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Background: More than 75% of patients with breast cancer treated with chemotherapy experience cognitive impairments (eg, memory and attention problems), commonly known as chemo-brain. Exercise, especially aerobic high-intensity interval training (HIIT), is associated with better cognitive function in healthy populations. However, clinical trials testing the impact of exercise interventions on chemotherapy-induced cognitive decline in patients with cancer are lacking, and the mechanisms through which exercise could improve cognitive function are unclear., Objective: The objective of the Improving Cognitive Function Through High-Intensity Interval Training in Breast Cancer Patients Undergoing Chemotherapy trial is to examine the effects of HIIT on cognitive function in patients with breast cancer undergoing chemotherapy., Methods: This 2-arm, single-center, pilot randomized controlled trial will randomize 50 patients with breast cancer undergoing chemotherapy to HIIT or attention control. The HIIT group will perform a supervised 16-week, thrice-weekly intervention, with each session including a 5-minute warm-up at 10% maximal power output (POmax), 10 sets of alternating 1-minute high-intensity (90% POmax) and 1-minute recovery (10% POmax) intervals, and a 5-minute cooldown (10% POmax). The attention control group will receive a stretching program with no exercise components and be asked to maintain their exercise levels for 16 weeks. The primary outcomes of the study are executive function and memory measured using the National Institutes of Health toolbox and resting-state connectivity and diffusion tensor imaging microstructure evaluated using magnetic resonance imaging. The secondary and tertiary outcomes include cardiorespiratory fitness, body composition, physical fitness, and psychosocial health. The study has been approved by the institutional review board of the Dana-Farber Cancer Institute (20-222)., Results: The trial was funded in January 2019, with recruitment started in June 2021. As of May 2022, a total of 4 patients have consented and been randomized (n=2, 50% to exercise; n=1, 25% to control; and n=1, 25% nonrandomized). Trial completion is expected in January 2024., Conclusions: This first-of-its-kind study incorporates a novel exercise intervention (ie, HIIT) and comprehensive cognitive measures. If positive, our findings will establish the pilot efficacy of HIIT on chemotherapy-induced cognitive function in patients with breast cancer, providing the foundation for future larger phase-II and phase-III trials to confirm the findings and potentially establish HIIT as a standard of care for women undergoing chemotherapy for breast cancer., Trial Registration: ClinicalTrials.gov NCT04724499; https://clinicaltrials.gov/ct2/show/NCT04724499., International Registered Report Identifier (irrid): DERR1-10.2196/39740., (©Rebekah Wilson, Dong-Woo Kang, Meghan Tahbaz, Mary Norris, Hajime Uno, Jennifer Ligibel, Jeffrey Guenette, Cameron Christopher, Christina Dieli-Conwright. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 07.04.2023.)

Background: Oncologists often order genomic testing to inform treatment for worsening cancer. The resulting correlation between genomic testing timing and prognosis, or "informative entry," can bias observational clinico-genomic research. The efficacy of existing approaches to this problem in clinico-genomic cohorts is poorly understood., Methods: We simulated clinico-genomic cohorts followed from an index date to death. Subgroups in each cohort who underwent genomic testing before death were "observed." We varied data generation parameters under four scenarios: (i) independent testing and survival times; (ii) correlated testing and survival times for all patients; (iii) correlated testing and survival times for a subset of patients; and (iv) testing and mortality exclusively following progression events. We examined the behavior of conditional Kendall tau (Tc) statistics, Cox entry time coefficients, and biases in overall survival (OS) estimation and biomarker inference across scenarios., Results: Scenario #1 yielded null Tc and Cox entry time coefficients and unbiased OS inference. Scenario #2 yielded positive Tc, negative Cox entry time coefficients, underestimated OS, and biomarker associations biased toward the null. Scenario #3 yielded negative Tc, positive Cox entry time coefficients, and underestimated OS, but biomarker estimates were less biased. Scenario #4 yielded null Tc and Cox entry time coefficients, underestimated OS, and biased biomarker estimates. Transformation and copula modeling did not provide unbiased results., Conclusions: Approaches to informative clinico-genomic cohort entry, including Tc and Cox entry time statistics, are sensitive to heterogeneity in genotyping and survival time distributions., Impact: Novel methods are needed for unbiased inference using observational clinico-genomic data., (©2023 American Association for Cancer Research.)

Accurate risk stratification is key to reducing cancer morbidity through targeted screening and preventative interventions. Multiple breast cancer risk prediction models are used in clinical practice, and often provide a range of different predictions for the same patient. Integrating information from different models may improve the accuracy of predictions, which would be valuable for both clinicians and patients. BRCAPRO is a widely used model that predicts breast cancer risk based on detailed family history information. A major limitation of this model is that it does not consider non-genetic risk factors. To address this limitation, we expand BRCAPRO by combining it with another popular existing model, BCRAT (i.e., Gail), which uses a largely complementary set of risk factors, most of them non-genetic. We consider two approaches for combining BRCAPRO and BCRAT: (1) modifying the penetrance (age-specific probability of developing cancer given genotype) functions in BRCAPRO using relative hazard estimates from BCRAT, and (2) training an ensemble model that takes BRCAPRO and BCRAT predictions as input. Using both simulated data and data from Newton-Wellesley Hospital and the Cancer Genetics Network, we show that the combination models are able to achieve performance gains over both BRCAPRO and BCRAT. In the Cancer Genetics Network cohort, we show that the proposed BRCAPRO + BCRAT penetrance modification model performs comparably to IBIS, an existing model that combines detailed family history with non-genetic risk factors.

