Suture-related keratitis following cataract surgery caused by methicillin-resistant Staphylococcus aureus

A 54-year old-man presented with a two-day history of severe pain and decreased vision. Examination revealed a corneal ulcer associated with a loose suture from cataract surgery done approximately two years ago. The suture was removed and the patient was started on topic antibiotic treatment with cefazolin and gentamycin. Cultures revealed methicillin-resistant Staphylococcus aureus (MRSA). The antibiotic regimen was changed to include vancomycin but the ulcer continued to progress. Three days later, the ulcer had perforated and an emergent corneal patch graft was performed. To our knowledge, this is the first reported case of suture-related MRSA keratitis after uncomplicated clear corneal cataract surgery

Associations between dietary patterns and post-bronchodilation lung function in the SAPALDIA cohort

Background: Chronic obstructive pulmonary disease (COPD) is not restricted to smokers. Dietary habits may contribute to the disease occurrence. Epidemiological studies point to a protective effect of fruit and vegetable intake against COPD. Objective: To investigate the associations between dietary patterns and parameters of lung function related to COPD in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA). Methods: Data were included from the second follow-up assessment of the SAPALDIA cohort in 2010-2011 using a food frequency questionnaire. Principal component factor analysis was used to derive dietary patterns, whose association with FEV1, FEV1/FVC, FEF2575, and COPD was investigated by applying multivariate regression analyses. Results: After adjustment for potential confounders, the “prudent dietary pattern” characterised by the predominant food groups vegetables, fruits, water, tea and coffee, fish, and nuts was positively associated with FEV1 (increase of 40 mL per SD, p < 0.001). Also for factor 3 (“high-carbohydrate diet”), we found a significant positive association with FEV1 (with an increase per SD of 36 mL, p = 0.006). Conclusions: The main results are consistent with a protective effect of a diet rich in fruits, vegetables, fish, and nuts against age-related chronic respiratory disease. If confirmed in prospective cohorts, our results may guide nutritional counselling towards respiratory health promotion

Associations between dietary patterns and post-bronchodilation lung function in the SAPALDIA cohort

Chronic obstructive pulmonary disease (COPD) is not restricted to smokers. Dietary habits may contribute to the disease occurrence. Epidemiological studies point to a protective effect of fruit and vegetable intake against COPD.; To investigate the associations between dietary patterns and parameters of lung function related to COPD in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA).; Data were included from the second follow-up assessment of the SAPALDIA cohort in 2010-2011 using a food frequency questionnaire. Principal component factor analysis was used to derive dietary patterns, whose association with FEV1, FEV1/FVC, FEF2575, and COPD was investigated by applying multivariate regression analyses.; After adjustment for potential confounders, the "prudent dietary pattern" characterised by the predominant food groups vegetables, fruits, water, tea and coffee, fish, and nuts was positively associated with FEV1 (increase of 40 mL per SD, p &lt; 0.001). Also for factor 3 ("high-carbohydrate diet"), we found a significant positive association with FEV1 (with an increase per SD of 36 mL, p = 0.006).; The main results are consistent with a protective effect of a diet rich in fruits, vegetables, fish, and nuts against age-related chronic respiratory disease. If confirmed in prospective cohorts, our results may guide nutritional counselling towards respiratory health promotion

Phenotypic and molecular insights into CASK-related disorders in males

Background: Heterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range from nonsyndromic ID to Ohtahara syndrome with cerebellar hypoplasia. However, the phenotypic spectrum in males has not been systematically evaluated to date. Methods: We identified a CASK alteration in 8 novel unrelated male patients by targeted Sanger sequencing, copy number analysis (MLPA and/or FISH) and array CGH. CASK transcripts were investigated by RT-PCR followed by sequencing. Immunoblotting was used to detect CASK protein in patient-derived cells. The clinical phenotype and natural history of the 8 patients and 28 CASK-mutation positive males reported previously were reviewed and correlated with available molecular data. Results: CASK alterations include one nonsense mutation, one 5-bp deletion, one mutation of the start codon, and five partial gene deletions and duplications; seven were de novo, including three somatic mosaicisms, and one was familial. In three subjects, specific mRNA junction fragments indicated in tandem duplication of CASK exons disrupting the integrity of the gene. The 5-bp deletion resulted in multiple aberrant CASK mRNAs. In fibroblasts from patients with a CASK loss-of-function mutation, no CASK protein could be detected. Individuals who are mosaic for a severe CASK mutation or carry a hypomorphic mutation still showed detectable amount of protein. Conclusions: Based on eight novel patients and all CASK-mutation positive males reported previously three phenotypic groups can be distinguished that represent a clinical continuum: (i) MICPCH with severe epileptic encephalopathy caused by hemizygous loss-of-function mutations, (ii) MICPCH associated with inactivating alterations in the mosaic state or a partly penetrant mutation, and (iii) syndromic/nonsyndromic mild to severe ID with or without nystagmus caused by CASK missense and splice mutations that leave the CASK protein intact but likely alter its function or reduce the amount of normal protein. Our findings facilitate focused testing of the CASK gene and interpreting sequence variants identified by next-generation sequencing in cases with a phenotype resembling either of the three groups

Evaluating Educational Interventions in Emergency Medicine

This article presents the proceedings of the 2012 Academic Emergency Medicine consensus conference breakout group charged with identifying areas necessary for future research regarding effectiveness of educational interventions for teaching emergency medicine ( EM ) knowledge, skills, and attitudes outside of the clinical setting. The objective was to summarize both medical and nonmedical education literature and report the consensus formation methods and results. The authors present final statements to guide future research aimed at evaluating the best methods for understanding and developing successful EM curricula using all types of educational interventions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94811/1/acem12022.pd

Male breast cancer in BRCA1 and BRCA2 mutation carriers : pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Background: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). Methods: We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. Results: Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 x 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 x 10(-12)). Conclusions: On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.Peer reviewe

Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers.The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.Peer reviewe

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification