Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults.

BACKGROUND: Many older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission. METHODS: In a phase 3 trial, we randomly assigned patients 30 to 70 years of age with BCR::ABL1-negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point. RESULTS: The data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85% vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P = 0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events was reported in the blinatumomab group than in the chemotherapy-only group. CONCLUSIONS: The addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. (Funded by the National Institutes of Health and others; E1910 ClinicalTrials.gov number, NCT02003222.).

The activities of suaveolol and other compounds from Hyptis suaveolens and Momordica charantia against the aetiological agents of African trypanosomiasis, leishmaniasis and malaria.

African trypanosomiasis and malaria are among the most severe health challenges to humans and livestock in Africa and new drugs are needed. Leaves of Hyptis suaveolens Kuntze (Lamiaceae) and Momordica charantia L. (Cucurbitaceae) were extracted with hexane, ethyl acetate, and then methanol, and subjected to silica gel column chromatography. Structures of six isolated compounds were elucidated through NMR and HR-EIMS spectrometry. Callistrisic acid, dehydroabietinol, suaveolic acid, suaveolol, and a mixture of suaveolol and suaveolic acid (SSA) were obtained from H. suaveolens, while karavilagenin D and momordicin I acetate were obtained from M. charantia. The isolated biomolecules were tested against trypomastigotes of Trypanosoma brucei brucei and T. congolense, and against Plasmodium falciparum. The most promising EC50 values were obtained for the purified suaveolol fraction, at 2.71 ± 0.36 µg/mL, and SSA, exhibiting an EC50 of 1.56 ± 0.17 µg/mL against T. b. brucei trypomastigotes. Suaveolic acid had low activity against T. b. brucei but displayed moderate activity against T. congolense trypomastigotes at 11.1 ± 0.5 µg/mL. Suaveolol and SSA were also tested against T. evansi, T. equiperdum, Leishmania major and L. mexicana but the antileishmanial activity was low. Neither of the active compounds, nor the mixture of the two, displayed any cytotoxic effect on human foreskin fibroblast (HFF) cells at even the highest concentration tested, being 200 µg/mL. We conclude that suaveolol and its mixture possessed significant and selective trypanocidal activity.

Sex Differences in Physiological Responses to a National Collegiate Athletic Association Division I Soccer Season.

ABSTRACT: McFadden, BA, Walker, AJ, Cintineo, HP, Bozzini, BN, Sanders, DJ, Chandler, AJ, and Arent, SM. Sex differences in physiological responses to a national collegiate athletic association division I soccer season. J Strength Cond Res XX(X): 000-000, 2024-Identifying physiological changes that occur in response to workload demands can help to elucidate athlete management and recovery strategies. The purpose of this study was to compare the physical and physiological demands between men and women throughout the course of a collegiate soccer season. Men (N = 23) and women (N = 26) soccer players participated in blood draws before preseason (T1) and every 4 weeks thereafter (T2-T4). Workload was determined at all practices and games via heart rate and global positioning satellite monitoring systems. Repeated measures multivariate analysis of variance and linear mixed models were used to assess workload and biomarker responses throughout the season (p < 0.05). Both teams experienced the highest workloads during the first 4 weeks of the season (p < 0.05), which was followed by several biomarker perturbations. Sex-by-Time interactions were observed for total cortisol, growth hormone, insulin-like growth factor-1, thyroxine, thyroid-stimulating hormone, vitamin D, and omega 3 fatty acid index (p < 0.05). Additional Sex effects were observed for free and total testosterone, estrogen, prolactin, sex-hormone binding globulin, creatine kinase, and iron levels (p < 0.05). Women soccer players experienced further Time effects for free cortisol, iron, ferritin, and percent transferrin saturation (p < 0.05). Male soccer players experienced additional Time effects for total testosterone, estrogen, creatine kinase, interleukin-6, triiodothyronine, and ferritin (p < 0.05). Despite similar patterns of change in workloads, differential fluctuations in physiological markers were observed between the sexes. Understanding sex differences in response to comparable workloads may enhance exercise prescriptions for better athlete management plans. Additional strategies to increase iron may be warranted in female athletes.

A Sex Comparison of the Physical and Physiological Demands of United States Marine Corps Recruit Training.

