Inherited breast cancer predisposition in Asians: multigene panel testing outcomes from Singapore.

Genetic testing for germline mutations in breast cancer predisposition genes can potentially identify individuals at a high risk of developing breast and/or ovarian cancer. There is a paucity of such mutational information for Asians. Panel testing of 25 cancer susceptibility genes and BRCA1/2 deletion/duplication analysis was performed for 220 Asian breast cancer patients or their family members referred for genetics risk assessment. All 220 participants had at least one high-risk feature: having a family history of breast and/or ovarian cancer in first- and/or second-degree relatives; having breast and ovarian cancer in the same individual or bilateral breast cancer; having early-onset breast cancer or ovarian cancer (⩽40 years of age). We identified 67 pathogenic variants in 66 (30.0%) patients. Of these, 19 (28.3%) occurred in BRCA1, 16 (23.9%) in BRCA2, 7 (10.4%) in PALB2, 6 (9.0%) in TP53, 2 (3.0%) in PTEN, 2 (3.0%) in CDH1 and 15 (22.4%) in other predisposition genes. Notably, 47.8% of pathogenic variants were in non-BRCA1/2 genes. Of the 66 patients with pathogenic mutations, 63.6% (42/66) were under the age of 40 years. Family history of breast and/or ovarian cancer is enriched in patients with BRCA1/2 pathogenic variants but less predictive for non-BRCA1/2 related pathogenic variations. We detected a median of three variants of unknown significance (VUS) per gene (range 0-21). Custom gene panel testing is feasible and useful for the detection of pathogenic mutations and should be done in the setting of a formal clinical cancer genetics service given the rate of VUS.

Predictive Factors for BRCA1 and BRCA2 Genetic Testing in an Asian Clinic-Based Population.

PURPOSE: The National Comprehensive Cancer Network (NCCN) has proposed guidelines for the genetic testing of the BRCA1 and BRCA2 genes, based on studies in western populations. This current study assessed potential predictive factors for BRCA mutation probability, in an Asian population. METHODS: A total of 359 breast cancer patients, who presented with either a family history (FH) of breast and/or ovarian cancer or early onset breast cancer, were accrued at the National Cancer Center Singapore (NCCS). The relationships between clinico-pathological features and mutational status were calculated using the Chi-squared test and binary logistic regression analysis. RESULTS: Of 359 patients, 45 (12.5%) had deleterious or damaging missense mutations in BRCA1 and/or BRCA2. BRCA1 mutations were more likely to be found in ER-negative than ER-positive breast cancer patients (P=0.01). Moreover, ER-negative patients with BRCA mutations were diagnosed at an earlier age (40 vs. 48 years, P=0.008). Similarly, triple-negative breast cancer (TNBC) patients were more likely to have BRCA1 mutations (P=0.001) and that these patients were diagnosed at a relatively younger age than non-TNBC patients (38 vs. 46 years, P=0.028). Our analysis has confirmed that ER-negative status, TNBC status and a FH of hereditary breast and ovarian cancer (HBOC) are strong factors predicting the likelihood of having BRCA mutations. CONCLUSIONS: Our study provides evidence that TNBC or ER-negative patients may benefit from BRCA genetic testing, particularly younger patients (<40 years) or those with a strong FH of HBOC, in Asian patients.

Correction of methylmalonic aciduria in vivo using a codon-optimized lentiviral vector.

Methylmalonic aciduria is a rare disorder of organic acid metabolism with limited therapeutic options, resulting in high morbidity and mortality. Positive results from combined liver/kidney transplantation suggest, however, that metabolic sink therapy may be efficacious. Gene therapy offers a more accessible approach for the treatment of methylmalonic aciduria than organ transplantation. Accordingly, we have evaluated a lentiviral vector-mediated gene transfer approach in an in vivo mouse model of methylmalonic aciduria. A mouse model of methylmalonic aciduria (Mut(-/-)MUT(h2)) was injected intravenously at 8 weeks of age with a lentiviral vector that expressed a codon-optimized human methylmalonyl coenzyme A mutase transgene, HIV-1SDmEF1αmurSigHutMCM. Untreated Mut(-/-)MUT(h2) and normal mice were used as controls. HIV-1SDmEF1αmurSigHutMCM-treated mice achieved near-normal weight for age, and Western blot analysis demonstrated significant methylmalonyl coenzyme A enzyme expression in their livers. Normalization of liver methylmalonyl coenzyme A enzyme activity in the treated group was associated with a reduction in plasma and urine methylmalonic acid levels, and a reduction in the hepatic methylmalonic acid concentration. Administration of the HIV-1SDmEF1αmurSigHutMCM vector provided significant, although incomplete, biochemical correction of methylmalonic aciduria in a mouse model, suggesting that gene therapy is a potential treatment for this disorder.

