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Belt electrode-skeletal muscle electrical stimulation (B-SES) involves the use of belt-shaped electrodes to contract multiple muscle groups simultaneously. Twitch contractions have been demonstrated to protect against denervation-induced muscle atrophy in rats, possibly through mitochondrial biosynthesis. This study examined whether inducing tetanus contractions with B-SES suppresses muscle atrophy and identified the underlying molecular mechanisms. We evaluated the effects of acute (60 Hz, 5 min) and chronic (60 Hz, 5 min, every alternate day for one week) B-SES on the tibialis anterior (TA) and gastrocnemius (GAS) muscles in Sprague-Dawley rats using belt electrodes attached to both ankle joints. After acute stimulation, a significant decrease in the glycogen content was observed in the left and right TA and GAS, suggesting that B-SES causes simultaneous contractions in multiple muscle groups. B-SES enhanced p70S6K phosphorylation, an indicator of the mechanistic target of rapamycin complex 1 activity. During chronic stimulations, rats were divided into control (CONT), denervation-induced atrophy (DEN), and DEN + electrically stimulated with B-SES (DEN + ES) groups. After seven days of treatment, the wet weight (n = 8-11 for each group) and muscle fiber cross-sectional area (CSA, n = 6 for each group) of the TA and GAS muscles were reduced in the DEN and DEN + ES groups compared with that in the CON group. The DEN + ES group showed significantly higher muscle weight and CSA than those in the DEN group. Although RNA-seq and pathway analysis suggested that mitochondrial biogenesis is a critical event in this phenomenon, mitochondrial content showed no difference. In contrast, ribosomal RNA 28S and 18S (n = 6) levels in the DEN + ES group were higher than those in the DEN group, even though RNA-seq showed that the ribosome biogenesis pathway was reduced by electrical stimulation. The mRNA levels of the muscle proteolytic molecules atrogin-1 and MuRF1 were significantly higher in DEN than those in CONT. However, they were more suppressed in DEN + ES than those in DEN. In conclusion, tetanic electrical stimulation of both ankles using belt electrodes effectively reduced denervation-induced atrophy in multiple muscle groups. Furthermore, ribosomal biosynthesis plays a vital role in this phenomenon., (© 2024. The Author(s).)

Importance: Postmastectomy radiation therapy (PMRT) improves local-regional disease control and patient survival. Hypofractionation (HF) regimens have comparable efficacy and complication rates with improved quality of life compared with conventional fractionation (CF) schedules. However, the use of HF after mastectomy in patients undergoing breast reconstruction has not been prospectively examined., Objective: To compare HF and CF PMRT outcomes after implant-based reconstruction., Design, Setting, and Participants: This randomized clinical trial assessed patients 18 years or older undergoing mastectomy and immediate expander or implant reconstruction for breast cancer (Tis, TX, or T1-3) and unilateral PMRT from March 8, 2018, to November 3, 2021 (median [range] follow-up, 40.4 [15.4-63.0] months), at 16 US cancer centers or hospitals. Analyses were conducted between September and December 2023., Interventions: Patients were randomized 1:1 to HF or CF PMRT. Chest wall doses were 4256 cGy for 16 fractions for HF and 5000 cGy for 25 fractions for CF. Chest wall toxic effects were defined as a grade 3 or higher adverse event., Main Outcomes and Measures: The primary outcome was the change in physical well-being (PWB) domain of the Functional Assessment of Cancer Therapy-Breast (FACT-B) quality-of-life assessment tool at 6 months after starting PMRT, controlling for age. Secondary outcomes included toxic effects and cancer recurrence., Results: Of 400 women (201 in the CF arm and 199 in the HF arm; median [range] age, 47 [23-79] years), 330 patients had PWB scores at baseline and at 6 months. There was no difference in the change in PWB between the study arms (estimate, 0.13; 95% CI, -0.86 to 1.11; P = .80), but there was a significant interaction between age group and study arm (P = .03 for interaction). Patients younger than 45 years had higher 6-month absolute PWB scores if treated with HF rather than CF regimens (23.6 [95% CI, 22.7-24.6] vs 22.0 [95% CI, 20.7-23.3]; P = .047) and reported being less bothered by adverse effects (mean [SD], 3.0 [0.9] in the HF arm and 2.6 [1.2] in the CF arm; P = .02) or nausea (mean [SD], 3.8 [0.4] in the HF arm and 3.6 [0.8] in the CF arm; P = .04). In the as-treated cohort, there were 23 distant (11 in the HF arm and 12 in the CF arm) and 2 local-regional (1 in the HF arm and 1 in the CF arm) recurrences. Chest wall toxic effects occurred in 39 patients (20 in the HF arm and 19 in the CF arm) at a median (IQR) of 7.2 (1.8-12.9) months. Fractionation was not associated with chest wall toxic effects on multivariate analysis (HF arm: hazard ratio, 1.02; 95% CI, 0.52-2.00; P = .95). Fewer patients undergoing HF vs CF regimens had a treatment break (5 [2.7%] vs 15 [7.7%]; P = .03) or required unpaid time off from work (17 [8.5%] vs 34 [16.9%]; P = .02)., Conclusions and Relevance: In this randomized clinical trial, the HF regimen did not significantly improve change in PWB compared with the CF regimen. These data add to the increasing experience with HF PMRT in patients with implant-based reconstruction., Trial Registration: ClinicalTrials.gov Identifier: NCT03422003.

Duration of response is an important endpoint used in drug development. Prolonged duration for response is often viewed as an early indication of treatment efficacy. However, there are numerous difficulties in studying the distribution of duration of response based on observed data subject to right censoring in practice. The most important obstacle is that the distribution of the duration of response is in general not identifiable in the presence of censoring due to the simple fact that there is no information on the joint distribution of time to response and time to progression beyond the largest follow-up time. In this article, we introduce the restricted duration of response as a replacement of the conventional duration of response. The distribution of restricted duration of response is estimable and we have proposed several nonparametric estimators in this article. The corresponding inference procedure and additional downstream analysis have been developed. Extensive numerical simulations have been conducted to examine the finite sample performance of the proposed estimators. It appears that a new regression-based two-step estimator for the survival function of the restricted duration of response tends to have a robust and superior performance, and we recommend its use in practice. A real data example from oncology has been used to illustrate the analysis for restricted duration of response., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Biomarker-driven trials are key for precision oncology but challenge design and analysis.

Background: Clinical trial participation at Comprehensive Cancer Centers (CCC) is inequitable for minoritized racial and ethnic groups with acute leukemia. CCCs care for a high proportion of adults with acute leukemia. It is unclear if participation inequities are due to CCC access, post-access enrollment, or both., Methods: We conducted a retrospective cohort study of adults with acute leukemia (2010-2019) residing within Massachusetts, the designated catchment area of the Dana-Farber/Harvard Cancer Center (DF/HCC). Individuals were categorized as non-Hispanic Asian (NHA), Black (NHB), White (NHW), Hispanic White (HW), or Other. Decomposition analyses assessed covariate contributions to disparities in (1) access to DF/HCC care and (2) post-access enrollment., Results: Of 3698 individuals with acute leukemia, 85.9% were NHW, 4.5% HW, 4.3% NHB, 3.7% NHA, and 1.3% Other. Access was lower for HW (age- and sex-adjusted OR = 0.64, 95% CI = 0.45 to 0.90) and reduced post-access enrollment for HW (aOR = 0.54, 95% CI =0.34 to 0.86) and NHB (aOR = 0.60, 95% CI = 0.39 to 0.92) compared to NHW. Payor and socioeconomic status (SES) accounted for 25.2% and 21.2% of the +1.1% absolute difference in HW access. Marital status and SES accounted for 8.0% and 7.0% of the -8.8% absolute disparity in HW enrollment; 76.4% of the disparity was unexplained. SES and marital status accounted for 8.2% and 7.1% of the -9.1% absolute disparity in NHB enrollment; 73.0% of the disparity was unexplained., Conclusions: A substantial proportion of racial and ethnic inequities in acute leukemia trial enrollment at CCCs are from post-access enrollment, the majority of which was not explained by sociodemographic factors., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Optimal methods for deploying electronic patient-reported outcomes to manage symptoms in routine oncologic practice remain uncertain. The electronic symptom management (eSyM) program asks chemotherapy and surgery patients to self-report 12 common symptoms regularly. Feedback from nurses and patients led to changing the recall period from the past 7 days to the past 24 hours., Methods: Using questionnaires submitted during the 16 weeks surrounding the recall period change, we assessed the likelihood of reporting severe or moderate and severe symptoms across 12 common symptoms and separately for the 5 most prevalent symptoms. Interrupted time-series analyses modeled the effects of the change using generalized linear mixed-effects models. Surgery and chemotherapy cohorts were analyzed separately. Study-wide effects were estimated using a meta-analysis method., Results: In total, 1692 patients from 6 institutions submitted 7823 eSyM assessments during the 16 weeks surrounding the recall period change. Shortening the recall period was associated with lower odds of severe symptom reporting in the surgery cohort (odds ratio = 0.65, 95% confidence interval = 0.46 to 0.93; P = .02) and lower odds of moderate and severe symptom reporting in the chemotherapy cohort (odds ratio = 0.83, 95% confidence interval = 0.71 to 0.97; P = .02). Among the most prevalent symptoms, 24-hour recall was associated with a lower rate of reporting postoperative constipation but no differences in reporting rates for other symptoms., Conclusion: A shorter recall period was associated with a reduction in the proportion of patients reporting moderate-severe symptoms. The optimal recall period may vary depending on whether electronic patient-reported outcomes are collected for active symptom management, as a clinical trial endpoint, or another purpose. ClinicalTrials.gov ID NCT03850912., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Adolescents and young adults frequently receive chemotherapy near death. We know less about the use of targeted agents and immunotherapy or trends over time., Methods: We conducted a retrospective cohort study of 1836 adolescents and young adults with cancer who died between 2009 and 2019 after receiving care at 1 of 3 sites (Dana-Farber Cancer Institute, Kaiser Permanente Northern California, and Kaiser Permanente Southern California). We reviewed electronic health data and medical records to examine use of cancer-directed therapy in the last 90 days of life, including chemotherapy, targeted therapy, immunotherapy, and investigational drugs., Results: Over the study period, 35% of adolescents and young adults received chemotherapy in the last 90 days of life; 24% received targeted therapy, 7% immunotherapy, and 5% investigational drugs. Additionally, 56% received at least 1 form of systemic cancer-directed therapy in the last 90 days of life. After adjustment for patient sex, race, ethnicity, age, site of care, diagnosis, and years from diagnosis to death, the proportion of adolescents and young adults receiving targeted therapy (odds ratio [OR] = 1.05 per year of death, 95% confidence interval [CI] = 1.02 to 1.10; P = .006), immunotherapy (OR = 1.27, 95% CI = 1.18 to 1.38; P < .0001), and any cancer-directed therapy (OR = 1.04, 95% CI = 1.01 to 1.08; P = .01) in the last 90 days of life increased over time., Conclusions: More than half of adolescents and young adults receive cancer therapy in the last 90 days of life, and use of novel agents such as targeted therapy and immunotherapy is increasing over time. Although some adolescents and young adults may wish to continue cancer therapy while living with advanced disease, efforts are needed to ensure that use of cancer-directed therapy meets preferences of adolescents and young adults approaching death., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Bone fractures represent a common health problem, particularly in an increasingly aging population. Bioresorbable magnesium (Mg) alloy-based implants offer promising alternatives to traditional metallic implants for the treatment of bone fractures because they eliminate the need for implant removal after healing. The Mg-Y-rare-earth (RE)-Zr alloy WE43, designed for orthopedic implants, has received European Conformity mark approval. However, currently, WE43 is not clinically used in certain countries possibly because of concerns related to RE metals. In this study, we investigated the use of a RE-free alloy, namely, Mg-Zn-Zr alloy (ZK30), as an implant for bone fractures. Hydrofluoric acid (HF) treatment was performed to improve the corrosion resistance of ZK30. HF-treated ZK30 (HF-ZK30) exhibited lower corrosion rate and higher biocompatibility than those of WE43 in in vitro experiments. After implanting a rod of HF-ZK30 into the fractured femoral bones of mice, HF-ZK30 held the bones and healed the fracture without deformation. Treatment results of HF-ZK30 were comparable to those of WE43, indicating the potential of HF-ZK30 as a bioresorbable and safe implant for bone repair., (© 2024 The Authors. Journal of Biomedical Materials Research Part A published by Wiley Periodicals LLC.)

