Genome-wide study identifies novel genes associated with bone toxicities in children with acute lymphoblastic leukaemia.

Bone toxicities are common among paediatric patients treated for acute lymphoblastic leukaemia (ALL) with potentially major negative impact on patients' quality of life. To identify the underlying genetic contributors, we conducted a genome-wide association study (GWAS) and a transcriptome-wide association study (TWAS) in 260 patients of European-descent from the DFCI 05-001 ALL trial, with validation in 101 patients of European-descent from the DFCI 11-001 ALL trial. We identified a significant association between rs844882 on chromosome 20 and bone toxicities in the DFCI 05-001 trial (p = 1.7 × 10-8). In DFCI 11-001 trial, we observed a consistent trend of this variant with fracture. The variant was an eQTL for two nearby genes, CD93 and THBD. In TWAS, genetically predicted ACAD9 expression was associated with an increased risk of bone toxicities, which was confirmed by meta-analysis of the two cohorts (meta-p = 2.4 × 10-6). In addition, a polygenic risk score of heel quantitative ultrasound speed of sound was associated with fracture risk in both cohorts (meta-p = 2.3 × 10-3). Our findings highlight the genetic influence on treatment-related bone toxicities in this patient population. The genes we identified in our study provide new biological insights into the development of bone adverse events related to ALL treatment.

Health Numeracy Is Associated With a Patient's Ability to Interpret Patient-Reported Outcome Measures Data.

BACKGROUND: Patient-reported outcome measures (PROMs) were originally developed as research tools; however, there is increasing interest in using PROMs to inform clinical care. Prior work has shown the benefits of implementing PROMs at the point of care, but a patient's health numeracy (their ability to understand and work with numbers) may affect their ability to interpret PROM results. MATERIALS AND METHODS: We recruited patients presenting to an outpatient orthopedic clinic. Forty-nine patients completed a survey that included demographic information, the short-form General Health Numeracy Test, and accuracy questions about four PROM displays (bar graph, table, line graph, pictograph) that indicated the same PROM results. RESULTS: Patients with higher health numeracy answered all display accuracy questions correctly (P=.016). Patients who preferred using the table were more likely to answer display accuracy questions incorrectly (odds ratio, 0.013, P=.024). The two most frequently preferred PROM formats were bar graphs and tables, and most patients preferred to learn about their PROM function scores via a combination of displays and verbal discussions. CONCLUSION: Patient health numeracy is associated with the ability to correctly interpret visual displays of PROMs. Implementation of PROMs at point of care currently does not account for health numeracy. Efforts to account for health numeracy when using PROMs at point of care may improve the efficacy of using PROMs to improve outcomes in orthopedic surgery. [Orthopedics. 202x;4x(x):xx-xx.].

Tree rings reveal the transient risk of extinction hidden inside climate envelope forecasts.

Given the importance of climate in shaping species' geographic distributions, climate change poses an existential threat to biodiversity. Climate envelope modeling, the predominant approach used to quantify this threat, presumes that individuals in populations respond to climate variability and change according to species-level responses inferred from spatial occurrence data-such that individuals at the cool edge of a species' distribution should benefit from warming (the "leading edge"), whereas individuals at the warm edge should suffer (the "trailing edge"). Using 1,558 tree-ring time series of an aridland pine (Pinus edulis) collected at 977 locations across the species' distribution, we found that trees everywhere grow less in warmer-than-average and drier-than-average years. Ubiquitous negative temperature sensitivity indicates that individuals across the entire distribution should suffer with warming-the entire distribution is a trailing edge. Species-level responses to spatial climate variation are opposite in sign to individual-scale responses to time-varying climate for approximately half the species' distribution with respect to temperature and the majority of the species' distribution with respect to precipitation. These findings, added to evidence from the literature for scale-dependent climate responses in hundreds of species, suggest that correlative, equilibrium-based range forecasts may fail to accurately represent how individuals in populations will be impacted by changing climate. A scale-dependent view of the impact of climate change on biodiversity highlights the transient risk of extinction hidden inside climate envelope forecasts and the importance of evolution in rescuing species from extinction whenever local climate variability and change exceeds individual-scale climate tolerances.