Effect of daily chlorhexidine bathing on hospital-acquired infection.

BACKGROUND: Results of previous single-center, observational studies suggest that daily bathing of patients with chlorhexidine may prevent hospital-acquired bloodstream infections and the acquisition of multidrug-resistant organisms (MDROs). METHODS: We conducted a multicenter, cluster-randomized, nonblinded crossover trial to evaluate the effect of daily bathing with chlorhexidine-impregnated washcloths on the acquisition of MDROs and the incidence of hospital-acquired bloodstream infections. Nine intensive care and bone marrow transplantation units in six hospitals were randomly assigned to bathe patients either with no-rinse 2% chlorhexidine-impregnated washcloths or with nonantimicrobial washcloths for a 6-month period, exchanged for the alternate product during the subsequent 6 months. The incidence rates of acquisition of MDROs and the rates of hospital-acquired bloodstream infections were compared between the two periods by means of Poisson regression analysis. RESULTS: A total of 7727 patients were enrolled during the study. The overall rate of MDRO acquisition was 5.10 cases per 1000 patient-days with chlorhexidine bathing versus 6.60 cases per 1000 patient-days with nonantimicrobial washcloths (P=0.03), the equivalent of a 23% lower rate with chlorhexidine bathing. The overall rate of hospital-acquired bloodstream infections was 4.78 cases per 1000 patient-days with chlorhexidine bathing versus 6.60 cases per 1000 patient-days with nonantimicrobial washcloths (P=0.007), a 28% lower rate with chlorhexidine-impregnated washcloths. No serious skin reactions were noted during either study period. CONCLUSIONS: Daily bathing with chlorhexidine-impregnated washcloths significantly reduced the risks of acquisition of MDROs and development of hospital-acquired bloodstream infections. (Funded by the Centers for Disease Control and Prevention and Sage Products; ClinicalTrials.gov number, NCT00502476.).

The effect of daily bathing with chlorhexidine on the acquisition of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and healthcare-associated bloodstream infections: results of a quasi-experimental multicenter trial.

OBJECTIVE: Spread of multidrug-resistant organisms within the intensive care unit (ICU) results in substantial morbidity and mortality. Novel strategies are needed to reduce transmission. This study sought to determine if the use of daily chlorhexidine bathing would decrease the incidence of colonization and bloodstream infections (BSI) because of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) among ICU patients. DESIGN, SETTING, AND PATIENTS: Six ICUs at four academic centers measured the incidence of MRSA and VRE colonization and BSI during a period of bathing with routine soap for 6 months and then compared results with a 6-month period where all admitted patients received daily bathing with a chlorhexidine solution. Changes in incidence were evaluated by Poisson and segmented regression modeling. INTERVENTIONS: Daily bathing with a chlorhexidine-containing solution. MEASUREMENTS AND MAIN RESULTS: Acquisition of MRSA decreased 32% (5.04 vs. 3.44 cases/1000 patient days, p = 0.046) and acquisition of VREdecreased 50% (4.35 vs. 2.19 cases/1000 patient days, p = 0.008) following the introduction of daily chlorhexidine bathing. Segmented regression analysis demonstrated significant reductions in VRE bacteremia (p = 0.02) following the introduction of chlorhexidine bathing. VRE-colonized patients bathed with chlorhexidine had a lower risk of developing VRE bacteremia (relative risk 3.35; 95% confidence interval 1.13-9.87; p = 0.035), suggesting that reductions in the level of colonization led to the observed reductions in BSI. CONCLUSION: We conclude that daily chlorhexidine bathing among ICU patients may reduce the acquisition of MRSA and VRE. The approach is simple to implement and inexpensive and may be an important adjunctive intervention to barrier precautions to reduce acquisition of VRE and MRSA and the subsequent development of healthcare-associated BSI.

The effect of a quality improvement collaborative to improve antimicrobial prophylaxis in surgical patients: a randomized trial.

