Analytical validation of HER2DX genomic test for early-stage HER2-positive breast cancer.

BACKGROUND: HER2DX, a multianalyte genomic test, has been clinically validated to predict breast cancer recurrence risk (relapse risk score), the probability of achieving pathological complete response post-neoadjuvant therapy (pCR likelihood score), and individual ERBB2 messenger RNA (mRNA) expression levels in patients with early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This study delves into the comprehensive analysis of HER2DX's analytical performance. MATERIALS AND METHODS: Precision and reproducibility of HER2DX risk, pCR, and ERBB2 mRNA scores were assessed within and between laboratories using formalin-fixed paraffin-embedded (FFPE) tumor tissues and purified RNA. Robustness was appraised by analyzing the impact of tumor cell content and protocol variations including different instruments, reagent lots, and different RNA extraction kits. Variability was evaluated across intratumor biopsies and genomic platforms [RNA sequencing (RNAseq) versus nCounter], and according to protocol variations. RESULTS: Precision analysis of 10 FFPE tumor samples yielded a maximal standard error of 0.94 across HER2DX scores (1-99 scale). High reproducibility of HER2DX scores across 29 FFPE tumors and 20 RNAs between laboratories was evident (correlation coefficients >0.98). The probability of identifying score differences >5 units was ≤5.2%. No significant variability emerged based on platform instruments, reagent lots, RNA extraction kits, or TagSet thaw/freeze cycles. Moreover, HER2DX displayed robustness at low tumor cell content (10%). Intratumor variability across 212 biopsies (106 tumors) was <4.0%. Concordance between HER2DX scores from 30 RNAs on RNAseq and nCounter platforms exceeded 90.0% (Cohen's κ coefficients >0.80). CONCLUSIONS: The HER2DX assay is highly reproducible and robust for the quantification of recurrence risk, pCR likelihood, and ERBB2 mRNA expression in early-stage HER2-positive breast cancer.

Can Acupuncture be a Part of the Treatment for Breast Cancer-Related Lymphedema? A Systematic Review of the Safety and Proposed Model for Care.

Acupuncture is a potential therapy for breast cancer-related lymphedema (BCRL). Despite a recent meta-analysis on efficacy, data on acupuncture safety in BCRL are lacking. Current clinical guidelines recommend avoiding needling in the upper extremity affected by lymph node dissection. We undertook a systematic review focusing on acupuncture safety and treatment protocols in clinical trials for BCRL. Literature searches were conducted in PubMed, Ovid, CINAHL, and Cochrane library. Eight clinical trials on acupuncture for BCRL were analyzed. The Standards of Acupuncture intervention (STRICTA 2010) and Cochrane risk of bias (RoB2 2019) were applied to assess methods for acupuncture interventions within Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework. Quantity and severity of adverse events (AE) were reviewed. A total of 189 subjects participated in 8 clinical trials with 2965 acupuncture treatments. No serious adverse events (SAE) were reported regardless of treatment laterality or protocol, with only a single grade 2 skin infection in 2,965 total treatments (0.034%), including 1,165 bilateral and 225 ipsilateral treatments. Our comprehensive review of clinical trials of acupuncture for BCRL demonstrated no significant adverse events in 2,965 treatments, including 1,390 in the affected limb. An approach for routine integration of acupuncture into BCRL maintenance therapy is proposed.

Interpreting Coronary Artery Disease Risk Through Gene-Environment Interactions in Gene Regulation.