The cell cycle is a series of events in the process of one cell giving rise to two daughter cells. The mitotic harvesting method, established by Terasima and Tolmach in the 1960s, causes minimal physiological stress on the cells and achieves a high degree of cell cycle synchrony by collecting only mitotic cells from a cultured cell system. The purpose of the present study is to validate the versatility of the mitotic harvesting method using human cervical cell line HeLa cells expressing Fluorescent Ubiquitination-based Cell Cycle Indicators (FUCCI) and to estimate the cell cycle-dependent changes in radiosensitivity in HeLa-FUCCI cells. The image analysis showed that cell cycle synchrony was maintained for at least 24 hours after mitotic cell collection. Also, the clonogenic assay demonstrated changes in radiosensitivity that were cell cycle dependent. These results indicate that the mitotic harvesting method using FUCCI-expressing cells has high versatility in the field of radiation cell biology.

Animals affect element cycling in ecosystems by consumption and excretion. Amphidromous shrimps frequently dominate low-mid altitude streams, where downstream connectivity to oceans is sustained. Although shrimps' direct influence on benthic communities has been studied, little is known about their influences on nutrient cycling. Here, we hypothesized that the dominance of shrimps alters nutrient mineralization by benthic macroinvertebrates in streams due to the difference in the quality and quantity of excretion between shrimps and aquatic insects. We tested this hypothesis through a field manipulative experiment, excretion measurements of animals, and field surveys. In the field manipulative experiment, the presence of shrimps slightly decreased the biomass of aquatic insects but tripled total benthic macroinvertebrate biomass directly through their own biomass. The mass-specific NH 4 + excretion rate by shrimps was similar to aquatic insects, and the areal NH 4 + excretion by benthic macroinvertebrates was increased by 2.5 times in the presence of shrimps. In contrast, shrimps excreted significantly less soluble reactive phosphorus (SRP) than aquatic insects, and the presence of shrimps did not affect areal SRP excretion by benthic macroinvertebrates. The field survey showed a positive correlation of NO 3 - concentration with the shrimp density, inferring the excess NH 4 + was nitrified. Although the nutrient concentration of stream water is frequently attributed to watershed conditions, the results of this study indicate that downstream connectivity to oceans may also influence nutrient dynamics of the stream through the density of amphidromous shrimps., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Between-group comparison based on the restricted mean survival time (RMST) is getting attention as an alternative to the conventional logrank/hazard ratio approach for time-to-event outcomes in randomized controlled trials (RCTs). The validity of the commonly used nonparametric inference procedure for RMST has been well supported by large sample theories. However, we sometimes encounter cases with a small sample size in practice, where we cannot rely on the large sample properties. Generally, the permutation approach can be useful to handle these situations in RCTs. However, a numerical issue arises when implementing permutation tests for difference or ratio of RMST from two groups. In this article, we discuss the numerical issue and consider six permutation methods for comparing survival time distributions between two groups using RMST in RCTs setting. We conducted extensive numerical studies and assessed type I error rates of these methods. Our numerical studies demonstrated that the inflation of the type I error rate of the asymptotic methods is not negligible when sample size is small, and that all of the six permutation methods are workable solutions. Although some permutation methods became a little conservative, no remarkable inflation of the type I error rates were observed. We recommend using permutation tests instead of the asymptotic tests, especially when the sample size is less than 50 per arm., (© 2020 John Wiley & Sons, Ltd.)

Organisms with annual life cycles are exposed to life stage specific thermal environments across seasons. Seasonal variation in thermal environments can vary across years and among sites. We investigated how organisms with annual life cycles respond to predictable seasonal changes in temperature and unpredictable thermal variation between habitats and years throughout their lives. Field surveys and historical records reveal that the spatially and temporally heterogeneous thermal environments inhabited by the annual mayfly Ephemerella maculata (Ephemerellidae) shift the date for transition to the next, life stage, so that the thermal phenotype of each life stage matches the thermal environment of the specific habitat and year. Laboratory studies of three distinct life stages of this mayfly reveal that life stage transitions are temperature dependent, facilitating timing shifts that are synchronized with the current season's temperatures. Each life stage exhibited specific thermal sensitivity and performance phenotypes that matched the ambient temperature typically experienced during that life stage. Our study across the whole life cycle reveals mechanisms that allow organisms to achieve lifetime eurythermy in a dynamic seasonal environment, despite having narrower thermal ranges for growth and development in each life stage.