INTRODUCTION: The U.S. Marine Corps (USMC) recruit training is a 13-week preparatory period for military service men and women. Differences in absolute performance capabilities between sexes may impact physical and physiological responses to the demands of recruit training. The purpose of this study was to monitor U.S. Marine Corps recruits throughout recruit training to comparatively assess workload, sleep, stress, and performance responses in men and women. MATERIALS AND METHODS: A total of 281 recruits (men = 182 and women = 99; age = 19 ± 2 years) were monitored and tested. Workload, sleep, and stress assessments occurred at week 2, week 7/8, and week 11 of training. Workload (energy expenditure per kg body mass [EEREL], distance [DIS], steps) and sleep (continuity and duration) were tracked over 72-hour periods using wearable accelerometry and heart rate technology. Stress responses were determined through salivary cortisol analyses. Performance testing, consisting of countermovement vertical jump (CMJ) and isometric mid-thigh pull (IMTP) performance relative to body mass, occurred at weeks 2 and 11. Linear mixed models were used to test for sex, time, and sex-by-time interactions (α < .05). RESULTS: On average, recruits covered 13.0 ± 2.7 km/day, expended 3,762 ± 765 calories/day, and slept 6.2 ± 1.1 hours/night. Sex-by-time interactions were found for DIS, steps, sleep duration, cortisol, and CMJREL performance (P < .05). Planned contrasts revealed that men covered more DIS than women at week 7/8 (P < .001). Women experienced greater step counts compared to men at week 11 (P = .004). Women experienced no significant change in sleep duration (P > .05), whereas men increased sleep duration from week 2 to week 7/8 (P = .03). Women experienced greater sleep duration at week 2 (P = .03) and week 11 (P = .02) compared to men. Women exhibited higher cortisol levels than men at week 2 (P < .001) and week 11 (P < .001). Women experienced declines in cortisol at week 7 compared to week 2 (P < .001). Men experienced no changes in cortisol response at any timepoint (P > .05). Both sexes experienced declines in CMJREL from week 2 to week 11 (P > .001). Sex main effects were observed for EEREL, DIS, CMJREL, and IMTPREL (P < .05) with men experiencing greater overall workloads and producing greater strength and power metrics. Sex main effects were also found for sleep continuity and cortisol (P < .05), for which men experienced lower values compared to women. Time main effects were observed for EEREL, DIS, steps, cortisol, CMJREL, and IMTPREL (P < .05). CONCLUSIONS: This study not only highlights the known sex differences between men and women but also sheds light on the different physical and physiological responses of each sex to military training. Interestingly, the greatest physical demands incurred earlier in the training cycle. Despite declining workloads, the stress response was maintained throughout the training, which may have implications for adaptation and performance. In addition, average sleep duration fell notably below recommendations for optimizing health and recovery. Effectively monitoring the demands and performance outcomes during recruit training is essential for determining individual fitness capabilities, as well as establishing the effectiveness of a training program. Individual performance assessments and adequately periodized workloads may help to optimize recruit training for both men and women.

United States Marine Corps Recruit Training Demands Associated With Performance Outcomes.