Real-World Experience among Elderly Metastatic Breast Cancer Patients Treated with CDK4/6 Inhibitor-Based Therapy.

The largest portion of breast cancer patients diagnosed after 70 years of age present with hormone receptor-positive (HR+) breast cancer subtypes. Cyclin-dependent kinase (CDK) 4/6 inhibitor treatment, in conjunction with endocrine therapy, has become standard-of-care for metastatic HR+ breast cancer. In total, 320 patients with metastatic breast cancer receiving CDK4/6 inhibitor combined with fulvestrant or an aromatase inhibitor were enrolled in an ongoing observational study or were included in an IRB-approved retrospective study. All patients receiving CDK4/6 inhibitor-based therapy that were ≥70 years of age (n = 111) displayed prolonged progression-free survival (27.6 months) as compared to patients <70 years of age (n = 209, 21.1 months, HR = 1.38, p < 0.05). Specifically, patients receiving a CDK4/6 inhibitor with an aromatase inhibitor who were ≥70 years of age (n = 79) displayed exceptionally prolonged progression-free survival (46.0 months) as compared to patients receiving the same treatment who were <70 years of age (n = 161, 21.8 months, HR = 1.71, p < 0.01). However, patients ≥70 years of age also experienced more frequent adverse responses to CDK4/6 inhibitor-based treatment leading to dose reduction, hold, or discontinuation than the younger cohort (69% and 53%, respectively). Treatment strategies that may decrease toxicity without affecting efficacy (such as dose titration) are worth further exploration.

Training Background and Demographic Characteristics of Primary Care Team Physicians in Professional Sports.

Background: Previous studies have shown that most professional head and orthopaedic team physicians are men, and most orthopaedic team physicians are fellowship-trained. It is unknown whether this holds true for primary care team physicians. Purpose: To evaluate the residency and fellowship training background as well as the demographic characteristics of primary care team physicians in professional sports. Study Design: Cross-sectional study. Methods: Publicly available information was used to determine the lead and supporting primary care team physicians for every US-based team in Major League Baseball, Major League Soccer, National Basketball Association, National Football League, National Hockey League, National Women's Soccer League, and Women's National Basketball Association. Data regarding training background and sex were obtained using internet-based sources. Results: We identified 310 primary care team physicians from all 165 US-based teams in the 7 leagues included in the study. Female physicians comprised 11.5% (19/165) of the lead primary care team physicians and 14.2% (44/310) of all primary care team physicians. Overall, 66.7% (110/165) of lead primary care team physicians and 75.5% (234/310) of all primary care team physicians were sports medicine fellowship-trained. There was a higher proportion of female (37.5%) and fellowship-trained (93.8%) physicians in women's professional sports leagues. Most primary care team physicians (244/310 [78.7%]) were trained in family medicine or internal medicine. Conclusion: Women constituted a small minority of primary care team physicians in professional sports. Most primary care team physicians were residency trained in family medicine or internal medicine and were sports medicine fellowship-trained. The proportion of female and fellowship-trained primary care team physicians was highest in the National Women's Soccer League and the Women's National Basketball Association.

Pediatric human nose organoids demonstrate greater susceptibility, epithelial responses, and cytotoxicity than adults during RSV infection.

Respiratory syncytial virus (RSV) is a common cause of respiratory infections, causing significant morbidity and mortality, especially in young children. Why RSV infection in children is more severe as compared to healthy adults is not fully understood. In the present study, we infect both pediatric and adult human nose organoid-air liquid interface (HNO-ALIs) cell lines with two contemporary RSV isolates and demonstrate how they differ in virus replication, induction of the epithelial cytokine response, cell injury, and remodeling. Pediatric HNO-ALIs were more susceptible to early RSV replication, elicited a greater overall cytokine response, demonstrated enhanced mucous production, and manifested greater cellular damage compared to their adult counterparts. Adult HNO-ALIs displayed enhanced mucus production and robust cytokine response that was well controlled by superior regulatory cytokine response and possibly resulted in lower cellular damage than in pediatric lines. Taken together, our data suggest substantial differences in how pediatric and adult upper respiratory tract epithelium responds to RSV infection. These differences in epithelial cellular response can lead to poor mucociliary clearance and predispose infants to a worse respiratory outcome of RSV infection.

