The relationship between visual impairments and activity of the neck/shoulder muscles among surgeons during simulated surgical tasks.

BACKGROUND: Minimally Invasive Surgery (MIS) has an impact on surgeons' musculoskeletal and visual systems. However, the relationship between visual symptoms and musculoskeletal problems is not well understood. AIM OF THE STUDY: This study used surface electromyography (sEMG) to examine changes in fatigue of the neck/shoulder muscles among surgeons with visual impairments when performing simulated surgical tasks in 2D and 3D viewing modes. DESIGN: Cross-sectional laboratory study. METHODS: Changes in median frequency (MDF, an indicator of muscle fatigue) were examined in 17 experienced gynaecologists. Four simulated surgical laparoscopy tasks were performed in 2D and 3D viewing modes. The MDF of three neck/shoulder muscles (cervical erector spinae, [CES], upper trapezii [UT], and anterior deltoids [AD]) were examined bilaterally. Visual parameters (accommodation, convergence, and stereoacuity) were measured prior to commencement. RESULTS: There was a downward shift of MDF from simple to more complex tasks for the right and left CES and AD muscles but not the UT, which was consistent for surgeons with mild accommodation/convergence impairment and/or good stereoacuity. There were significant differences in the level of muscle fatigue of the neck/shoulder muscles according to the severity of visual impairment, muscle side, task and surgical performance level. CONCLUSIONS: The results show a relationship between the degree of visual impairments and muscle fatigue of the neck/shoulder muscles among MIS surgeons. These findings have important implications in understanding the concurrence of musculoskeletal problems and visual symptoms.

The contribution of respiratory and hearing protection use to psychological distress in the workplace: a scoping review.

OBJECTIVE: Workers from various industries use personal protective equipment (PPE) including masks, respirators, and hearing protection to reduce their exposures to workplace hazards. Many studies have evaluated the physiological impacts of PPE use, but few have assessed the psychological impacts. The aim of the present study was to carry out a scoping review to compile existing evidence and determine the extent of knowledge on workplace mask, respirator or hearing protection use as a psychosocial hazard (stressor) that could result in a stress response and potentially lead to psychological injury. METHODS: The scoping review followed recognized methods and was conducted using Ovid Emcare, PubMed, Sage Journals, ScienceDirect, Scopus, SpringerLink, Google Scholar and preprint databases (OSF Preprints and medRxiv). Articles on the stressors associated with the use of masks, respirators, and hearing protection were included. The extracted data included author(s) name, year of publication, title of article, study design, population data, stressors assessed, and key findings. RESULTS: We retrieved 650 articles after removal of duplicates, of which 26 were deemed eligible for inclusion for review. Identified factors associated with PPE use that could potentially create a stress response were identified: communication impacts, physical impacts, psychological illness symptoms, cognitive impacts, and perceived PPE-related impacts. Evidence for respirators suggest that there may be psychological injury associated with their use. However, hearing protection appears to have a protective effect in reducing psychological symptoms such as anxiety, depression, and aggression. CONCLUSIONS: Mask or respirator use may lead to an increase in work-related stress. Whereas hearing protection may have protective effects against psychological symptoms and improves speech intelligibility. More research is needed to better understand potential psychosocial impacts of mask, respirator and/or hearing protection use.

Using touchscreen mobile devices-when, where and how: a one-week field study.

