Use of Optical Redox Imaging to Quantify Alveolar Macrophage Redox State in Infants: Proof of Concept Experiments in a Murine Model and Human Tracheal Aspirates Samples.

Emerging data indicate that lung macrophages (LM) may provide a novel biomarker to classify disease endotypes in bronchopulmonary dysplasia (BPD), a form of infant chronic lung disease, and that augmentation of the LM phenotype may be a potential therapeutic target. To contribute to this area of research, we first used Optical Redox Imaging (ORI) to characterize the responses to H2O2-induced oxidative stress and caffeine treatment in an in vitro model of mouse alveolar macrophages (AM). H2O2 caused a dose-dependent decrease in NADH and an increase in FAD-containing flavoproteins (Fp) and the redox ratio Fp/(NADH + Fp). Caffeine treatment did not affect Fp but significantly decreased NADH with doses of ≥50 µM, and 1000 µM caffeine treatment significantly increased the redox ratio and decreased the baseline level of mitochondrial ROS (reactive oxygen species). However, regardless of whether AM were pretreated with caffeine or not, the mitochondrial ROS levels increased to similar levels after H2O2 challenge. We then investigated the feasibility of utilizing ORI to examine macrophage redox status in tracheal aspirate (TA) samples obtained from premature infants receiving invasive ventilation. We observed significant heterogeneity in NADH, Fp, Fp/(NADH + Fp), and mitochondrial ROS of the TA macrophages. We found a possible positive correlation between gestational age and NADH and a negative correlation between mean airway pressure and NADH that provides hypotheses for future testing. Our study demonstrates that ORI is a feasible technique to characterize macrophage redox state in infant TA samples and supports further use of this method to investigate lung macrophage-mediated disease endotypes in BPD.

Modified Approaches to Treating Anxiety for Children With Visual-Spatial Problems: A Strengths-Based Perspective.

Anxiety disorders are common and impairing1 and affect as many as 30% of youth with2 and without3 neurodevelopmental disorders. Nonverbal learning disability (NVLD) is an understudied neurodevelopmental disorder with an estimated prevalence of 3% in North American children and adolescents.4 Although definitions of NVLD vary, all include a core deficit of difficulty with visual-spatial processing. Importantly, anxiety is also a common psychiatric comorbidity for youth with NVLD, affecting roughly one-third of these youth.4,5 In youth with neurodevelopmental disorders, treatment is often sought or received for comorbid conditions (eg, anxiety, attention-deficit/hyperactivity disorder) or associated impairments, rather than for the symptoms or core deficits of the neurodevelopmental disorder itself.6 Considerable work has examined the adaptation of anxiety disorder treatments for children with attention-deficit/hyperactivity disorder7 and autism.8 Comparatively little work has explored treatment approaches for children with NVLD. Given the overlap of anxiety symptoms and visual-spatial problems in NVLD,9,10 herein we consider how these cognitive problems might interfere with patients' abilities to engage with common treatment approaches.

Secondary (additional) findings from the 100,000 Genomes Project: Disease manifestation, health care outcomes, and costs of disclosure.

PURPOSE: The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial adenomatous polyposis, MYH-associated polyposis, multiple endocrine neoplasia (MEN), and von Hippel-Lindau. Here, we report disclosure processes, manifestation of AF-related disease, outcomes, and costs. METHODS: An observational study in an area representing one-fifth of England. RESULTS: Data were collected from 89 adult AF recipients. At disclosure, among 57 recipients of a cancer-predisposition-associated AF and 32 recipients of an FH-associated AF, 35% and 88%, respectively, had personal and/or family history evidence of AF-related disease. During post-disclosure investigations, 4 cancer-AF recipients had evidence of disease, including 1 medullary thyroid cancer. Six women with an HBOC AF, 3 women with a Lynch syndrome AF, and 2 individuals with a MEN AF elected for risk-reducing surgery. New hyperlipidemia diagnoses were made in 6 FH-AF recipients and treatment (re-)initiated for 7 with prior hyperlipidemia. Generating and disclosing AFs in this region cost £1.4m; £8680 per clinically significant AF. CONCLUSION: Generation and disclosure of AFs identifies individuals with and without personal or familial evidence of disease and prompts appropriate clinical interventions. Results can inform policy toward secondary findings.

