A multi-institutional study on the association between BRCA1/BRCA2 mutational status and triple-negative breast cancer in familial breast cancer patients

Triple-negative breast cancer (TNBC) accounts for 12–24 % of all breast cancers. Here, we studied 221 familial breast and/or ovarian cancer patients from 37 hospitals using a comprehensive approach to identify large genomic rearrangements (LGRs) as well as sequence variants, and investigated the association between BRCA1/2 mutational status and TNBC. We performed direct sequencing or mutation scanning followed by direct sequencing. Then, 143 BRCA1/2 mutation-negative patients were screened for LGRs. In this study, the prevalence of BRCA1/2 mutations was high (36.9 %). The prevalence of BRCA1 mutations was similar to that of BRCA2 mutations: 49.4 versus 50.6 %, respectively. TNBC was diagnosed in 35.2 % of BRCA1/2 mutation carriers and 57.1 % of BRCA1 mutation carriers. Conversely, two-thirds of TNBC patients carried BRCA1/2 mutation(s), and about half were BRCA1 mutation carriers. When stratified by the mutated gene, TNBC prevalence in BRCA1 mutation carriers was significantly lower when there was a family history of ovarian cancer. Our multinomial logistic regression model demonstrated that no single factor was sufficient, and at least two factors, such as a patient with family history of both breast cancer and ovarian cancer or a patient diagnosed at a relatively young age (<40 years) with a TNBC phenotype, are necessary to indicate BRCA1/2 genetic testing in this population. Our results suggest that TNBC is a strong predictor for the presence of a BRCA1 mutation in this population, but additional risk factors should also be evaluated to ascertain a 10 % or higher prior probability of BRCA1/2 mutation testing.     

Luminal pressure gradient and risk of arteriovenous fistula nonmaturation

While arteriovenous fistula (AVF) nonmaturation is a major issue of hemodialysis care, an effective treatment to improve AVF maturation remains lacking. AVF introduces pulsatile arterial blood flow into its venous limb and produces high luminal pressure gradient, which may have adverse effect on vascular remodeling. As such, the aim of the present study is to investigate effect of luminal pressure gradient on AVF nonmaturation. This single-center, prospective observational study includes patients receiving autologous AVF creation. Participants received early postoperative ultrasound 5–7 days after surgery to collect parameters including diameters, flow rates, and volume at inflow and outflow sites. Luminal pressure gradient was estimated by using modified Bernoulli equation. The outcome was spontaneous AVF maturation within 8 weeks after surgery without intervention. Thirty patients were included, of which the mean age was 66.9 years and 70% were male. At the end of study, 13 (43.3%) patients had spontaneous AVF maturation. All demographic and laboratory characteristics were similar between patients with mature and nonmature AVF. Regarding ultrasonographic parameters, nonmature AVF showed significantly higher inflow/outflow diameter ratio, inflow velocity, and luminal pressure gradient. While these 3 parameters were significantly correlated, multivariate logistic regression showed their significant association with AVF nonmaturation. Receiver operating characteristic curve exhibited their high predictive value for AVF nonmaturation. Our findings showed that higher inflow/outflow ratio, inflow velocity, and AVF luminal pressure gradient in early postoperative ultrasound predicted risk of AVF nonmaturation. Reducing inflow/outflow diameter ratio or inflow rate may be an approach to improve AVF maturation. The predictive value of this early assessment might have impact on the clinical practice of AVF care.     