INTRODUCTION: United States Marine Corps' (USMC) recruit training is a 13-week program designed to maximize physical and mental performance adaptations. The purpose of this study was to evaluate the training demands and characteristics that are associated with performance outcomes during USMC recruit training. MATERIALS AND METHODS: A total of 196 recruits (M = 97 and W = 99) were monitored and tested throughout training. Laboratory-based performance testing occurred at the start of weeks 2 and 11 and consisted of body mass assessments, countermovement vertical jump, and isometric mid-thigh pull. Military-specific performance testing occurred twice within the first 8 weeks of training and included the physical fitness test (PFT) and combat fitness test (CFT) implemented by the USMC. Resilience data were collected at week 2 using the Connor-Davidson Resilience Scale. Workload, sleep, and stress responses were monitored at weeks 2, 7, and 11. Recruits were provided with a wearable tracking device which utilized heart rate and accelerometry-based technology to determine energy expenditure (EE), distances (DIS), and sleep metrics. Data were averaged over a 3-day period. Salivary cortisol testing occurred at the start of each monitoring week. Change scores were calculated for performance tests, and body mass was calculated from data obtained at week 2 to week 11. Area under the curve was calculated for the workload, sleep metrics, and cortisol responses using the trapezoidal method. Pearson product-moment correlations (r) were used to assess the relationships between training demands and performance. An α level of 0.05 was used to establish significance. RESULTS: A moderate positive correlation was found between changes in body mass and peak power (P < .001; r = 0.43). Weak positive correlations were found between changes in body mass and peak force (P = .002; r = 0.28), as well as body mass and resilience (P = .03; r = 0.19). A moderate negative correlation was observed between changes in body mass and PFT (P < .001; r = -0.49). A weak negative correlation was found between changes in body mass and EE (P = .003; r = -0.24). A weak negative correlation was found between changes in peak power and EE (P = .001; r = -0.29). A weak positive correlation was found between changes in peak power and changes in CFT (P = .05; r = 0.19) A weak negative correlation was found between changes in sleep continuity and CFT (P = .02; r = -0.20). A weak negative correlation was found between cortisol and changes in PFT (P = .05; r = -0.20). A weak negative correlation was found between cortisol and both EE (P = .001; r = -0.27) and DIS (P = .045; r = -0.16). A weak negative correlation was found between EE and sleep continuity (P < .001; r = -0.34). Weak negative correlations were found between sleep duration and both DIS (P = .01; r = -0.18) and steps (P = .003; r = -0.21). CONCLUSIONS: Increases in body mass throughout training were positively associated with strength and power changes, but negatively related to PFT scores. Changes in peak power related to improvements in CFT scores; however, higher workloads (i.e., EE) were negatively associated with peak power. The identification of the USMC physical and physiological training demands that are associated with performance outcomes may be a valuable resource to guide conditioning efforts to boost military readiness.

Association between class III obesity and overall survival in previously untreated younger patients with acute myeloid leukemia enrolled on SWOG S1203.

There has been ongoing debate on the association between obesity and outcomes in acute myeloid leukemia (AML). Currently few studies have stratified outcomes by class I obesity, class II obesity, and class III obesity, and a more nuanced understanding is becoming increasingly important with the rising prevalence of obesity. We examined the association between body mass index (BMI) and outcomes in previously untreated AML in younger patients (age ≤60) enrolled in SWOG S1203 (n = 729). Class III obesity was associated with an increased rate of early death (p = 0.004) and worse overall survival (OS) in multivariate analysis (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.62-3.80 versus normal weight). Class III obesity was also associated with worse OS after allogeneic hematopoietic cell transplant (HR 2.37, 95% CI 1.24-4.54 versus normal weight). These findings highlight the unique risk of class III obesity in AML, and the importance of further investigation to better characterize this patient population.

The effects of a brand-specific, hemp-derived cannabidiol product on physiological, biochemical, and psychometric outcomes in healthy adults: a double-blind, randomized clinical trial.

BACKGROUND: Cannabidiol (CBD) is a non-psychoactive phyto-cannabinoid derived from the Cannabis sativa plant. CBD exhibits various interactions at receptor sites, prompting the research of its potential anti-inflammatory, immunomodulatory, psychological, and pain-relieving effects. This study aimed to investigate the physiological, biochemical, and psychometric effects of a brand-specific, hemp-derived CBD product in healthy adults over a 12-week observation period. METHODS: 54 healthy males and females (age = 25 ± 7y; BMI = 24.82 ± 3.25 kg/m2) recruited from a large Southeastern University completed the study. Participants arrived at the laboratory after > 8 h of fasting, and > 48 h without alcohol consumption and vigorous exercise. Following baseline measurements (height, weight, blood pressure, electrocardiogram (ECG), and blood work), participants were stratified by sex and randomized to either CBD or placebo groups. Products were administered double-blinded, with both given in liquid form containing medium-chain triglyceride oil, while the CBD product specifically contained 50 mg/mL of CBD. Participants were instructed to consume 1 mL of their product twice daily and were given enough product to last until their next laboratory visit. Data were collected at baseline and on days 30 ± 3, 60 ± 3, and 90 ± 3. Blood was drawn for analysis of immune and inflammatory biomarkers. Chronic pain among participants was calculated using urine samples according to the foundational pain index (FPI). Self-reported psychometric questionnaires were utilized (Cohen's Perceived Stress Scale, Pittsburgh Sleep Quality Index, Profile of Mood States,10-item Likert scale for perceived pain) to assess stress, sleep quality, mood state, and body discomfort. To determine overall wellbeing, participants completed a daily survey indicating if they missed work or school due to illness. Change from baseline was calculated for each measure, and mixed effects models were used to determine differences between groups over time while adjusting for baseline values (α = 0.05). Data are presented as mean ± standard deviation. RESULTS: There were no Group-by-Time interactions or Group or Time main effects for immune or inflammatory biomarkers (p > 0.05). Analyses revealed no Group-by-Time interactions or main effects observed for perceived stress, sleep quality, overall mood disturbance, and all the profile of mood state subscales (p > 0.05), except "vigor-activity." A Time main effect was found for the sub-score for "vigor-activity" (p = 0.007; Pre CBD = 19.5 ± 5.2, Post CBD = 17.3 ± 5.3; Pre PL = 19.0 ± 5.7, Post PL = 17.9 ± 7.1), which decreased from Visit 3 to Visit 4 (p = 0.025) and from Visit 3 to Visit 5 (p = 0.014). There was a Group main effect for FPI (p = 0.028; Pre CBD = 11.9 ± 14.4, Post CBD = 8.8 ± 10.9; Pre PL = 9.0 ± 14.2, Post PL = 12.9 ± 11.5), indicating that the placebo group had greater increases in pain over the intervention compared to the CBD group. No significant differences were found between groups in the incidence and prevalence of "colds or flus" (p > 0.05). DISCUSSION: CBD was safe and well tolerated in healthy adults. These findings show pain was lower in the CBD group, suggesting a potentially positive effect for consumption of CBD. "Vigor-activity" decreased across the intervention, which may be a confounding effect of the academic semester. While the dosage chosen was safe, more research may be warranted using higher doses as these may be needed to observe further therapeutic effects in healthy populations.