GWAS and eQTL studies identified thousands of genetic variants associated with complex traits and gene expression. Despite the important role of environmental exposures in complex traits, only a limited number of environmental factors were measured in these studies. Measuring molecular phenotypes in tightly controlled cellular environments provides a more tractable setting to study gene-environment interactions in the absence of other confounding variables. We performed RNA-seq and ATAC-seq in endothelial cells exposed to retinoic acid, dexamethasone, caffeine, and selenium to model genetic and environmental effects on gene regulation in the vascular endothelium-a common site of pathology in cardiovascular disease. We found that genes near regions of differentially accessible chromatin were more likely to be differentially expressed [OR = (3.41, 6.52), [Formula: see text]]. Furthermore, we confirmed that environment-specific changes in transcription factor binding are a key mechanism for cellular response to environmental stimuli. Single nucleotide polymorphisms (SNPs) in these transcription response factor footprints for dexamethasone, caffeine, and retinoic acid were enriched in GTEx eQTLs from artery tissues, indicating that these environmental conditions are latently present in GTEx samples. Additionally, SNPs in footprints for response factors in caffeine are enriched in colocalized eQTLs for coronary artery disease (CAD), suggesting a role for caffeine in CAD risk. By combining GWAS, eQTLs, and response genes, we annotated environmental components that can increase or decrease disease risk through changes in gene expression in 43 genes. Interestingly, each treatment may amplify or buffer genetic risk for CAD, depending on the particular SNP or gene considered.

Cross-boundary human impacts compromise the Serengeti-Mara ecosystem.

Protected areas provide major benefits for humans in the form of ecosystem services, but landscape degradation by human activity at their edges may compromise their ecological functioning. Using multiple lines of evidence from 40 years of research in the Serengeti-Mara ecosystem, we find that such edge degradation has effectively "squeezed" wildlife into the core protected area and has altered the ecosystem's dynamics even within this 40,000-square-kilometer ecosystem. This spatial cascade reduced resilience in the core and was mediated by the movement of grazers, which reduced grass fuel and fires, weakened the capacity of soils to sequester nutrients and carbon, and decreased the responsiveness of primary production to rainfall. Similar effects in other protected ecosystems worldwide may require rethinking of natural resource management outside protected areas.

High-throughput allele-specific expression across 250 environmental conditions.

Gene-by-environment (GxE) interactions determine common disease risk factors and biomedically relevant complex traits. However, quantifying how the environment modulates genetic effects on human quantitative phenotypes presents unique challenges. Environmental covariates are complex and difficult to measure and control at the organismal level, as found in GWAS and epidemiological studies. An alternative approach focuses on the cellular environment using in vitro treatments as a proxy for the organismal environment. These cellular environments simplify the organism-level environmental exposures to provide a tractable influence on subcellular phenotypes, such as gene expression. Expression quantitative trait loci (eQTL) mapping studies identified GxE interactions in response to drug treatment and pathogen exposure. However, eQTL mapping approaches are infeasible for large-scale analysis of multiple cellular environments. Recently, allele-specific expression (ASE) analysis emerged as a powerful tool to identify GxE interactions in gene expression patterns by exploiting naturally occurring environmental exposures. Here we characterized genetic effects on the transcriptional response to 50 treatments in five cell types. We discovered 1455 genes with ASE (FDR < 10%) and 215 genes with GxE interactions. We demonstrated a major role for GxE interactions in complex traits. Genes with a transcriptional response to environmental perturbations showed sevenfold higher odds of being found in GWAS. Additionally, 105 genes that indicated GxE interactions (49%) were identified by GWAS as associated with complex traits. Examples include GIPR-caffeine interaction and obesity and include LAMP3-selenium interaction and Parkinson disease. Our results demonstrate that comprehensive catalogs of GxE interactions are indispensable to thoroughly annotate genes and bridge epidemiological and genome-wide association studies.

Extreme Wildlife Declines and Concurrent Increase in Livestock Numbers in Kenya: What Are the Causes?