BACKGROUND: Quality improvement collaboratives are used to improve health care quality, but their efficacy remains controversial. OBJECTIVE: To assess the effects of a quality improvement collaborative on preoperative antimicrobial prophylaxis. DESIGN: Longitudinal cluster randomized trial, with the quality improvement collaborative as the intervention. SETTING: United States. PARTICIPANTS: 44 acute care hospitals, each of which randomly sampled approximately 100 selected surgical cases (cardiac, hip or knee replacement, and hysterectomy) at both the baseline and remeasurement phases. INTERVENTION: All hospitals received a comparative feedback report. Hospitals randomly assigned to the intervention group (n = 22) participated in a quality improvement collaborative comprising 2 in-person meetings led by experts, monthly teleconferences, and receipt of supplemental materials over 9 months. MEASUREMENTS: Change in the proportion of patients receiving at least 1 antibiotic dose within 60 minutes of surgery (primary outcome) and change in the proportions of patients given any antibiotics, given antibiotics for 24 hours or less, given an appropriate drug, and given a single preoperative dose and receipt of any of the 5 measures (secondary outcome). RESULTS: The groups did not differ in the change in proportion of patients who received a properly timed antimicrobial prophylaxis dose (-3.8 percentage points [95% CI, -13.9 to 6.2 percentage points]) after adjustment for region, hospital size, and surgery type. Similarly, the groups did not differ in individual measures of antibiotic duration; use of appropriate drug; receipt of a single preoperative dose; or an all-or-none measure combining timing, duration, and selection. LIMITATIONS: Hospitals volunteered for the effort, thereby resulting in selection for participants who were motivated to change. Implementation of the surgical infection prevention measure reporting requirements by the Centers for Medicare & Medicaid Services and The Joint Commission may have motivated improvement in prophylaxis performance. CONCLUSION: At a time of heightened national attention toward measures of antimicrobial prophylaxis performance, the trial did not demonstrate a benefit of participation in a quality improvement collaborative over performance feedback for improvement of these measures.

The impact of hospital practice on central venous catheter associated bloodstream infection rates at the patient and unit level: a multicenter study.

OBJECTIVE: Little is known about factors driving variation in bloodstream infection (BSI) rates between institutions. The objectives of this study are to (1) identify patient, process of care, and hospital factors that influence intensive care unit (ICU)-level BSI rates and (2) compare those factors to individual risk factors identified in a cohort analysis. DESIGN: In this multicenter prospective observational study, the authors measured the process of care for 2970 randomly sampled central venous catheter insertions over 13 months. SETTING: Medical, surgical, and medical/surgical ICUs of 37 domestic and 13 international hospitals. RESULTS: Significant correlates of unit-level BSI rates were percentage of female patients, patients on dialysis, ICU bed size, percentage of practitioners with low numbers of previous insertions, and percentage inserted by nurses. Patient-level analysis identified gender, age, posttransplant, postsurgery, and use of the line for parenteral nutrition. CONCLUSIONS: Factors that influence unit-to-unit variation may differ from factors identified in studies of individual patient risk.

Improving methicillin-resistant Staphylococcus aureus surveillance and reporting in intensive care units.

BACKGROUND: Routine culturing of patients in intensive care units (ICUs) for methicillin-resistant Staphylococcus aureus (MRSA) identifies unrecognized carriers and facilitates timely isolation. However, the benefit of surveillance in detecting prevalent and incident carriers likely varies among ICUs. In addition, many assessments underestimate the incidence of acquisition by including prevalent carriers in the at-risk population. METHODS: We performed a retrospective cohort study using accurate at-risk populations to evaluate the range of benefit of admission and weekly surveillance cultures in detecting otherwise unrecognized MRSA in 12 ICUs in 5 states. RESULTS: We assessed 142 ICU-months. Among the 12 ICUs, the admission prevalence of imported MRSA was 5%-21%, with admission surveillance providing 30%-135% increases in rates of detection. The monthly hospital-associated incidence was 2%-6%, with weekly surveillance providing 7%-157% increases in detection. The common practice of reporting incidence using the total number of patients or total patient-days underestimated incidence by one-third. Surgical ICUs had lower MRSA importation but higher MRSA incidence. Overall, routine surveillance prevented the misclassification of 17% (unit range, 11%-29%) of "incident" carriers, compared with clinical cultures, and increased precaution days by 18% (unit range, 11%-91%). CONCLUSIONS: Routine surveillance significantly increases the detection of MRSA, but this benefit is not uniform across ICUs, even with high compliance and the use of correct denominators.

A multicenter intervention to prevent catheter-associated bloodstream infections.