Importance: Greenhouse gas (GHG) emissions from health care are substantial and disproportionately harm persons with cancer. Emissions from a central component of oncology care, outpatient clinician visits, are not well described, nor are the reductions in emissions and human harms that could be obtained through decentralizing this aspect of cancer care (ie, telemedicine and local clinician care when possible)., Objective: To assess potential reductions in GHG emissions and downstream health harms associated with telemedicine and fully decentralized cancer care., Design, Setting, and Participants: This population-based cohort study and counterfactual analyses using life cycle assessment methods analyzed persons receiving cancer care at Dana-Farber Cancer Institute between May 2015 and December 2020 as well as persons diagnosed with cancer over the same period from the Cancer in North America (CiNA) public dataset. Data were analyzed from October 2023 to April 2024., Main Outcomes and Measures: The adjusted per-visit day difference in GHG emissions in kilograms of carbon dioxide (CO2) equivalents between 2 periods: an in-person care model period (May 2015 to February 2020; preperiod) and a telemedicine period (March to December 2020; postperiod), and the annual decrease in disability-adjusted life-years in a counterfactual model where care during the preperiod was maximally decentralized nationwide., Results: Of 123 890 included patients, 73 988 (59.7%) were female, and the median (IQR) age at first diagnosis was 59 (48-68) years. Patients were seen over 1.6 million visit days. In mixed-effects log-linear regression, the mean absolute reduction in per-visit day CO2 equivalent emissions between the preperiod and postperiod was 36.4 kg (95% CI, 36.2-36.6), a reduction of 81.3% (95% CI, 80.8-81.7) compared with the baseline model. In a counterfactual decentralized care model of the preperiod, there was a relative emissions reduction of 33.1% (95% CI, 32.9-33.3). When demographically matched to 10.3 million persons in the CiNA dataset, decentralized care would have reduced national emissions by 75.3 million kg of CO2 equivalents annually; this corresponded to an estimated annual reduction of 15.0 to 47.7 disability-adjusted life-years., Conclusions and Relevance: This cohort study found that using decentralization through telemedicine and local care may substantially reduce cancer care's GHG emissions; this corresponds to small reductions in human mortality.

