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Graphical abstract Sleep disorders are linked to development of type 2 diabetes and increase the risk of developing diabetes complications. Treating sleep disorders might therefore play an important role in the prevention of diabetes progression. However, the detection and treatment of sleep disorders are not part of standardised care for people with type 2 diabetes. To highlight the importance of sleep disorders in people with type 2 diabetes, we provide a review of the literature on the prevalence of sleep disorders in type 2 diabetes and the association between sleep disorders and health outcomes, such as glycaemic control, microvascular and macrovascular complications, depression, mortality and quality of life. Additionally, we examine the extent to which treating sleep disorders in people with type 2 diabetes improves these health outcomes. We performed a literature search in PubMed from inception until January 2021, using search terms for sleep disorders, type 2 diabetes, prevalence, treatment and health outcomes. Both observational and experimental studies were included in the review. We found that insomnia (39% [95% CI 34, 44]), obstructive sleep apnoea (55–86%) and restless legs syndrome (8–45%) were more prevalent in people with type 2 diabetes, compared with the general population. No studies reported prevalence rates for circadian rhythm sleep–wake disorders, central disorders of hypersomnolence or parasomnias. Additionally, several cross-sectional and prospective studies showed that sleep disorders negatively affect health outcomes in at least one diabetes domain, especially glycaemic control. For example, insomnia is associated with increased HbA1c levels (2.51 mmol/mol [95% CI 1.1, 4.4]; 0.23% [95% CI 0.1, 0.4]). Finally, randomised controlled trials that investigate the effect of treating sleep disorders in people with type 2 diabetes are scarce, based on a small number of participants and sometimes inconclusive. Conventional therapies such as weight loss, sleep education and cognitive behavioural therapy seem to be effective in improving sleep and health outcomes in people with type 2 diabetes. We conclude that sleep disorders are highly prevalent in people with type 2 diabetes, negatively affecting health outcomes. Since treatment of the sleep disorder could prevent diabetes progression, efforts should be made to diagnose and treat sleep disorders in type 2 diabetes in order to ultimately improve health and therefore quality of life. Supplementary Information The online version contains peer-reviewed but unedited supplementary material including a slideset of the figures for download, available at 10.1007/s00125-021-05541-0.

BRIP1 is a moderate susceptibility epithelial ovarian cancer (EOC) gene. Having identified the BRIP1 c.1045G>C missense variant in a number of families with EOC, we aimed to investigate the frequency of this and BRIP1.2392C>T pathogenic variant in patients with breast cancer (BC) and/or EOC. A case-control study of 3,767 cases and 2,043 controls was undertaken investigating the presence of these variants using Sanger sequencing and gene panel data. Individuals with BC and/or EOC were grouped by family history. BRIP1 c.1045G>C was associated with increased risk of BC/EOC (OR = 37.7; 95% CI 5.3-444.2; P=0.0001). The risk was highest for women with EOC (OR=140.8; 95% CI 23.5-1723.0; PT was associated with smaller risks for BC/EOC (OR=5.4; 95%CI 2.4-12.7; P=0.0003), EOC (OR=5.9; 95% CI 1.3-23.0; p=0.0550), and BC (OR=5.3; 95%CI 2.3-12.9; P=0.0009). Our study highlights the importance of BRIP1 as an EOC susceptibility gene, especially in familial EOC. The variant BRIP1 c.1045G>C, rs149364097, is of particular interest as its dominant-negative effect may confer a higher risk of EOC than that of the previously reported BRIP1 c.2392C>T nonsense variant. Dominant-negative missense variants may confer higher risks than their loss-of-function counterparts.

Polygenic risk scores (PRS) for disease risk stratification show great promise for application in general populations, but most are based on data from individuals of white European origin. We assessed two well validated PRS (SNP18, SNP143) in the Predicting-Risk-of-Cancer-At-Screening (PROCAS) study in North-West England for breast cancer prediction based on ethnicity. Overall, 9475 women without breast cancer at study entry, including 645 who subsequently developed invasive breast cancer or ductal carcinoma in situ provided DNA. All were genotyped for SNP18 and a subset of 1868 controls were genotyped for SNP143. For white Europeans both PRS discriminated well between individuals with and without cancer. For n=395 Black (n=112), Asian (n=119), mixed (n=44) or Jewish (n=120) women without cancer both PRS overestimated breast cancer risk, being most marked for women of Black and Jewish origin (p

PURPOSE To investigate the contribution of PALB2 pathogenic gene variants (PGVs, PALB2_PGV) and the CHEK2 c.1100delC (CHEK2_1100delC) PGV to familial breast and ovarian cancer, and PALB2_PGV associated breast cancer pathology. METHODS Outcomes of germline PALB2_PGV and CHEK2_1100delC testing were recorded in 3,127 women with histologically confirmed diagnoses of invasive breast cancer, carcinoma in situ, or epithelial nonmucinous ovarian cancer, and 1,567 female controls. Breast cancer pathology was recorded in PALB2_PGV cases from extended families. RESULTS Thirty-five PALB2 and 44 CHEK2_1100delC PGVs were detected in patients (odds ratio [OR] PALB2 breast-ovarian = 5.90 [95% CI: 1.92-18.36], CHEK2 breast-ovarian = 4.46 [95% CI: 1.86-10.46], PALB2 breast = 6.16 [95% CI: 1.98-19.21], CHEK2 breast = 4.89 [95% CI: 2.01-11.34]). Grade 3 ER-positive HER2-negative, grade 3 and triple negative (TN) tumors were enriched in cases with PALB2 PGVs compared with all breast cancers known to our service (respectively: 15/43, 254/1,843, P = 0.0005; 28/37, 562/1,381, P = 0.0001; 12/43, 204/1,639, P

BackgroundWhile the likelihood of identifying constitutional breast cancer-associated BRCA1, BRCA2 and TP53 pathogenic variants (PVs) increases with earlier diagnosis age, little is known about the correlation with age at diagnosis in other predisposition genes. Here, we assessed the contribution of known breast cancer-associated genes to very early onset disease.MethodsSequencing of BRCA1, BRCA2, TP53 and CHEK2 c.1100delC was undertaken in women with breast cancer diagnosed ≤30 years. Those testing negative were screened for PVs in a minimum of eight additional breast cancer-associated genes. Rates of PVs were compared with cases ≤30 years from the Prospective study of Outcomes in Sporadic vs Hereditary breast cancer (POSH) study.ResultsTesting 379 women with breast cancer aged ≤30 years identified 75 PVs (19.7%) in BRCA1, 35 (9.2%) in BRCA2, 22 (5.8%) in TP53 and 2 (0.5%) CHEK2 c.1100delC. Extended screening of 184 PV negative women only identified eight additional actionable PVs. BRCA1/2 PVs were more common in women aged 26–30 years than in younger women (p=0.0083) although the younger age group had rates more similar to those in the POSH cohort. Out of 26 women with ductal carcinoma in situ (DCIS) alone, most were high-grade and 11/26 (42.3%) had a PV (TP53=6, BRCA2=2, BRCA1=2, PALB2=1). This PV yield is similar to the 61 (48.8%) BRCA1/2 PVs identified in 125 women with triple-negative breast cancer. The POSH cohort specifically excluded pure DCIS which may explain lower TP53 PV rates in this group (1.7%).ConclusionThe rates of BRCA1, BRCA2 and TP53 PVs are high in very early onset breast cancer, with limited benefit from testing of additional breast cancer-associated genes.

Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values-8 as genome-wide significant, and p-values-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants.Results: None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values5. The strongest evidence was found for rs4674019 (p-value=2.27x10-7), which showed genome-wide significant interaction (p-value=3.8x10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. Conclusions: In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT–breast cancer risk association.

Background: There has been huge progress over the last 30 years in identifying the familial component of breast cancer. Summary: Currently around 20% is explained by the high-risk genes BRCA1 and BRCA2, a further 2% by other high-penetrance genes, and around 5% by the moderate risk genes ATM and CHEK2. In contrast, the more than 300 low-penetrance single-nucleotide polymorphisms (SNP) now account for around 28% and they are predicted to account for most of the remaining 45% yet to be found. Even for high-risk genes which confer a 40–90% risk of breast cancer, these SNP can substantially affect the level of breast cancer risk. Indeed, the strength of family history and hormonal and reproductive factors is very important in assessing risk even for a BRCA carrier. The risks of contralateral breast cancer are also affected by SNP as well as by the presence of high or moderate risk genes. Genetic testing using gene panels is now commonplace. Key-Messages: There is a need for a more parsimonious approach to panels only testing those genes with a definite 2-fold increased risk and only testing those genes with challenging management implications, such as CDH1 and TP53, when there is strong clinical indication to do so. Testing of SNP alongside genes is likely to provide a more accurate risk assessment.

BackgroundNephroblastomatosis is a recognised precursor for the development of Wilms tumour (WT), the most common childhood renal tumour. While the majority of WT is sporadic in origin, germline intragenic mutations of predisposition genes such as WT1, REST and TRIM28 have been described in apparently isolated (non-familial) WT.Despite constitutional CNVs being a well-studied cause of developmental disorders, their role in cancer predisposition is less well defined, so that the interpretation of cancer risks associated with specific CNVs can be complex.ObjectiveTo highlight the role of a constitutional deletion CNV (delCNV) encompassing the REST tumour suppressor gene in diffuse hyperplastic perilobar nephroblastomatosis (HPLN).Methods/resultsArray comparative genomic hybridisation in an infant presenting with apparently sporadic diffuse HPLN revealed a de novo germline CNV, arr[GRCh37] 4q12(57,385,330–57,947,405)x1. The REST tumour suppressor gene is located at GRCh37 chr4:57,774,042–57,802,010.ConclusionThis delCNV encompassing REST is associated with nephroblastomatosis. Deletion studies should be included in the molecular work-up of inherited predisposition to WT/nephroblastomatosis. Detection of delCNVs involving known cancer predisposition genes can yield insights into the relationship between underlying genomic architecture and associated tumour risk.

Several studies found associations between poor sleep quality and aggression in general and (forensic) psychiatric populations. Both poor sleep and aggression have been related previously to general psychopathology, but studies rarely have addressed this possible confounding factor appropriately. The current study aimed to replicate the association between sleep quality and aggression in a forensic psychiatric sample, including adjustment for psychopathology. We used cross-sectional data from an observational study in forensic psychiatric inpatients (n = 166). Poor sleep quality was significantly associated with higher self-reported aggression, independent of general psychopathology. Poor sleep quality accounted for a substantial part of the variance in aggression. This was observed for self-reported physical aggression, verbal aggression, anger, and hostility, all showing relations with poor sleep quality that were not better accounted for by general psychopathology. Poor sleep quality was related to higher clinician-rated hostility as well, however, this association was weak and the explained variance low. These results confirm and substantiate previously found associations between sleep quality and aggression in forensic psychiatric patients. They highlight the importance of targeting sleep problems as part of the treatment of psychiatric patients with disruptive behavior and encourage further research aimed at unraveling the relation between sleep and aggression.

IMPORTANCE Study of the association of regional facial dysfunction with quality of life will lead to a better understanding of quality of life in facial palsy.OBJECTIVE To determine the association of regional facial dysfunction with facial palsy-related quality of life.DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort analysis included patients with flaccid and nonflaccid (synkinetic) facial palsy treated at a tertiary care facial nerve center; the flaccid facial palsy group included 529 patients, and the nonflaccid facial palsy group included 391 patients. Data were included from all patients with facial palsy who had an eFACE score and Facial Clinimetric Evaluation (FaCE) scale total score acquired at the same time from February 1, 2014, through October 31, 2017. Linear regression analysis was performed to calculate the amount of variance in quality of life explained by the severity of facial palsy (eFACE). A relative weight analysis was performed for the contribution of each individual eFACE item in estimating quality of life.MAIN OUTCOMES AND MEASURES Facial palsy severity was measured using all 15 individual eFACE items (rated on a scale of 0 to 200, where 0 represents complete flaccidity, 100 represents a balanced aesthetic appearance, and 200 represents the worst imaginable hypertonia of a patient with synkinesis, with a transformation used for values from 101 to 200), and facial palsy-related quality of life was measured using the FaCE scale total score (range, 0 [worst] to 100 [best]).RESULTS Data of 920 individual patients (59.5% female; mean [SD] age, 48.6 [16.6] years) were available. The eFACE composite score accounted for 21.2% of the quality-of-life variance in the flaccid group and 13.9% in the nonflaccid group. With the use of all 15 individual eFACE items, these proportions increased to 29.7% and 16.8%, respectively. In both groups, oral commissure movement with smile was found to be the most important contributing item (relative weight, 0.108 [95% CI, 0.075-0.148] for the flaccid group and 0.025 [95% CI, 0.005-0.052] for the nonflaccid group). Items related to the function of periocular muscles were found to be of low importance.CONCLUSIONS AND RELEVANCE The present study suggests that the function of individual facial regions is not equally important for estimating facial palsy-related quality of life. The ability to smile is of greatest importance among patients with flaccid and nonflaccid facial palsy. The true importance of periocular function in the estimation of quality of life should be studied further in future research.

Genome-wide analysis identifies 32 loci associated with breast cancer susceptibility, accounting for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype(1-3). To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 x 10(-8)), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

Background: Tools to quantify layperson assessments of facial palsy are lacking. In this study, artificial intelligence was applied to develop a proxy for layperson assessments, and compare sensitivity to existing outcome measures.Methods: Artificially intelligent emotion detection software was used to develop the emotionality quotient. The emotionality quotient was defined as the percentage probability of perceived joy over the percentage probability of perceived negative emotions during smiling, as predicted by the software. The emotionality quotient was used to analyze the emotionality of voluntary smiles of normal subjects and unilateral facial palsy patients before and after smile reanimation. The emotionality quotient was compared to oral commissure excursion and layperson assessments of facial palsy patients.Results: In voluntary smiles of 10 normal subjects, 100 percent joy and no negative emotion was detected (interquartile ranges, 0/1). Median preoperative emotionality quotient of 30 facial palsy patients was 15/-60 (interquartile range, 73/62). Postoperatively, median emotionality quotient was 84/0 (interquartile range, 28/5). In 134 smile reanimation patients, no correlation was found between postoperative oral commissure excursion and emotionality quotient score. However, in 61 preoperative patients, a moderate correlation was found between layperson-assessed disfigurement and negative emotion perception (correlation coefficient, 0.516; p Conclusions: Computer vision artificial intelligence software detected less joy and more negative emotion in smiles of facial palsy patients compared with normal subjects. Following smile reanimation, significantly more joy and less negative emotion were detected. The emotionality quotient was correlated with layperson assessments. The simplicity, sensitivity, and objectivity of the emotionality quotient render it an attractive tool to serve as a potential proxy for layperson assessment, an ideal outcome measure in facial palsy.

