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Challenges for some women meeting the physical employment standards (PES) for ground close combat (GCC) roles stem from physical fitness and anthropometric characteristics. The purpose of this study was to identify the modifiable and nonmodifiable characteristics predictive of passing GCC‐based PES tasks and determine the modifiable characteristics suitable to overcome nonmodifiable limitations. 107 adults (46 women) underwent multiday testing assessing regional and total lean mass (LM), percent body fat (BF%), aerobic capacity (V̇O2peak), strength, power, and PES performance. Predictors with p‐value <0.200 were included in stepwise logistic regression analysis or binary logistic regression when outcomes among sexes were insufficient. Relative and absolute arm LM (OR: 4.617–8.522, p < 0.05), leg LM (OR: 2.463, p < 0.05), and upper body power (OR: 2.061, p < 0.05) predicted medicine ball chest throw success. Relative and absolute arm LM (OR: 3.734–11.694, p < 0.05), absolute trunk LM (OR: 2.576, p < 0.05), and leg LM (OR: 2.088, p < 0.05) predicted casualty drag success. Upper body power (OR: 3.910, p < 0.05), absolute trunk LM (OR: 2.387, p < 0.05), leg LM (OR: 2.290, p < 0.05), and total LM (OR: 1.830, p < 0.05) predicted maximum single lift success. Relative and absolute arm LM (OR: 3.488–7.377, p < 0.05), leg LM (OR: 1.965, p < 0.05), and upper body power (OR: 1.957, p < 0.05) predicted water can carry success. %BF (OR: 0.814, p = 0.007), V̇O2peak (OR: 1.160, p = 0.031), and lower body strength (OR: 1.059, p < 0.001) predicted repeated lift and carry success. V̇O2peak (OR: 1.540, p < 0.001) predicted 2‐km ruck march success. Modifiable characteristics were the strongest predictors for GCC‐based PES task success to warrant their improvement for enhancing PES performance for women. Highlights: Women in GCC roles require sufficient military‐specific physical fitness and anthropometric parameters, independent of sex, for successfully passing GCC‐based PES tasks as part of assessment testing and selection procedures for GCC roles.Passing GCC‐based PES tasks involving heavy lifting, dragging, pushing/throwing, and carrying may benefit from increased upper body (arm and trunk) and lower body lean mass and upper body power and maximal strength, whereas passing material handling tasks may benefit from lower percent body fat, greater lower body muscular strength, and higher aerobic capacity with the latter important for passing load carriage tasks.Military trainers should target modifiable characteristics, including upper body lean mass, power, and maximal strength to improve GCC‐based PES task performance in women. [ABSTRACT FROM AUTHOR]

Introduction Several challenges face the U.S. Marine Corps (USMC) and other services in their efforts to design recruit training to augment warfighter mobility and resilience in both male and female recruits as part of an integrated model. Strength and power underpin many of the physical competencies required to meet the occupational demands one might face in military. As the military considers adopting force plate technology to assess indices of strength and power, an opportunity presents itself for the use of machine learning on large datasets to deduce the relevance of variables related to performance and injury risk. The primary aim of this study was to determine whether cluster analysis on baseline strength and power data derived from countermovement jump (CMJ) and isometric mid-thigh pull (IMTP) adequately partitions men and women entering recruit training into distinct performance clusters. The secondary aim of this study is then to assess the between-cluster frequencies of musculoskeletal injury (MSKI). Materials and Methods Five hundred and sixty-five males (n  = 386) and females (n  = 179) at the Marine Corps Recruit Depots located at Parris Island and San Diego were enrolled in the study. Recruits performed CMJ and IMTP tests at the onset of training. Injury data were collected via medical chart review. Combat fitness test (CFT) and physical fitness test (PFT) results were provided to the study team by the USMC. A k -means cluster analysis was performed on CMJ relative peak power, IMTP relative peak force, and dynamic strength index. Independent sample t -tests and Cohen's d effect sizes assessed between-cluster differences in CFT and PFT performance. Differences in cumulative incidence of lower extremity %MSKIs were analyzed using Fisher's exact test. Relative risk and 95% confidence intervals (CIs) were also calculated. Results The overall effects of cluster designation on CMJ and IMTP outcomes ranged from moderate (relative peak power: d  = −0.68, 95% CI, −0.85 to −0.51) to large (relative peak force: d  = −1.69, 95% CI, −1.88 to −1.49; dynamic strength index: d  = 1.20, 95% CI, 1.02-1.38), indicating acceptable k -means cluster partitioning. Independent sample t -tests revealed that both men and women in cluster 2 (C2) significantly outperformed those in cluster 1 (C1) in all events of the CFT and PFT (P  < .05). The overall and within-gender effect of cluster designation on both CFT and PFT performance ranged from small (d  > 0.2) to moderate (d  > 0.5). Men in C2, the high-performing cluster, demonstrated a significantly lower incidence of ankle MSKI (P  = .04, RR = 0.2, 95% CI, 0.1-1.0). No other between-cluster differences in MSKI were statistically significant. Conclusions Our results indicate that strength and power metrics derived from force plate tests effectively partition USMC male and female recruits into distinct performance clusters with relevance to tactical and physical fitness using k -means clustering. These data support the potential for expanded use of force plates in assessing readiness in a cohort of men and women entering USMC recruit training. The ability to pre-emptively identify high and low performers in the CFT and PFT can aid in leadership developing frameworks for tailoring training to enhance combat and physical fitness with benchmark values of strength and power. [ABSTRACT FROM AUTHOR]