Barriers and facilitators to implementing medications for opioid use disorder and naloxone distribution in Veterans Affairs emergency departments.

OBJECTIVES: Safer opioid prescribing patterns, naloxone distribution, and medications for opioid use disorder (M-OUD) are an important part of decreasing opioid-related adverse events. Veterans are more likely to experience these adverse events compared to the general population. Despite treatment guidelines and ED-based opioid safety programs implemented throughout Veterans Affairs (VA) Medical Centers, many Veterans with OUD do not receive these harm reduction interventions. Prior research in other health care settings has identified barriers to M-OUD initiation and naloxone distribution; however, little is known about how this may be similar or different for health care professionals in VA ED and urgent care centers. METHODS: We conducted qualitative interviews with VA health care professionals and staff using a semistructured interview guide. We analyzed the data addressing barriers and facilitators to M-OUD treatment in the ED and naloxone distribution using descriptive matrix analysis, followed by team consensus. RESULTS: We interviewed 19 VA staff in various roles. Respondent concerns and considerations regarding the initiation of M-OUD in the ED included M-OUD initiation falling outside of ED's scope of providing acute treatment, lack of VA-approved M-OUD protocols and follow-up procedures, staffing concerns, and educational gaps. Respondents reported that naloxone was important but lacked clarity on who should prescribe it. Some respondents stated that an automated system to prescribe naloxone would be helpful, and others felt that it would not offer needed support and education to patients. Some respondents reported that naloxone would not address opioid misuse, which other respondents felt was a belief due to stigma around substance use and lack of education about treatment options. CONCLUSIONS: Our VA-based research highlights similarities of barriers and facilitators, seen in other health care settings, when implementing opioid safety initiatives. Education and training, destigmatizing substance use disorder care, and leveraging technology are important facilitators to increasing access to lifesaving therapies for OUD treatment and harm reduction.

Comparison of virtual to in-person academic detailing on naloxone prescribing rates at three U.S. Veterans Health Administration regional networks.

INTRODUCTION: Academic detailing, an educational outreach that promotes evidence-based practices to improve the quality of care for patients, has primarily been delivered using one-on-one in-person interactions. In 2018, the U.S. Department of Veterans Affairs (VA) Pharmacy Benefits Management implemented a pilot virtual academic detailing program to increase naloxone prescribing among veterans at risk for opioid overdose or death. The aim of this evaluation was to compare virtual and in-person academic detailing on naloxone prescribing rates at VA. METHODS: A retrospective quasi-experimental pretest-posttest non-equivalent groups design was used to compare virtual academic detailing and in-person academic detailing on naloxone prescribing rates 12 months before and after providers received a naloxone-specific encounter at three VA regional networks between January 1, 2018 to May 31, 2020. Subgroup analysis was performed on rural providers. Generalized estimating equation models were constructed to compare the difference in naloxone prescribing rates before and after receiving virtual or in-person academic detailing controlling for provider-level characteristics. RESULTS: Providers who received virtual (N = 67) or in-person (N = 186) academic detailing had significant increases in naloxone prescribing, but the differences in the naloxone rates between the groups were not statistically significant (difference in changes in naloxone rates=+0.63; 95% CI: -2.23, 3.48). Similar findings were reported for rural providers. DISCUSSION: Providers who received naloxone-related in-person or virtual academic detailing had increased naloxone prescribing rates; however, there were no differences between the two types of modalities. Virtual academic detailing is a viable alternative for delivering academic detailing and allows academic detailers to expand their reach to rural providers.

Implementation of a pharmacy-led virtual academic detailing program at the US Veterans Health Administration.