KEY POINTS: Synkinesis can decrease quality of life in facial palsy patients. Patient-perceived severity of synkinesis may be of additional value in predicting facial palsy related-quality of life. We analyzed the additional value of the SAQ total score (perceived severity of synkinesis) in predicting FaCE total scores (quality of life) in 92 patients cross-sectionally. SAQ total score accounted for a relatively large improvement in the prediction of FaCE total scores (R2 change = 0.113, total R2 = 0.428). Patient-perceived severity synkinesis should be included in clinical management and studies of synkinesis. This article is protected by copyright. All rights reserved.

Sleep disturbances frequently co-occur with posttraumatic stress disorder (PTSD). Insomnia and nightmares are viewed as core symptoms of PTSD. Yet, relations between disturbed sleep and PTSD are far more complex: PTSD is linked to a broad range of sleep disorders and disturbed sleep markedly affects PTSD-outcome. This article provides a concise overview of the literature on prevalent comorbid sleep disorders, their reciprocal relation with PTSD and possible underlying neurophysiological mechanisms. Furthermore, diagnostic procedures, standard interventions—particularly first choice non-pharmacological therapies—and practical problems that often arise in the assessment and treatment of sleep disturbances in PTSD are described. Finally, we will present some perspectives on future multidisciplinary clinical and experimental research to develop new, more effective sleep therapies to improve both sleep and PTSD.

Whilst panel testing of an extended group of genes including BRCA1/2 is commonplace, these studies have not been subdivided by histiotype or by a priori BRCA1/2 probability. Patients with a breast cancer diagnosis undergoing extended panel testing were assessed for frequency of actionable variants in breast cancer genes other than BRCA1/2 by histiotype and Manchester score (MS) to reflect a priori BRCA1/2 likelihood. Rates were adjusted by prior testing for BRCA1/2 in an extended series. 95/1398 (6.3%) who underwent panel testing were found to be positive for actionable non-BRCA1/2 breast/ovarian cancer genes (ATM, BARD1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, TP53). As expected, PALB2, CHEK2 and ATM were predominant with 80-(5.3%). The highest rate occurred in Grade-3 ER+/HER2− breast cancers-(9.6%). Rates of non-BRCA actionable genes was fairly constant over all likelihoods of BRCA1/2 but adjusted rates were three times higher with MS &lt, 9 (BRCA1/2 = 1.5%, other = 4.7%), but was only 1.6% compared to 79.3% with MS ≥ 40. Although rates of detection of non-BRCA actionable genes are relatively constant across BRCA1/2 likelihoods this disguises an overall adjusted low frequency in high-likelihood families which have been heavily pre-tested for BRCA1/2. Any loss of detection sensitivity for BRCA1/2 actionable variants in breast cancer panels should lead to bespoke BRCA1/2 testing being conducted first.

Importance Understanding how the quality of life of adults (≥18 years) with peripheral facial palsy can be estimated using clinician measures of facial function and patient-reported variables might aid in counseling patients and in conducting research. Objectives To analyze associations between clinician-graded facial function and patient-reported quality of life in adults with peripheral facial palsy, compare associations between facial function and the physical and social functions of quality of life, and examine factors that might influence the associations. Data Sources A literature search was conducted in PubMed, Embase, CINAHL, Web of Science and PsycInfo on June 4, 2020, with no restrictions on the start date. Study Selection Twenty-three studies reporting an association between clinician-graded facial function and patient-reported quality of life in adults with peripheral facial palsy were included. Facial function instruments included the House-Brackmann, Sunnybrook Facial Grading System, and electronic clinician-graded facial function assessment. Quality-of-life instruments included the Facial Disability Index and Facial Clinimetric Evaluation Scale. Data Extraction and Synthesis Data extraction and qualitative synthesis were performed according to the Meta-analysis of Observational Studies in Epidemiology guidelines. Record screening, data extraction, and quality assessments were done by 2 researchers independently. Data were pooled using random-effects models. Main Outcomes and Measures The main outcome was the association between facial function and quality of life, quantified by Pearsonr, Spearman ρ, or regression analysis. Results In total, 23 studies (3746 participants) were included. In the 21 studies that reported on the sex of the cohorts, there were 2073 women (57.3%). Mean or median age ranged from 21 to 64 years and mean or median duration of palsy ranged from newly diagnosed to 12 years. Bell palsy (n = 1397), benign tumor (n = 980), and infection (n = 257) were the most common etiologic factors. Pooled correlation coefficients were 0.424 (95% CI, 0.375-0.471) to 0.533 (95% CI, 0.447-0.610) between facial function and Facial Clinimetric Evaluation Scale total, 0.324 (95% CI, 0.128-0.495) to 0.397 (95% CI, 0.242-0.532) between facial function and Facial Clinimetric Evaluation Scale social function, 0.423 (95% CI, 0.322-0.514) to 0.605 (95% CI, −0.124-0.910) between facial function and Facial Disability Index physical function, and 0.166 (95% CI, 0.044-0.283) to 0.208 (95% CI, 0.031-0.373) between facial function and Facial Disability Index social function. Conclusions and Relevance Associations noted in this systematic review and meta-analysis were overall low to moderate, suggesting that only a small part of quality of life is explained by facial function. Associations were higher between facial function and physical function than social function of quality of life.

Purpose Women at increased familial breast cancer risk have been offered screening starting at an earlier age and increased frequency than national Screening Programmes for over 30 years. There are limited data on longer-term largescale implementation of this approach on cancer diagnosis. Methods Women at our institution at ≥ 17% lifetime breast cancer risk have been offered enhanced screening with annual mammography starting at age 35 or 5-years younger than youngest affected relative, with upper age limit 50 for moderate and 60 for high-risk. Breast cancer pathology, stage and receptor status were assessed as well as survival from cancer diagnosis by Kaplan–Meier analysis. Results Overall 14,311 women were seen and assessed for breast cancer risk, with 649 breast cancers occurring in 129,119 years follow up (post-prevalent annual incidence = 4.55/1000). Of 323/394 invasive breast cancers occurring whilst on enhanced screening, most were lymph-node negative (72.9%), T1 (≤ 20 mm, 73.2%) and stage-1 (61.4%), 126/394 stage2–4 (32%). 10-year breast cancer specific survival was 91.3% (95% CI 87.4–94.0) better than the 75.9% (95% CI 74.9–77.0) published for England in 2013–2017. As expected, survival was significantly better for women with screen detected cancers (p n = 75; 95% CI 84.2–97.6). Women with lobular breast cancers had worse 10-year survival at 85.9% (95% CI 66.7–94.5). Breast cancer specific survival was good for 119 BRCA1/2 carriers with 20-year survival in BRCA1:91.2% (95% CI 77.8–96.6) and 83.8% (62.6–93.5) for BRCA2. Conclusions Targeted breast screening in women aged 30–60 years at increased familial risk is associated with good long-term survival that is substantially better than expected from population data.

Purpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58–23.95; P ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2. Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

Layperson assessments are becoming increasingly important in the evaluation of surgical procedures of the face, including smile reanimation. In this study, the authors set out to answer 3 questions: (1) are esthetic scores more dependent on the assessor or the person that is being assessed, (2) how does smile reanimation change esthetic scores, (3) do sex and age of the patient and assessor explain some of the esthetic outcomes?Thirty-five assessors scored pre and postoperative photographs of 21 facial palsy patients undergoing smile reanimation. Linear mixed-effect models were used to investigate the effects of assessor and patient factors on esthetic outcome assessments, to examine changes after smile reanimation, and to determine whether sex and age explained part of the esthetic outcomes.Fifty-eight percent of variation in the esthetic scores can be explained by some assessors being more positive in their esthetic scoring compared to other assessors. Twenty-nine percent was attributed to patient baseline esthetic scores. Overall esthetic scores improved after smile reanimation. Sex and age of the patient and assessor could not explain variation in the esthetic scores.Esthetic appearance highly depends on "who is looking.'' These findings are important for preoperative counseling, and for those treating and educating patients with facial palsy.

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:107 issue:5 pages:837-848 ispartof: location:United States status: published

Little is known about facial function assessments of inexperienced observers in facial palsy. In this observational study learning curve was examined of two inexperienced observers assessing facial function of 100 patients using the Sunnybrook Facial Grading System. Interobserver agreement gradually improved over time, stabilizing after approximately 70 assessments. Best agreement on the voluntary movement subscore was observed, followed by synkinesis and resting symmetry subscores. Inexperienced observers can perform facial function assessments in facial palsy, but should be adequately trained first.

Background Sleep disorders are a risk factor for developing a variety of mental disorders, have a negative impact on their remission rates and increase the risk of relapse. Early identification and treatment of sleep disorders is therefore of paramount importance. Unfortunately, in mental health care sleep disorders are often poorly recognized and specific treatment frequently occurs late or not at all. This protocol-paper presents a randomized controlled trial investigating the clinical relevance of early detection and treatment of sleep disorders in mental health care. The two aims of this project are 1) to determine the prevalence of sleep disorders in different mental disorders, and 2) to investigate the contribution of early identification and adequate treatment of sleep disorders in individuals with mental disorders to their sleep, mental disorder symptoms, general functioning, and quality of life. Methods Patients newly referred to a Dutch mental health institute for psychiatric treatment will be screened for sleep disorders with the self-assessment Holland Sleep Disorders Questionnaire (HSDQ). Patients scoring above the cut-off criteria will be invited for additional diagnostic evaluation and, treatment of the respective sleep disorder. Participants will be randomly assigned to two groups: Immediate sleep diagnostics and intervention (TAU+SI-T0), or delayed start of sleep intervention (TAU+SI-T1; 6 months after inclusion). The effect of sleep treatment as add-on to treatment as usual (TAU) will be tested with regard to sleep disorder symptoms, general functioning, and quality of life (in collaboration with a psychiatric sleep centre). Discussion This trial will examine the prevalence of different sleep disorders in a broad range of mental disorders, providing information on the co-occurrence of specific sleep and mental disorders. Further, this study is the first to investigate the impact of early treatment of sleep disorders on the outcome of many mental disorders. Moreover, standard sleep interventions will be tailored to specific mental disorders, to increase their efficacy. The results of this trial may contribute considerably to the improvement of mental health care. Trial registration This clinical trial has been retrospectively registered in the Netherlands Trial Register (NL8389; https://www.trialregister.nl/trial/8389) on February 2th, 2020.

Three-dimensional stereophotogrammetry is not much used in assessing facial palsy and a comprehensive understanding of sources of variation in these measurements is lacking. The present study assessed intra- and interobserver reliability of a novel three-dimensional stereophotogrammetry measurement of facial asymmetry and examined sources of variation in these outcomes. Three photographs (rest, closed mouth smile, and maximum smile) were made of 60 participants, 30 facial palsy patients and 30 control subjects. All images were analyzed twice by 2 observers independently, to determine intra- and interobserver reliability. Variance component analysis was performed to investigate sources of variation in the outcomes. Intraobserver reliability was good with intraclass correlation coefficients ranging from 0.715 to 0.999. Interobserver reliability ranged from 0.442 to 0.929. Reliability of the smile image measurements was not clearly different from the rest images. Variation in measurement results was largely due to the status of a participant, facial palsy versus control. When splitting the sample, the facial expression was a major source of variation. Acceptable reliability of the proposed 3D facial asymmetry measurement was found, in facial palsy patients and control subjects. Interobserver reliability was marked less compared to intraobserver reliability. For follow-up data only one observer should assess 3D stereophotogrammetry measurements.

Background Parotidectomy in melanoma of the coronal scalp and face with clinically involved cervical lymph node metastasis is based on predicted cervical lymphatic drainage described by O'Brien. Methods In total, 40 parotidectomies with en bloc therapeutic neck dissection were retrospectively analyzed. Results Lymphatic spread of melanoma to the parotid lymph nodes was observed in 10 of 40 specimens (25%). Eight of the 10 parotid-positive patients developed a recurrence vs 17 of the 30 parotid-negative patients (P = 0.28). There were no differences in overall survival, melanoma-specific survival, and disease-free survival between the parotid-positive and parotid-negative patients. Conclusion Although in this series no survival differences were found, parotidectomy still merits a sustained role in therapeutic neck dissection procedures to improve regional control and to prevent facial nerve damage after surgery for a second relapse from occult metastases in the parotid.

OBJECTIVES To investigate the correlation between facial palsy severity and quality of life in a broad cohort of facial palsy patients and to elucidate factors that influence this relationship. STUDY DESIGN Retrospective study. METHODS Records of patients presenting with a clinician-graded facial function (eFACE) and facial palsy-specific quality-of-life patient-reported outcome measure (FaCE) scale from the same moment were reviewed. Multiple linear regression was performed to study the effect of various variables on FaCE total score. RESULTS A total of 920 of 1,304 patients were included, 59.9% female with a mean (standard deviation) age of 48.6 (16.7) years and a median (interquartile range palsy duration of 9.6 [2.2; 42.2] months. A multiple linear regression model predicting FaCE total score was established, finding 10 significant variables: eFACE; viral, malignant, and congenital etiologies; overweight status; anxiety; chronic pain; previous treatment; radiotherapy; and duration of palsy (R2 = 0.261, P

The temporalis muscle transposition is a reliable, one-stage reanimation technique for longstanding facial paralysis. In the variation described by Rubin, the muscle is released from the temporal bone and folded over the zygomatic arch towards the modiolus. This results in unsightly temporal hollowing and zygomatic bulging. We present a modification of this technique, which preserves the temporal fat pad in its anatomical location as well as conceals temporal hollowing and prevents zygomatic bulging.The data of 23 patients treated with this modification were analysed. May classification was used for evaluation of mouth reanimation. Experts and patients scored visibility of the contour deformity on a 100-mm visual analogue scale (VAS) (score 0 = poor/100 = best). 3D images of the face were used to measure temporal hollowing and zygomatic bulging. 3D images were compared to those of controls with a similar gender and age distribution.After a median follow-up of 5.7 years, all patients achieved symmetry at rest. Eleven patients achieved symmetry while smiling with closed lips (May classification "Good"). A median (interquartile range [IQR]) VAS score of 19 (6; 41) was given by experts and 25 (5; 59) by patients themselves. 3D volumes of zygomatic bulging differed from those of control subjects, although all volume differences were small (medianOn the basis of our results, we conclude that our modified Rubin temporalis transposition technique provides an elegant way to conceal bulging over the zygomatic arch and prevents temporal hollowing, without the need for fascial extensions to reach the modiolus. (C) 2018 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Objective The objective of this study was to investigate the long-term effect and treatment stability of selective neurectomy for refractory periocular synkinesis. Methods We performed a retrospective review of all patients treated with highly selective neurectomy for refractory periocular synkinesis between August 2009 and August 2015. Primary outcome was time to recommencing treatment for periocular synkinesis. Palpebral fissure width was measured preoperatively, postoperatively, and at long-term ( > 2.5 years) follow-up. Mean units of botulinum toxin used pre- and postoperatively were compared. Results Of the 12 patients, 10 could be included. Only one was free of treatment for periocular synkinesis at a follow-up of 3.5 years. The other nine patients recommenced treatment with botulinum toxin after a median time of 1.2 (interquartile range 0.6-2.6) years. Palpebral fissure width while smiling was significantly different between the pre- and postoperative (P = 0.008) and preoperative and long-term (P = 0.008) measurements. Postoperatively, previously refractory patients demonstrated good response to botulinum toxin treatments. Conclusion This study demonstrates that most patients require renewed pharmacological treatment of periocular synkinesis after neurectomy. Although the effect of neurectomy in the treatment of refractory synkinesis does not appear to be sustained, patients usually experience a symptom-free interval and demonstrate larger palpebral fissure width at long-term follow-up compared to preoperative measurements. Level of evidence 4. Laryngoscope, 128:2291-2295, 2018.

Summary Poor sleep quality is closely related to aggression, but despite the promise of new therapeutic possibilities, a systematic synthesis of observational research on the association between sleep quality and aggression is lacking. This systematic review and meta-analysis examined the association between sleep quality and aggression, using the academic databases PubMed and PsycINFO. Subjective and objective measures of sleep quality were included, as well as multiple measures of aggression, assessing aggressive and externalizing behavior, anger, hostility and irritability. Ninety-two observational articles, containing 96 studies, encompassing a total of 58.154 children, adolescents and adults were sourced out of 7161 references identified. Methodological quality was moderate or strong in 76% of studies. Data for meta-analysis was available from 74 studies. Poorer sleep quality was associated with higher aggression in 80.8% of studies. Pooled results showed a correlation of 0.28 (95%CI 0.25–0.31; I2 = 90.1%) and odds ratio of 3.61 (95%CI 1.13–11.51; I2 = 88.3%). Effect estimates and heterogeneity varied according to population type and measurement instruments, but not according to article quality or age group. Our findings confirm that poor sleep quality is consistently associated with higher aggression. As most evidence is cross-sectional, more prospective and high-quality experimental evidence is required to elucidate cause-effect and optimize prevention and treatment of aggression.

Summary Nerve reconstructions are the preferred technique for short-standing facial paralysis, most commonly using the contralateral facial nerve or ipsilateral hypoglossal nerve. The hypoglossal nerve provides a strong motor signal, whereas the signal of a cross-face nerve graft is weaker but spontaneous. Spontaneity in facial expression is believed to be important for psychological wellbeing. Therefore, a combination of the two procedures incorporates the best of both: a strong motor signal and a spontaneous smile. This study aimed to objectify this expected benefit. Of the 20 patients who received a hypoglossal–facial nerve anastomosis from 1995 to 2015 in our institutions, 12 patients were included in this study, 5 with and 7 without a cross-face nerve graft. The outcomes were compared using photographs, disease-specific quality of life (Facial Clinimetric Evaluation (FaCE) scale), a self-reported synkinesis scale (Synkinesis Assessment Questionnaire) and the presence of a spontaneous smile. Significant differences were found in preoperative excursion of the affected side of the mouth and the change in excursion. Median Total FaCE scores were considerably larger (18.3 points) for patients who underwent the combined procedure. A spontaneous smile was observed both with ( n = 2) and without ( n = 1) a cross-face nerve graft. The addition of a cross-face nerve graft to a hypoglossal–facial nerve anastomosis resulted in a positive trend in disease-specific quality of life. This benefit could also be present with the combination of a cross-face nerve graft with another nerve transfer such as a masseteric-facial nerve anastomosis.

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer. ispartof: JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE vol:113 issue:3 pages:329-337 ispartof: location:United States status: published

PURPOSERisk-stratified breast cancer prevention requires accurate identification of women at sufficiently different levels of risk. We conducted a comprehensive evaluation of a model integrating classical risk factors and a recently developed 313-variant polygenic risk score (PRS) to predict breast cancer risk.METHODSFifteen prospective cohorts from six countries with 237,632 women (7,529 incident breast cancer patients) of European ancestry aged 19-75 years at baseline were included. Calibration of five-year risk was assessed by comparing predicted and observed proportions of cases overall and within risk categories. Risk stratification for women of European ancestry aged 50-70 years in those countries was evaluated by the proportion of women and future breast cancer cases crossing clinically-relevant risk thresholds.RESULTSThe model integrating classical risk factors and PRS accurately predicted five-year risk. For women younger than 50 years, median (range) expected-to-observed ratio across the cohorts was 0.94 (0.72 to 1.01) overall and 0.9 (0.7 to 1.4) at the highest risk decile. For women 50 years or older, these ratios were 1.04 (0.73 to 1.31) and 1.2 (0.7 to 1.6), respectively. The proportion of women in the general population identified above the 3% five-year risk threshold (used for recommending risk-reducing medications in the US) ranged from 7.0% in Germany (∼841,000 of 12 million) to 17.7% in the US (∼5.3 of 30 million). At this threshold, 14.7% of US women were re-classified by the addition of PRS to classical risk factors, identifying 12.2% additional future breast cancer cases.CONCLUSIONEvaluation across multiple prospective cohorts demonstrates that integrating a 313-SNP PRS into a risk model substantially improves its ability to stratify women of European ancestry for applying current breast cancer prevention guidelines.