Background: People with HIV (PWH) have increased frailty risk at younger ages compared with the general population. Multimorbidity is associated with frailty, yet effects of specific comorbidities on transition to frailty in PWH are unknown., Setting: Prospective study of 219 PWH age 45 years or older in the National NeuroAIDS Tissue Consortium., Methods: Frailty status was categorized using Fried frailty phenotype criteria. Comorbidities [bone disease, cardiovascular disease, cerebrovascular disease, liver disease, renal disease, diabetes, chronic obstructive pulmonary disease (COPD), hypertension, obesity, cancers, neuropsychiatric conditions] were assessed from longitudinal data. Associations between baseline comorbidities and transition to frailty within 30 months were analyzed using Kaplan-Meier and Cox regression models. Grip strength was assessed using mixed-effects models., Results: At baseline, the median age was 61 years, 73% were male 98% were on antiretroviral therapy, 29% had ≥3 comorbidities, 27% were robust, and 73% were pre-frail. Cerebrovascular disease, diabetes, and COPD were independent predictors of transition to frailty within 30 months in models adjusted for age, sex, and multimorbidity (≥3 additional comorbidities) [hazard ratios (95% confidence intervals) 2.52 (1.29 to 4.93), 2.31 (1.12 to 4.76), and 1.82 (0.95 to 3.48), respectively]. Furthermore, cerebrovascular disease, diabetes, COPD, or liver disease co-occurring with multimorbidity was associated with substantially increased frailty hazards compared with multimorbidity alone (hazard ratios 4.75-7.46). Cerebrovascular disease was associated with decreased baseline grip strength (P = 0.0001), whereas multimorbidity, diabetes, and COPD were associated with declining grip strength (P < 0.10)., Conclusions: In older PWH, cerebrovascular disease, diabetes, COPD, or liver disease co-occurring with multimorbidity is associated with substantially increased risk of becoming frail within 30 months. Interventions targeting these comorbidities may ameliorate frailty and age-related functional decline in PWH., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: With the availability of multigene panel testing (MGPT) for hereditary cancer risk assessment, clinicians need to assess the likelihood of pathogenic germline variants (PGVs) across numerous genes in parallel. This study's aim was to develop and validate a clinical prediction model (PREMMplus) for MGPT risk assessment., Materials and Methods: PREMMplus was developed in a single-institution cohort of 7,280 individuals who had undergone MGPT. Logistic regression models with Least Absolute Shrinkage and Selection Operator regularization were used to examine candidate predictors (age, sex, ethnicity, and personal/family history of 18 cancers/neoplasms) to estimate one's likelihood of carrying PGVs in 19 genes (broadly categorized by phenotypic overlap and/or relative penetrance: 11 category A [ APC , BRCA1 / 2 , CDH1 , EPCAM , MLH1 , MSH2 , MSH6 , biallelic MUTYH , PMS2 , and TP53 ] and eight category B genes [ ATM , BRIP1 , CDKN2A , CHEK2 , PALB2 , PTEN , RAD51C , and RAD51D ]). Model performance was validated in nonoverlapping data sets of 8,691 and 14,849 individuals with prior MGPT ascertained from clinic- and laboratory-based settings, respectively., Results: PREMMplus (score ≥ 2.5%) had 93.9%, 91.7%, and 89.3% sensitivity and 98.3%, 97.5%, and 97.8% negative-predictive value (NPV) for identifying category A gene PGV carriers in the development and validation cohorts, respectively. PREMMplus assessment (score ≥ 2.5%) had 89.9%, 85.6%, and 84.2% sensitivity and 95.0%, 93.5%, and 93.5% NPV, respectively, for identifying category A/B gene PGV carriers. Decision curve analyses support MGPT for individuals predicted to have ≥ 2.5% probability of a PGV., Conclusion: PREMMplus accurately identifies individuals with PGVs in a diverse spectrum of cancer susceptibility genes with high sensitivity/NPV. Individuals with PREMMplus scores ≥ 2.5% should be considered for MGPT.

Belt electrode skeletal muscle electrical stimulation (B-SES) can simultaneously contract multiple muscle groups. Although the beneficial effects of B-SES in clinical situations have been elucidated, its molecular mechanism remains unknown. In this study, we developed a novel rodent B-SES ankle stimulation system to test whether low-frequency stimulation prevents denervation-induced muscle atrophy. Electrical stimulations (7‒8 Hz, 30 min) with ankle belt electrodes were applied to Sprague-Dawley rats daily for one week. All animals were assigned to the control (CONT), denervation-induced atrophy (DEN), and DEN + electrical stimulation (ES) groups. The tibialis anterior (TA) and gastrocnemius (GAS) muscles were used to examine the effect of ES treatment. After seven daily sessions of continuous stimulation, muscle wet weight (n = 8-11), and muscle fiber cross-sectional area (CSA, n = 4-6) of TA and GAS muscles were lower in DEN and DEN + ES than in CON. However, it was significantly higher in DEN than DEN + ES, showing that ES partially prevented muscle atrophy. PGC-1α, COX-IV, and citrate synthase activities (n = 6) were significantly higher in DEN + ES than in DEN. The mRNA levels of muscle proteolytic molecules, Atrogin-1 and Murf1, were significantly higher in DEN than in CONT, while B-SES significantly suppressed their expression (p < 0.05). In conclusion, low-frequency electrical stimulation of the bilateral ankles using belt electrodes (but not the pad electrodes) is effective in preventing denervation-induced atrophy in multiple muscles, which has not been observed with pad electrodes. Maintaining the mitochondrial quantity and enzyme activity by low-frequency electrical stimulation is key to suppressing muscle protein degradation., (© 2022. The Author(s).)

A 65-year-old woman presented to the emergency outpatient department with a chief complaint of left hypochondriac pain and a rapidly expanding tumor mass. Abdominal contrast-enhanced computed tomography(CT)revealed a tumor in the transverse colon and an extensive abdominal wall abscess. A colonoscopy further confirmed a tumor in the transverse colon, and the patient was diagnosed with transverse colon cancer, abdominal wall infiltration, and abdominal wall abscess. Abscess drainage was performed, and abscess cavity shrinkage was noted. Infection control progressed favorably. A transverse colectomy was performed, and the abdominal wall of the infiltration site was only partially excised. Postoperative chemotherapy was performed, and the progress was carefully followed up. Increased tumor markers were noted 12 months postoperatively, and abdominal CT revealed a 20-mm tumor in the abdominal wall. With a diagnosis of local recurrence, the abdominal wall tumor was excised. The tumor markers normalized postoperatively and chemotherapy was completed. The patient has survived without relapses for 30 months since excision.

