From the Cover: Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2

In the Ashkenazi Jewish (AJ) population of Israel, 11% of breast cancer and 40% of ovarian cancer are due to three inherited founder mutations in the cancer predisposition genes BRCA1 and BRCA2. For carriers of these mutations, risk-reducing salpingo-oophorectomy significantly reduces morbidity and mortality. Population screening for these mutations among AJ women may be justifiable if accurate estimates of cancer risk for mutation carriers can be obtained. We therefore undertook to determine risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained irrespective of personal or family history of cancer. Families harboring mutations in BRCA1 or BRCA2 were ascertained by identifying mutation carriers among healthy AJ males recruited from health screening centers and outpatient clinics. Female relatives of the carriers were then enrolled and genotyped. Among the female relatives with BRCA1 or BRCA2 mutations, cumulative risk of developing either breast or ovarian cancer by age 60 and 80, respectively, were 0.60 (± 0.07) and 0.83 (± 0.07) for BRCA1 carriers and 0.33 (± 0.09) and 0.76 (± 0.13) for BRCA2 carriers. Risks were higher in recent vs. earlier birth cohorts (P = 0.006). High cancer risks in BRCA1 or BRCA2 mutation carriers identified through healthy males provide an evidence base for initiating a general screening program in the AJ population. General screening would identify many carriers who are not evaluated by genetic testing based on family history criteria. Such a program could serve as a model to investigate implementation and outcomes of population screening for genetic predisposition to cancer in other populations.Inherited mutations in BRCA1 and BRCA2 predispose to high risks of breast and ovarian cancer. Among female mutation carriers, presymptomatic surgical measures significantly reduce morbidity and mortality (1, 2). In particular, risk-reducing salpingo-oophorectomy (i.e., the removal of ovaries and fallopian tubes from a woman without ovarian cancer) reduces risk both of breast cancer and of ovarian cancer, as well as overall mortality (1). However, for many mutation carriers identified following their first cancer diagnosis, genetic testing was not previously indicated because family history did not suggest inherited cancer predisposition (3–5, 6). From a prevention perspective, it is a missed opportunity to identify a woman as a BRCA1 or BRCA2 mutation carrier only after she develops cancer.Among Ashkenazi (European) Jews (AJ), three mutations, BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT, account for the great majority of inherited cancer risk due to BRCA1 and BRCA2 (7). In the AJ population, 2.5% of persons carry one of these three mutations (8), and the mutations account for 11% of breast cancer (3) and 40% of ovarian cancer (9, 10). These observations suggest that genetic testing in the AJ population for these mutations fulfills WHO criteria for population screening (11, 12): The disease is an important public health burden to the target population; prevalence and attributable risk of disease due to the mutations are known; and effective interventions exist. However, one necessary piece of information remains unknown: What is the disease risk to mutation carriers ascertained from the general population, rather than carriers identified based on family history (13)?Previous studies assessing cancer risks due to mutations in BRCA1 and BRCA2 ascertained carriers through high-incidence families (14), through a single index case with breast or ovarian cancer (3, 15) or through both affected and unaffected carriers (16). In a 1997 study of AJ volunteers, most index cases had no previous cancer diagnosis, but the percentage of index cases with a family history of breast cancer was approximately double that of unselected AJs (17). In principle, these strategies could have yielded risk estimates different from those of carriers ascertained from the local host population, if cancer risk in BRCA1 or BRCA2 carriers were influenced by familial factors other than the BRCA1 or BRCA2 mutation, such as modifier genes or shared environment (18). In addition, in almost all of these studies, risk estimates were based on imputing carrier status, rather than on direct genetic testing of BRCA1 and BRCA2. This year, the Recommendation Statement on BRCA Testing from the US Preventive Services Task Force recommended against population screening for BRCA1 and BRCA2 mutations, because cancer risk to mutation carriers in the general population was not yet known (19). To address this gap, in this study we assessed breast and ovarian cancer risks in confirmed carriers of BRCA1 and BRCA2 mutations ascertained from the general population. The study was undertaken in the AJ population, because screening for only three founder mutations is sufficient to capture nearly all inherited cancer risk in this population due to BRCA1 and BRCA2 (7).     