This cross-sectional study explored the objectively measured Touchscreen Mobile Device (TSMD) use in free-living conditions. Data on TSMD use, gross body posture (lying, sitting, standing, stepping), and location of use (workplace, home, other) were collected over seven consecutive days from 54 adults (mean ± SD, 38 ± 10 years). The average duration of TSMD use was 152 ± 91 min/day, with a TSMD engagement of 51 ± 35 times/day. Participants under 30 years spent significantly more time on their TSMD, averaging 230 ± 108 min/day. By location, 54 ± 17% of use occurred at home and 24 ± 15% at work. The most common posture adopted during any TSMD use was sitting (77 ± 5 2 min/day), with participants also spending considerable time lying down in the home environment (39 ± 49 min/day). These findings provide valuable insights into how adults are using TSMDs, including the postures and locations of use. Further research is needed on the health and wellbeing implications of these usage patterns. Practitioner summary: This study explored Touchscreen Mobile Device (TSMD) use in free-living conditions among 54 adults (mean ± standard deviation, 38 ± 10 years). Participants under 30 years spent significantly more time on their devices. More than half of the time spent using TSMD occurred at home while sitting and lying down.Abbreviations: TSMD: touchscreen mobile device; SD: standard deviation; MSD: musculoskeletal disorder; HDR: higher degree by research; SEES: School of Earth and Environmental Sciences; UK: The United Kingdom; USA: United States of America; SAS: statistical analysis system; ANOVA: analysis of variance; SPSS: statistical package for the social sciences; h: hour; min/d: minutes per day; d: day; ICC: intraclass correlation; CI: confidence interval; min: minute; GPS: global positioning systemsHighlightsTouchscreen mobile device use and gross body posture were quantified objectively.The most common postures for touchscreen mobile device use were lying and sitting.Touchscreen mobile devices were used around twice as much at home than at work.Use at home, with a predominance of the lying posture, needs further investigation.

Impact of accommodation, convergence and stereoacuity on perceived symptoms and surgical performance among surgeons.

BACKGROUND: Minimally invasive surgery (MIS) is not without impact on surgeons' neck/shoulder/head and eyes. However, the mechanisms for concurrent symptoms are not clear. This study aims to examine the effect of visual impairments on physical symptoms and surgical performance among surgeons performing simulated surgical tasks using two-dimensional (2D) and three-dimensional (3D) viewing modes. METHODS: Gynaecologists with experience in laparoscopy performed four simulated surgical tasks in the 2D and 3D viewing modes. Visual parameters (accommodation, convergence and stereoacuity) were measured prior to commencement. Objective performance measures were derived from the laparoscopic tasks, and surgeons also self-reported their mental and physical workload using the NASA-TLX. In addition, perceived symptoms were measured using Visual Analogue Scales, the Simulator Sickness Questionnaire and the Computer Vision Syndrome Questionnaire. RESULTS: Seventeen healthy gynaecologists participated in this study. There were significant relationships between visual impairments and both the perceived symptoms and surgical performance scores of MIS surgeons. Surgeons with a higher number of accommodation/convergence dysfunctions and/or poorer stereoacuity tended to have poorer objective performance scores on simulated surgical tasks in both viewing modes. NASA-TLX scores indicated that surgeons with poorer stereoacuity also perceived themselves to have been less successful at accomplishing tasks. However, these surgeons also reported less intense physical symptoms and simulator sickness. CONCLUSIONS: Surgeons' performance for the simulated surgical tasks correlated with visual functions, and it also impacted on the symptoms experienced. Regular screening of surgeons' vision and vision therapy may be required to decrease physical symptoms and improve surgical performance.

Visual symptoms, Neck/shoulder problems and associated factors among surgeons performing Minimally Invasive Surgeries (MIS): A comprehensive survey.

PURPOSE: Minimally Invasive Surgery (MIS) is demanding on the musculoskeletal and visual systems. Prevalence, severity and association of neck/shoulder problems and visual symptoms were examined among MIS surgeons. The associations of workplace and individual factors with these symptoms independently and combined were also examined. METHODS: MIS surgeons completed a comprehensive online survey inclusive of 52 questions about individual and workplace physical factors, neck/shoulder problems and visual symptoms. Binary logistic regression models were conducted to determine the associations of the neck/shoulder problems, visual symptoms and combined symptoms with workplace and individual factors. RESULTS: 290 surgeons completed the survey. Neck/shoulder problems and visual symptoms were reported by 31.0% and 29.0%, respectively, 15.5% reported both problems. The prevalence and severity of neck/shoulder problems and visual symptoms were significantly associated (p < 0.001). Several workplace and individual factors were associated with these symptoms (p ≤ 0.05). CONCLUSIONS: Several factors in the workplace environment (temperature, asymmetrical weight bearing and forward head movement) and individual (being female and wearing vision correction glasses) were significantly associated with neck/shoulder problems and visual symptoms. Evaluation of different strategies to minimise the strain on the neck/shoulder region and the visual system is required.