PURPOSE: To provide a summary of the implementation of a virtual academic detailing pilot program at the US Department of Veterans Affairs (VA). SUMMARY: In September 2018, VA Pharmacy Benefits Management implemented a virtual academic detailing ("e-Detailing") pilot program across 3 regional networks. Academic detailing involves multifaceted collaborative outreach delivered by trained healthcare clinicians to other clinicians using targeted educational interventions that improve clinical decision-making. Across VA, academic detailing programs are primarily staffed by specially trained clinical pharmacist specialists. Implementation began with an in-person meeting to train academic detailers on using the virtual academic detailing platform (VA Video Connect) and virtual soft skills, which was followed by regular facilitation meetings to address issues and share experiences. During e-Detailing program implementation, coronavirus disease 2019 (COVID-19) emerged, prompting the US Department of Health and Human Services to declare a public health emergency. VA followed with restrictions on nonessential travel for all employees, thus hampering in-person academic detailing activities. Fortunately, e-Detailing provided an alternative channel for academic detailers across VA to continue delivering critical outreach to providers during the pandemic. Qualitative assessment of academic detailers' and providers' perceptions on e-Detailing highlighted the need for local leadership support for e-Detailing and telehealth, the efficiency of virtual compared to in-person visits, and potential time savings resulting from avoidance of long commutes. CONCLUSION: The timing of e-Detailing implementation during the COVID-19 pandemic illustrates the need and potential for a virtual platform to deliver timely provider outreach.

A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

Telomere Instability in Lynch Syndrome Families Leads to Some Shorter Telomeres in MSH2+/- Carriers.

Lynch syndrome (LS) is an inherited predisposition to early onset of various cancers, caused by mutation in a DNA mismatch repair (MMR) gene. In heterozygous MMR+/- carriers, somatic mutation, loss or silencing of the wild type allele increases the mutation rate, facilitating the initiation of MMR-defective cancers. These cancers are characterized by instability at short tandem repeats (STRs) and in telomeric DNA. We have investigated telomere length in saliva DNA from LS and control families, using single telomere analysis at XpYp and 12q and by qPCR to measure total telomeric DNA. Single telomere analysis showed a trend for shorter XpYp telomeres in MSH2+/- carriers compared to MLH1+/- carriers or controls, but this was masked in the comparative analysis of total telomeric DNA. Comparison of age-adjusted telomere length within families showed that neither MSH2+/- or MLH1+/- children had consistently shorter or longer telomeres than their MMR+/- parent, indicating the absence of an inter-generational effect on telomere length. Unexpectedly however, wildtype children in families with MSH2 mutations, had significantly longer XpYp telomeres than their MMR+/- parent. Altogether our data suggest that MMR insufficiency, particularly in MSH2+/- carriers, increases telomere instability and somatic cell turnover during the lifetime of LS mutation carriers but has minimal consequences for telomere length in the germline.

Virtual academic detailing (e-Detailing): A vital tool during the COVID-19 pandemic.

As the coronavirus disease (COVID-19) pandemic continues its course in 2020, telehealth technology provides opportunities to connect patients and providers. Health policies have been amended to allow easy access to virtual health care, highlighting the field's dynamic ability to adapt to a public health crisis. Academic detailing, a peer-to-peer collaborative outreach designed to improve clinical decision-making, has traditionally relied on in-person encounters for effectiveness. A growth in the adoption of telehealth technology translates to increases in academic detailing reach for providers unable to meet with academic detailers in person. The U.S. Department of Veterans Affairs (VA) has used academic detailing to promote and reinforce evidence-based practices and has encouraged more virtual academic detailing (e-Detailing). Moreover, VA academic detailers are primarily clinical pharmacy specialists who provide clinical services and education and have made meaningful contributions to improving health care at VA. Amid the COVID-19 pandemic and physical isolation orders, VA academic detailers have continued to meet with providers to disseminate critical health care information in a timely fashion by using video-based telehealth. When working through the adoption of virtual technology for the delivery of medical care, providers may need time and nontraditional delivery of "evidence" before eliciting signals for change. Academic detailers are well suited for this role and can develop plans to help address provider discomfort surrounding the use of telehealth technology. By using e-Detailing as a method for both familiarizing and normalizing health professionals with video-based telehealth technology, pharmacists are uniquely poised to deliver consultation and direct-care services. Moreover, academic detailing pharmacists are ambassadors of change, serving an important role navigating the evolution of health care in response to emergent public health crises and helping define the norms of care delivery to follow.

