The epidemiology and transmission of methicillin-resistant Staphylococcus aureus in the community in Singapore: study protocol for a longitudinal household study.

BACKGROUND/AIM: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common multidrug-resistant organisms in healthcare settings worldwide, but little is known about MRSA transmission outside of acute healthcare settings especially in Asia. We describe the methods for a prospective longitudinal study of MRSA prevalence and transmission. METHODS: MRSA-colonized individuals were identified from MRSA admission screening at two tertiary hospitals and recruited together with their household contacts. Participants submitted self-collected nasal, axilla and groin (NAG) swabs by mail for MRSA culture at baseline and monthly thereafter for 6 months. A comparison group of households of MRSA-negative patients provided swab samples at one time point. In a validation sub-study, separate swabs from each site were collected from randomly selected individuals, to compare MRSA detection rates between swab sites, and between samples collected by participants versus those collected by trained research staff. Information on each participant's demographic information, medical status and medical history, past healthcare facilities usage and contacts, and personal interactions with others were collected using a self-administered questionnaire. DISCUSSION/CONCLUSION: Understanding the dynamics of MRSA persistence and transmission in the community is crucial to devising and evaluating successful MRSA control strategies. Close contact with MRSA colonized patients may to be important for MRSA persistence in the community; evidence from this study on the extent of community MRSA could inform the development of household- or community-based interventions to reduce MRSA colonization of close contacts and subsequent re-introduction of MRSA into healthcare settings. Analysis of longitudinal data using whole-genome sequencing will yield further information regarding MRSA transmission within households, with significant implications for MRSA infection control outside acute hospital settings

Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.Peer reviewe

Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk

Abstract: In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859–1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482–1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene

Images of the month 2: No laughing matter: Symptomatic Chiari malformation type I

10.7861/clinmed.2022-0243Clinical Medicine224368-36

Factors affecting PACES success rate–A Singapore experience

10.29333/ejgm/12177Electronic Journal of General Medicine195em388-em38

Steroid-Decorated Antibiotic Microparticles for Inhaled Anti-Infective Therapy

Despite advances in vaccination and antimicrobial therapy, community-acquired pneumonia (CAP) remains as a leading cause of morbidity and mortality worldwide. As the severity of CAP has been linked to the extent of inflammation in the body, adjunctive therapeutic measures aimed at modulating the immune response have therefore become increasingly attractive in recent years. In particular, for CAP patients with underlying medical conditions such as chronic obstructive pulmonary disease (COPD), a steroid–antibiotic combination will no doubt be a useful and timely therapeutic intervention. Unfortunately, no combined steroid–antibiotic dry powder formulation is available commercially or has been reported in the academic literature. The aim of this work was hence to develop a novel steroid–antibiotic dry powder inhaler formulation [ciprofloxacin hydrochloride (CIP) and beclomethasone dipropionate (BP)] for inhaled anti-infective therapy. The spray-dried powder was of respirable size (d50 of ∼2.3 μm), partially crystalline and had BP preferentially deposited on the particle surface. Favorably, when formulated as a binary mix, both CIP and BP showed much higher drug release and fine particle fractions (of the loaded dose) over their singly delivered counterparts, and had robust activity against the respiratory tract infection-causing bacteria Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus.ASTAR (Agency for Sci., Tech. and Research, S’pore)Accepted versio

Two truncating variants in FANCC and breast cancer risk

Abstract: Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants

Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry.

BACKGROUND: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. METHODS: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. RESULTS: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10-6) and AC058822.1 (P = 1.47 × 10-4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. CONCLUSIONS: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10-5), demonstrating the importance of diversifying study cohorts