Key PointsQuestionCan a video time-stamping method be used to measure spontaneity of smile after dually innervated gracilis smile reanimation surgery? FindingsIn this cohort study of 25 patients treated with dually innervated gracilis free muscle transfers vs 24 patients treated with masseteric nerve-driven transfers (n=11) or cross-face nerve graft-driven gracilis (n=13), a spontaneous smile was present in a median of 33% of smiles, which was more than was present in masseteric nerve-driven transfers (20%) but less than in cross-face nerve graft-driven smile reanimation surgery (75%). MeaningDual innervation may improve synchronicity compared with masseteric nerve transfer but not to the level of cross-face nerve graft-driven gracilis free muscle transfer.This cohort study assesses the outcomes of dually innervated gracilis free muscle transfers using a novel clinical assessment tool.ImportanceSurgeons have sought to optimize outcomes of smile reanimation surgery by combining inputs from nerve-to-masseter and cross-face nerve grafts. An objective assessment tool could help surgeons evaluate outcomes to determine the optimal neural sources for smile reanimation. ObjectiveTo evaluate the use of a novel video time-stamping method and standard outcome measurement tools to assess outcomes of facial reanimation surgery using various innervation strategies. Design, Setting, and ParticipantsCohort study assessing the outcomes of dually innervated gracilis free muscle transfers vs single-source innervated gracilis transfer performed at a tertiary care facial nerve center between 2007 and 2017 using a novel, video time-stamping spontaneity assessment method. The statistical analyses were performed in 2018. InterventionsDually innervated gracilis free muscle transfers or single-source innervated gracilis transfer. Main Outcomes and MeasuresSpontaneous smiling was assessed by clinicians and quantified using blinded time-stamped video recordings of smiling elicited while viewing humorous video clips. ResultsThis retrospective cohort study included 25 patients (12 men and 13 women; median [range] age, 38.4 [29.3-46.0] years) treated with dually innervated gracilis free functional muscle graft for unilateral facial palsy between 2007 and 2017. Smile spontaneity assessment was performed in 17 patients and was compared with assessment performed in 24 patients treated with single-source innervated gracilis transfer (ie, nerve-to-masseter-driven or cross-face nerve graft-driven gracilis [n=13]) (demographic data not available for NTM and CFNG cohorts). The use of time-stamped video assessment revealed that spontaneous synchronous oral commissure movement in a median percentage of smiles was 33% in patients with dually innervated gracilis (interquartile range [IQR], 0%-71%), 20% of smiles in patients with nerve-to-masseter-driven gracilis (IQR, 0%-50%), and 75% of smiles in patients with cross-face nerve graft-driven gracilis (IQR, 0%-100%). Clinicians graded smile spontaneity in dually innervated cases as absent in 40% (n=6 of 15), trace in 33% (n=5 of 15) and present in 27% (n=4 of 15). No association was demonstrated between clinician-reported spontaneity and objectively measured synchronicity. Conclusions and RelevanceDually innervated gracilis free muscle transfers may improve smile spontaneity compared with masseteric nerve-driven transfers but not to the level of cross-face nerve graft-driven gracilis transfers. Quantifying spontaneity is notoriously difficult, and most authors rely on clinical assessment. Our results suggest that clinicians may rate presence of spontaneity higher than objective measures, highlighting the importance of standardized assessment techniques. Level of Evidence4.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study (GWAS) including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status and tumor grade. We identified 32 novel susceptibility loci (P-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate PIn-silico analyses showed these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 37.6% for triple-negative and 54.2% for luminal A-like disease. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 −8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 −7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 −7 , HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

Studies investigating sleep and personality disorders consistently demonstrate a relation between personality disorders characterized by behavioral disinhibition and/or emotional dysregulation (traditionally termed cluster B personality disorders) and poor sleep. This finding is in line with previous studies associating insomnia with impulsive behavior, since this is a core characteristic of both antisocial and borderline personality disorder. The current study investigates a group (n = 112) of forensic psychiatric inpatients with antisocial or borderline personality disorder or traits thereof. Subjective sleep characteristics and impulsivity were assessed with the Pittsburgh Sleep Quality Index, the Sleep Diagnosis List, and the Barratt Impulsiveness Scale, respectively. More than half of the patients (53.6%) report poor sleep quality and 22.3% appears to suffer from severe chronic insomnia. Both poor sleep quality and chronic insomnia are significantly associated with self-reported impulsivity, in particular with attentional impulsiveness. This association was not significantly influenced by comorbid disorders. Actively treating sleep problems in these patients may not only improve sleep quality, mental health, and physical well-being, but may also have impact on impulsivityrelated health risks by increasing self-control.

Objective: To investigate whether the self-management intervention was implemented as intended. Additionally, we studied involvement in and satisfaction with the intervention among patients, their partners and therapists. Design: Mixed method, prospective study. Setting: Outpatient facilities of hospitals/rehabilitation centres. Participants: Stroke patients, their partners and therapists from the experimental arm of the Restore4Stroke Self-Management study. Intervention: ‘Plan Ahead!’ is a 10-week self-management intervention for stroke patients and partners, consisting of seven two-hour group sessions. Proactive action planning, education and peer support are main elements of this intervention. Main measures: Session logs, questionnaires for therapists, patients and their partners, and focus groups. Data analysis: Qualitative data were analysed with thematic analysis supplemented by quasi-statistics. Quantitative data were reported as descriptive statistics. Results: The study sample consisted of 53 patients and 26 partners taking part in the intervention, and all therapists delivering the intervention ( N = 19). At least three-quarters of the intervention sessions were attended by 33 patients and 24 partners. On a scale from 1 to 10, patients, partners and therapists rated the intervention with mean scores of 7.5 (SD1.6), 7.8 (SD.7) and 7.4 (SD.7), respectively. Peer support was the most frequently appreciated element for participants and therapists. The proactive action planning tool was adequately applied in 76 of the 96 sessions. Conclusion: Although the target audience was reached and both participants and therapists were satisfied with the intervention, the proactive action planning tool that distinguishes the current intervention from existing stroke-specific self-management interventions was only partly implemented according to protocol.

Purpose To improve breast cancer risk stratification to enable more targeted early detection/prevention strategies that will better balance risks and benefits of population screening programmes. Methods 9362 of 57,902 women in the Predicting-Risk-Of-Cancer-At-Screening (PROCAS) study who were unaffected by breast cancer at study entry and provided DNA for a polygenic risk score (PRS). The PRS was analysed alongside mammographic density (density-residual-DR) and standard risk factors (Tyrer-Cuzick-model) to assess future risk of breast cancer based on tumour stage receptor expression and pathology. Results 195 prospective incident breast cancers had a prediction based on TC/DR/PRS which was informative for subsequent breast cancer overall [IQ-OR 2.25 (95% CI 1.89–2.68)] with excellent calibration-(0.99). The model performed particularly well in predicting higher stage stage 2+ IQ-OR 2.69 (95% CI 2.02–3.60) and ER + BCs (IQ-OR 2.36 (95% CI 1.93–2.89)). DR was most predictive for HER2+ and stage 2+ cancers but did not discriminate as well between poor and extremely good prognosis BC as either Tyrer-Cuzick or PRS. In contrast, PRS gave the highest OR for incident stage 2+ cancers, [IQR-OR 1.79 (95% CI 1.30–2.46)]. Conclusions A combined approach using Tyrer-Cuzick/DR/PRS provides accurate risk stratification, particularly for poor prognosis cancers. This provides support for reducing the screening interval in high-risk women and increasing the screening interval in low-risk women defined by this model. Electronic supplementary material The online version of this article (10.1007/s10549-019-05210-2) contains supplementary material, which is available to authorized users.