Safety of Retrograde Tibial-Pedal Access and Intervention in Patients with Single Remaining Non-Occluded Infra-Popliteal Runoff Artery.

BACKGROUND: The adaptation of retrograde tibial-pedal access for peripheral angiogram and intervention is limited by the lack of operator experience and concern for small distal vessel injury. This study evaluates the safety of the retrograde tibial-pedal access for peripheral angiogram and intervention in patients with two vessel infra-popliteal artery chronic total occlusions, where the access point is the sole remaining non-occluded infra-popliteal artery. METHODS: A retrospective analysis of 5687 consecutive patients who underwent peripheral angiograms by retrograde tibial-pedal access via the single remaining non-occluded infra-popliteal artery was performed. Patients who had retrograde tibial-pedal access at the sole remaining infra-popliteal artery confirmed by angiography were included. Clinical and ultrasound data of the accessed infra-popliteal vessel up to 6 months were collected. RESULTS: The cohort consisted of 314 patients (152 males; mean age 77.9 years). At 6 months, access vessel complications occurred in 15 patients (4.8%). Access vessel occlusion occurred in 9 out of 314 patients (2.9%), arteriovenous fistula in 4 (1.3%), with spontaneous resolution in 2, pseudoaneurysm requiring thrombin injection in 2 (0.6%) and non-cardiovascular death in 1 (0.3%). No uncontrolled bleeding, procedure-related hospitalizations or limb amputations occurred. CONCLUSIONS: Routine primary retrograde tibial-pedal access for lower extremity peripheral artery diagnostic angiography and intervention in patients with single infra-popliteal artery runoff can be safety performed in an outpatient setting with infrequent and manageable complications.

The Safety of the Volar Intraarticular Extended Window (VIEW) Approach for Intra-articular Distal Radius Fractures.

BACKGROUND: A novel volar approach to intra-articular distal radius fractures has been introduced for treatment of intra-articular distal radius fractures, in which volar extrinsic ligaments are released to create a volar window into the radiocarpal joint (Volar Intraarticular Extended Window [VIEW] approach). Our purpose was to evaluate the safety of VIEW approach for treatment of intra-articular distal radius fractures. METHODS: A retrospective chart review was performed for 13 patients with intra-articular distal radius fractures treated operatively with the VIEW surgical technique using an intra-articular window in the volar capsule to aid in reduction and fixation. Postoperative radiographs were reviewed to assess for ulnocarpal translocation by assessing lunate uncovering and radial-carpal distance. RESULTS: Thirteen patients were treated with the VIEW approach with mean follow-up of 28 weeks (range, 7-67 weeks; SD, 18 weeks). The mean postoperative lunate uncovering was 34.6% (SD, 7.7%) and mean radial-carpal distance was 4.6 mm (SD, 1.5 mm). Postoperatively, mean intra-articular step-off was 0.9 mm (SD, 1.2 mm) and mean intra-articular gap was 1.2 mm (SD, 1.0 mm). No patients reported clinical symptoms of wrist instability. CONCLUSIONS: Using the VIEW approach during a volar approach to intra-articular distal radius fractures is safe and does not lead to carpal instability. Surgeons can consider using the approach when direct visualization of the articular surface may be beneficial for reduction or fixation. LEVEL OF EVIDENCE: Therapeutic IV.

Determinants of response to CDK4/6 inhibitors in the real-world setting.

Despite widespread use and a known mechanism of action for CDK4/6 inhibitors in combination with endocrine therapy, features of disease evolution and determinants of therapeutic response in the real-world setting remain unclear. Here, a cohort of patients treated with standard-of-care combination regimens was utilized to explore features of disease and determinants of progression-free survival (PFS) and overall survival (OS). In this cohort of 280 patients, >90% of patients were treated with palbociclib in combination with either an aromatase inhibitor (AI) or fulvestrant (FUL). Most of these patients had modified Scarff-Bloom-Richardson (SBR) scores, and ER, HER2, and PR immunohistochemistry. Both the SBR score and lack of PR expression were associated with shorter PFS in patients treated with AI combinations and remained significant in multivariate analyses (HR = 3.86, p = 0.008). Gene expression analyses indicated substantial changes in cell cycle and estrogen receptor signaling during the course of treatment. Furthermore, gene expression-based subtyping indicated that predominant subtypes changed with treatment and progression. The luminal B, HER2, and basal subtypes exhibited shorter PFS in CDK4/6 inhibitor combinations when assessed in the pretreatment biopsies; however, they were not associated with OS. Using unbiased approaches, cell cycle-associated gene sets were strongly associated with shorter PFS in pretreatment biopsies irrespective of endocrine therapy. Estrogen receptor signaling gene sets were associated with longer PFS particularly in the AI-treated cohort. Together, these data suggest that there are distinct pathological and biological features of HR+/HER2- breast cancer associated with response to CDK4/6 inhibitors. Clinical trial registration number: NCT04526587.