Product Distribution of Steady-State and Pulsed Electrochemical Regeneration of 1,4-NADH and Integration with Enzymatic Reaction.

The direct electrochemical reduction of nicotinamide adenine dinucleotide (NAD+) results in various products, complicating the regeneration of the crucial 1,4-NADH cofactor for enzymatic reactions. Previous research primarily focused on steady-state polarization to examine potential impacts on product selectivity. However, this study explores the influence of dynamic conditions on the selectivity of NAD+ reduction products by comparing two dynamic profiles with steady-state conditions. Our findings reveal that the main products, including 1,4-NADH, several dimers, and ADP-ribose, remained consistent across all conditions. A minor by-product, 1,6-NADH, was also identified. The product distribution varied depending on the experimental conditions (steady state vs. dynamic) and the concentration of NAD+, with higher concentrations and overpotentials promoting dimerization. The optimal yield of 1,4-NADH was achieved under steady-state conditions with low overpotential and NAD+ concentrations. While dynamic conditions enhanced the 1,4-NADH yield at shorter reaction times, they also resulted in a significant amount of unidentified products. Furthermore, this study assessed the potential of using pulsed electrochemical regeneration of 1,4-NADH with enoate reductase (XenB) for cyclohexenone reduction.

Drug resistance in animal trypanosomiases: Epidemiology, mechanisms and control strategies.

Animal trypanosomiasis (AT) is a complex of veterinary diseases known under various names such as nagana, surra, dourine and mal de caderas, depending on the country, the infecting trypanosome species and the host. AT is caused by parasites of the genus Trypanosoma, and the main species infecting domesticated animals are T. brucei brucei, T. b. rhodesiense, T. congolense, T. simiae, T. vivax, T. evansi and T. equiperdum. AT transmission, again depending on species, is through tsetse flies or common Stomoxys and tabanid flies or through copulation. Therefore, the geographical spread of all forms of AT together is not restricted to the habitat of a single vector like the tsetse fly and currently includes almost all of Africa, and most of South America and Asia. The disease is a threat to millions of companion and farm animals in these regions, creating a financial burden in the billions of dollars to developing economies as well as serious impacts on livestock rearing and food production. Despite the scale of these impacts, control of AT is neglected and under-resourced, with diagnosis and treatments being woefully inadequate and not improving for decades. As a result, neither the incidence of the disease, nor the effectiveness of treatment is documented in most endemic countries, although it is clear that there are serious issues of resistance to the few old drugs that are available. In this review we particularly look at the drugs, their application to the various forms of AT, and their mechanisms of action and resistance. We also discuss the spread of veterinary trypanocide resistance and its drivers, and highlight current and future strategies to combat it.

Immunohistochemical Expression of Lymphatic Endothelial Markers in Blue Rubber Bleb Nevus Syndrome.