BACKGROUND: Education-based interventions can reduce the incidence of catheter-associated bloodstream infection. The generalizability of findings from single-center studies is limited. OBJECTIVE: To assess the effect of a multicenter intervention to prevent catheter-associated bloodstream infections. DESIGN: An observational study with a planned intervention. SETTING: Twelve intensive care units and 1 bone marrow transplantation unit at 6 academic medical centers. PATIENTS: Patients admitted during the study period. INTERVENTION: Updates of written policies, distribution of a 9-page self-study module with accompanying pretest and posttest, didactic lectures, and incorporation into practice of evidence-based guidelines regarding central venous catheter (CVC) insertion and care. MEASUREMENTS: Standard data collection tools and definitions were used to measure the process of care (ie, the proportion of nontunneled catheters inserted into the femoral vein and the condition of the CVC insertion site dressing for both tunneled and nontunneled catheters) and the incidence of catheter-associated bloodstream infection. RESULTS: Between the preintervention period and the postintervention period, the percentage of CVCs inserted into the femoral vein decreased from 12.9% to 9.4% (relative ratio, 0.73; 95% confidence interval [CI], 0.61-0.88); the total proportion of catheter insertion site dressings properly dated increased from 26.6% to 34.4% (relative ratio, 1.29; 95% CI, 1.17-1.42), and the overall rate of catheter-associated bloodstream infections decreased from 11.2 to 8.9 infections per 1,000 catheter-days (relative rate, 0.79; 95% CI, 0.67-0.93). The effect of the intervention varied among individual units. CONCLUSIONS: An education-based intervention that uses evidence-based practices can be successfully implemented in a diverse group of medical and surgical units and reduce catheter-associated bloodstream infection rates.

Duration of colonization with methicillin-resistant Staphylococcus aureus among patients in the intensive care unit: implications for intervention.

OBJECTIVES: To determine the duration of methicillin-resistant Staphylococcus aureus (MRSA) colonization or infection before entry and during hospitalization in the intensive care unit (ICU) and the characteristics of patients who tested positive for MRSA. DESIGN: Prospective observational cohort survey. SETTING: A combined medical and coronary care ICU with 16 single-bed rooms in a 427-bed tertiary care Veteran Affairs Medical Center. PATIENTS: A total of 720 ICU patients associated with 845 ICU admissions were followed up for the detection of MRSA from January 13, 2003, to October 12, 2003. MRSA colonization was detected in patients by using active surveillance cultures (ASCs) of nasal swab specimens obtained within 48 hours of ICU entry and 3 times weekly thereafter. The duration of colonization during ICU stay and before ICU entry was calculated after a review of surveillance culture results, clinical culture results, and medical history. RESULTS: Ninety-three (11.0%) of 845 ICU admissions involved patients who were colonized with MRSA at the time of ICU entry, and 21 admissions (2.5%) involved patients who acquired MRSA during ICU stay. ASCs were positive for MRSA in 84 (73.6%) of the 114 admissions associated with MRSA positivity and were the sole means of identifying MRSA in 50 cases (43.8%). More than half of the MRSA-associated admissions involved patients who were transferred from hospital wards. The total bed-days of care for 38 admissions involving patients who tested positive for MRSA before ICU entry (1131 days) was nearly 20% higher than the total bed-days of care for all admissions associated with MRSA positivity (970 days). Admissions involving MRSA-positive patients were associated with a longer length of hospitalization before ICU entry (P < .001), longer length of ICU stay (P < .001), longer overall length of hospitalization (P < .001), and greater inpatient mortality than admissions involving MRSA-negative patients (P < .001). A total of 22.8% of all bed-care days were dedicated to MRSA-positive patients in the ICU, and 55 (48.2%) of 114 admissions associated with MRSA positivity involved patients who were colonized for the duration of their ICU stay. CONCLUSIONS: In our unit, ASCs were an effective means to identify MRSA colonization among patients admitted to the ICU. Unfortunately, the majority of identified patients had long durations of stay in our own hospital before ICU entry, with prolonged MRSA colonization. Enhanced efforts to control MRSA will have to account for the prevalence of MRSA within hospital wards and to direct control efforts at these patients in the future.

Comparing bloodstream infection rates: the effect of indicator specifications in the evaluation of processes and indicators in infection control (EPIC) study.

