative risk = 1.3; 95% confidence interval = .90-1.90) and neither pregabalin nor lidocaine impacted acute postoperative pain, opioid consumption, pain interference, or quality of life. Our pilot trial successfully demonstrated feasibility and provided promising data for conducting further trials of intraoperative lidocaine infusions during breast cancer surgeries. Clinical trial number: NCT02240199 PERSPECTIVE: This article reports the findings of a pilot randomized, controlled trial evaluating the effects of perioperative pregabalin and intraoperative lidocaine infusions in patients undergoing breast cancer surgery. This trial demonstrated the feasibility of conducting a larger trial and provided promising data that these interventions may decrease the development of persistent pain.

Relation between socioeconomic variables and surgical, systemic and radiation treatment in a cohort of patients with breast cancer in an urban Canadian centre

Background: Studies have shown an association between socioeconomic status and breast cancer treatment. We examined the relation between socioeconomic status and the treatment of breast cancer (surgical, systemic and radiation) in a universal health care system. Methods: Data from a single urban Canadian centre were collected for consecutive patients who received a diagnosis of breast cancer from January 2010 to December 2011. Variables included patient and disease factors, surgery type, systemic and radiation treatment, and breast reconstruction. Socioeconomic variables were obtained from 2006 Canadian census data. We used multivariable logistic regression to identify predictors of breast cancer treatment. Results: A total of 721 patients were treated for breast cancer during the study period. Socioeconomic variables were not related to type of breast surgery for breast cancer. Age less than 50 years, having a first-degree relative with breast cancer and income status were predictors of breast reconstruction. Employment status was a consistent predictor of systemic and radiation treatment. Conclusion: Employment consistently predicted systemic and radiation treatment, and age and income were predictors of breast reconstruction in a universal health care system. Further research is required to determine precisely how socioeconomic factors affect care and to minimize possible disparities in delivery of health care services.

Contexte: Des études ont montré un lien entre la situation socio-économique et le traitement du cancer du sein. Nous avons analysé ce lien entre la situation socioéconomique et le traitement (chirurgie, chimiothérapie, radiothérapie) du cancer du sein dans un système de santé universel. Méthodes: Les données d'un seul centre urbain canadien ont été compilées pour les patientes consécutives ayant reçu un diagnostic de cancer du sein entre janvier 2010 et décembre 2011. Les variables incluaient des facteurs propres aux patientes et à la maladie, le type de chirurgie, la chimiothérapie, la radiothérapie et la reconstruction mammaire. Les variables socio-économiques proviennent des données du recensement canadien de 2006. Nous avons utilisé la régression logistique multivariée pour identifier les prédicteurs du traitement du cancer du sein. Résultats: En tout, 721 patientes ont été traitées pour un cancer du sein durant la période de l'étude. Les variables socio-économiques n'ont pas influé sur le type de chirurgie mammaire pour cancer du sein. L'âge inférieur à 50 ans, un cancer du sein chez une parente au premier degré et le revenu ont été des prédicteurs de la reconstruction mammaire. La situation professionnelle a été un prédicteur fiable du traitement systémique et de la radiothérapie. Conclusion: L'emploi a été un prédicteur fiable du traitement systémique et de la radiothérapie, et l'âge et le revenu ont été des prédicteurs de la reconstruction mammaire, dans un système de santé universel. Il faudra approfondir la recherche pour déterminer plus précisément l'influence des facteurs socio-économiques sur les soins et pour réduire les possibles disparités dans leur prestation.

Twin-to-twin transfusion syndrome neurodevelopmental follow-up study (neurodevelopmental outcomes for children whose twin-to-twin transfusion syndrome was treated with placental laser photocoagulation).

BACKGROUND: Twin-to-twin transfusion syndrome (TTTS) is a serious complication of 10-15% of twin or triplet pregnancies in which multiple fetuses share a single placenta. Communicating placental vessels allow one fetus (the donor) to pump blood to the other (the recipient). Mortality rates without intervention are high, approaching 100% in some series, with fetal deaths usually due to cardiac failure. Surgical correction using laser photocoagulation of communicating placental vessels was developed in the 1980s and refined in the 1990s. Since it was introduced in Victoria in 2006, laser surgery has been performed in approximately 120 pregnancies. Survival of one or more fetuses following laser surgery is currently > 90%, however the neurodevelopmental outcomes for survivors remain incompletely understood. Prior to laser therapy, at least one in five survivors of TTTS had serious adverse neurodevelopmental outcomes (usually cerebral palsy). Current estimates of neurological impairment among survivors following laser surgery vary from 4 to 31% and long-term follow-up data are limited. METHODS: This paper describes the methodology for a retrospective cohort study in which children aged 24 months and over (corrected for prematurity), who were treated with laser placental photocoagulation for TTTS at Monash Health in Victoria, Australia, will undergo comprehensive neurodevelopmental assessment by a multidisciplinary team. Evaluation will include parental completion of pre-assessment questionnaires of social and behavioural development, a standardised medical assessment by a developmental paediatrician or paediatric neurologist, and age-appropriate cognitive and academic, speech and fine and gross motor assessments by psychologists, speech and occupational therapists or physiotherapists. Assessments will be undertaken at the Murdoch Children's Research Institute/Royal Children's Hospital, at Monash Health or at another mutually agreed location. Results will be recorded in a secure online database which will facilitate future related research. DISCUSSION: This will be the first study to report and evaluate neurodevelopmental outcomes following laser surgery for twin-to-twin transfusion syndrome in Victoria, and will inform clinical practice regarding follow-up of children at risk of adverse outcomes.