Characteristics of headaches among surgeons and associated factors: A cross-sectional study.

BACKGROUND: Surgeons performing Minimally Invasive Surgery (MIS) report significant neck/shoulder problems and visual symptoms. Headache is another commonly reported symptom but publications about the characteristics and associated risk factors are limited. PURPOSE OF THE STUDY: To determine the characteristics of headache among MIS surgeons and the associations of headache with neck/shoulder problems, visual symptoms and other associated factors. DESIGN: A cross-sectional study. METHODS: A comprehensive online survey was sent to MIS surgeons inclusive of 63 questions about individual and workplace physical factors, characteristics of headache, neck/shoulder problems and visual symptoms. Binary logistic regression models were conducted to determine the associations of the prevalence and severity of headache with risk factors. THE MAIN FINDINGS: Headaches in the last 7 days were reported by 36% of surgeons, with 37% of these of moderate to severe intensity. Frequent intense headaches were often preceded by neck pain. Surgeons with headache were eight times more likely to also experience visual symptoms and four times more likely to experience neck/shoulder problems. Several factors (frequently adopting forward head movement, surgical specialty, sex and age) were significantly associated with headaches (p ≤ 0.05). CONCLUSIONS: This study revealed headaches were present in one-third of MIS surgeons. During surgery, surgeons report adopting non-neutral neck/shoulder/head positions, which may explain headaches, neck/shoulder problems and visual symptoms. Evidence based strategies to assist surgeons better manage these symptoms are warranted.

Comparison of Clinical Outcomes among Intensive Care Unit Patients Receiving One or Two Grams of Ceftriaxone Daily.

Intensive care unit (ICU) patients may experience ceftriaxone underexposure, but clinical outcomes data are lacking. The objective of this study was to determine the impact of ceftriaxone dosing on clinical outcomes among ICU patients without central nervous system (CNS) infection. A retrospective study of ICU patients receiving intravenous, empirical ceftriaxone for non-CNS infections was conducted. Patients ≥18 years of age who received ≤2 g of ceftriaxone daily for ≥72 h were included and categorized as receiving ceftriaxone 1 g or 2 g daily. The primary, composite outcome was treatment failure, defined as inpatient mortality and/or antibiotic escalation due to clinical worsening. Propensity score matching was performed based on the probability of receiving 2 g of ceftriaxone daily. Multivariable logistic regression determined the association between ceftriaxone dose and treatment failure in a propensity-matched cohort. A total of 212 patients were included in the propensity-matched cohort. The most common diagnoses (83.0%) were pneumonia and urinary tract infection. Treatment failure occurred in 17.0% and 5.7% of patients receiving 1 g and 2 g daily, respectively (P = 0.0156). Overall inpatient mortality was 8.5%. Ceftriaxone 2 g dosing was associated with a reduced likelihood of treatment failure (adjusted odds ratio [aOR] = 0.190; 95% confidence interval [CI] = 0.059 to 0.607). Other independent predictors of treatment failure included sequential organ failure assessment score (aOR = 1.440; 95% CI = 1.254 to 1.653) and creatinine clearance at 72 h from ceftriaxone initiation (aOR = 0.980; 95% CI = 0.971 to 0.999). Therefore, ceftriaxone at 2 g daily, when used as appropriate antimicrobial coverage, may be appropriate for ICU patients with lower mortality risk.

Neck/Shoulder Problems and Visual Disturbances Among Surgeons: A Scoping Review.