There is growing evidence of escalating wildlife losses worldwide. Extreme wildlife losses have recently been documented for large parts of Africa, including western, Central and Eastern Africa. Here, we report extreme declines in wildlife and contemporaneous increase in livestock numbers in Kenya rangelands between 1977 and 2016. Our analysis uses systematic aerial monitoring survey data collected in rangelands that collectively cover 88% of Kenya's land surface. Our results show that wildlife numbers declined on average by 68% between 1977 and 2016. The magnitude of decline varied among species but was most extreme (72-88%) and now severely threatens the population viability and persistence of warthog, lesser kudu, Thomson's gazelle, eland, oryx, topi, hartebeest, impala, Grevy's zebra and waterbuck in Kenya's rangelands. The declines were widespread and occurred in most of the 21 rangeland counties. Likewise to wildlife, cattle numbers decreased (25.2%) but numbers of sheep and goats (76.3%), camels (13.1%) and donkeys (6.7%) evidently increased in the same period. As a result, livestock biomass was 8.1 times greater than that of wildlife in 2011-2013 compared to 3.5 times in 1977-1980. Most of Kenya's wildlife (ca. 30%) occurred in Narok County alone. The proportion of the total "national" wildlife population found in each county increased between 1977 and 2016 substantially only in Taita Taveta and Laikipia but marginally in Garissa and Wajir counties, largely reflecting greater wildlife losses elsewhere. The declines raise very grave concerns about the future of wildlife, the effectiveness of wildlife conservation policies, strategies and practices in Kenya. Causes of the wildlife declines include exponential human population growth, increasing livestock numbers, declining rainfall and a striking rise in temperatures but the fundamental cause seems to be policy, institutional and market failures. Accordingly, we thoroughly evaluate wildlife conservation policy in Kenya. We suggest policy, institutional and management interventions likely to succeed in reducing the declines and restoring rangeland health, most notably through strengthening and investing in community and private wildlife conservancies in the rangelands.

Injuries and illnesses in the preparticipation evaluation data of 1693 college student-athletes.

BACKGROUND: While the preparticipation evaluation (PPE) is widely used by medical practitioners, its overall effectiveness is unknown, in part because there are no standardized or centralized mechanisms to collect and analyze medical history information. PURPOSE: To report on the injuries and illnesses identified with the use of an electronic PPE (ePPE) completed by first-time National Collegiate Athletic Association Division 1 varsity sport participants (N = 1693; 797 women, 896 men) upon entry to a single institution between 2010 and 2013. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. RESULTS: In total, 3126 discrete past injuries were reported (women, 1473 injuries; men, 1653 injuries). Time loss from sport participation averaged 31.4 days for each injury (women, 32.2 days; men, 30.7 days), and aggregate time loss from sport for all student-athletes before the ePPE was 256 years. Eleven percent of student-athletes had injuries that were unresolved and still symptomatic at the time of the ePPE. Thirty percent of injured student-athletes had a history of ≥1 surgeries for an injury (women, 176; men, 213), and these accounted for 57% of the time lost from sport before college participation. Head injuries accounted for 9% (110 women, 173 men), and loss of consciousness was reported in 19% of these. One in 3 student-athletes answered "yes" to ≥1 of the American Heart Association questions on cardiovascular health. While 15% of women reported a history of stress fracture, only 3% reported a diagnosed eating disorder. CONCLUSION: While some data in this population are self-evident, we were not aware of the high frequency of past injuries, the magnitude of time lost from sport, the high frequency of past surgery, and the number of participants still symptomatic from injuries. The ePPE is a valuable tool for collecting and analyzing aggregate injury and illness data in athletes, such as the finding that 11% of injuries that were reported were unresolved and still symptomatic.

Leveraging human-centered design in chronic disease prevention.

Bridging the knowing-doing gap in the prevention of chronic disease requires deep appreciation and understanding of the complexities inherent in behavioral change. Strategies that have relied exclusively on the implementation of evidence-based data have not yielded the desired progress. The tools of human-centered design, used in conjunction with evidence-based data, hold much promise in providing an optimal approach for advancing disease prevention efforts. Directing the focus toward wide-scale education and application of human-centered design techniques among healthcare professionals will rapidly multiply their effective ability to bring the kind of substantial results in disease prevention that have eluded the healthcare industry for decades. This, in turn, would increase the likelihood of prevention by design.

QuASAR: quantitative allele-specific analysis of reads.