Addressing Opportunities and Barriers in Telehealth Neurologic Physical Therapy: Strategies to Advance Practice.

BACKGROUND AND PURPOSE: Since the COVID-19 pandemic, the use and implementation of telehealth has expanded, with implementation moving ahead of best practice recommendations due to necessity. Telehealth has improved access and care coordination for patients with various neurologic conditions; however, information regarding therapeutic intensity, safety, and appropriateness is lacking. In 2021, the Academy of Neurologic Physical Therapy formed a Telehealth Taskforce to provide clinical and educational resources for its members and the neurologic physical therapy (PT) community. The purpose of this special interest article is to provide consensus-driven best practice resources developed by the Taskforce and describe the process of creating these resources to assist with telehealth implementation in neurologic PT practice, advocate for continued utilization, and shine light on opportunities for future research. SUMMARY OF KEY POINTS: In this special interest article, we describe the process, challenges, and opportunities of developing and disseminating resources to educate, train, and support telehealth implementation in neurologic clinical practice. Four key strategies to facilitate telehealth implementation emerged: (1) increase knowledge of resources related to telehealth and mobile applications; (2) develop and disseminate evidence-based and consensus-based best practice recommendations for telehealth in neurologic PT; (3) provide future recommendations for integrating telehealth in PT, education, research, and clinical practice; and (4) encourage advocacy for inclusion of telehealth within the PT community. We explain the need to continue research and provide recommendations to expand telehealth research in neurologic clinical practice. RECOMMENDATIONS FOR CLINICAL PRACTICE: This article highlights the potential and future of telehealth in neurologic PT practice. Our recommendations provide current clinical tools and resources for telehealth implementation following a knowledge-to-action framework and suggest areas for future research.Video Abstract available for more insights from the authors (see the Video, the Supplemental Digital Content, available at: http://links.lww.com/JNPT/A447).

Is outpatient spine surgery associated with new, persistent opioid use in opioid-naïve patients? A retrospective national claims database analysis.

BACKGROUND CONTEXT: Although spine procedures have historically been performed inpatient, there has been a recent shift to the outpatient setting for selected cases due to increased patient satisfaction and reduced cost. Effective postoperative pain management while limiting over-prescribing of opioids, which may lead to persistent opioid use, is critical to performing spine surgery in the outpatient setting. PURPOSE: To assess if there is an increased risk for new, persistent opioid use between inpatient and outpatient spine procedures. STUDY DESIGN: Retrospective analysis using national administrative claims database. PATIENT SAMPLE: A total of 390,049 opioid-naïve patients with a perioperative opioid prescription who underwent an inpatient or outpatient spine surgery. OUTCOME MEASURES: Patients with perioperative opioid prescriptions who filled ≥ 1 opioid prescription between 90- and 180-days following surgery were defined as new, persistent opioid users. METHODS: We utilized a claims database to identify opioid-naïve patients who underwent lumbar or cervical fusion, total disc arthroplasty, or decompression procedures. We constructed a multivariable logistic regression to evaluate the association between inpatient versus outpatient surgery and the development of new, persistent opioid use while adjusting for several patient factors. RESULTS: A total of 19,205 (11.7%) inpatient and 18,546 (8.2%) outpatient patients developed new, persistent opioid use. Outpatient lumbar and cervical spine surgery patients were significantly less likely to develop new, persistent opioid use following surgery compared to inpatient spine surgery patients (OR = 0.71 [95% confidence interval {CI}: 0.69, 0.73], p < .001). Average morphine milligram equivalents (MMEs) (inpatient = 1,476 MME +/- 22.7, outpatient = 1,072 MME +/- 18.5, p < .001) and average MMEs per day (inpatient = 91.6 MME +/- 0.32, outpatient = 77.7 MME +/- 0.28, p < .001) were lower in the outpatient cohort compared to the inpatient. CONCLUSION: Our results support the shift from inpatient to outpatient spine procedures, as outpatient procedures were not associated with an increased risk for new, persistent opioid use. As more patients become candidates for outpatient spine surgery, predictors of new, persistent opioid use should be considered during risk stratification. LEVEL OF EVIDENCE: Level III Prognostic Study. MINI ABSTRACT: We utilized a national administrative claims database to identify opioid-naïve patients who underwent common spine procedures. Outpatient lumbar and cervical spine surgery patients were significantly less likely to be new, persistent opioid users following surgery compared to inpatient spine surgery patients. Our results support the shift to outpatient spine procedures.