Background & Aims: Genetic testing uptake for cancer susceptibility in family members of patients with cancer is suboptimal. Among relatives of patients with pancreatic ductal adenocarcinoma (PDAC), The GENetic Education, Risk Assessment, and TEsting (GENERATE) study evaluated 2 online genetic education/testing delivery models and their impact on patient-reported psychological outcomes., Methods: Eligible participants had ≥1 first-degree relative with PDAC, or ≥1 first-/second-degree relative with PDAC with a known pathogenic germline variant in 1 of 13 PDAC predisposition genes. Participants were randomized by family, between May 8, 2019, and June 1, 2021. Arm 1 participants underwent a remote interactive telemedicine session and online genetic education. Arm 2 participants were offered online genetic education only. All participants were offered germline testing. The primary outcome was genetic testing uptake, compared by permutation tests and mixed-effects logistic regression models. We hypothesized that Arm 1 participants would have a higher genetic testing uptake than Arm 2. Validated surveys were administered to assess patient-reported anxiety, depression, and cancer worry at baseline and 3 months postintervention., Results: A total of 424 families were randomized, including 601 participants (n = 296 Arm 1; n = 305 Arm 2), 90% of whom completed genetic testing (Arm 1 [87%]; Arm 2 [93%], P = .014). Arm 1 participants were significantly less likely to complete genetic testing compared with Arm 2 participants (adjusted ratio [Arm1/Arm2] 0.90, 95% confidence interval 0.78-0.98). Among participants who completed patient-reported psychological outcomes questionnaires (Arm 1 [n = 194]; Arm 2 [n = 206]), the intervention did not affect mean anxiety, depression, or cancer worry scores., Conclusions: Remote genetic education and testing can be a successful and complementary option for delivering genetics care. (Clinicaltrials.gov, number NCT03762590)., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Limitations of using the traditional Cox's hazard ratio for summarizing the magnitude of the treatment effect on time-to-event outcomes have been widely discussed, and alternative measures that do not have such limitations are gaining attention. One of the alternative methods recently proposed, in a simple 2-sample comparison setting, uses the average hazard with survival weight (AH), which can be interpreted as the general censoring-free person-time incidence rate on a given time window. In this paper, we propose a new regression analysis approach for the AH with a truncation time τ. We investigate 3 versions of AH regression analysis, assuming (1) independent censoring, (2) group-specific censoring, and (3) covariate-dependent censoring. The proposed AH regression methods are closely related to robust Poisson regression. While the new approach needs to require a truncation time τ explicitly, it can be more robust than Poisson regression in the presence of censoring. With the AH regression approach, one can summarize the between-group treatment difference in both absolute difference and relative terms, adjusting for covariates that are associated with the outcome. This property will increase the likelihood that the treatment effect magnitude is correctly interpreted. The AH regression approach can be a useful alternative to the traditional Cox's hazard ratio approach for estimating and reporting the magnitude of the treatment effect on time-to-event outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Biometric Society.)

Current algorithms for diagnosing Lynch syndrome (LS) include multistep molecular tumor tests to distinguish LS-associated from sporadic colorectal cancer (CRC), which add cost and complexity to the evaluation. We hypothesized that PREMM5, a clinical LS prediction tool, could be an alternative approach to screen for LS, thereby lessening the need for specialized molecular diagnostics. We reviewed a consecutively ascertained institutional cohort of 1058 CRC patients on whom pathologic and clinical data were available, including prior LS germline testing. Data from MMR-D/MSI-H CRC patients were reviewed and PREMM5 scores were calculated for each individual. Using a PREMM5 score cutoff ≥ 2.5% to characterize the need for germline testing, we determined the rate of pathogenic/likely pathogenic germline variants (PGVs) in LS genes in patients with PREMM5 scores ≥ 2.5% versus < 2.5%. Sensitivity and negative predictive values (NPV) of PREMM5 were calculated for all MMR-D/MSI-H CRC patients, and those with MLH1-deficient CRC. MMR IHC and/or MSI results were available on 572/1058 cases. We identified 74/572 (12.9%) cases as MMR-D/MSI-H, of which 28/74 (37.8%) harbored a LS PGV. 11/49 (22.4%) patients with MLH1-deficient CRC harbored a LS PGV. PREMM5 had 100% sensitivity (95% CI: 87.7-100 for any MMR-D/MSI-H; 95% CI: 71.5-100 for MLH1-deficient CRC) and 100% NPV (95% CI: 83.2-100 for any MMR-D/MSI-H; 95% CI: 82.4-100 for MLH1-deficient CRC) for identifying LS PGVs in these cohorts. PREMM5 accurately distinguishes LS- from non-LS-associated MMR-D/MSI-H CRC without additional somatic molecular testing. These findings are particularly relevant for limited-resource settings where advanced molecular diagnostics may be unavailable., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

The pattern of the difference between two survival curves we often observe in randomized clinical trials for evaluating immunotherapy is not proportional hazards; the treatment effect typically appears several months after the initiation of the treatment (ie, delayed difference pattern). The commonly used logrank test and hazard ratio estimation approach will be suboptimal concerning testing and estimation for those trials. The long-term restricted mean survival time (LT-RMST) approach is a promising alternative for detecting the treatment effect that potentially appears later in the study. A challenge in employing the LT-RMST approach is that it must specify a lower end of the time window in addition to a truncation time point that the RMST requires. There are several investigations and suggestions regarding the choice of the truncation time point for the RMST. However, little has been investigated to address the choice of the lower end of the time window. In this paper, we propose a flexible LT-RMST-based test/estimation approach that does not require users to specify a lower end of the time window. Numerical studies demonstrated that the potential power loss by adopting this flexibility was minimal, compared to the standard LT-RMST approach using a prespecified lower end of the time window. The proposed method is flexible and can offer higher power than the RMST-based approach when the delayed treatment effect is expected. Also, it provides a robust estimate of the magnitude of the treatment effect and its confidence interval that corresponds to the test result., (© 2023 John Wiley & Sons Ltd.)