New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies.

GJA8 encodes connexin 50 (Cx50), a transmembrane protein involved in the formation of lens gap junctions. GJA8 mutations have been linked to early onset cataracts in humans and animal models. In mice, missense mutations and homozygous Gja8 deletions lead to smaller lenses and microphthalmia in addition to cataract, suggesting that Gja8 may play a role in both lens development and ocular growth. Following screening of GJA8 in a cohort of 426 individuals with severe congenital eye anomalies, primarily anophthalmia, microphthalmia and coloboma, we identified four known [p.(Thr39Arg), p.(Trp45Leu), p.(Asp51Asn), and p.(Gly94Arg)] and two novel [p.(Phe70Leu) and p.(Val97Gly)] likely pathogenic variants in seven families. Five of these co-segregated with cataracts and microphthalmia, whereas the variant p.(Gly94Arg) was identified in an individual with congenital aphakia, sclerocornea, microphthalmia and coloboma. Four missense variants of unknown or unlikely clinical significance were also identified. Furthermore, the screening of GJA8 structural variants in a subgroup of 188 individuals identified heterozygous 1q21 microdeletions in five families with coloboma and other ocular and/or extraocular findings. However, the exact genotype-phenotype correlation of these structural variants remains to be established. Our data expand the spectrum of GJA8 variants and associated phenotypes, confirming the importance of this gene in early eye development.

Does the performance of five back-associated exercises relate to the presence of low back pain? A cross-sectional observational investigation in regional Australian council workers.

OBJECTIVES: Investigate the relationships between the ability/inability to perform five physical test exercises and the presence or absence of low back pain (LBP). SETTING: Regional Australian council training facility. PARTICIPANTS: Consecutive participants recruited during 39 back education classes (8-26 participants per class) for workers in general office/administration, parks/gardens maintenance, roads maintenance, library, child care and management. Total sample (n=539) was reduced through non-consent and insufficient demographic data to n=422. Age 38.6±15.3 years, range 18-64 years, 67.1% male. METHODS: Cross-sectional, exploratory, observational investigation. LBP presence was ascertained from a three-response option questionnaire: 0=none/rarely (no) 1=sometimes (some), 2=mostly/always (most). Statistical correlation was performed with the number of the five test exercises the individual successfully performed: (1) extension in lying: 3 s; (2) 'toilet squat'; feet flat, feet touched: 3 s; (3) full squat then stand up: 5 times; (4) supine sit-up, knees flexed: 10 times; and (5) leg extension, supine bilateral: 10 times. INTERVENTIONS: Nil. RESULTS: For the group 'no-some', 94.3% completed 4-5 test exercises, while for group 'With', 95.7% completed 0-1 test exercises. The relationship between LBP presence and number of exercises performed was highly significant (χ2(10)=300.61, p<0.001). Furthermore, multinomial logistic regression predicting LBP (0=no, 1=some, 2=most) from the number of exercises completed, substantially improved the model fit (initial-2LL=348.246, final-2LL=73.620, χ2(2)=274.626, p<0.001). As the number of exercises performed increased, the odds of reporting 'some LBP' or 'most LBP' dropped substantially (ORs of 0.34 and 0.17, respectively). CONCLUSION: The ability to complete/not complete five test exercises correlated statistically and significantly with a higher LBP absence/presence in a general working population. Training individuals to complete such exercises could facilitate reductions in LBP incidence; however, causality cannot be inferred. Randomised trials are recommended to establish the potential efficacy of exercise-based approaches, considering these five selected exercises, for predicting and managing LBP.