A Pilot Study Exploring Temporal Development of Gut Microbiome/Metabolome in Breastfed Neonates during the First Week of Life.

Purpose: Exclusive breastfeeding promotes gut microbial compositions associated with lower rates of metabolic and autoimmune diseases. Its cessation is implicated in increased microbiome-metabolome discordance, suggesting a vulnerability to dietary changes. Formula supplementation is common within our low-income, ethnic-minority community. We studied exclusively breastfed (EBF) neonates' early microbiome-metabolome coupling in efforts to build foundational knowledge needed to target this inequality. Methods: Maternal surveys and stool samples from seven EBF neonates at first transitional stool (0-24 hours), discharge (30-48 hours), and at first appointment (days 3-5) were collected. Survey included demographics, feeding method, medications, medical history and tobacco and alcohol use. Stool samples were processed for 16S rRNA gene sequencing and lipid analysis by gas chromatography-mass spectrometry. Alpha and beta diversity analyses and Procrustes randomization for associations were carried out. Results: Firmicutes, Proteobacteria, Bacteroidetes and Actinobacteria were the most abundant taxa. Variation in microbiome composition was greater between individuals than within (p=0.001). Palmitic, oleic, stearic, and linoleic acids were the most abundant lipids. Variation in lipid composition was greater between individuals than within (p=0.040). Multivariate composition of the metabolome, but not microbiome, correlated with time (p=0.030). Total lipids, saturated lipids, and unsaturated lipids concentrations increased over time (p=0.012, p=0.008, p=0.023). Alpha diversity did not correlate with time (p=0.403). Microbiome composition was not associated with each samples' metabolome (p=0.450). Conclusion: Neonate gut microbiomes were unique to each neonate; respective metabolome profiles demonstrated generalizable temporal developments. The overall variability suggests potential interplay between influences including maternal breastmilk composition, amount consumed and living environment.

Has the Use of Electrodiagnostic Studies for Carpal Tunnel Syndrome Changed After the 2016 American Academy of Orthopaedic Surgeons Clinical Practice Guideline?

PURPOSE: A 2016 American Academy of Orthopaedic Surgeons (AAOS) clinical practice guideline (CPG) de-emphasized the need for electrodiagnostic studies (EDS) for carpal tunnel syndrome (CTS). We tested the hypothesis that use of EDS decreased after the AAOS CPG. METHODS: Using a national administrative claims database, we measured the proportion of patients with a diagnosis of CTS who underwent EDS within 1 year after diagnosis between 2011 and 2019. Using an interrupted time series design, we defined 2 time periods (pre-CPG and post-CPG) and compared EDS usage between the periods using segmented regression analysis. We conducted a subgroup analysis of preoperative EDS usage in patients who underwent carpal tunnel release. RESULTS: Of 2,081,829 patients with CTS, 315,449 (15.2%) underwent EDS within 1 year after diagnosis. The segmented regression analysis showed a decrease in the level of EDS usage after publication of the AAOS CPG (-11.50 per 1,000 patients [95% CI, -1.47 to -0.95 per 1,000 patients]); however, the rate of EDS usage increased in the post-CPG period (+1.75 per 1,000 patients per quarter [95% CI, 0.97-2.54 per 1,000 patients per quarter]). Of 473,753 eligible patients who underwent carpal tunnel release, 139,186 (29.4%) underwent EDS within 6 months before surgery. After publication of the AAOS CPG, preoperative EDS usage decreased by -23.57 per 1,000 patients (95% CI, -37.72 to -9.42 per 1,000 patients). However, these decreasing trends in EDS usage predated the 2016 AAOS CPG. CONCLUSIONS: The overall and preoperative EDS usage for CTS has been decreasing since at least 2014, predating the 2016 AAOS CPG, reflecting the rapid implementation of evidence into practice. However, EDS usage has increased in the post-CPG period, and a considerable proportion of patients who underwent carpal tunnel release still received EDS. CLINICAL RELEVANCE: Given its high costs and disputed value, routine EDS usage should be considered for further deimplementation initiatives.