Simple Summary: Nabpaclitaxel plus gemcitabine is the standard of care treatment for advanced pancreatic ductal adenocarcinoma (PDAC), the third leading cause of cancer-related deaths worldwide. This therapy reported improved overall survival in metastatic PDAC. Despite the efficacy of available treatments, the poor outcome for patients with PDAC necessitates the need for novel therapies. In a preclinical study, a neutralizing monoclonal antibody specific to human platelet-derived growth factor receptor alpha (PDGFRα) has proven its efficacy in advanced PDAC. Further, a PDGFRα monoclonal antibody, olaratumab, in combination with chemotherapy demonstrated clinical benefit in patients with soft tissue sarcoma. In light of the above findings, the current trial evaluates the efficacy and safety of olaratumab and nabpaclitaxel plus gemcitabine combination therapy in treatment-naïve patients with metastatic PDAC. However, the combination therapy failed to improve survival outcomes compared with chemotherapy alone. Nevertheless, the safety profile of olaratumab was consistent with the previous studies. The efficacy and safety of olaratumab plus nabpaclitaxel and gemcitabine in treatment-naïve participants with metastatic pancreatic ductal adenocarcinoma was evaluated. An initial phase 1b dose-escalation trial was conducted to determine the olaratumab dose for the phase 2 trial, a randomized, double-blind, placebo-controlled trial to compare overall survival (OS) in the olaratumab arm vs. placebo arms. In phase 1b, 22 participants received olaratumab at doses of 15 and 20 mg/kg with a fixed dose of nabpaclitaxel and gemcitabine. In phase 2, 159 participants were randomized to receive olaratumab 20 mg/kg in cycle 1 followed by 15 mg/kg in the subsequent cycles (n = 81) or the placebo (n = 78) on days 1, 8, and 15 of a 28-day cycle, plus nabpaclitaxel and gemcitabine. The primary objective of the trial was not met, with a median OS of 9.1 vs. 10.8 months (hazard ratio [HR] = 1.05; 95% confidence interval [CI]: 0.728, 1.527; p = 0.79) and the median progression-free survival (PFS) was 5.5 vs. 6.4 months (HR = 1.19; 95% CI: 0.806, 1.764; p = 0.38), in the olaratumab vs. placebo arms, respectively. The most common treatment-emergent adverse event of any grade across both arms was fatigue. Olaratumab plus chemotherapy failed to improve the OS or PFS in participants with metastatic PDAC. There were no new safety signals. [ABSTRACT FROM AUTHOR]