OBJECTIVE: Bloodstream infection (BSI) rates are used as comparative clinical performance indicators; however, variations in definitions and data-collection approaches make it difficult to compare and interpret rates. To determine the extent to which variation in indicator specifications affected infection rates and hospital performance rankings, we compared absolute rates and relative rankings of hospitals across 5 BSI indicators. DESIGN: Multicenter observational study. BSI rate specifications varied by data source (clinical data, administrative data, or both), scope (hospital wide or intensive care unit specific), and inclusion/exclusion criteria. As appropriate, hospital-specific infection rates and rankings were calculated by processing data from each site according to 2-5 different specifications. SETTING: A total of 28 hospitals participating in the EPIC study. PARTICIPANTS: Hospitals submitted deidentified information about all patients with BSIs from January through September 1999. RESULTS: Median BSI rates for 2 indicators based on intensive care unit surveillance data ranged from 2.23 to 2.91 BSIs per 1000 central-line days. In contrast, median rates for indicators based on administrative data varied from 0.046 to 7.03 BSIs per 100 patients. Hospital-specific rates and rankings varied substantially as different specifications were applied; the rates of 8 of 10 hospitals were both greater than and less than the mean. Correlations of hospital rankings among indicator pairs were generally low (rs=0-0.45), except when both indicators were based on intensive care unit surveillance (rs = 0.83). CONCLUSIONS: Although BSI rates seem to be a logical indicator of clinical performance, the use of various indicator specifications can produce remarkably different judgments of absolute and relative performance for a given hospital. Recent national initiatives continue to mix methods for specifying BSI rates; this practice is likely to limit the usefulness of such information for comparing and improving performance.

Enhanced identification of postoperative infections among inpatients.

We evaluated antimicrobial exposure, discharge diagnoses, or both to identify surgical site infections (SSI). This retrospective cohort study in 13 hospitals involved weighted, random samples of records from 8,739 coronary artery bypass graft (CABG) procedures, 7,399 cesarean deliveries, and 6,175 breast procedures. We compared routine surveillance to detection through inpatient antimicrobial exposure (> 9 days for CABG, > 2 days for cesareans, and > 6 days for breast procedures), discharge diagnoses, or both. Together, all methods identified SSI after 7.4% of CABG, 5.0% of cesareans, and 2.0% of breast procedures. Antimicrobial exposure had the highest sensitivity, 88%-91%, compared with routine surveillance, 38%-64%. Diagnosis codes improved sensitivity of detection of antimicrobial exposure after cesareans. Record review confirmed SSI after 31% to 38% of procedures that met antimicrobial surveillance criteria. Sufficient antimicrobial exposure days, together with diagnosis codes for cesareans, identified more postoperative SSI than routine surveillance methods. This screening method was efficient, readily standardized, and suitable for most hospitals.

Preventing central venous catheter-associated primary bloodstream infections: characteristics of practices among hospitals participating in the Evaluation of Processes and Indicators in Infection Control (EPIC) study.

OBJECTIVES: To describe the conceptual framework and methodology of the Evaluation of Processes and Indicators in Infection Control (EPIC) study and present results of CVC insertion characteristics and organizational practices for preventing BSIs. The goal of the EPIC study was to evaluate relationships among processes of care, organizational characteristics, and the outcome of BSI. DESIGN: This was a multicenter prospective observational study of variation in hospital practices related to preventing CVC-associated BSIs. Process of care information (eg, barrier use during insertions and experience of the inserting practitioner) was collected for a random sample of approximately 5 CVC insertions per month per hospital during November 1998 to December 1999. Organization demographic and practice information (eg, surveillance activities and staff and ICU nurse staffing levels) was also collected. SETTING: Medical, surgical, or medical-surgical ICUs from 55 hospitals (41 U.S. and 14 international sites). PARTICIPANTS: Process information was obtained for 3,320 CVC insertions with an average of 58.2 (+/- 16.1) insertions per hospital. Fifty-four hospitals provided policy and practice information. RESULTS: Staff spent an average of 13 hours per week in study ICU surveillance. Most patients received nontunneled, multiple lumen CVCs, of which fewer than 25% were coated with antimicrobial material. Regarding barriers, most clinicians wore masks (81.5%) and gowns (76.8%); 58.1% used large drapes. Few hospitals (18.1%) used an intravenous team to manage ICU CVCs. CONCLUSIONS: Substantial variation exists in CVC insertion practice and BSI prevention activities. Understanding which practices have the greatest impact on BSI rates can help hospitals better target improvement interventions.