Predictors of Residual Severe Tricuspid Regurgitation After Transcatheter Mitral Valve Repair.

Background: Severe tricuspid regurgitation (TR) may persist after a mitral transcatheter edge-to-edge repair (M-TEER) and is associated with worsened clinical outcomes and survival. It is unclear which patients with concomitant mitral regurgitation (MR) and TR will have TR reduction after M-TEER. The aim of this study was to identify the predictors of residual TR after transcatheter edge-to-edge repair (TEER). Methods: Data were collected from the Northwell TEER registry, a prospectively maintained mandatory database including 4 high-volume transcatheter aortic valve replacement/TEER centers. Transthoracic echocardiograms, both pre-TEER and post-TEER, were evaluated. Univariate and multivariate logistic regression analyses were performed to identify predictors of severe TR after M-TEER. Significant TR reduction was defined as a reduction in TR grade by at least 1+ with moderate (2+) or less TR at 1 month. Results: Of the 479 patients who underwent M-TEER, 107 patients with concomitant severe MR/TR were included. Successful MR reduction occurred in 89 patients (84%) and a significant TR reduction in 45 (42%). On the univariate analysis, the only predictors of severe residual TR were right atrial area and unsuccessful M-TEER. On the multivariate logistic regression model, the only predictor variable for patients with a reduction in TR was MR reduction of ≥3+ with M-TEER. Conclusions: In patients with concomitant severe MR and TR, TR reduction after isolated M-TEER occurs in only ∼40% of patients. MR grade reduction ≥3+ was the only independent predictor for TR reduction. Other clinical and echocardiographic variables (including pulmonary hypertension, right ventricular function, tricuspid annular dilation, atrial fibrillation, and presence of a cardiac implantable electrical device) were not associated with residual TR. Inability to predict TR reduction after M-TEER highlights the importance of establishing transcatheter tricuspid valve therapies and should factor in heart-team discussions.

Comparison of clinical outcomes between use of overexpanding an undersized versus nominal-sized SAPIEN 3 ultra transcatheter heart valve in patients with borderline annulus area.

BACKGROUND: For patients with borderline annulus areas that fall between two valve sizes, overinflating a smaller balloon-expandable transcatheter heart valve (THV) may be preferable to nominal sizing of a larger THV. OBJECTIVES: To evaluate the outcomes of nominal preparation versus over-expanding an under-sized SAPIEN 3 Ultra (S3U) transcatheter heart valve (OE-THV) in cases with borderline annuli. METHODS: 958 patients that underwent TAVR with the S3U at four high-volume TAVR centers between January 2017 and December 2020 were retrospectively reviewed. 336 patients were identified as borderline annuli size, of which 146 (44%) received OE-THVs and 190 (56%) received nominal-sized THVs. The primary composite endpoint included: in-hospital mortality, aortic injury, moderate/severe paravalvular leak (PVL), permanent pacemaker implant (PPM), stroke, or conversion to surgery. RESULTS: Baseline characteristics were similar except for a larger percentage of females in the OE-THV (53.42% vs. 42.11%, p = 0.04). TAVR with OE-THV resulted a reduction in the primary composite endpoint (13.69% vs. 22.63%, p = 0.04). On subgroup analysis, there was no difference between 20 mm OE-THV versus 23 mm nominal or 23 mm OE-THV versus 26 mm nominal, but there was a reduction in the primary composite endpoint in patients with larger annuli that received a 26 mm OE-THV compared to the 29 mm nominally sized THV (9.7% vs. 27.4%, p = 0.02). At 1 month and 1 year follow-up, there was no significant difference in mortality, PVL rates, NYHA class, and/or KCCQ score. CONCLUSION: Overinflating a smaller-sized S3U THV may be a safer option in comparison to nominal sizing in patients with borderline annular area.