In the British Army, ground close combat roles have opened to women, however, they must pass the newly developed, gender-neutral Role Fitness Tests for Soldiers (RFT(S)). Due to physiological differences between sexes, training that optimally prepares both sexes for military occupational demands and the RFT(S) is needed. The purpose of this study was to determine the efficacy of a 12-week periodized strength and power programme with concurrent interval training on RFT(S) performance and determine if performance adaptations differed between sexes. 39 recruit-aged (18-35 yrs) participants, including 21 men (29 ± 1 yrs) and 18 women (27 ± 1 yrs), completed the study. Participants performed 3 training sessions per week that included strength and power resistance training followed by interval training. Pre- to post-training, improvements were observed for seated medicine ball throw (4.5%, p < 0.001), casualty drag (29.8%, p < 0.001), single lift (8.9%, p < 0.001), water can carry (13.8%, p = 0.012), repeated lift and carry (6.5%, p < 0.001), 2-km load carriage (7.2%, p < 0.001) and 2-km run (3.2%, p = 0.021). Pre- to post-training improvements were also observed for maximal squat (27.0%, p < 0.001), bench press (8.9%, p < 0.001) and deadlift (24.6%, p < 0.001) maximal strength, but not upper body power or aerobic capacity. No differences in RFT(S) improvements were observed between sexes, however men performed better than women in all RFT(S) and physical performance measures. Concurrent resistance and interval training improves military occupational performance in men and women; however, women may need more training than men to pass the gender-neutral RFT(S). [ABSTRACT FROM AUTHOR]

Simple Summary: Soft tissue sarcomas (STSs) are rare and highly heterogeneous tumors that are difficult to treat. Gemcitabine plus docetaxel is an effective treatment for advanced STS. However, the prognosis for patients remains poor, and thus there is an urgent medical need for novel and effective therapies to improve long-term outcomes. The aim of the ANNOUNCE 2 trial was to explore the addition of olaratumab (O) to gemcitabine (G) and docetaxel (D) for advanced STS. Patients were randomized 1:1 from two cohorts (O-naïve and O-pretreated) to 21-day cycles of olaratumab, gemcitabine, and docetaxel. A total of 167 and 89 patients were enrolled in the O-naïve and O-pretreated cohorts, respectively. There was no statistically significant difference in the primary endpoint of overall survival between the two arms in the O-naïve population. No new safety signals were observed. Gemcitabine plus docetaxel is an effective treatment regimen for advanced soft tissue sarcomas (STSs). However, the prognosis for patients remains poor, and thus there is an urgent medical need for novel and effective therapies to improve long-term outcomes. The aim of the ANNOUNCE 2 trial was to explore the addition of olaratumab (O) to gemcitabine (G) and docetaxel (D) for advanced STS. Adults with unresectable locally advanced/metastatic STS, ≤2 prior lines of systemic therapy, and ECOG PS 0–1 were eligible. In Phase 2, patients were randomized 1:1 from two cohorts (O-naïve and O-pretreated) to 21-day cycles of olaratumab (20 mg/kg Cycle 1 and 15 mg/kg other cycles, Days 1 and 8), gemcitabine (900 mg/m2, Days 1 and 8), and docetaxel (75 mg/m2, Day 8). The primary objective was overall survival (OS) in the O-naïve population (α level = 0.20). Secondary endpoints included OS (O-pretreated), other efficacy parameters, patient-reported outcomes, safety, pharmacokinetics, and immunogenicity. A total of 167 and 89 patients were enrolled in the O-naïve and O-pretreated cohorts, respectively. Baseline patient characteristics were well balanced. No statistically significant difference in OS was observed between the investigational vs. control arm for either cohort (O-naïve cohort: HR = 0.95 (95% CI: 0.64−1.40), p = 0.78, median OS, 16.8 vs. 18.0 months; O-pretreated cohort: HR = 0.67 (95% CI: 0.39−1.16), p = 0.15, median OS 19.8 vs. 17.3 months). Safety was manageable across treatment arms. There was no statistically significant difference in the primary endpoint of OS between the two arms in the O-naïve population, and therefore based on hierarchical evaluation no other outcomes in this study can be considered statistically significant. No new safety signals were observed. [ABSTRACT FROM AUTHOR]