Characterization and antibacterial properties of N-halamine-derivatized cross-linked polymethacrylamide nanoparticles

N-halamine-derivatized cross-linked polymethacrylamide nanoparticles with sizes ranging between 18 ± 2.0 and 460 ± 60 nm were prepared via surfactant-free dispersion co-polymerization of methacrylamide (MAA) and the cross-linking monomer N,N-methylenebisacrylamide (MBAA) in an aqueous continuous phase, followed by a chlorination process using sodium hypochlorite. The effect of various polymerization parameters (monomer concentration, initiator type and concentration, polymerization duration, polymerization temperature, and the weight ratio [MBAA]/[MAA]) on the size and size distribution of the produced cross-linked P(MAA–MBAA) nanoparticles was elucidated. The effect of various chlorination parameters (hypochlorite concentration, chlorination period and temperature) on the bound oxidative chlorine atom (Cl) content of the P(MAA–MBAA) nanoparticles was also investigated. The bactericidal activity of these chloramine-derivatized nanoparticles was tested against two common bacterial pathogens (Escherichia coli and Staphylococcus aureus), and they were found to be highly potent. Furthermore, these nanoparticles also exerted their antimicrobial activity against multi-drug resistant (MDR) bacteria, further demonstrating their efficacy.     

Nuclear wastewater decontamination by 3D-Printed hierarchical zeolite monoliths

The selective removal of radioactive cationic species, specifically ¹³⁷Cs⁺ and ⁹⁰Sr²⁺, from contaminated water is critical for nuclear waste remediation processes and environmental cleanup after accidents, such as the Fukushima Daiichi Nuclear Power Plant disaster in 2011. Nanoporous silicates, such as zeolites, are most commonly used for this process but in addition to acting as selective ion exchange media must also be deployable in a correct physical form for flow columns. Herein, Digital Light Processing (DLP) three-dimensional (3D) printing was utilized to form monoliths from zeolite ion exchange powders that are known to be good for nuclear wastewater treatment. The monoliths comprise 3D porous structures that will selectively remove radionuclides in an engineered form that can be tailored to various sizes and shapes as required for any column system and can even be made with fine-grained powders unsuitable for normal gravity flow column use. 3D-printed monoliths of zeolites chabazite and 4A were made, characterized, and evaluated for their ion exchange capacities for cesium and strontium under static conditions. The 3D-printed monoliths with 50 wt% zeolite loadings exhibit Cs and Sr uptake with an equivalent ion-capacity as their pristine powders. These monoliths retain their porosity, shape and mechanical integrity in aqueous media, providing a great potential for use to not only remove radionuclides from nuclear wastewater, but more widely in other aqueous separation-based applications and processes.

3D-printed monoliths of zeolites chabazite and 4A were made, characterized, and shown effective for removing strontium and caesium from water.     

Effects of Aging Torque Controllers on Screw Tightening Force and Bacterial Micro-Leakage on the Implant-Abutment Complex

Aim: We assess the accuracy of torque controllers after several aging processes and the bacterial leakage on implant-abutment complexes (IAC). Methods: A total of 12 spring-type and 12 friction-type torque controllers and 48 IAC (24 conical and 24 hexagonal connections) were evaluated. Chemical, mechanical, temperature, and pressure-aging methods were applied individually to replicate clinical use. Torque controller accuracy was analyzed before and after aging using a calibrated gauge. To assess bacterial leakage, the IAC were suspended in a bacterial medium for 24 h. Direct Contact Test (DCT) and Polymerase Chain Reaction Test (RT-PCR) analyzed the infiltration of F. nucleatum and P. gingivalis into the IAC micro-gap. Results: A significant decrease in torque after 10 days of aging was found. The spring-type torque controller was affected the most, regardless of the aging method (P < 0.05). PCR results indicated that all groups exhibited significantly more bacterial leakage, regardless of the method used (P < 0.05). The conical IAC demonstrated more bacterial leakage of P. gingivalis compared with the hexagonal IAC (P = 0.07). DCT found bacterial growth in the IAC only before aging and was not identified after aging. Conclusion: Aging affects torque accuracy. A reduction in force was noticed after 10 days. The conical IAC exhibits more bacterial leakage, although this was not statistically significant.     