Real-World Experience with CDK4/6 Inhibitors for Metastatic HR+/HER2- Breast Cancer at a Single Cancer Center.

BACKGROUND: A study was initiated at Roswell Park Comprehensive Cancer Center to capture the real-world experience related to the use of CDK4/6 inhibitors (Ciclibs) for the treatment of metastatic hormone receptor-positive and HER2-negative breast cancer (HR+/HER2-). PATIENTS AND METHODS: A total of 222 patients were evaluated who received CDK4/6 inhibitors in the period from 2015 to 2021. Detailed clinical and demographic information was obtained on each patient and used to define clinical and demographic features associated with progression-free survival on CDK4/6 inhibitor-based therapies. RESULTS: In this real-world analysis, the majority of patients received palbociclib as the CDK4/6 inhibitor with letrozole or fulvestrant as the predominant endocrine therapies. The median progression-free survival (PFS) in the letrozole (27.6 months) and fulvestrant (17.2 months) groups were comparable to that observed in clinical trials. As expected, age at start of the treatment and menopausal status influenced endocrine therapy utilization but were not associated with PFS. Patients with recurrent disease had shorter PFS (P = .0024) than those presenting with de novo metastasis. The presence of visceral metastasis trended toward shorter PFS (P = .051). Similarly, prior endocrine therapy (P = .003) or chemotherapy (P = .036) was associated with shorter PFS. Body mass index was not associated with PFS or with dose interruption and/or modification. While the number of minorities in this analysis is limited (n = 26), these patients as a group had statistically shorter PFS on treatment (P = .002). CONCLUSIONS: The real-world progression-free survival with CDK4/6 inhibitors mimics that observed in the clinical trial. A number of clinical and demographic features were associated with PFS on CDK4/6 inhibitor-based therapy. Further studies are ongoing to validate these findings incorporating additional cancer centers.

Whole-Genome Sequencing Identifies PPARGC1A as a Putative Modifier of Cancer Risk in BRCA1/2 Mutation Carriers.

While BRCA1 and BRCA2 mutations are known to confer the largest risk of breast cancer and ovarian cancer, the incomplete penetrance of the mutations and the substantial variability in age at cancer onset among carriers suggest additional factors modifying the risk of cancer in BRCA1/2 mutation carriers. To identify genetic modifiers of BRCA1/2, we carried out a whole-genome sequencing study of 66 ovarian cancer patients that were enriched with BRCA carriers, followed by validation using data from the Pan-Cancer Analysis of Whole Genomes Consortium. We found PPARGC1A, a master regulator of mitochondrial biogenesis and function, to be highly mutated in BRCA carriers, and patients with both PPARGC1A and BRCA1/2 mutations were diagnosed with breast or ovarian cancer at significantly younger ages, while the mutation status of each gene alone did not significantly associate with age of onset. Our study suggests PPARGC1A as a possible BRCA modifier gene. Upon further validation, this finding can help improve cancer risk prediction and provide personalized preventive care for BRCA carriers.

UACA locus is associated with breast cancer chemoresistance and survival.

Few germline genetic variants have been robustly linked with breast cancer outcomes. We conducted trans-ethnic meta genome-wide association study (GWAS) of overall survival (OS) in 3973 breast cancer patients from the Pathways Study, one of the largest prospective breast cancer survivor cohorts. A locus spanning the UACA gene, a key regulator of tumor suppressor Par-4, was associated with OS in patients taking Par-4 dependent chemotherapies, including anthracyclines and anti-HER2 therapy, at a genome-wide significance level ([Formula: see text]). This association was confirmed in meta-analysis across four independent prospective breast cancer cohorts (combined hazard ratio = 1.84, [Formula: see text]). Transcriptome-wide association study revealed higher UACA gene expression was significantly associated with worse OS ([Formula: see text]). Our study identified the UACA locus as a genetic predictor of patient outcome following treatment with anthracyclines and/or anti-HER2 therapy, which may have clinical utility in formulating appropriate treatment strategies for breast cancer patients based on their genetic makeup.