The Korea Cohort Consortium: The Future of Pooling Cohort Studies

ObjectivesWe introduced the cohort studies included in the Korean Cohort Consortium (KCC), focusing on large-scale cohort studies established in Korea with a prolonged follow-up period. Moreover, we also provided projections of the follow-up and estimates of the sample size that would be necessary for big-data analyses based on pooling established cohort studies, including population-based genomic studies.MethodsWe mainly focused on the characteristics of individual cohort studies from the KCC. We developed “PROFAN”, a Shiny application for projecting the follow-up period to achieve a certain number of cases when pooling established cohort studies. As examples, we projected the follow-up periods for 5000 cases of gastric cancer, 2500 cases of prostate and breast cancer, and 500 cases of non-Hodgkin lymphoma. The sample sizes for sequencing-based analyses based on a 1:1 case-control study were also calculated.ResultsThe KCC consisted of 8 individual cohort studies, of which 3 were community-based and 5 were health screening-based cohorts. The population-based cohort studies were mainly organized by Korean government agencies and research institutes. The projected follow-up period was at least 10 years to achieve 5000 cases based on a cohort of 0.5 million participants. The mean of the minimum to maximum sample sizes for performing sequencing analyses was 5917–72 102.ConclusionsWe propose an approach to establish a large-scale consortium based on the standardization and harmonization of existing cohort studies to obtain adequate statistical power with a sufficient sample size to analyze high-risk groups or rare cancer subtypes.     

Evaluation of Five User-Friendly Whole Genome Sequencing Software for Mycobacterium tuberculosis in Clinical Application

BackgroundWhole genome sequencing (WGS) is an increasingly useful tool for tuberculosis (TB) diagnosis and disease management. In this study, we evaluated the utility of user-friendly WGS tools in reporting resistance profiles and identifying lineages of clinical TB isolates from South Korea.MethodsForty clinical samples from TB patients showing discrepancies between their rapid molecular and conventional drug susceptibility tests were used in this study. Among these clinical isolates, 37 strains were successfully evaluated via WGS software, using the GenTB, TB Profiler, PhyResSE, CASTB, and Mykrobe.ResultsMore accurate and faster susceptibility results could be obtained with isoniazid than with rifampin. Using the phenotypic test as the gold standard, the isoniazid concordance rate between phenotypic drug susceptibility test (DST) and WGS (GenTB: 45.9%, TB profiler: 40.5%, PhyResSE: 40.5%, CASTB: 48.6%, and Mykrobe: 43.2%) was much higher than between phenotypic DST and rapid molecular genotypic DST (18.9%) among the 37 strains. In contrast, the rifampin concordance rate between phenotypic DST and WGS and that between phenotypic DST and rapid molecular genotypic DST was similar (81.1–89.2%). We also found novel mutations associated with INH in katG and ahpC gene region, not covered by the line probe assay. In addition, lineage analysis identified 81.1% of these samples as L2 East Asian lineage strains, and 18.9% as L4 Euro-American lineage strains.ConclusionWGS may play a pivotal role in TB diagnosis and the detection of drug resistance, genetic diversity, and transmission dynamics in the near future because of its accuracy, speed, and extensibility.     

The KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD): A Korean Chronic Kidney Disease Cohort

The KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD) was launched in 2011 with the support of the Korea Disease Control and Prevention Agency. The study was designed with the aim of exploring the various clinical features and characteristics of chronic kidney disease (CKD) in Koreans, and elucidating the risk factors for CKD progression and adverse outcomes of CKD. For the cohort study, nephrologists at 9 tertiary university-affiliated hospitals participated in patient recruitment and follow-up. Biostatisticians and epidemiologists also participated in the basic design and structuring of the study. From 2011 until 2016, the KNOW-CKD Phase I recruited 2238 adult patients with CKD from stages G1 to G5, who were not receiving renal replacement therapy. The KNOW-CKD Phase II recruitment was started in 2019, with an enrollment target of 1500 subjects, focused on diabetic nephropathy and hypertensive kidney diseases in patients with reduced kidney function who are presumed to be at a higher risk of adverse outcomes. As of 2021, the KNOW-CKD investigators have published articles in the fields of socioeconomics, quality of life, nutrition, physical activity, renal progression, cardiovascular disease and outcomes, anemia, mineral bone disease, serum and urine biomarkers, and international and inter-ethnic comparisons. The KNOW-CKD researchers will elaborate a prediction model for various outcomes of CKD such as the development of end-stage kidney disease, major adverse cardiovascular events, and death.     