Purpose: Models used to predict the probability of an individual having a pathogenic homozygous or heterozygous variant in a mismatch repair gene, such as MMRpro, are widely used. Recently, MMRpro was updated with new colorectal cancer penetrance estimates. The purpose of this study was to evaluate the predictive performance of MMRpro and other models for individuals with a family history of colorectal cancer., Methods: We performed a validation study of 4 models, Leiden, MMRpredict, PREMM 5 , and MMRpro, using 784 members of clinic-based families from the United States. Predicted probabilities were compared with germline testing results and evaluated for discrimination, calibration, and predictive accuracy. We analyzed several strategies to combine models and improve predictive performance., Results: MMRpro with additional tumor information (MMRpro+) and PREMM 5 outperformed the other models in discrimination and predictive accuracy. MMRpro+ was the best calibrated with an observed to expected ratio of 0.98 (95% CI = 0.89-1.08). The combination models showed improvement over PREMM 5 and performed similar to MMRpro+., Conclusion: MMRpro+ and PREMM 5 performed well in predicting the probability of having a pathogenic homozygous or heterozygous variant in a mismatch repair gene. They serve as useful clinical decision tools for identifying individuals who would benefit greatly from screening and prevention strategies., Competing Interests: Conflict of Interest G.P. is a cofounder and equity holder in Phaeno Inc., a member of the Scientific Advisory Board of Konica Minolta Precision Medicine, Inc (which includes Ambry Genetics and Invicro), and a consultant for Delfi Diagnostics and Foundation Medicine, Inc. D.B. and G.P. colead the BayesMendel lab, which develops and maintains the BayesMendel software package. This includes a variety of risk assessment tools including BRCAPRO, PancPRO, MelaPRO, MMRpro, and PanelPRO and is licensed for commercial use. All licensing revenues are used for software maintenance and upgrades. Neither BayesMendel lab leaders nor members derive personal income from BayesMendel licenses. D.B. and G.P. are coinventor of the Ask2me tool, which is commercially licensed. D.B.’s conflicts of interest are managed by Harvard T.H. Chan School of Public Health. S.S. has been a consultant for Myriad Genetics, Inc and has rights to the inventor portion of licensing revenues for the PREMM model. Z.K.S.’s immediate family member serves as a consultant in Ophthalmology for Alcon, Adverum Biotechnologies, Gyroscope Therapeutics Limited, Neurogene Inc, and REGENXBIO Inc, outside the submitted work. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: Data on the occurrence times of multiple outcomes, reflecting the temporal profile of disease burden/progression, have been used to estimate treatment effects in various recent randomized trials. Most procedures for analyzing these data require specific model assumptions. When the assumptions are not met, the results may be misleading. Robust, model-free procedures for study design and analysis that enable clinically meaningful interpretations are warranted., Methods: For each treatment group, we constructed and summarized the estimated mean cumulative count of events over time by the area under the curve (AUC), which can be interpreted as the mean total event-free time lost from multiple undesirable outcomes. A higher curve, and resulting larger AUC, implies a worse treatment. The treatment effect is quantified by the ratio and/or difference of AUCs. The timing and occurrence of recurrent heart failure hospitalizations (HFHs) and cardiovascular (CV) death from Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF), comparing sacubitril/valsartan with valsartan, are presented for illustration. We also discuss the design of future studies on the basis of the proposed method., Results: With 48 months of follow-up, estimated AUCs, representing the total event-free time lost to HFHs and CV death, were 11.3 and 13.1 event-months for sacubitril/valsartan and valsartan, respectively. The ratio of these AUCs was 0.86 (95% confidence interval, 0.75 to 1.00; P=0.049), a 14% reduction of disease burden favoring combination therapy. A future study, similar to PARAGON-HF, designed using the new proposal would require fewer patients would than a conventional time-to-first-event analysis., Conclusions: The proposed method is robust and model-free and provides a clinically interpretable, time-scale summary of the treatment effect. (Funded by National Institutes of Health.).