Panels of single nucleotide polymorphisms (SNPs) stratify risk for breast cancer in women from the general population, but studies are needed assess their use in a fully comprehensive model including classical risk factors, mammographic density and more than 100 SNPs associated with breast cancer. A case–control study was designed (1,668 controls, 405 cases) in women aged 47–73 years attending routine screening in Manchester UK, and enrolled in a wider study to assess methods for risk assessment. Risk from classical questionnaire risk factors was assessed using the Tyrer–Cuzick model; mean percentage visual mammographic density was scored by two independent readers. DNA extracted from saliva was genotyped at selected SNPs using the OncoArray. A predefined polygenic risk score based on 143 SNPs was calculated (SNP143). The odds ratio (OR, and 95% confidence interval, CI) per interquartile range (IQ‐OR) of SNP143 was estimated unadjusted and adjusted for Tyrer–Cuzick and breast density. Secondary analysis assessed risk by oestrogen receptor (ER) status. The primary polygenic risk score was well calibrated (O/E OR 1.10, 95% CI 0.86–1.34) and accuracy was retained after adjustment for Tyrer–Cuzick risk and mammographic density (IQ‐OR unadjusted 2.12, 95% CI% 1.75–2.42; adjusted 2.06, 95% CI 1.75–2.42). SNP143 was a risk factor for ER+ and ER− breast cancer (adjusted IQ‐OR, ER+ 2.11, 95% CI 1.78–2.51; ER− 1.81, 95% CI 1.16–2.84). In conclusion, polygenic risk scores based on a large number of SNPs improve risk stratification in combination with classical risk factors and mammographic density, and SNP143 was similarly predictive for ER‐positive and ER‐negative disease., What's new? Panels of single nucleotide polymorphisms (SNPs) stratify risk for breast cancer in women from the general population, but studies are needed to assess their use in a fully‐comprehensive model including classical questionnaire risk factors, mammographic density, and more than 100 SNPs associated with breast cancer. In this study, the predictive ability of a predefined panel of 143 SNPs was assessed after adjustment for questionnaire risk factors and mammography density using women from a U.K. cohort. The panel showed substantial improvement in risk stratification in combination with classical risk factors and mammographic density, for both oestrogen receptor‐positive and negative breast cancer.

Importance: Knowledge of factors associated with health-related quality of life in patients with facial palsy may aid in better interpreting outcomes of research and treatment.Objective: To identify factors associated with health-related quality of life in patients with facial palsy.Design, Setting, and Participants: The inclusion period for participants in this cross-sectional study at the University Medical Center Groningen, a tertiary referral center for facial reanimation surgery, was March 1 to June 1, 2019. Patients aged at least 18 years with facial palsy who had undergone surgery for facial palsy between January 1, 2007, and January 1, 2018, and patients visiting the outpatient clinic of the University of Groningen Department of Plastic Surgery for their facial palsy between March 1 and June 1, 2019, were also asked to participate. Of 276 patients invited, 145 gave informed consent. Twenty patients did not respond after consent, 3 patients withdrew from the study, and 1 patient was wrongly included.Main Outcomes and Measures: Health-related quality of life was measured using the Facial Clinimetric Evaluation Scale and the Facial Disability Index (physical score and social score). Facial function was assessed with the Sunnybrook Facial Grading System. Other variables were investigated using validated questionnaires, including the Duke University Religion Index, Ten-Item Personality Inventory, and Hospital Anxiety and Depression Scale. Multivariable linear regression analyses with stepwise backward selection were performed to identify associations with health-related quality of life. Because 44 Sunnybrook composite scores were missing, a sensitivity analysis was performed that excluded the Sunnybrook composite scores from the multivariable analysis.Results: In total, 121 patients with facial palsy were included; their median age was 62 years (interquartile range, 48-71 years), and 63 (52%) were women. Sunnybrook composite score (β = 0.4; 95% CI, 0.2-0.5), extraversion (β = 2.6; 95% CI, 0.4-4.8), and anxiety (β = -2.4; 95% CI, -4.1 to -0.8) were associated with the Facial Clinimetric Evaluation Scale total score (R2 = 0.380; 95% CI, 0.212-0.548). The Sunnybrook composite score was associated with the Facial Disability Index physical score (β = 0.2; 95% CI, 0.0-0.4) (R2 = 0.084; 95% CI, -0.037 to 0.205). Bilateral facial palsy (β = -21.2; 95% CI, -32.3 to -10.1), extraversion (β = 2.7; 95% CI, 1.3-4.1), conscientiousness (β = 2.7; 95% CI, 0.2-5.2), emotional stability (β = 3.3; 95% CI, 1.7-4.8), and depression (β = -1.3; 95% CI, -2.5 to -0.1) were associated with the Facial Disability Index social score (R2 = 0.400; 95% CI, 0.262-0.538). In the sensitivity analysis, the Sunnybrook composite score was associated with age (Spearman ρ = -0.252).Conclusions and Relevance: Bilateral facial palsy, age, severity of facial palsy, mental distress, and personality traits should be taken into account in future research and treatment of patients with facial palsy.

Outcome tracking in facial palsy is multimodal, consisting of patient-reported outcome measures, clinician-graded scoring systems, objective assessment tools, and novel tools for layperson and spontaneity assessment. Patient-reported outcome measures are critical to understanding burden of disease in facial palsy and effects of interventions from the patient perspective. Clinician-graded scoring systems are inherently subjective and no 1 single system satisfies all needs. Objective assessment tools quantify facial movements but can be laborious. Recent advances in facial recognition technology have enabled automated facial measurements. Novel assessment tools analyze attributes such as spontaneous smile, emotional expressivity, disfigurement, and attractiveness as determined by laypersons.

Background: In longstanding facial palsy, gracilis free functional muscle transfer (FFMT) is currently considered to be the gold standard in smile reanimation. An alternative to muscle free flaps is local muscle transposition, with the temporalis muscle transposition being the preferred procedure, because of its direction of pull when transposed. The present study aimed to compare outcomes of gracilis FFMT neurotised by the masseteric nerve and temporalis muscle transposition in longstanding facial palsy using patient-reported and aesthetic outcomes.Methods: A cross-sectional comparison of gracilis FFMT and temporalis muscle transpositions was performed. Pre- and postoperative excursion measures were obtained. Patients were asked to answer a satisfaction questionnaire, quality of life questionnaire (FaCE scale) and a depression and anxiety questionnaire (HADS). Laypeople were asked to rate the pre- and postoperative aesthetic appearance.Results: Of 28 eligible patients, 10 gracilis and 12 temporalis patients participated. No significant differences were found between both groups in postoperative quality of life or depression/anxiety. Layperson observers judged the aesthetic appearance to be similar.Conclusion: In the present study, gracilis FFMT did not lead to superior quality of life and aesthetic outcomes compared to temporalis muscle transpositions. The facial nerve specialist should perform the procedure he or she expects to lead to optimal results for the patient. (C) 2018 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