BACKGROUND: Minimally invasive surgeries are the surgical techniques that lower the size of incisions needed but may increase the physical problems such as neck/shoulder problems and visual disturbances among surgeons. This study aims to determine the prevalence, severity, proposed risk factors, and evidence for a relationship for neck/shoulder problems and visual disturbances (separately and concurrently) among surgeons. MATERIALS AND METHODS: A scoping review using the five-stage framework proposed by Arksey and O'Malley was conducted. This included identification of a research question and relevant studies, study selection, charting of data and collating, summarizing, and reporting of the results. Databases searched were PubMed, Embase, CINAHL, Cochrane Library and Web of Science, and Scopus, alongside a hand-search. An Appraisal tool for Cross-Sectional Studies was used to determine methodological quality of studies. RESULTS: Ten articles met the inclusion criteria from 744 identified. Prevalence were reported by all the studies and ranged from 6% to 74% (neck); 7%-35% (right shoulder); 8%-39% (left shoulder); 9%-80% (both shoulders), and 0.4%-63% (visual disturbances). Severity of these concerns was assessed in four studies and was variable. The risk factors for neck/shoulder problems and visual disturbances included workplace physical ergonomic factors, surgery factors, and surgeon-related factors. None of the included studies proposed a relationship between neck/shoulder problems and visual disturbances. CONCLUSIONS: There was great variability in the reported prevalence of neck/shoulder problems and visual disturbances among surgeons. Neck/shoulder problems and visual disturbances shared several risk factors, but the link between the two issues has not been fully investigated.

Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers.

Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 x 10(-3)) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (P(trend) < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR = 0.78, 95% CI: 0.69-0.90, P(trend) = 3.6 x 10(-4) and HR = 1.25, 95% CI: 1.10-1.41, P(trend) = 4.2 x 10(-4)), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR = 1.55, 95% CI: 1.25-1.92, P(trend) = 6 x 10(-5) and HR = 1.37, 95% CI: 1.16-1.62, P(trend) = 1.7 x 10(-4)). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.

Exploring the link between MORF4L1 and risk of breast cancer.

INTRODUCTION: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. METHODS: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. RESULTS: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to γ-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively. CONCLUSIONS: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.

Weighing up the evidence used by direct-to-consumer stem cell businesses.

Hundreds of businesses across the United States offer direct-to-consumer stem-cell-based interventions that have not been approved by the Food and Drug Administration. Here, we characterize the types of evidence used on the websites of 59 stem cell businesses in the Southwest United States to market their services. We identify over a dozen forms of evidence, noting that businesses are less likely to rely on "gold-standard" scientific evidence, like randomized clinical trials, and instead draw substantially on forms of evidence that we identify as being "ambiguous." Ambiguous evidence has some scientific or medical basis, but its interpretation is highly context-dependent. These findings highlight the interpretive responsibility placed on prospective patients. We identify actions for regulators and professional societies to assist with evaluating evidence, but caution that focusing on the (in)validity of particular evidence types is unlikely to eliminate demand for stem-cell-based treatments in this complex marketplace.

Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers.

INTRODUCTION: Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies. METHODS: We successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers. RESULTS: SNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P < 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r² = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, P(trend) = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, P(trend) = 0.018). CONCLUSIONS: This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations.

RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies.

RAD51 is an important component of double-stranded DNA-repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5' untranslated region (UTR) of RAD51, 135G-->C, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G-->C SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91-1.51) among heterozygotes and 3.18 (95% CI 1.39-7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G-->C variant affects RAD51 splicing within the 5' UTR. Thus, 135G-->C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers.

Pooled analysis indicates that the GSTT1 deletion, GSTM1 deletion, and GSTP1 Ile105Val polymorphisms do not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers.