MOTIVATION: Expression quantitative trait loci (eQTL) studies have discovered thousands of genetic variants that regulate gene expression, enabling a better understanding of the functional role of non-coding sequences. However, eQTL studies are costly, requiring large sample sizes and genome-wide genotyping of each sample. In contrast, analysis of allele-specific expression (ASE) is becoming a popular approach to detect the effect of genetic variation on gene expression, even within a single individual. This is typically achieved by counting the number of RNA-seq reads matching each allele at heterozygous sites and testing the null hypothesis of a 1:1 allelic ratio. In principle, when genotype information is not readily available, it could be inferred from the RNA-seq reads directly. However, there are currently no existing methods that jointly infer genotypes and conduct ASE inference, while considering uncertainty in the genotype calls. RESULTS: We present QuASAR, quantitative allele-specific analysis of reads, a novel statistical learning method for jointly detecting heterozygous genotypes and inferring ASE. The proposed ASE inference step takes into consideration the uncertainty in the genotype calls, while including parameters that model base-call errors in sequencing and allelic over-dispersion. We validated our method with experimental data for which high-quality genotypes are available. Results for an additional dataset with multiple replicates at different sequencing depths demonstrate that QuASAR is a powerful tool for ASE analysis when genotypes are not available. AVAILABILITY AND IMPLEMENTATION: http://github.com/piquelab/QuASAR. CONTACT: fluca@wayne.edu or rpique@wayne.edu SUPPLEMENTARY INFORMATION: Supplementary Material is available at Bioinformatics online.

Risk factors for tibial stress injuries: a case-control study.

OBJECTIVE: To identify physical and behavioral characteristics related to the incidence of tibial stress injuries (TSIs). DESIGN: Case-control study. No clinical care was conducted. SETTING: Research laboratories in the San Francisco (the United States) and Gold Coast (Australia) areas. PARTICIPANTS: Forty-eight patients (21 men and 27 women) with acute TSI, and 36 (16 men and 20 women) age-matched, sex-matched, height-matched, weight-matched, and activity-matched controls with no history of TSI. INDEPENDENT VARIABLES: Height, weight, body mass index, bone, lean and fat mass, lower limb alignment anomalies, foot type, orthotics, calcium, recent weight change, menstrual history, oral contraceptive use, medications, smoking, alcohol, sleep, training type, and intensity. Differences in continuous variables were tested using 1-way analysis of variance. Categorical variable comparisons were performed with Fisher exact test. MAIN OUTCOME MEASURE: Tibial stress injury. RESULTS: Tibial stress injury cases had 2.7% more fat (P < 0.001) and 2.6% less muscle (P < 0.001) as well as lower trochanteric bone mineral content (BMC) (P < 0.001), lumbar spine (LS) area (P < 0.001), femoral neck BMC (P < 0.001), length (P < 0.05), area (P < 0.001), cortical width (P < 0.01), cross-sectional moment of inertia (P < 0.001), and index of bending strength (P < 0.001) than controls. Controls had lower LS BMC (P < 0.01), length (P < 0.001), and broadband ultrasound attenuation (P < 0.001). The use of orthotic insoles was more prevalent in TSI cases than controls (25% vs 5.6%, respectively; P < 0.02), as were foot anomalies (56.3% vs 27.8%, respectively; P = 0.01). CONCLUSIONS: Tibial stress injury cases had lower lean and higher fat mass, a tendency for smaller bones, and for foot anomalies compared with uninjured matched controls. bone mineral density was normal for both groups. CLINICAL RELEVANCE: Enhancing lean mass and limiting gains in fat may provide some protection against TSI. Individuals with small skeletal frames are advised to increase training loads particularly gradually and to reduce training intensity at the first sign of pain in the shins.

Advancing the preparticipation physical evaluation (PPE): an ACSM and FIMS joint consensus statement.