The hazard ratio (HR) has been the most popular measure to quantify the magnitude of treatment effect on time-to-event outcomes in clinical research. However, the traditional Cox's HR approach has several drawbacks. One major issue is that there is no clear interpretation when the proportional hazards (PH) assumption does not hold, because the estimated HR is affected by study-specific censoring time distribution in non-PH cases. Another major issue is that the lack of a group-specific absolute hazard value in each group obscures the clinical significance of the magnitude of the treatment effect. Given these, we propose average hazard with survival weight (AH-SW) as a summary metric of event time distribution and will use difference in AH-SW (DAH-SW) or ratio of AH-SW (RAH-SW) to quantify the treatment effect magnitude. The AH-SW is interpreted as a person-time incidence rate that does not depend on random censoring. It is defined as the ratio of cumulative incidence probability and restricted mean survival time (RMST), which can be estimated non-parametrically. Numerical studies demonstrate that DAH-SW and RAH-SW offer almost identical power to Cox's HR-based tests under PH scenarios and can be more powerful for delayed-difference patterns often seen in immunotherapy trials. Like median and RMST differences, the proposed approach is a good model-free alternative to the HR-based approach for evaluating the treatment effect magnitude. Such a model-free measure will increase the likelihood that results from clinical studies are correctly interpreted and generalized to future populations., (© 2023 John Wiley & Sons Ltd.)

Adolescents, young adults with cancer receive limited psychosocial and spiritual support near death.

The cell cycle dependence of radiosensitivity has yet to be fully determined, as it is technically difficult to achieve a high degree of cell cycle synchronization in cultured cell systems and accurately detect the cell cycle phase of individual cells simultaneously. We used human cervical carcinoma HeLa cells expressing fluorescent ubiquitination-based cell cycle indicators (FUCCI), and employed the mitotic harvesting method that is one of the cell cycle synchronization methods. The imaging analysis confirmed that the cell cycle is highly synchronized after mitotic cell harvesting until 18-20 h of the doubling time has elapsed. Also, flow cytometry analysis revealed that the S and G2 phases peak at approximately 12 and 14-16 h, respectively, after mitotic harvesting. In addition, the clonogenic assay showed the changes in surviving fractions following exposure to X-rays according to the progress through the cell cycle. These results indicate that HeLa-FUCCI cells become radioresistant in the G1 phase, become radiosensitive in the early S phase, rapidly become radioresistant in the late S phase, and become radiosensitive again in the G2 phase. Our findings may contribute to the further development of combinations of radiation and cell cycle-specific anticancer agents.

Inequitable uptake of novel therapies (NT) in non-cancer settings are known for patients with lower socioeconomic status (SES), People of Color (POC), and older adults. NT uptake equity in acute myeloid leukemia (AML) is not well known. We performed a retrospective cohort study (1/2014-8/2022) of the United States nationwide Flatiron Health TM electronic health record-derived, de-identified database. We estimated sociodemographic associations with AML NT receipt using incidence rate ratios (IRR). Odds ratios (OR) assessed differences in venetoclax (the most common NT) receipt at community sites and between site characteristics and NT adoption. Of 8081 patients (139 sites), 3102 (38%) received a NT. NT use increased annually (IRR 1.14, 95% confidence interval [1.07, 1.22]). NT receipt was similar between Non-Hispanic-Whites and POC (IRR 1.03, [0.91, 1.17]) and as age increased (IRR 1.02 [0.97, 1.07]). At community sites, Non-Hispanic-Whites were less likely to receive venetoclax (OR 0.77 [0.66, 0.91]); older age (OR 1.05 [1.04, 1.05]) and higher area-level SES were associated with venetoclax receipt (OR 1.23 [1.05, 1.43]). Early NT adopting sites had more prescribing physicians (OR 1.25 [1.13, 1.43]) and higher SES strata patients (OR 2.81 [1.08, 7.66]). Inequities in AML NT uptake were seen by SES; for venetoclax, differential uptake reflects its label indication for older adults and those with comorbidities., (© 2023. The Author(s).)