Purpose: Liver metastasis (LM) is reported in approximately 40% of patients with advanced/ metastatic gastric/gastroesophageal junction adenocarcinoma (metastatic esophagogastric adenocarcinoma; mGEA) and is associated with a worse prognosis. This post-hoc analysis from the RAINBOW trial reported the efficacy, safety, and biomarker outcomes of ramucirumab and paclitaxel combination treatment (RAM+PAC) in patients with (LM+) and without (LM−) LM at baseline. Materials and Methods: Patients (n=665) were randomly assigned on a 1:1 basis to receive either RAM+PAC (LM+: 150, LM−: 180) or placebo and paclitaxel (PL+PAC) (LM+: 138, LM−: 197). The overall survival (OS) and progression-free survival (PFS) were evaluated using stratified Kaplan–Meier and Cox regression models. The correlation of dichotomized biomarkers (VEGF-C, D; VEGFR-1,2) with efficacy in the LM+ versus LM− subgroups was analyzed using the Cox regression model with reported interaction P-values. Results: The presence of LM was associated with earlier progression than those without LM, particularly in patients receiving PL+PAC (hazard ratio [HR], 1.68). RAM+PAC treatment improved OS and PFS irrespective of LM status but showed greater improvement in LM+ than that in LM− (OS HR, 0.71 [LM+] vs. 0.88 [LM−]; PFS HR, 0.47 [LM+] vs. 0.76 [LM−]). Treatment-emergent adverse events were similar between patients with and without LM. No predictive relationship was observed between biomarker levels (VEGF-C, D; VEGFR-1,2) and efficacy outcome (OS, PFS) (all interaction P-values >0.05). Conclusions: RAM provided a significant benefit, irrespective of LM status; however, its effect was numerically stronger in patients with LM. Therefore, RAM+PAC is a clinically meaningful therapeutic option for patients with mGEA and LM. [ABSTRACT FROM AUTHOR]

Simple Summary: There is conflicting evidence on the impact of TP53 co-mutations on survival in patients with EGFR-mutated advanced non-small cell lung cancer (aNSCLC). This observational study used data from a de-identified database to assess the role of TP53 co-mutation on survival in patients with EGFR-mutated aNSCLC (n = 356). We observed a significant decrease in survival outcomes (namely real-world progression-free survival [rwPFS] and overall survival [OS]) duration in the group of aNSCLC patients with presence of TP53 co-mutation compared to those with wild-type TP53 tumors. TP53 co-mutations were also associated with worse outcomes by subgroups, including type of EGFR-mutation and first-line treatment. Together, these findings indicated negative impact of TP53 co-mutation in outcomes for patients with EGFR-mutated aNSCLC. TP53 co-mutations have shown association with poor prognosis in various solid tumors. For EGFR-mutated advanced non-small cell lung cancer (aNSCLC), conflicting results exist regarding its impact on survival. Clinical outcomes and genomic data were obtained retrospectively from the real-world (rw) de-identified clinicogenomic database. Patients who initiated therapy for EGFR-mutated aNSCLC between January 2014 and December 2020 were identified. Clinical outcomes were evaluated by TP53-mutational status. In 356 eligible EGFR-mutated aNSCLC patients (median age 68 years), 210 (59.0%) had TP53 co-mutation and 146 (41.0%) had TP53 wild-type tumor. Unadjusted analysis showed significantly shorter survival in patients with TP53 co-mutation versus TP53 wild-type (rw progression-free survival [rwPFS]: HR = 1.4, 95% CI 1.1–1.9, p = 0.0196; overall survival [OS]: HR = 1.6, 95% CI 1.1–2.2, p = 0.0088). Multivariable analysis confirmed independent association between TP53 co-mutation and worse rwPFS (HR = 1.4, 95% CI 1.0–0.9, p = 0.0280) and OS (HR = 1.4, 95% CI 1.0–2.0, p = 0.0345). Directionally consistent findings were observed for response rates, and subgroups by EGFR-activating mutation and first-line (1 L) therapy, with more pronounced negative effect in 1 L EGFR-TKI subgroup. TP53 co-mutations negatively affected survival in patients with EGFR-mutated aNSCLC receiving standard 1 L therapy in real-world practice. [ABSTRACT FROM AUTHOR]