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.

Controlled feeding trials with ungulates: a new application of in vivo dental molding to assess the abrasive factors of microwear.

Microwear, the quantification of microscopic scratches and pits on the occlusal surfaces of tooth enamel, is commonly used as a paleodietary proxy. For ungulates (hoofed mammals), scratch-dominant microwear distinguishes modern grazers from browsers, presumably as a result of abrasion from grass phytoliths (biogenic silica). However, it is also likely that exogenous grit (i.e. soil, dust) is a contributing factor to these scratch-dominant patterns, which may reflect soil ingestion that varies with feeding height and/or environmental conditions (e.g. dust production in open and/or arid habitats). This study assessed the contribution of exogenous grit to tooth wear by measuring the effects of fine- and medium-grained silica sand on tooth enamel using a novel live-animal tooth-molding technique. It therefore constitutes the first controlled feeding experiment using ungulates and the first in vivo experiment using abrasives of different sizes. Four sheep were fed three diet treatments: (1) a mixture of Garrison and Brome hay (control), (2) hay treated with fine-grained silica sand (180-250 µm) and (3) hay treated with medium-grained silica sand (250-425 µm). We found a significant increase in pit features that was correlated with an increase in grain size of grit, corroborating earlier chewing simulation experiments that produced pits through grit-induced abrasion (i.e. the 'grit effect'). Our results support an interpretation of large silica grains fracturing to create smaller, more abundant angular particles capable of abrasion, with jaw movement defining feature shape (i.e. scratch or pit).

The origins of Western mind-body exercise methods.

Background: Over recent decades, mind-body exercise methods have gained international popularity and importance in the management of musculoskeletal disorders. Objectives: The scope of this paper was to investigate: the origins of Western mind-body methods, their philosophies, exercises, and relationship with mainstream healthcare over the last two centuries. Major findings: Within a few decades of the turn of the 20th century, a cluster of mind-body exercise methods emerged from at least six pioneering founders: Checkley, Müller, Alexander, Randell, Pilates, and Morris. Each was based upon a similar exercise philosophy and similar functional movement-harmonizing exercises. This renaissance of independent mind-body schools occurred in parallel with the demise of the 18th and 19th century gymnasium Physical Culture movement and the concurrent emergence of bodybuilding and strength training. Even though mostly forgotten today, Western mind-body exercise methods enjoyed celebrated success during the first half of the 20th century, were hailed by medical and allied health practitioners and practiced by millions from society's elite to deprived minorities. Conclusions: Rediscovering the Western mind-body exercise movement is hoped to facilitate official healthcare establishment recognition of this kind of training as an integral entity. This may widen research opportunities and consolidate approaches toward: optimal musculoskeletal rehabilitation and injury prevention, promotion of a healthy active lifestyle environment in the modern world, and enhancement of the natural pain-free human athletic look, feel, and performance.

Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study.

BACKGROUND: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations. OBJECTIVE: To report the first year's screening results for all men at enrollment in the study. DESIGN, SETTING AND PARTICIPANTS: We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrollment, and those men with PSA >3 ng/ml were offered prostate biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types. RESULTS AND LIMITATIONS: We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%-double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups. CONCLUSIONS: The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease. PATIENT SUMMARY: In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment.

Rapid detection of point mutations in Plasmodium falciparum genes associated with antimalarial drugs resistance by using High-Resolution Melting analysis.

We have developed a High-Resolution DNA Melting method to detect mutations related to Plasmodium falciparum resistance. This method is based on real-time PCR followed by High Resolution Melting ramping from 67 degrees C to 80 degrees C with fluorescence data acquisition set at 0.1 degrees C increments. The accuracy of the technique was assessed using 177 P. falciparum clinical isolates and two reference strains. Results perfectly matched those obtained by DNA sequencing for some important genetic markers of P. falciparum resistance. This technique could be of great value for epidemiological studies, especially in developing countries.