The hazard ratio (HR) remains the most frequently employed metric in assessing treatment effects on survival times. However, the difference in restricted mean survival time (RMST) has become a popular alternative to the HR when the proportional hazards assumption is considered untenable. Moreover, independent of the proportional hazards assumption, many comparative effectiveness studies aim to base contrasts on survival probability rather than on the hazard function. Causal effects based on RMST are often estimated via inverse probability of treatment weighting (IPTW). However, this approach generally results in biased results when the assumed propensity score model is misspecified. Motivated by the need for more robust techniques, we propose an empirical likelihood-based weighting approach that allows for specifying a set of propensity score models. The resulting estimator is consistent when the postulated model set contains a correct model; this property has been termed multiple robustness. In this report, we derive and evaluate a multiply robust estimator of the causal between-treatment difference in RMST. Simulation results confirm its robustness. Compared with the IPTW estimator from a correct model, the proposed estimator tends to be less biased and more efficient in finite samples. Additional simulations reveal biased results from a direct application of machine learning estimation of propensity scores. Finally, we apply the proposed method to evaluate the impact of intrapartum group B streptococcus antibiotic prophylaxis on the risk of childhood allergic disorders using data derived from electronic medical records from the Children's Hospital of Philadelphia and census data from the American Community Survey., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Objective: Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) remain prevalent despite viral suppression on antiretroviral therapy (ART). Vascular disease contributes to HAND, but peripheral markers that distinguish vascular cognitive impairment (VCI) from HIV-related etiologies remain unclear., Design: Cross-sectional study of vascular injury, inflammation, and central nervous system (CNS) injury markers in relation to HAND., Methods: Vascular injury (VCAM-1, ICAM-1, CRP), inflammation (IFN-γ, IL-1β, IL-6, IL-8, IL-15, IP-10, MCP-1, VEGF-A), and CNS injury (NFL, total Tau, GFAP, YKL-40) markers were measured in plasma and CSF from 248 individuals (143 HIV+ on suppressive ART and 105 HIV- controls)., Results: Median age was 53 years, median CD4 + cell count, and duration of HIV infection were 505 cells/μl and 16 years, respectively. Vascular injury, inflammation, and CNS injury markers were increased in HIV+ compared with HIV- individuals ( P < 0.05). HAND was associated with increased plasma VCAM-1, ICAM-1, and YKL-40 ( P  < 0.01) and vascular disease ( P  = 0.004). In contrast, inflammation markers had no significant association with HAND. Vascular injury markers were associated with lower neurocognitive T scores in age-adjusted models ( P  < 0.01). Furthermore, plasma VCAM-1 correlated with NFL ( r  = 0.29, P  = 0.003). Biomarker clustering separated HAND into three clusters: two clusters with high prevalence of vascular disease, elevated VCAM-1 and NFL, and distinctive inflammation profiles (CRP/ICAM-1/YKL-40 or IL-6/IL-8/IL-15/MCP-1), and one cluster with no distinctive biomarker elevations., Conclusions: Vascular injury markers are more closely related to HAND and CNS injury in PWH on suppressive ART than inflammation markers and may help to distinguish relative contributions of VCI to HAND., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest None.

Purpose: Adolescents and young adults (AYAs) with cancer receive high rates of medically intensive measures at the end of life. This study aimed to characterize the prevalence and timing of conversations about goals of care and advance care planning among AYAs at the end of life as one potential influence on care received., Methods: This was a review of electronic health data and medical records for 1,929 AYAs age 12-39 years who died after receiving care at one of three sites between 2003 and 2019, including documented conversations about goals of care and advance care planning, and care received., Results: A majority of AYAs were female (54%) and White (61%); 12% were Asian, 8% Black, and 27% Hispanic. Most patients had documented discussions about prognosis (86%), goals of care (83%), palliative care (79%), hospice (79%), and preferred location of death (64%). When last documented goals of care were evaluated, 69% of patients wanted care focused on palliation; however, 29% of those with palliative goals spent time in the intensive care unit (ICU) in the last month of life, and 32% had multiple emergency room (ER) visits. When goals-of-care discussions happened earlier, >30 days before death, AYAs were less likely to receive chemotherapy in the last 14 days of life ( P = .001), ICU care ( P < .001), ER visits ( P < .001), and hospitalizations in the last month ( P < .001)., Conclusion: High rates of medically intensive measures among AYAs near the end of life do not appear to be the result of a lack of discussions about goals of care and advance care planning. Although some interventions may be used to support palliative goals, earlier discussions have potential to reduce late-life intensive measures.

Introduction: The spread of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) is a serious concern in companion animal medicine owing to their ability to develop multidrug resistance. Cefmetazole (CMZ) is a candidate drug for treating ESBL-E infections; however, its regimen in dogs has not been established. In this study, we investigated the pharmacokinetic (PK) indices of CMZ in dogs and performed PK-pharmacodynamic (PD) analyses using Monte Carlo Simulation (MCS)., Methods: In total, six healthy dogs received an intravenous bolus dose of CMZ (40 mg/kg body weight). Serum CMZ concentrations were evaluated using liquid chromatography-mass spectrometry, and PK indices were determined based on non-compartmental analysis. The PK-PD cut-off (COPD) values were calculated as the highest minimum inhibitory concentration (MIC) that achieved ≥90% probability of target attainment for a target value of unbounded drug concentration exceeding 40% of the dosing interval. The cumulative fraction of response (CFR) was calculated based on the MIC distribution of wild-type ESBL-E from companion animals., Results: The area under the concentration-time curve and elimination half-time were 103.36 ± 7.49 mg·h/L and 0.84 ± 0.07 h, respectively. MCS analysis revealed that COPD values for regimens of 40 mg/kg q12, q8h, and q6h were ≤ 0.5, ≤2, and ≤ 4 μg/mL, respectively. A regimen of 40 mg/kg q6h was estimated to achieve a CFR of 80-90% for Escherichia coli and Klebsiella pneumoniae . By contrast, all regimens exhibited a CFR of ≤70% for Proteus mirabilis and Enterobacter cloacae., Discussion: We conclude that CMZ at 40 mg/kg q6h could be a viable treatment regimen for dogs infected with ESBL-producing Escherichia coli and Klebsiella pneumoniae ., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Kusumoto, Motegi, Uno, Yokono and Harada.)