Aim: To estimate real-world (rw) outcomes for first-line therapy in patients with advanced EGF receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), focusing on specific mutation types. Patients & methods: Retrospective observational study (n = 244 patients). Results: Univariate/multivariate analyses showed longer rw progression-free survival (rwPFS) and rwPFS2 in patients with ex19del versus Leu858Arg mutations. Median overall survival was 12.3 months longer with ex19del versus Leu858Arg mutations (HR: 1.47 [95% CI: 0.96-2.25]; p = 0.074). With EGFR-tyrosine kinase inhibitor monotherapy, unadjusted rwPFS for ex19del mutations was longer than for Leu858Arg mutations (HR: 1.62 [95% CI: 1.03-2.56]; p = 0.036). Conclusion: In this rw cohort of patients with advanced EGFR+ NSCLC, ex19del mutations conferred a prognostic advantage over Leu858Arg mutations, with significantly better rwPFS and rwPFS2. [ABSTRACT FROM AUTHOR]

Introduction Elevated rates of musculoskeletal injuries (MSIs) and attrition are documented in military recruit training. By identifying and addressing modifiable risk factors, the rate of successful training completion and military readiness can be enhanced. Despite their impact, the causes of MSIs and attrition among U.S. Marine Corps (USMC) recruits remain underexplored. This study investigates demographic, psychological, and physiological predictors of MSIs and attrition among USMC recruits. Materials and Methods In this prospective cohort study, we evaluated USMC recruits at Marine Corps Recruit Depot, Parris Island and San Diego. Recruits were briefed and invited to volunteer. All recruits who were medically cleared to participate in recruit training were eligible to participate in the study. We gathered baseline data on potential predictors at the start of training, with follow-up data on MSIs and attrition collected post-training. Analyzed predictors encompassed dynamic and static strength measures from countermovement jumps, isometric mid-thigh pulls; and participant surveys. We employed multiple logistic regression to discern risk factors for MSI and attrition. Results Our study comprised 584 USMC recruits (183 female recruits, 19.49 ± 1.88 years, 160.10 ± 7.17 cm, 61.19 ± 8.05 kg; 401 males, 18.94 ± 1.92 years, 172.97 ± 7.26 cm, 73.86 ± 11.04 kg). We observed 193 MSIs in 135 recruits, with 80.31% affecting the lower extremity (LE). Notably, lower relative peak power (odds ratio [OR] 0.91 [0.89, 0.94], P  < .001) and shorter eccentric deceleration duration (OR 0.99 [0.99, 1.00], P  = .005) were significant predictors of MSIs. Specifically, for LE MSIs, similar trends were noted for relative peak power and eccentric deceleration duration, with additional risks associated with lower body mass index (OR 0.93 [0.86, 0.99], P  = .036) and previous LE MSIs (OR 2.25 [1.18, 4.27], P  = .013). Attrition was more likely with a reduced eccentric deceleration impulse (OR 0.98 [0.97, 0.99], P  < .001) and prolonged time to peak force (OR 1.36 [1.17, 1.59], P  < .001) and cigarette use (OR 2.12 [1.01, 4.43], P  = .046). Conclusions MSIs and attrition during USMC recruit training significantly undermine force readiness and escalate costs. Our research has pinpointed several modifiable risk factors, chiefly reduced muscular power and cigarette smoking. We advocate for neuromuscular training programs to bolster strength and power, integrated nutrition and exercise strategies for optimal body composition, and support for smoking cessation to alleviate the incidence of MSIs and curtail attrition. Initiating training with a gradual increase in activity intensity can provide a critical window to correct pre-existing neuromuscular imbalances and weaknesses, particularly those stemming from prior MSIs. Effectively addressing these risk factors is pivotal for diminishing the rates of MSIs and attrition among recruits, thereby enhancing overall military readiness and operational efficiency. [ABSTRACT FROM AUTHOR]