Robust estimates of demographic parameters are critical for effective wildlife conservation and management but are difficult to obtain for elusive species. We estimated the breeding and adult population sizes, as well as the minimum population size, in a high-density brown bear population on the Shiretoko Peninsula, in Hokkaido, Japan, using DNA-based pedigree reconstruction. A total of 1288 individuals, collected in and around the Shiretoko Peninsula between 1998 and 2020, were genotyped at 21 microsatellite loci. Among them, 499 individuals were identified by intensive genetic sampling conducted in two consecutive years (2019 and 2020) mainly by noninvasive methods (e.g., hair and fecal DNA). Among them, both parents were assigned for 330 bears, and either maternity or paternity was assigned to 47 and 76 individuals, respectively. The subsequent pedigree reconstruction indicated a range of breeding and adult (≥4 years old) population sizes: 128-173 for female breeders and 66-91 male breeders, and 155-200 for female adults and 84-109 male adults. The minimum population size was estimated to be 449 (252 females and 197 males) in 2019. Long-term continuous genetic sampling prior to a short-term intensive survey would enable parentage to be identified in a population with a high probability, thus enabling reliable estimates of breeding population size for elusive species., Competing Interests: The authors declare no competing interests., (© 2022 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Importance: Medicare's Oncology Care Model (OCM) was an alternative payment model that tied performance-based payments to cost and quality goals for participating oncology practices. A major concern about the OCM regarded inclusion of high-cost cancer therapies, which could potentially disincentivize oncologists from prescribing novel therapies., Objective: To examine whether oncologist participation in the OCM changed the likelihood that patients received novel therapies vs alternative treatments., Design, Setting, and Participants: This cohort study of Surveillance, Epidemiology, and End Results (SEER) Program data and Medicare claims compared patient receipt of novel therapies for patients treated by oncologists participating vs not participating in the OCM in the period before (January 2015-June 2016) and after (July 2016-December 2018) OCM initiation. Participants included Medicare fee-for-service beneficiaries in SEER registries who were eligible to receive 1 of 10 novel cancer therapies that received US Food and Drug Administration approval in the 18 months before implementation of the OCM. The study excluded the Hawaii registry because complete data were not available at the time of the data request. Patients in the OCM vs non-OCM groups were matched on novel therapy cohort, outcome time period, and oncologist specialist status. Analysis was conducted between July 2021 and April 2022., Exposures: Oncologist participation in the OCM., Main Outcomes and Measures: Preplanned analyses evaluated patient receipt of 1 of 10 novel therapies vs alternative therapies specific to the patient's cancer for the overall study sample and for racial subgroups., Results: The study included 2839 matched patients (760 in the OCM group and 2079 in the non-OCM group; median [IQR] age, 72.7 [68.3-77.6] years; 1591 women [56.0%]). Among patients in the non-OCM group, 33.2% received novel therapies before and 40.1% received novel therapies after the start of the OCM vs 39.9% and 50.3% of patients in the OCM group (adjusted difference-in-differences, 3.5 percentage points; 95% CI, -3.7 to 10.7 percentage points; P = .34). In subgroup analyses, second-line immunotherapy use in lung cancer was greater among patients in the OCM group vs non-OCM group (adjusted difference-in-differences, 17.4 percentage points; 95% CI, 4.8-30.0 percentage points; P = .007), but no differences were seen in other subgroups. Over the entire study period, patients with oncologists participating in the OCM were more likely to receive novel therapies than those with oncologists who were not participating (odds ratio, 1.47; 95% CI, 1.09-1.97; P = .01)., Conclusions and Relevance: This study found that participation in the OCM was not associated with oncologists' prescribing novel therapies to Medicare beneficiaries with cancer. These findings suggest that OCM financial incentives did not decrease patient access to novel therapies.

Importance: Challenges in the therapeutic relationship between clinicians and parents of children with cancer have been shown to emerge immediately after diagnosis, but little is known about whether such relationships improve over time., Objective: To better understand the potential evolution of parent-clinician relationships over the first year after diagnosis of pediatric cancer., Design, Setting, and Participants: This survey study was conducted from November 2015 to September 2020 at Dana-Farber Cancer Institute/Boston Children's Hospital and Texas Children's Hospital. Participants were oncology clinicians (attending physicians and fellows or nurse practitioners) and parents of children (aged <18 years) with a cancer diagnosis. Surveys were completed at study enrollment (soon after diagnosis [baseline]) and at the 3-month and 12-month follow-up., Exposures: Children had to have had at least 3 previous clinical visits with a primary oncology clinician., Main Outcomes and Measures: Survey instruments included the parent and clinician versions of the Relationship Challenges Scale, and factors associated with changes in relationships, including parental, clinician, and health care system attributes, were measured., Results: Survey participants included 150 parents (118 women [78.7%]; 98 with White race and ethnicity [65.3%]) and 49 clinicians (39 [79.6%] women; 39 with White race and ethnicity [79.6%]). Parents reported on 175 relationships with clinicians, and clinicians reported on 98 relationships with parents at all 3 time points (baseline, 3-month follow-up, and 12-month follow-up). Of the 175 relationships, 33 (18.9%) were considered to be challenging by parents at baseline, 27 (15.4%) were considered to be challenging at the 3-month follow-up, and 32 (18.3%) were considered to be challenging at the 12-month follow-up. Of the 33 challenging relationships at baseline, 20 (60.6%) resolved at the 12-month follow-up, whereas 13 (39.4%) had persistent challenges. However, 19 relationships that were not challenging at baseline had new challenges at the 12-month follow-up, corresponding to 59.4% of all challenges at the 12-month follow-up. No clinician behaviors were associated with improvement. Strategies used frequently (≥50%) by clinicians in their relationships that were associated with improvement included holding family meetings, apologizing, adapting to the parent's communication style, and devoting extra time and attention., Conclusions and Relevance: Results of this study showed that some parents experienced challenging relationships with their child's oncology clinicians beginning at diagnosis and throughout the first year after diagnosis. Although many such relationships improved, others worsened, reflecting the vulnerable and stressful nature of parent-clinician relationships.

Mammals exhibit several types of diel activity pattern, including nocturnal, diurnal, crepuscular, and cathemeral. These patterns vary inter- and intra-specifically and are affected by environmental factors, individual status, and interactions with other individuals or species. Determining the factors that shape diel activity patterns is challenging but essential for understanding the behavioral ecology of animal species, and for wildlife conservation and management. Using camera-trap surveys, we investigated the species distributions and activity patterns of terrestrial mammals on the Shiretoko Peninsula, Hokkaido, Japan, with particular focus on brown bears and sika deer. From June to October 2019, a total of 7,530 observations were recorded by 65 camera-traps for eight species, including two alien species. The diel activity pattern of brown bears was diurnal/crepuscular, similar to that of bears in North America, but different from European populations. Bear observations were more frequent during the autumnal hyperphagia period, and adult females and sub-adults were more diurnal than adult males. In addition, bears inside the protected area were more diurnal than those outside it. These findings suggest that appetite motivation, competitive interactions between conspecifics, and human activities potentially affect bear activity patterns. Similar to other sika deer populations and other deer species, the diel activity patterns of sika deer were crepuscular. Deer showed less variation in activity patterns among months and sex-age classes, while adult males were observed more frequently during the autumn copulation period, suggesting that reproductive motivation affects their activity patterns.