BackgroundPathogenic variants in BRCA1 or BRCA2 are identified in ~20% of families with multiple individuals with early-onset breast/ovarian cancer. Extensive searches for additional highly penetrant genes or alternative mutational mechanisms altering BRCA1/2 have not explained the missing heritability. For the first time, we report transgenerational epigenetic silencing of BRCA1 due to promoter hypermethylation in two families with breast/ovarian cancer.MethodsBRCA1 promoter methylation of ten CpG dinucleotides in breast/ovarian cancer families without germline BRCA1/2 pathogenic variants was assessed by pyrosequencing and clonal bisulfite sequencing. RNA and DNA sequencing of BRCA1 from lymphocytes was undertaken to establish allelic expression and the presence of germline variants.FindingsBRCA1 promoter hypermethylation was identified in two of 49 families with multiple women affected with grade 3 breast/high grade serous ovarian cancer. Soma-wide BRCA1 promoter hypermethylation was confirmed in blood, buccal mucosa and hair follicles. Methylation levels were ~50%, consistent with the silencing of one allele and confirmed by clonal bisulfite sequencing. RNA sequencing revealed allelic loss of BRCA1 expression in both families and this segregated with a novel heterozygous variant c.-107A>T in the BRCA1 5’UTR.InterpretationOur results indicate a novel mechanism for familial breast/ovarian cancer, caused by epigenetic silencing of the BRCA1 promoter, segregating with an in cis 5’UTR variant in two independent families. We propose that methylation analyses are indicated in all families affected by early onset breast/ovarian cancer without a BRCA1/2 pathogenic variant.FundingFunded by Prevent Breast Cancer (GA 12-006 and GA 15-002) and the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007).

Objective: The diagnosis of cleft palate only (CP) and possibly associated anomalies is frequently missed. According to Dutch national standards, neonatal screening should be performed within two hours after birth. The palate is usually inspected by palpation. Opinions differ on effectiveness of this method. Design: A retrospective preliminary quantitative and qualitative study. Setting: Tertiary clinical care in Erasmus Medical Center-Sophia’s Children’s Hospital Rotterdam-the Netherlands. Participants: Dutch speaking parents of 29 children with a CP born in the Netherlands in 2007 and 2008 and treated by the Rotterdam Cleft Lip and Palate Team; 8 parents were interviewed. Interventions/methods: Data were retrieved from patient records, a telephonic questionnaire and open interviews. The data were analysed by ATLAS.ti software. Results: In 18 out of 29 cases (62%) the diagnosis had been delayed. These children had feeding problems and nasal regurgitation. Parents felt that health professionals in general have insufficient knowledge on cleft palate only and associated feeding problems, which added to the parents’ uncertainty. Conclusion: The high incidence of delay in the diagnosis of cleft palate suggests that the current method of palpation is insufficient. Additional anomalies may be missed as well. It is recommended to add visual inspection with a tongue blade. Parents risk psychological problems when professionals fail to provide adequate professional support.

Barrett's esophagus, with gastroesophageal reflux disease and obesity as risk factors, predisposes to esophageal adenocarcinoma (EAC). Recently a British genome wide association study identified two Barrett's esophagus susceptibility loci mapping within the major histocompatibility complex (MHC; rs9257809) and closely to the Forkhead-F1 (FOXF1; rs9936833) coding gene. An interesting issue is whether polymorphisms associated with Barrett's esophagus, are also implicated in esophageal carcinoma (EC), and more specifically EAC genesis. Assessing the individual genetic susceptibility can help identify high risk patients more prone to benefit from surveillance programs. Our hypothesis: Barrett associated MHC and FOXF1 variants modify EC risk in Caucasians. In a Dutch case-control study, 431 patients with EC and 605 healthy controls were included. Polymorphisms at chromosomes 6p21 (MHC) and 16q24 (FOXF1) were determined by means of real-time polymerase chain reaction (RT-PCR). Logistic regression analysis was used to calculate odds ratios with 95% confidence intervals. The FOXF1 rs9936833 variant C allele was associated with an increased EAC susceptibility; OR, [95% CI]; 1.21, [0.99-1.47]. A sex-stratified analysis revealed a similar association in males; 1.24 [1.00-1.55]. The variant MHC rs9257809 G allele as well as the MHC heterozygous AG genotype significantly increased ESCC risk; 1.76 [1.16-2.66] and 1.74 [1.08-2.80], respectively. Sex-stratification showed that the variant G allele was especially present in female patients; 2.32 [1.04-5.20]. In conclusion, this study provides evidence that MHC rs9257809 and FOXF1 rs9936833 variants, associated with Barrett's esophagus, also increase ESCC and EAC susceptibility in Caucasians. FOX proteins are transcription factors involved in organogenesis of the GI tract, while MHC haplotypes are strongly associated with smoking behavior, a crucial risk factor for ESCC. Assessing the individual genetic susceptibility can help identify high risk patients more prone to benefit from (Barrett) surveillance programs.

The sensitivity of testing BRCA1 and BRCA2 remains unresolved as the frequency of deep intronic splicing variants has not been defined in high-risk familial breast/ovarian cancer families. This variant category is reported at significant frequency in other tumour predisposition genes, including NF1 and MSH2. We carried out comprehensive whole gene RNA analysis on 45 high-risk breast/ovary and male breast cancer families with no identified pathogenic variant on exonic sequencing and copy number analysis of BRCA1/2. In addition, we undertook variant screening of a 10-gene high/moderate risk breast/ovarian cancer panel by next-generation sequencing. DNA testing identified the causative variant in 50/56 (89%) breast/ovarian/male breast cancer families with Manchester scores of ≥50 with two variants being confirmed to affect splicing on RNA analysis. RNA sequencing of BRCA1/BRCA2 on 45 individuals from high-risk families identified no deep intronic variants and did not suggest loss of RNA expression as a cause of lost sensitivity. Panel testing in 42 samples identified a known RAD51D variant, a high-risk ATM variant in another breast ovary family and a truncating CHEK2 mutation. Current exonic sequencing and copy number analysis variant detection methods of BRCA1/2 have high sensitivity in high-risk breast/ovarian cancer families. Sequence analysis of RNA does not identify any variants undetected by current analysis of BRCA1/2. However, RNA analysis clarified the pathogenicity of variants of unknown significance detected by current methods. The low diagnostic uplift achieved through sequence analysis of the other known breast/ovarian cancer susceptibility genes indicates that further high-risk genes remain to be identified.

Background The Manchester Triage System (MTS) determines an inappropriately low level of urgency (undertriage) to a minority of children. The aim of the study was to assess the clinical severity of undertriaged patients in the MTS and to define the determinants of undertriage. Methods Patients who had attended the emergency department (ED) were triaged according to the MTS. Undertriage was defined as a 'low urgent' classification (levels 3, 4 and 5) under the MTS; as a 'high urgent' classification (levels 1 and 2) under an independent reference standard based on abnormal vital signs (level 1), potentially life-threatening conditions (level 2), and a combination of resource use, hospitalisation, and follow-up for the three lowest urgency levels. In an expert meeting, three experienced paediatricians used a standardised format to determine the clinical severity. The clinical severity had been expressed by possible consequences of treatment delay caused by undertriage, such as the use of more interventions and diagnostics, longer hospitalisation, complications, morbidity, and mortality. In a prospective observational study we used logistic regression analysis to assess predictors for undertriage. Results In total, 0.9% (119/13,408) of the patients were undertriaged. In 53% (63/119) of these patients, experts considered undertriage as clinically severe. In 89% (56/63) of these patients the high reference urgency was determined on the basis of abnormal vital signs. The prospective observational study showed undertriage was more likely in infants (especially those younger than three months), and in children assigned to the MTS 'unwell child' flowchart (adjusted OR(