The GSTP1, GSTM1, and GSTT1 detoxification genes all have functional polymorphisms that are common in the general population. A single study of 320 BRCA1/2 carriers previously assessed their effect in BRCA1 or BRCA2 mutation carriers. This study showed no evidence for altered risk of breast cancer for individuals with the GSTT1 and GSTM1 deletion variants, but did report that the GSTP1 Ile105Val (rs1695) variant was associated with increased breast cancer risk in carriers. We investigated the association between these three GST polymorphisms and breast cancer risk using existing data from 718 women BRCA1 and BRCA2 mutation carriers from Australia, the UK, Canada, and the USA. Data were analyzed within a proportional hazards framework using Cox regression. There was no evidence to show that any of the polymorphisms modified disease risk for BRCA1 or BRCA2 carriers, and there was no evidence for heterogeneity between sites. These results support the need for replication studies to confirm or refute hypothesis-generating studies.

Change in Compliance of Staff at 4 Vietnam Universities after the Enactment of Smoke-free Environment Decree.

BACKGROUND: The Tobacco Control Law in Vietnam was adopted in 2012 and came into force from May 2013, followed by a number of guiding sub-law legal documents. Smoke-free campus policy in university is considered an important measure to protect people from secondhand smoking as well as staffs and students will be in favour of the policy. Furthermore, there has been evidence suggested that smoke-free policy had positive impact on active smoking as well as anti-smoking attitude. METHODS: A cross-sectional self-administered study of staff at 4 universities were conducted in 2 phases, Phase 1 as early introduction of the Law (n = 900) and Phase 2 as 1-year post (n = 885). Demographics, tobacco consumption, compliance status and compliance with awareness towards the campus smoking regulations were assessed in both phases. RESULTS: Daily smoking prevalence decreased significantly (P < .05) 1 year after implementing the smoke-free policy, while a significant increase in occasional smoking (P < .01). Compliance of staff to the regulation the campus should be indoor smoke-free was significantly increase at Phase 2 compared to Phase 1, however participants reported there would be places on campus that smokers frequently violated the smoke-free regulations. CONCLUSIONS: The study indicated a significant positive change in compliance of staff at the 4 universities after the implementation of the Tobacco Control Law, included the smoke-free policy. Although the prevalence of tobacco smoking in this study was low, the proportion of respondents who reported to reduce infringement the smoke-free policy suggests support for staff smokers would be beneficial. Raising awareness and enforcement is likely to enhance the long-term outcomes of the implementation of smoke-free environment.

Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: results from the International BRCA1/2 Carrier Cohort Study.

BACKGROUND: Several reproductive and hormonal factors are known to be associated with ovarian cancer risk in the general population, including parity and oral contraceptive (OC) use. However, their effect on ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has only been investigated in a small number of studies. METHODS: We used data on 2,281 BRCA1 carriers and 1,038 BRCA2 carriers from the International BRCA1/2 Carrier Cohort Study to evaluate the effect of reproductive and hormonal factors on ovarian cancer risk for mutation carriers. Data were analyzed within a weighted Cox proportional hazards framework. RESULTS: There were no significant differences in the risk of ovarian cancer between parous and nulliparous carriers. For parous BRCA1 mutation carriers, the risk of ovarian cancer was reduced with each additional full-term pregnancy (P trend = 0.002). BRCA1 carriers who had ever used OC were at a significantly reduced risk of developing ovarian cancer (hazard ratio, 0.52; 95% confidence intervals, 0.37-0.73; P = 0.0002) and increasing duration of OC use was associated with a reduced ovarian cancer risk (P trend = 0.0004). The protective effect of OC use for BRCA1 mutation carriers seemed to be greater among more recent users. Tubal ligation was associated with a reduced risk of ovarian cancer for BRCA1 carriers (hazard ratio, 0.42; 95% confidence intervals, 0.22-0.80; P = 0.008). The number of ovarian cancer cases in BRCA2 mutation carriers was too small to draw definitive conclusions. CONCLUSIONS: The results provide further confirmation that OC use, number of full-term pregnancies, and tubal ligation are associated with ovarian cancer risk in BRCA1 carriers to a similar relative extent as in the general population.