Antioxidant activity from the stem bark of<Emphasis Type="Italic">Albizzia julibrissin</Emphasis>

The antioxidant activity of the stem bark from Albizzia julibrissin was evaluated for its potential to scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals, to inhibit the generation of the hydroxyl radical (*OH), total reactive oxygen species (ROS) and to scavenge authentic peroxynitrites (ONOO-). The methanol extract of A. julibrissin exhibited strong antioxidant activity in the tested model systems. Therefore, it was further fractionated using several solvents. The antioxidant activity of the individual fractions were in the order of ethyl acetate (EtOAc) > n-butanol (n-BuOH) > dichloromethane (CH2Cl2) > and water (H2O). The ethyl acetate soluble fraction, which exhibited strong antioxidant activity, was further purified by repeated silicagel, Sephadex LH-20 and RP-18 gel column chromatography. Sulfuretin (1) and 3',4',7-trihydroxyflavone (2) were isolated as the active principles. Compounds 1 and 2 exhibited good activity in all tested model systems. Compound 1 exhibited five times more inhibitory activity on the total ROS than Trolox. Compound 2 showed six times stronger DPPH radical scavenging activity than L-ascorbic acid. These results show the possible antioxidant activity of the A. julibrissin crude extract and its major constituents.     

Growth and Gastrointestinal Tolerance in Healthy Term Infants Fed Milk-Based Infant Formula Supplemented with Five Human Milk Oligosaccharides (HMOs): A Randomized Multicenter Trial

Background: Five of the most abundant human milk oligosaccharides (HMOs) in human milk are 2′-fucosyllactose (2′-FL), 3-fucosyllactose (3-FL), lacto-N-tetraose (LNT), 3′-sialyllactose (3′-SL) and 6′-sialyllactose (6′-SL). Methods: A randomized, double-blind, controlled parallel feeding trial evaluated growth in healthy term infants fed a control milk-based formula (CF; n = 129), experimental milk-based formula (EF; n = 130) containing five HMOs (5.75 g/L; 2′-FL, 3-FL, LNT, 3′-SL and 6′-SL) or human milk (HM; n = 104). Results: No significant differences (all p ≥ 0.337, protocol evaluable cohort) were observed among the three groups for weight gain per day from 14 to 119 days (D) of age, irrespective of COVID-19 or combined non-COVID-19 and COVID-19 periods. There were no differences (p ≥ 0.05) among the three groups for gains in weight and length from D14 to D119. Compared to the CF group, the EF group had more stools that were soft, frequent and yellow and were similar to the HM group. Serious and non-serious adverse events were not different among groups, but more CF-fed infants were seen by health care professionals for illness from study entry to D56 (p = 0.044) and D84 (p = 0.028) compared to EF-fed infants. Conclusions: The study demonstrated that the EF containing five HMOs supported normal growth, gastrointestinal (GI) tolerance and safe use in healthy term infants.     

RESEARCH LETTER: Uptake of research findings into clinical practice: a controlled study of the impact of a brief external intervention on the use of corticosteroids in preterm delivery

To the Editor: There are a large number of studies addressing the impact of continuing medical education (Davis et al. 1995) and clinical guidelines (Grimshaw & Russell 1993) on changing clinical practice, but comparatively little on the impact of purchasers of health care. There is some evidence that financial incentives and penalties can influence practice (Greco & Eisenberg 1993). It has been suggested that purchasers can play an important role in implementing research findings (Haines & Jones 1994). Indeed, the separation of purchasers and providers has been viewed as an opportunity to use knowledge about effectiveness to improve health services (Dunning et al. 1994). We report a study the aim of which was to explore the impact that a specific brief external intervention might have on a detailed aspect of clinical practice: the use of corticosteroids in preterm labour. The intervention was initiated by public health physicians on behalf of a Health Authority. It formed a part of the Getting Research Into Practice (GRIP) initiative in the old Oxford Health Region, UK.  The administration of corticosteroids to mothers expected to deliver prematurely reduces neonatal mortality and morbidity (Crowley et al. 1990). The first trial which suggested that corticosteroids were effective in this role was published in 1972, and evidence from 12 trials was assembled in a systematic review published in January 1990 (Crowley et al. 1990). Despite the accumulating evidence, in 1991 many women delivering prematurely in the UK and elsewhere were not receiving corticosteroids (Anon 1992;Donaldson 1992). The apparent failure of obstetricians to make full use of this treatment has been cited as an example of the delayed implementation of research findings that can occur in clinical practice (Haines & Jones 1994; Enkin 1996).