While the preparticipation physical evaluation (PPE) is widely accepted, its usage and content are not standardized. Implementation is affected by cost, access, level of participation, participant age/sex, and local/regional/national mandate. PPE screening costs are generally borne by the athlete, family, or club. Screening involves generally agreed-upon questions based on expert opinion and tested over decades of use. No large-scale prospective controlled tracking programs have examined PPE outcomes. While the panel did not reach consensus on electrocardiogram screening as a routine part of PPE, all agreed that a history and physical exam focusing on cardiac risk is essential, and an ECG should be used where risk is increased. The many areas of consensus should help the American College of Sports Medicine and the Fédération Internationale du Médicine du Sport in developing a universally accepted PPE. An electronic PPE, using human-centered design, would be comprehensive, would provide a database given that PPE is mandatory in many locations, would simplify PPE administration, would allow remote access to clinical data, and would provide the much-needed data for prospective studies in this area.

Test-retest and interrater reliability of the functional lower extremity evaluation.

STUDY DESIGN: Repeated-measures clinical measurement reliability study. OBJECTIVES: To establish the reliability and face validity of the Functional Lower Extremity Evaluation (FLEE). BACKGROUND: The FLEE is a 45-minute battery of 8 standardized functional performance tests that measures 3 components of lower extremity function: control, power, and endurance. The reliability and normative values for the FLEE in healthy athletes are unknown. METHODS: A face validity survey for the FLEE was sent to sports medicine personnel to evaluate the level of importance and frequency of clinical usage of each test included in the FLEE. The FLEE was then administered and rated for 40 uninjured athletes. To assess test-retest reliability, each athlete was tested twice, 1 week apart, by the same rater. To assess interrater reliability, 3 raters scored each athlete during 1 of the testing sessions. Intraclass correlation coefficients were used to assess the test-retest and interrater reliability of each of the FLEE tests. RESULTS: In the face validity survey, the FLEE tests were rated as highly important by 58% to 71% of respondents but frequently used by only 26% to 45% of respondents. Interrater reliability intraclass correlation coefficients ranged from 0.83 to 1.00, and test-retest reliability ranged from 0.71 to 0.95. CONCLUSION: The FLEE tests are considered clinically important for assessing lower extremity function by sports medicine personnel but are underused. The FLEE also is a reliable assessment tool. Future studies are required to determine if use of the FLEE to make return-to-play decisions may reduce reinjury rates.

Advancing the preparticipation physical evaluation: an ACSM and FIMS joint consensus statement.

: While the preparticipation physical evaluation (PPE) is widely accepted, its usage and content are not standardized. Implementation is affected by cost, access, level of participation, participant age/sex, and local/regional/national mandate. Preparticipation physical evaluation screening costs are generally borne by the athlete, family, or club. Screening involves generally agreed-upon questions based on expert opinion and tested over decades of use. No large-scale prospective controlled tracking programs have examined PPE outcomes. While the panel did not reach consensus on electrocardiogram (ECG) screening as a routine part of PPE, all agreed that a history and physical exam focusing on cardiac risk is essential, and an ECG should be used where risk is increased. The many areas of consensus should help the American College of Sports Medicine and Fédération Internationale du Médicine du Sport in developing a universally accepted PPE. An electronic PPE, using human-centered design, would be comprehensive, would provide a database given that PPE is mandatory in many locations, would simplify PPE administration, would allow remote access to clinical data, and would provide the much-needed data for prospective studies in this area.

Prevention and management of non-communicable disease: the IOC consensus statement, Lausanne 2013.

