Creation, doubling, and splitting, of vortices in intracavity second harmonic generation

We demonstrate generation and frequency doubling of unit charge vortices in a linear astigmatic resonator. Topological instability of the double charge harmonic vortices leads to well separated vortex cores that are shown to rotate, and become anisotropic, as the resonator is tuned across resonance

An interferometric gravitational wave detector as a quantum-gravity apparatus

As a consequence of the extreme precision of the measurements it performs, an interferometric gravitational wave detector is a macroscopic apparatus for which quantum effects are not negligible. I observe that this property can be exploited to probe some aspects of the interplay between Quantum Mechanics and Gravity.Comment: LaTex, 7 pages. Version accepted for publication in Nature. Under press embargo until publicatio

The national portfolio for postgraduate family medicine training in South Africa : a descriptive study of acceptability, educational impact, and usefulness for assessment

Background: Since 2007 a portfolio of learning has become a requirement for assessment of postgraduate family medicine training by the Colleges of Medicine of South Africa. A uniform portfolio of learning has been developed and content validity established among the eight postgraduate programmes. The aim of this study was to investigate the portfolio's acceptability, educational impact, and perceived usefulness for assessment of competence. Methods: Two structured questionnaires of 35 closed and open-ended questions were delivered to 53 family physician supervisors and 48 registrars who had used the portfolio. Categorical and nominal/ordinal data were analysed using simple descriptive statistics. The open-ended questions were analysed with ATLAS.ti software. Results: Half of registrars did not find the portfolio clear, practical or feasible. Workshops on portfolio use, learning, and supervision were supported, and brief dedicated time daily for reflection and writing. Most supervisors felt the portfolio reflected an accurate picture of learning, but just over half of registrars agreed. While the portfolio helped with reflection on learning, participants were less convinced about how it helped them plan further learning. Supervisors graded most rotations, suggesting understanding the summative aspect, while only 61% of registrars reflected on rotations, suggesting the formative aspects are not yet optimally utilised. Poor feedback, the need for protected academic time, and pressure of service delivery impacting negatively on learning. Conclusion: This first introduction of a national portfolio for postgraduate training in family medicine in South Africa faces challenges similar to those in other countries. Acceptability of the portfolio relates to a clear purpose and guide, flexible format with tools available in the workplace, and appreciating the changing educational environment from university-based to national assessments. The role of the supervisor in direct observations of the registrar and dedicated educational meetings, giving feedback and support, cannot be overemphasized

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

The West of Scotland Cohort of Mitochondrial Individuals with the m.3243A>G Variant: Variations in Phenotypes and Predictors of Disease Severity

BACKGROUND: The m.3243A>G variant is the commonest mitochondrial (mt) DNA pathogenic variant and a frequent cause of mitochondrial disease. Individuals present with a variety of clinical manifestations from diabetes to neurological events resembling strokes. Due to this, patients are commonly cared for by a multidisciplinary team. OBJECTIVES: This project aimed to identify patients with confirmed mt.3243A>G-related mitochondrial disease attending the Muscle Clinic at Queen Elizabeth University Hospital in Glasgow. We explored potential correlates between clinical phenotypes and mtDNA heteroplasmy levels, HbA1c levels, body mass index, and specific clinical manifestations. We investigated if there were discrepancies between non-neurological speciality labelling in clinical records and individuals\u27 phenotypes. METHODS: Data were gathered from the West of Scotland electronic records. Phenotypes were ascertained by a clinician with expertise in mitochondrial disorders. Statistical analyses were applied to study relationships between tissue heteroplasmy, HbA1c and clinical phenotypes including body mass index (BMI). RESULTS: Forty-six individuals were identified from 31 unrelated pedigrees. Maternally inherited diabetes and deafness was the prominent syndromic phenotype (48%). A significant association was found between overall number of symptoms and bowel dysmotility (p < 0.01). HbA1c was investigated as a predictor of severity with potential association seen. Although used widely as a prognosticator, neither corrected blood nor urine mtDNA heteroplasmy levels were associated with increased number of symptoms. In 74.1% of records, syndromic phenotypes were incorrectly used by non-neurological specialities. CONCLUSIONS: This m.3243 A > G patient cohort present with marked clinical heterogeneity. Urine and blood heteroplasmy levels are not reliable predictors of disease severity. HbA1c may be a novel predictor of disease severity with further research required to investigate this association. We infer that prognosis may be worse in patients with low BMIs and in those with bowel dysmotility. These results underscore a multidisciplinary approach and highlight a problem with inaccurate use of the existing nomenclature