Purpose: We examined radiation therapy (RT) use among patients with early-stage breast cancer and analyzed the contribution of patient, cancer, and regional factors to the likelihood of RT receipt across Health Service Areas., Methods and Materials: We identified 13,176 patients aged 66 to 79 years in the Surveillance, Epidemiology, and End Results (SEER) Program-Medicare database who were diagnosed with lymph node-negative breast cancer in 2007 to 2011 and were treated with breast-conserving surgery. Patients were stratified as being at high risk or low risk for recurrence based on National Comprehensive Cancer Network Guidelines. Receipt of RT was studied with 5 modeling approaches to determine whether RT use and regional variation in its use changed based on the risk level of the cohort. Multivariable mixed-effects logistic regression was performed for each outcome. Choropleth maps were used to describe patterns of RT use., Results: Among high-risk patients, 70.1% received RT, compared with 72.6% of low-risk patients ( P  = .002). Among patients receiving RT, 60.9% were classified as high-risk, compared with 63.0% of patients who did not receive RT ( P  = .002). In multivariable analyses, patients in all rural areas had lower odds of receiving RT compared with the entire cohort (odds ratio [OR], 0.73; P < .001) and had lower odds of being high-risk and receiving RT (OR, 0.69; P < .001). Black patients (OR, 0.73; P  = .001) and Asian patients (OR, 0.74; P  = .004) had decreased likelihood of receiving RT compared with the entire cohort. The regional interclass correlation coefficient (ICC) for the model predicting receipt of RT among all patients was 0.05 and among low-risk patients was 0.06. The regional ICC dropped to 0.02 for the model predicting being both high-risk and receiving RT among all patients., Conclusions: We observed regional and racial and ethnic disparities in RT receipt among our cohort. Reassuringly, less regional variability was observed for RT receipt among those at high risk for recurrence. Future work is needed to understand the causes of these regional disparities to better serve patients who may benefit from treatment., (© 2022 The Author(s).)

Large clinical datasets derived from insurance claims and electronic health record (EHR) systems are valuable sources for precision medicine research. These datasets can be used to develop models for personalized prediction of risk or treatment response. Efficiently deriving prediction models using real world data, however, faces practical and methodological challenges. Precise information on important clinical outcomes such as time to cancer progression are not readily available in these databases. The true clinical event times typically cannot be approximated well based on simple extracts of billing or procedure codes. Whereas, annotating event times manually is time and resource prohibitive. In this paper, we propose a two-step semi-supervised multi-modal automated time annotation (MATA) method leveraging multi-dimensional longitudinal EHR encounter records. In step I, we employ a functional principal component analysis approach to estimate the underlying intensity functions based on observed point processes from the unlabeled patients. In step II, we fit a penalized proportional odds model to the event time outcomes with features derived in step I in the labeled data where the non-parametric baseline function is approximated using B-splines. Under regularity conditions, the resulting estimator of the feature effect vector is shown as root-n consistent. We demonstrate the superiority of our approach relative to existing approaches through simulations and a real data example on annotating lung cancer recurrence in an EHR cohort of lung cancer patients from Veteran Health Administration., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Obesity is a significant contributor to breast cancer recurrence and mortality. A central mechanism by which obesity stimulates cancer progression is through chronic, low-grade inflammation in adipose tissue. Exercise interventions to target chronic inflammation has a potential to improve obesity- and breast cancer-related outcomes; however, no studies have investigated the roles of exercise in modulating adipose tissue inflammation in breast cancer survivors. Also, it is unclear which exercise prescription would be optimal to maximize the outcomes. Therefore, we designed a randomized controlled trial (Taking AIM at Breast Cancer: Targeting Adiposity and Inflammation with Movement to Improve Prognosis in Breast Cancer Survivors [AIM] Trial) to examine the mechanisms by which different modalities of exercise impact chronic inflammation as a biomarker of breast cancer prognosis., Methods: The AIM trial is a prospective, three-armed, phase II randomized controlled trial investigating the effects of a 16-week supervised circuit aerobic and resistance exercise (CARE) program versus a traditional aerobic and resistance exercise (TARE) program and attention control (AC) on adipose tissue inflammation in breast cancer survivors. 276 patients who are diagnosed with stage 0-III breast cancer, post-treatment, sedentary, and centrally obese are randomized to one of the three groups. The CARE and TARE groups participate in thrice-weekly supervised exercise sessions for 16 weeks. The AC group are offered the CARE program after the intervention period. The primary endpoint is adipose tissue inflammation assessed by core biopsy and blood draw. The secondary and tertiary endpoints are sarcopenic obesity, physical fitness and function, and patient reported outcomes. The exploratory outcomes are long-term breast cancer outcomes., Discussion: This is the first randomized controlled trial examining the effects of exercise on adipose tissue inflammation in obese, breast cancer survivors. Our findings are anticipated to contribute to a better understanding of exercise modalities and mechanisms on adipose tissue inflammation that can potentially improve breast cancer prognosis., Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03091842 identifier [NCT#03091842]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kang, Wilson, Gonzalo-Encabo, Norris, Hans, Tahbaz, Dawson, Nguyen, Normann, Yunker, Sami, Uno, Ligibel, Mittelman and Dieli-Conwright.)