A prostate-targeted biopsy (TB) core is usually collected from a site where magnetic resonance imaging (MRI) indicates possible cancer. However, the extent of the lesion is difficult to accurately predict using MRI or TB alone. Therefore, we performed several biopsies around the TB site (perilesional [p] TB) and analyzed the association between the positive cores obtained using TB and pTB and the Prostate Imaging Reporting and Data System (PI-RADS) scores. This retrospective study included patients who underwent prostate biopsies. The extent of pTB was defined as the area within 10 mm of a TB site. A total of 162 eligible patients were enrolled. Prostate cancer (PCa) was diagnosed in 75.2% of patients undergoing TB, with a positivity rate of 50.7% for a PI-RADS score of 3, 95.8% for a PI-RADS score of 4, and 100% for a PI-RADS score of 5. Patients diagnosed with PCa according to both TB and pTB had significantly higher positivity rates for PI-RADS scores of 4 and 5 than for a PI-RADS score of 3 ( p < 0.0001 and p = 0.0009, respectively). Additional pTB may be performed in patients with PI-RADS ≥ 4 regions of interest for assessing PCa malignancy.

The synthesis of sulfur-embedded hexapyrrolohexaazacoronene (HPHAC) analog 2 and its corresponding desulfurized and rearranged compounds was achieved from tetrafluoroisothianaphthene. Structures of all the new π-skeletons were determined by X-ray crystallography. Comparison of the electronic spectrum of 2 with those of its derivatives revealed less involvement of the sulfur atom in π-conjugation. Similar to the reference HPHAC ( 1 ), compound 2 and its derivatives exhibited reversible oxidation behavior. The aromaticity of both neutral and dication states has been investigated through DFT calculations.

Importance: In patients with cancer who have venous thromboembolism (VTE) events, long-term anticoagulation with low-molecular-weight heparin (LMWH) is recommended to prevent recurrent VTE. The effectiveness of a direct oral anticoagulant (DOAC) compared with LMWH for preventing recurrent VTE in patients with cancer is uncertain., Objective: To evaluate DOACs, compared with LMWH, for preventing recurrent VTE and for rates of bleeding in patients with cancer following an initial VTE event., Design, Setting, and Participants: Unblinded, comparative effectiveness, noninferiority randomized clinical trial conducted at 67 oncology practices in the US that enrolled 671 patients with cancer (any invasive solid tumor, lymphoma, multiple myeloma, or chronic lymphocytic leukemia) who had a new clinical or radiological diagnosis of VTE. Enrollment occurred from December 2016 to April 2020. Final follow-up was in November 2020., Intervention: Participants were randomized in a 1:1 ratio to either a DOAC (n = 335) or LMWH (n = 336) and were followed up for 6 months or until death. Physicians and patients selected any DOAC or any LMWH (or fondaparinux) and physicians selected drug doses., Main Outcomes and Measures: The primary outcome was the recurrent VTE rate at 6 months. Noninferiority of anticoagulation with a DOAC vs LMWH was defined by the upper limit of the 1-sided 95% CI for the difference of a DOAC relative to LMWH of less than 3% in the randomized cohort that received at least 1 dose of assigned treatment. The 6 prespecified secondary outcomes included major bleeding, which was assessed using a 2.5% noninferiority margin., Results: Between December 2016 and April 2020, 671 participants were randomized and 638 (95%) completed the trial (median age, 64 years; 353 women [55%]). Among those randomized to a DOAC, 330 received at least 1 dose. Among those randomized to LMWH, 308 received at least 1 dose. Rates of recurrent VTE were 6.1% in the DOAC group and 8.8% in the LMWH group (difference, -2.7%; 1-sided 95% CI, -100% to 0.7%) consistent with the prespecified noninferiority criterion. Of 6 prespecified secondary outcomes, none were statistically significant. Major bleeding occurred in 5.2% of participants in the DOAC group and 5.6% in the LMWH group (difference, -0.4%; 1-sided 95% CI, -100% to 2.5%) and did not meet the noninferiority criterion. Severe adverse events occurred in 33.8% of participants in the DOAC group and 35.1% in the LMWH group. The most common serious adverse events were anemia and death., Conclusions and Relevance: Among adults with cancer and VTE, DOACs were noninferior to LMWH for preventing recurrent VTE over 6-month follow-up. These findings support use of a DOAC to prevent recurrent VTE in patients with cancer., Trial Registration: ClinicalTrials.gov Identifier: NCT02744092.