Background: CYP2D6 is involved in the oxidative metabolism of approximately 20% of all clinically used medications. Genotyping cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6), is a challenge because of the high complexity of the locus. Methods: Twenty-nine CYP2D6 sequence variants were genotyped in 50 deidentified patient samples and 29 Coriell DNAs by Invader assay, and results were compared with Infiniti assay and Sanger sequencing. To determine CYP2D6 copy number, 3 TaqMan real-time hydrolysis probes were used and results were compared with long-range PCR. Discrimination of the duplicated alleles was done on 17 DNA samples with 3 copies of CYP2D6 by long-range PCR followed by Invader genotyping and single nucleotide extension for the comparison. Results: Complete concordance was observed for all samples between platforms except for 2 samples due to the lack of the *45 allele in the Infiniti panel. Reproducibility with the Invader assay and TaqMan copy number was 100%. Analytical sensitivity using DNA with 2 copies was determined to be 10 ng DNA for the Invader assay and 1 ng/µL DNA for the TaqMan assay, respectively. Complete concordance and reproducibility were observed for duplicated allele discrimination with the exception of 1 sample, determined to be *29/*43X2 by the Invader test and *1X2/*29 by the Infiniti method, which did not test for *43. Conclusions: This validation study showed that Invader and TaqMan assay combined panel provides an attractive, valid, highly accurate, and reproducible approach for CYP2D6 genotyping for clinical implementation. [ABSTRACT FROM AUTHOR]

The chicken embryo is an established model system for studying early vertebrate development. One of the major advantages of this model is the facility to perform manipulations in ovo and then continue incubation and observe the effects on embryonic development. However, in common with other vertebrate models, there is a tendency to disregard the sex of the experimental chicken embryos, and this can lead to erroneous conclusions, a lack of reproducibility, and wasted efforts. That this neglect is untenable is emphasised by the recent demonstration that avian cells and tissues have an inherent sex identity and that male and female tissues respond differently to the same stimulus. These sexually dimorphic characteristics dictate that analyses and manipulations involving chicken embryos should always be performed using tissues/embryos of known sex. Current sexing protocols are unsuitable in many instances because of the time constraints imposed by most in ovo procedures. To address this lack, we have developed a real-time chicken sexing assay that is compatible with in ovo manipulations, reduces the number of embryos required, and conserves resources. [ABSTRACT FROM AUTHOR]

Background: Patient-reported outcomes have been associated with survival in numerous studies across cancer types, including breast cancer. However, the Brief Pain Inventory-Short Form (BPI-SF) and the Rotterdam Symptom Checklist (RSCL) have rarely been investigated in this regard in breast cancer.Methods: Here we describe a post hoc analysis of the prognostic effect of baseline scores of these instruments on survival in a phase III trial of patients with advanced breast cancer who received gemcitabine plus paclitaxel or paclitaxel alone after anthracycline-based adjuvant or neoadjuvant therapy. The variables for this analysis were baseline BPI-SF "worst pain" and BPI-SF "pain interference" scores, and four RSCL subscales (each transformed to 0-100). Univariate and multivariate Cox models were used, the latter in the presence of 11 demographic/clinical variables. Kaplan-Meier curves and log-rank tests were used to compare survival for patients by BPI-SF or RSCL scores.Results: Of 529 randomized patients, 286 provided BPI-SF data and 336 provided RSCL data at baseline. Univariate analyses identified BPI-SF worst pain and pain interference (both hazard ratios [HR], 1.07 for a 1-point increase; both p ≤ 0.0061) and three of four RSCL subscales [activity level, physical distress, and health-related quality of life (HRQOL) (HR, 0.86-0.91 for 10-point increase all p ≤ 0.0104)], to have significant prognostic effect for survival. BPI-SF worst pain (p = 0.0342) and RSCL activity level (p = 0.0004) were prognostic in the multivariate analysis. Median survival for patients categorized by BPI-SF worst pain score was 23.8 (n = 91), 17.9 (n = 94) and 14.6 (n = 94) months for scores 0, 1-4, and 5-10, respectively (log-rank p = 0.0065). Median survival was 23.8 and 14.6 months for patients (n = 330) with above- and below-median RSCL activity level scores respectively (log-rank p < 0.0001).Conclusion: Pretreatment BPI-SF worst pain and RSCL activity scores provide distinct prognostic information for survival in patients receiving paclitaxel or gemcitabine plus paclitaxel for advanced breast cancer even after controlling for multiple demographic and clinical factors.Trial Registration: Clinicaltrials.gov, NCT00006459. [ABSTRACT FROM AUTHOR]