Unfinished Business in Classifying HPV-Positive Oropharyngeal Carcinoma: Identifying the Bad Apples in a Good Staging Barrel

This commentary highlights three important findings in the study by Vijayvargiya et al, published in this journal, involving 9554 oropharyngeal cancer patients from the SEER database. Firstly, there is improved performance in outcome prediction with TNM-8 in HPV+ OPC. However, heterogeneity exists, especially in TNM-8 stage I disease, and there is need for ongoing improvement in risk stratification. Several anatomical and non-anatomical prognostic factors have been proposed. Among them, radiologic extranodal extension has emerged as one of the promising parameters to be considered for future staging. These baseline prognostic factors should address sensitivity, specificity, and diagnostic accuracy to serve different clinical needs. Secondly, cure is possible for some patients presenting with M1 disease. Optimal management of such patients remains to be explored, and clinical trials targeting de novo M1 disease should be encouraged to optimize outcomes for this subset. Finally, methodologies to address missing tumor HPV status in historical cohorts have been discussed, including using baseline demographics and clinical characteristics, as well as statistical procedures such as multiple imputation.     

Interleukin 6 in Intact and Injured Mouse Peripheral Nerves

The multifunctional cytokine interleukin 6 (IL-6) has direct growth, survival and differentiation effects on peripheral and central neurons. Furthermore, it can modulate the production by non-neuronal cells of other cytokines and growth factors, and thereby affect nerve cells indirectly. We have studied IL-6 expression and production in intact and injured peripheral nerves of C57/BL/6NHSD mice, which display the normal rapid progression of Wallerian degeneration. The IL-6 mRNA was detected in nerves degenerating in vitro or in vivo , but not in intact nerves. In vitro - and in vivo -degenerating nerve segments and neuroma nerve segments synthesized and secreted IL-6. The onset of IL-6 production was rapid and prolonged. It was detected as early as 2 h after injury and persisted for the entire period of 21 days tested after the injury. Of the non-neuronal cells that reside in intact and injured nerves, macrophages and fibroblasts were the major contributors to IL-6 production. We also studied IL-6 production in intact and injured nerves of mutant C57BL/6-WLD/OLA/NHSD mice, which display very slow progression of Wallerian degeneration. Injured nerves of C57BL/6-WLD/OLA/NHSD mice produced significantly lower amounts of IL-6 than did rapidly degenerating nerves of C57/BL/6NHSD mice.     

Red Blood Cell Distribution Width (RDW) and long-term survival in patients with ST Elevation Myocardial Infarction

Introduction

High RDW values are associated with adverse prognosis in many clinical conditions including short and medium term outcome of patients with ST Elevation Myocardial Infarction (STEMI). The aim of the present study was to evaluate the association between RDW and long term mortality in STEMI patients undergoing primary angioplasty (PPCI).

Material and methods

A cohort of 535 STEMI patients undergoing PPCI were divided into two groups (RDW > 14%, RDW ≤ 14%) using CHAID and CART methods. The association between RDW and 5-year all-cause mortality was assessed using Cox’s proportional hazards analysis.

Results

A total of 37 patients died during follow up of 5 years (mean: 1059, median: 1013, range 2–2130 days). RDW > 14% was associated with increased risk of all-cause mortality (HR = 5, CI 95% 2.7– 9.9, p < 0.001). In multivariate analysis, RDW > 14 remained significantly associated with increased risk for all-cause mortality (HR = 3.8, CI 95% 1.8– 7.99, p < 0.001). Patients with RDW above 14% did not have lower ejection fraction, higher CPK or more conventional risk factors.

Conclusion

RDW value above 14 is independently associated with increased long term all-cause mortality in patients with STEMI undergoing PPCI.     

Complex Febrile Seizures

In the context of a prospective cohort study, we examined the associations between individual complex features of both first (n = 428) and recurrent (n = 240) febrile seizures and factors shown to predict outcome in children with febrile seizures. Thirty-five percent of first and 33% of recurrent febrile seizures had one or more complex features (focal onset, duration ≥10 min, or multiple seizures during the illness episode). There were strong correlations between focality and prolonged duration for both first and recurrent febrile seizures. A low fever at the time of the seizure was marginally associated with prolonged duration. Most factors associated with either recurrent febrile seizures or subsequent unprovoked seizures were not associated with either the initial seizure being complex or the likelihood that a recurrence would be complex. However, in children with recurrent febrile seizures, complex features tended to repeat. This factor was statistically significant and particularly striking for prolonged duration. Genetic or other constitutional factors may explain why the prolonged feature recurs. Eleven (2.5%) children had three or four risk factors for recurrent febrile seizures and a first febrile seizure that was prolonged. Eight (72.7%) of them experienced a recurrent febrile seizure that was prolonged. This very small group of children may be candidates for abortive therapy to be administered at the onset of a recurrent seizure.