Research into the application of antiaromatic compounds as molecular materials is an attractive strategy in the development of electronic materials. Antiaromatic compounds have traditionally been considered to be unstable, and thus, the creation of stable antiaromatic compounds has been sought in the field of organic chemistry. Recently, some studies have been reported on the synthesis, isolation, and elucidation of the physical properties of compounds with stability and definitive antiaromatic properties. In general, antiaromatic compounds are considered to be more susceptible to substituents due to their inherently narrow HOMO-LUMO gap compared to aromatic compounds. However, there have been no studies examining substituent effects in antiaromatic compounds. In this study, we have developed a synthetic method to introduce various substituents into π-extended hexapyrrolohexaazacoronene (homoHPHAC + ), one of the stable and clearly antiaromatic compounds, and investigated the substituent effects on the optical, redox, and geometrical properties and paratropicity of a series of compounds. In addition, the properties of the two-electron oxidized form, homoHPHAC 3+ , were investigated. Control of electronic properties by introducing substituents into antiaromatic compounds provides a new design guideline for molecular materials., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Little is known about patient-specific risk factors for skin neoplasia in individuals with Lynch syndrome (LS)., Objective: Identify clinical factors associated with development of skin neoplasms in LS., Methods: Clinical data were systematically collected on a cohort of LS carriers (confirmed pathogenic germline variants in MLH1, MSH2, MSH6, PMS2, or EPCAM) age ≥18 undergoing clinical genetics care at Dana-Farber Cancer Institute from January 2000 to March 2020. Multivariable logistic regression was performed to evaluate clinical factors associated with skin neoplasia., Results: Of 607 LS carriers, 9.2% had LS-associated skin neoplasia and 15.0% had non-LS-associated skin neoplasia; 58.2% (353/607) had documentation of prior dermatologic evaluation; 29.7% (38/128) with skin neoplasms lacked a history of visceral LS-associated malignancy. LS-associated skin neoplasms were significantly associated with male sex, age, race, MLH1 pathogenic germline variants, MSH2/EPCAM pathogenic germline variants, and personal history of non-LS skin neoplasms. Non-LS-associated skin neoplasms was significantly associated with age, number of first- and second-degree relatives with non-LS-associated skin neoplasms, and personal history of LS-associated skin neoplasms., Limitations: Single-institution observational study; demographic homogeneity., Conclusions: Skin neoplasms are common in individuals with LS. We identified clinical factors associated with LS- and non-LS-associated skin neoplasms. Regular dermatologic surveillance should be considered for all LS carriers., Competing Interests: Conflicts of interest Dr Uno reports prior consulting/advisory payments from Roche. Dr Syngal reports prior consulting fees from Myriad Genetic Laboratories, Inc, and inventor/royalties from the PREMM model. Dr Yurgelun reports consulting/scientific advisory board fees and research funding from Janssen Pharmaceuticals as well as payments for peer review services from UpToDate. Drs Zhong, Horiguchi, Ukaegbu, LeBoeuf, Nambudiri, and Ms Chittenden have no conflicts of interest to declare., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Adult survivors of pediatric central nervous system (CNS) tumors are at the highest risk for morbidity and late mortality among all childhood cancers due to a high burden of chronic conditions, and environmental and lifestyle factors. This study aims to epidemiologically characterize young adult survivors of pediatric CNS tumors using body mass index (BMI) to assess risk factors for obesity. Using a cross-sectional design, young adults (18-39 years) previously treated for pediatric CNS tumors and followed in a survivorship clinic during 2016-2021 were examined. Demographic, BMI, and diagnosis information were extracted from medical records of the most recent clinic visit. Data were assessed using a two-sample t-test, Fisher's exact test, and multivariable logistical regression. 198 survivors (53% female, 84.3% White) with a BMI status of underweight (4.0%), healthy weight (40.9%), overweight (26.8%), obesity (20.2%), and severe obesity (8.1%) were examined. Male sex (OR, 2.414; 95% CI, 1.321 to 4.414), older age at follow-up (OR, 1.103; 95% CI, 1.037 to 1.173), and craniopharyngioma diagnosis (OR, 5.764; 95% CI, 1.197 to 27.751) were identified as significant ( p < 0.05) obesity-related (≥25.0 kg/m 2 ) risk factors. The majority of patients were overweight or obese. As such, universal screening efforts with more precise determinants of body composition than BMI, risk stratification, and targeted lifestyle interventions are warranted during survivorship care.

Synthesis of unusual phenanthroporphyrins was achieved by a stepwise precursor method. Precursor porphyrins fused with aryl-substituted bicyclo[2.2.2]octadiene afforded the corresponding arylbenzoporphyrins (arylBPs) by a retro Diels-Alder reaction. Unusual phenanthroporphyrins were obtained via the intramolecular Scholl reaction of arylBPs. X-ray crystallographic analysis revealed a distorted, helical porphyrin plane. Red-shifted absorptions of tetraphenanthroporphyrin are observed at ca. 580 nm for the B band and at 700 - 900 nm for the Q bands. Analysis of magnetic circular dichroism spectra and time-dependent density functional theory calculations was used to explain the optical properties and electronic structures.

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.)

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.

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.)

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.)