Background: Many cancer patients experience high symptom burden. Healthcare in the USA is reactive, not proactive, and doctor-patient communication is often suboptimal. As a result, symptomatic patients may suffer between clinic visits. In research settings, systematic assessment of electronic patient-reported outcomes (ePROs), coupled with clinical responses to severe symptoms, has eased this symptom burden, improved health-related quality of life, reduced acute care needs, and extended survival. Implementing ePRO-based symptom management programs in routine care is challenging. To study methods to overcome the implementation gap and improve symptom control for cancer patients, the National Cancer Institute created the Cancer-Moonshot funded Improving the Management of symPtoms during And following Cancer Treatment (IMPACT) Consortium., Methods: Symptom Management IMplementation of Patient Reported Outcomes in Oncology (SIMPRO) is one of three research centers that make up the IMPACT Consortium. SIMPRO, a multi-disciplinary team of investigators from six US health systems, seeks to develop, test, and integrate an electronic symptom management program (eSyM) for medical oncology and surgery patients into the Epic electronic health record (EHR) system and associated patient portal. eSyM supports real-time symptom tracking for patients, automated clinician alerts for severe symptoms, and specialized reports to facilitate population management. To rigorously evaluate its impact, eSyM is deployed through a pragmatic stepped wedge cluster-randomized trial. The primary study outcome is the occurrence of an emergency department treat-and-release event within 30 days of starting chemotherapy or being discharged following surgery. Secondary outcomes include hospitalization rates, chemotherapy use (time to initiation and duration of therapy), and patient quality of life and satisfaction. As a type II hybrid effectiveness-implementation study, facilitators and barriers to implementation are assessed throughout the project., Discussion: Creating and deploying eSyM requires collaboration between dozens of staff across diverse health systems, dedicated engagement of patient advocates, and robust support from Epic. This trial will evaluate eSyM in routine care settings across academic and community-based healthcare systems serving patients in rural and metropolitan locations. This trial's pragmatic design will promote generalizable results about the uptake, acceptability, and impact of an EHR-integrated, ePRO-based symptom management program., Trial Registration: ClinicalTrials.gov NCT03850912 . Registered on February 22, 2019. Last updated on November 9, 2021., (© 2022. The Author(s).)

gem-Difluoromethylene moieties are attractive in medicinal chemistry due to their ability to mimic other more ubiquitous functional groups. Thus, effective asymmetric methods for their construction are highly desirable, especially for the industrial production of chiral drugs. Using a Pd-catalyzed asymmetric [4+2] cycloaddition between substituted-2-alkylidenetrimethylene carbonates and gem-difluoroalkyl ketones, we were able to easily access chiral 1,3-dioxanes that contain a tetrasubstituted difluoroalkyl stereogenic center in cyclic and acyclic skeletons. A novel phosphoramidite ligand, which contains a bulky 1,1-dinaphthylmethanamino moiety, was developed to provide the products in high yield with excellent enantio-, diastereo-, and regioselectivity. Strikingly, the gem-difluoro substitution pattern promotes the reaction, and pentafluoroethylketone, an α,α-difluorinated β-ketoester, and a β-ketosulfone are suitable substrates for this method., (© 2022 Wiley-VCH GmbH.)

Background: Latina and Hispanic breast cancer survivors (LHBCS) are at increased risk for long-term complications and poorer metabolic health, including metabolic dysregulation (MetD) before and following breast cancer diagnosis. MetD can increase risk of cancer recurrence, death, and comorbid conditions by increasing inflammation and cancer cell proliferation. While exercise improves physical fitness and metabolic outcomes in breast cancer survivors, there is a lack of studies including underrepresented and disadvantaged minority groups such as LHBCS., Methods: Our 12-month randomized (exercise or attention control) controlled trial (the ROSA trial) aims to utilize a progressive combined aerobic and resistance exercise program to improve MetD, insulin resistance, and visceral adiposity among obese LHBCS. We aim to recruit 160 women with Stage I-III breast cancer who are sedentary, centrally obese, and have completed treatment (e.g., surgery, radiation, chemotherapy) prior to enrollment. Participants randomized to the exercise group receive 16-weeks of virtually supervised aerobic and resistance training, followed by 16-weeks of unsupervised home-based aerobic and resistance exercise, and 16-weeks of follow-up. The attention control group receive a 12-month home-based stretching program. Primary and secondary outcomes are measured every 4-weeks during study visits., Discussion: The ROSA trial is the first exercise oncology trial targeting high-risk sedentary, obese LHBCS to improve MetD-related outcomes. Results of this trial will help illuminate how exercise impacts health-related outcomes, survivorship, and recurrence, and inform future exercise oncology guidelines to reduce health disparities among minority cancer survivors., Competing Interests: Author FF was employed by the company Gerson Lehrman Group, LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gonzalo-Encabo, Wilson, Kang, Norris, Uno, Christopher, Chow, Sami, Fox, Ligibel and Dieli-Conwright.)