Morbidity and mortality from preventable, non-communicable chronic disease (NCD) threatens the health of our populations and our economies. The accumulation of vast amounts of scientific knowledge has done little to change this. New and innovative thinking is essential to foster new creative approaches that leverage and integrate evidence through the support of big data, technology and design thinking. The purpose of this paper is to summarise the results of a consensus meeting on NCD prevention sponsored by the IOC in April 2013. Within the context of advocacy for multifaceted systems change, the IOC's focus is to create solutions that gain traction within healthcare systems. The group of participants attending the meeting achieved consensus on a strategy for the prevention and management of chronic disease that includes the following: (1) Focus on behavioural change as the core component of all clinical programmes for the prevention and management of chronic disease. (2) Establish actual centres to design, implement, study and improve preventive programmes for chronic disease. (3) Use human-centred design in the creation of prevention programmes with an inclination to action, rapid prototyping and multiple iterations. (4) Extend the knowledge and skills of Sports and Exercise Medicine (SEM) professionals to build new programmes for the prevention and treatment of chronic disease focused on physical activity, diet and lifestyle. (5) Mobilise resources and leverage networks to scale and distribute programmes of prevention. True innovation lies in the ability to align thinking around these core strategies to ensure successful implementation of NCD prevention and management programmes within healthcare. The IOC and SEM community are in an ideal position to lead this disruptive change. The outcome of the consensus meeting was the creation of the IOC Non-Communicable Diseases ad hoc Working Group charged with the responsibility of moving this agenda forward.

Prevention and management of non-communicable disease: the IOC consensus statement, Lausanne 2013.

Morbidity and mortality from preventable, non-communicable chronic disease (NCD) threatens the health of our populations and our economies. The accumulation of vast amounts of scientific knowledge has done little to change this. New and innovative thinking is essential to foster new creative approaches that leverage and integrate evidence through the support of big data, technology, and design thinking. The purpose of this paper is to summarize the results of a consensus meeting on NCD prevention sponsored by the International Olympic Committee (IOC) in April, 2013. Within the context of advocacy for multifaceted systems change, the IOC's focus is to create solutions that gain traction within health care systems. The group of participants attending the meeting achieved consensus on a strategy for the prevention and management of chronic disease that includes the following: 1. Focus on behavioural change as the core component of all clinical programs for the prevention and management of chronic disease. 2. Establish actual centres to design, implement, study, and improve preventive programs for chronic disease. 3. Use human-centered design in the creation of prevention programs with an inclination to action, rapid prototyping and multiple iterations. 4. Extend the knowledge and skills of Sports and Exercise Medicine (SEM) professionals to build new programs for the prevention and treatment of chronic disease focused on physical activity, diet and lifestyle. 5. Mobilize resources and leverage networks to scale and distribute programs of prevention. True innovation lies in the ability to align thinking around these core strategies to ensure successful implementation of NCD prevention and management programs within health care. The IOC and SEM community are in an ideal position to lead this disruptive change. The outcome of the consensus meeting was the creation of the IOC Non-Communicable Diseases ad-hoc Working Group charged with the responsibility of moving this agenda forward.

Prevention and management of noncommunicable disease: the IOC Consensus Statement, Lausanne 2013.

Morbidity and mortality from preventable, noncommunicable chronic disease (NCD) threatens the health of our populations and our economies. The accumulation of vast amounts of scientific knowledge has done little to change this. New and innovative thinking is essential to foster new creative approaches that leverage and integrate evidence through the support of big data, technology, and design thinking. The purpose of this paper is to summarize the results of a consensus meeting on NCD prevention sponsored by the International Olympic Committee (IOC) in April 2013. Within the context of advocacy for multifaceted systems change, the IOC's focus is to create solutions that gain traction within health care systems. The group of participants attending the meeting achieved consensus on a strategy for the prevention and management of chronic disease that includes the following: 1. Focus on behavioral change as the core component of all clinical programs for the prevention and management of chronic disease. 2. Establish actual centers to design, implement, study, and improve preventive programs for chronic disease. 3. Use human-centered design (HCD) in the creation of prevention programs with an inclination to action, rapid prototyping and multiple iterations. 4. Extend the knowledge and skills of Sports and Exercise Medicine (SEM) professionals to build new programs for the prevention and treatment of chronic disease focused on physical activity, diet, and lifestyle. 5. Mobilize resources and leverage networks to scale and distribute programs of prevention. True innovation lies in the ability to align thinking around these core strategies to ensure successful implementation of NCD prevention and management programs within health care. The IOC and SEM community are in an ideal position to lead this disruptive change. The outcome of the consensus meeting was the creation of the IOC Non-Communicable Diseases ad hoc Working Group charged with the responsibility of moving this agenda forward.