No evidence that CDKN1B (p27) polymorphisms modify breast cancer risk in BRCA1 and BRCA2 mutation carriers.

The p27(kip1) protein functions as an inhibitor of cyclin dependent kinase-2, and shows loss of expression in a large percentage of BRCA1 and BRCA2 breast cancer cases. We investigated the association between CDKN1B gene variants and breast cancer risk in 2359 female BRCA1 and BRCA2 mutation carriers from Australia, the UK, and the USA. Samples were genotyped for five single nucleotide polymorphisms, including coding variant rs2066827 (V109G). Cox regression provided no convincing evidence that any of the polymorphisms modified disease risk for BRCA1 or BRCA2 carriers, either alone or as a haplotype. Borderline associations were observed for homozygote carriers of the rs3759216 rare allele, but were opposite in effect for BRCA1 and BRCA2 carriers (adjusted hazard ratio (HR) 0.72 (95% CI = 0.53-0.99; P = 0.04 for BRCA1, HR 1.47 (95% CI = 0.99-2.18; P = 0.06 for BRCA2). The 95% confidence intervals for per allele risk estimates excluded a twofold risk, indicating that common CDKN1B polymorphisms do not markedly modify breast cancer risk among BRCA1 or BRCA2 carriers.

No association of TGFB1 L10P genotypes and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a multi-center cohort study.

BACKGROUND: The transforming growth factor beta-1 gene (TGFB1) is a plausible candidate for breast cancer susceptibility. The L10P variant of TGFB1 is associated with higher circulating levels and secretion of TGF-beta, and recent large-scale studies suggest strongly that this variant is associated with breast cancer risk in the general population. METHODS: To evaluate whether TGFB1 L10P also modifies the risk of breast cancer in BRCA1 or BRCA2 mutation carriers, we undertook a multi-center study of 3,442 BRCA1 and 2,095 BRCA2 mutation carriers. RESULTS: We found no evidence of association between TGFB1 L10P and breast cancer risk in either BRCA1 or BRCA2 mutation carriers. The per-allele HR for the L10P variant was 1.01 (95%CI: 0.92-1.11) in BRCA1 carriers and 0.92 (95%CI: 0.81-1.04) in BRCA2 mutation carriers. CONCLUSIONS: These results do not support the hypothesis that TGFB1 L10P genotypes modify the risk of breast cancer in BRCA1 or BRCA2 mutation carriers.

No evidence that GATA3 rs570613 SNP modifies breast cancer risk.

GATA-binding protein 3 (GATA3) is a transcription factor that is crucial to mammary gland morphogenesis and differentiation of progenitor cells, and has been suggested to have a tumor suppressor function. The rs570613 single nucleotide polymorphism (SNP) in intron 4 of GATA3 was previously found to be associated with a reduction in breast cancer risk in the Cancer Genetic Markers of Susceptibility project and in pooled analysis of two case-control studies from Norway and Poland (P (trend) = 0.004), with some evidence for a stronger association with estrogen receptor (ER) negative tumours [Garcia-Closas M et al. (2007) Cancer Epidemiol Biomarkers Prev 16:2269-2275]. We genotyped GATA3 rs570613 in 6,388 cases and 4,995 controls from the Breast Cancer Association Consortium (BCAC) and 5,617 BRCA1 and BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). We found no association between this SNP and breast cancer risk in BCAC cases overall (OR(per-allele) = 1.00, 95% CI 0.94-1.05), in ER negative BCAC cases (OR(per-allele) = 1.02, 95% CI 0.91-1.13), in BRCA1 mutation carriers RR(per-allele) = 0.99, 95% CI 0.90-1.09) or BRCA2 mutation carriers (RR(per-allele) = 0.93, 95% CI 0.80-1.07). We conclude that there is no evidence that either GATA3 rs570613, or any variant in strong linkage disequilibrium with it, is associated with breast cancer risk in women.