We conducted a randomized controlled trial in older adults with hematologic malignancies to determine the impact of geriatrician consultation embedded in our oncology clinic alongside standard care. From February 2015 to May 2018, transplant-ineligible patients aged ≥75 years who presented for initial consultation for lymphoma, leukemia, or multiple myeloma at Dana-Farber Cancer Institute (Boston, MA, USA) were eligible. Pre-frail and frail patients, classified based on phenotypic and deficit-accumulation approaches, were randomized to receive either standard oncologic care with or without consultation with a geriatrician. The primary outcome was 1-year overall survival. Secondary outcomes included unplanned care utilization within 6 months of follow-up and documented end-of-life (EOL) goals-of-care discussions. Clinicians were surveyed as to their impressions of geriatric consultation. One hundred sixty patients were randomized to either geriatric consultation plus standard care (n=60) or standard care alone (n=100). The median age of the patients was 80.4 years (standard deviation = 4.2). Of those randomized to geriatric consultation, 48 (80%) completed at least one visit with a geriatrician. Consultation did not improve survival at 1 year compared to standard care (difference: 2.9%, 95% confidence interval: -9.5% to 15.2%, P=0.65), and did not significantly reduce the incidence of emergency department visits, hospital admissions, or days in hospital. Consultation did improve the odds of having EOL goals-of-care discussions (odds ratio = 3.12, 95% confidence interval: 1.03 to 9.41) and was valued by surveyed hematologic-oncology clinicians, with 62.9%-88.2% of them rating consultation as useful in the management of several geriatric domains.

Tropo(thio)ne-embedded homoHPHACs and their dications were synthesised by an electrophilic annulation of secoHPHAC and successive oxidation. 13 C NMR spectra of the dications represented global 22π homoaromaticity via homoconjugation, while alkylation of a thiocarbonyl-bridged homoHPHAC produced a 24π antiaromatic monocation.

Importance: Patient factors help explain disparities in breast cancer treatments and outcomes., Objective: To determine the extent to which geospatial variation in initial breast cancer care can be attributed to region vs patient factors with the aim of guiding quality improvement efforts., Design, Setting, and Participants: This was a retrospective population-based cohort study from January 1, 2007, through December 31, 2016, using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database that included 31 571 patients diagnosed with stage I to III breast cancer from 2007 through 2013. Five metrics of care delivery were defined: stage I at diagnosis, chemotherapy receipt, radiation therapy receipt, endocrine therapy (ET) initiation (year 1), and ET continuation (years 3-5). Data analysis was performed from January to June 2021., Exposures: Stage I diagnosis and treatment with chemotherapy, radiation therapy, or ET., Main Outcomes and Measures: For each metric, total variance was attributed proportionally to 4 domains-random, patient factors (eg, age, race and ethnicity, socioeconomic status), region (health service area [HSA]), and unexplained-using hierarchical multivariable modeling., Results: Of 31 571 total patients (median [IQR] age, 71 [68-75] years), 19 391 (61.4%) had stage I disease at diagnosis. Among eligible patients, 17 297 of 21 190 (81.6%) received radiation therapy, 7204 of 9903 (72.8%) received chemotherapy, 13 115 of 26 855 (48.8%) initiated ET, and 13 944 of 26 855 (52.1%) continued ET. Geospatial density (ie, heat) maps highlight regional performance patterns. For all 5 metrics, region/HSA explained more observed variation (24%-48%) than patient factors (1%-4%); the largest share of variation was unexplained (35%-54%). The metrics with the largest proportion of total variance attributed to region/HSA were ET initiation and continuation (28% and 39%, respectively)., Conclusions and Relevance: In this cohort study, there was substantial unexplained geospatial variation in initial breast cancer care. The variance attributed to region/HSA was multifold larger than that explained by patient factors. The importance of patient factors such as race and ethnicity notwithstanding, future quality improvement efforts should focus on reducing unwarranted geospatial variation, especially including optimizing the delivery of ET in low-performing regions.

Identifying appropriate indicator species for the impact of deer on forest vegetation is crucial for forest management in deer habitats and is required to be sensitive to temporal and spatial variations in deer density. Dryopteris crassirhizoma was selected as a new indicator to evaluate the response to these variations. We examined the population-level characteristics, morphological characteristics at the individual level, and grazing intensity of D. crassirhizoma at temporally different deer density sites in Hokkaido, Japan. The response of D. crassirhizoma to spatial variation in deer density was also examined within and between two regions in Hokkaido, Japan. Although the population-level characteristics and morphological characteristics did not significantly respond to short-term decreases in deer density, grazing intensity significantly decreased with decreasing deer density. The grazing intensity was also positively related to the spatial variation of deer density within both regions, but the estimated coefficient of the grazing intensity differed between regions. We concluded that D. crassirhizoma can be a useful indicator species of the impact of deer on forest vegetation. The grazing intensity of the indicator species was sensitive to temporal and spatial variations in deer density within the region.

DNA microarrays are useful to detect microorganisms for various purposes including clinical testing and food safety. However, conventional DNA microarrays need complicated operations such as amplification, fluorescence labeling, and washing steps. To address this issue, we previously developed the signaling probe-based DNA microarray system that can eliminate these steps, and demonstrated a direct detection of bacterial genes. Nonetheless, this system requires well-designed probe sets due to the fluorescence resonance energy transfer (FRET)-based mode of action. Up to date, the probe design was highly dependent on the trial-and-error processes. In this study, we propose a strategy to rationally design the sequences of signaling probes based on the thermodynamic analysis. This analysis aided to improve the probe performance approximately 2.8 times, without experiments, by suppressing the secondary structure formation of the probes. We successfully demonstrated the specific and amplification-free detection of 5S rRNA from total RNA extracted from Escherichia coli within 30 min., (Copyright © 2021 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)