Comparison of SARS-CoV-2 Test Positivity in NCAA Division I Student Athletes vs Nonathletes at 12 Institutions.

Importance: The COVID-19 pandemic initially led to the abrupt shutdown of collegiate athletics until guidelines were established for a safe return to play for student athletes. Currently, no literature exists that examines the difference in SARS-CoV-2 test positivity between student athletes and nonathletes at universities across the country. Objective: To identify the difference in risk of COVID-19 infection between student athlete and nonathlete student populations and evaluate the hypothesis that student athletes may display increased SARS-CoV-2 test positivity associated with increased travel, competition, and testing compared with nonathletes at their respective universities. Design, Setting, and Participants: In this cross-sectional analysis, a search of publicly available official university COVID-19 dashboards and press releases was performed for all 65 Power 5 National Collegiate Athletic Association (NCAA) Division I institutions during the 2020 to 2021 academic year. Data were analyzed at the conclusion of the academic year. Schools that released at least 4 months of testing data, including the fall 2020 football season, for student athletes and nonathlete students were included in the analysis. Power 5 NCAA Division I student athletes and their nonathlete student counterparts were included in the analysis. Exposure: Designation as a varsity student athlete. Main Outcomes and Measures: The main outcome was SARS-CoV-2 test positivity for student athletes and nonathlete students at the included institutions for the 2020 to 2021 academic year, measured as a relative risk for student athletes. Results: Among 12 schools with sufficient data available included in the final analysis, 555 372 student athlete tests and 3 482 845 nonathlete student tests were performed. There were 9 schools with decreased test positivity in student athletes compared with nonathlete students (University of Arkansas: 0.01% vs 3.52%; University of Minnesota: 0.63% vs 5.96%; Penn State University: 0.74% vs 6.58%; Clemson University: 0.40% vs 1.88%; University of Louisville: 0.75% vs 3.05%; Purdue University: 0.79% vs 2.97%; University of Michigan: 0.40% vs 1.12%; University of Illinois: 0.17% vs 0.40%; University of Virginia: 0.64% vs 1.04%) (P < .001 for each). The median (range) test positivity in these 9 schools was 0.46% (0.01%-0.79%) for student athletes and 1.04% (0.40%-6.58%) for nonathlete students. In 1 school, test positivity was increased in the student athlete group (Stanford University: 0.20% vs 0.05%; P < .001). Overall, there were 2425 positive tests (0.44%) among student athletes and 30 567 positive tests (0.88%) among nonathlete students, for a relative risk of 0.50 (95% CI, 0.48-0.52; P < .001). There was no statistically significant difference in student athlete test positivity between included schools; however, test positivity among nonathlete students varied considerably between institutions, ranging from 133 of 271 862 tests (0.05%) at Stanford University to 2129 of 32 336 tests (6.58%) at Penn State University. Conclusions and Relevance: This study found that in the setting of SARS-CoV-2 transmission mitigation protocols implemented by the NCAA, participation in intercollegiate athletics was not associated with increased SARS-CoV-2 test positivity. This finding suggests that collegiate athletics may be held without an associated increased risk of infection among student athletes.

Climate-driven, but dynamic and complex? A reconciliation of competing hypotheses for species' distributions.

Estimates of the percentage of species "committed to extinction" by climate change range from 15% to 37%. The question is whether factors other than climate need to be included in models predicting species' range change. We created demographic range models that include climate vs. climate-plus-competition, evaluating their influence on the geographic distribution of Pinus edulis, a pine endemic to the semiarid southwestern U.S. Analyses of data on 23,426 trees in 1941 forest inventory plots support the inclusion of competition in range models. However, climate and competition together only partially explain this species' distribution. Instead, the evidence suggests that climate affects other range-limiting processes, including landscape-scale, spatial processes such as disturbances and antagonistic biotic interactions. Complex effects of climate on species distributions-through indirect effects, interactions, and feedbacks-are likely to cause sudden changes in abundance and distribution that are not predictable from a climate-only perspective.