INTRODUCTION: Blue rubber bleb nevus syndrome (BRBNS) is an uncommon vascular anomaly characterized by multifocal cutaneous, visceral, and other soft tissue or solid organ venous malformations. We observed that BRBNS lesions express immunohistochemical markers of lymphatic differentiation. METHODS: BRBNS histopathologic specimens assessed at our institution during the past 27 years were reviewed. Slides from 19 BRBNS lesions were selected from 14 patients (9 cutaneous, 9 gastrointestinal, and 1 hepatic). We recorded the involved anatomical compartments and presence/absence of thrombi or vascular smooth muscle. Immunohistochemical endothelial expression of PROX1 (nuclear) and D2-40 (membranous/cytoplasmic) was evaluated semi-quantitatively. RESULTS: Endothelial PROX1 immunopositivity was noted in all specimens; the majority (89.5%) demonstrated staining in more than 10% of cells. D2-40 immunopositivity was present in one-third (33%) of cutaneous lesions and only 1 gastrointestinal lesion. CONCLUSION: Endothelial cells in BRBNS almost always express 1 or more immunohistochemical markers of lymphatic differentiation.

Mapping the transporter-substrate interactions of the Trypanosoma cruzi NB1 nucleobase transporter reveals the basis for its high affinity and selectivity for hypoxanthine and guanine and lack of nucleoside uptake.

Trypanosoma cruzi is a protozoan parasite and the etiological agent of Chagas disease, a debilitating and sometimes fatal disease that continues to spread to new areas. Yet, Chagas disease is still only treated with two related nitro compounds that are insufficiently effective and cause severe side effects. Nucleotide metabolism is one of the known vulnerabilities of T. cruzi, as they are auxotrophic for purines, and nucleoside analogues have been shown to have genuine promise against this parasite in vitro and in vivo. Since purine antimetabolites require efficient uptake through transporters, we here report a detailed characterisation of the T. cruzi NB1 nucleobase transporter with the aim of elucidating the interactions between TcrNB1 and its substrates and finding the positions that can be altered in the design of novel antimetabolites without losing transportability. Systematically determining the inhibition constants (Ki) of purine analogues for TcrNB1 yielded their Gibbs free energy of interaction, ΔG0. Pairwise comparisons of substrate (hypoxanthine, guanine, adenine) and analogues allowed us to determine that optimal binding affinity by TcrNB1 requires interactions with all four nitrogen residues of the purine ring, with N1 and N9, in protonation state, functioning as presumed hydrogen bond donors and unprotonated N3 and N7 as hydrogen bond acceptors. This is the same interaction pattern as we previously described for the main nucleobase transporters of Trypanosoma brucei spp. and Leishmania major and makes it the first of the ENT-family genes that is functionally as well as genetically conserved between the three main kinetoplast pathogens.

Monitoring training, performance, biomarkers, and psychological state throughout a competitive season: a case study of a triathlete.

INTRODUCTION: Ironman triathletes undergo high workloads during competition preparation which can result in nonfunctional overreaching or overtraining syndrome if not matched with adequate recovery. PURPOSE: The purpose of this case study was to observe changes in physiological and psychological status over the course of a competitive season in a free-living triathlete. METHODS: The subject was a 41-year-old triathlete competing in three 113.1-km events. Over the course of a 40-week period, the participant arrived at the laboratory every 4 weeks and underwent body composition testing via air displacement plethysmography, a blood draw for analysis of various biomarkers, and a treadmill-based lactate threshold test. Workload during training and competitions was monitored via a wearable heart rate-monitoring device. RESULTS: Throughout the season, training volume remained high (12.5 ± 3.4 h/week) and body mass and fat-free mass (FFM) continuously decreased, while biomarkers including cortisol, testosterone, and markers of immunological status exhibited minor changes. Laboratory performance remained relatively consistent, while competition performance continually improved. Following the completion of the competitive period, training volume decreased, FFM remained below baseline levels, free cortisol increased, and both free and total testosterone decreased. CONCLUSIONS: Workload and recovery seem to have been properly managed throughout the season, evidenced by minimal fluctuations in endocrine and immunological markers. The reason for changes observed in testosterone, cortisol, and body composition following the last competition is unclear, though it may be attributed to changes in stressors and recovery practices outside of training. It is recommended that athletes follow a structured plan during the transition period into the offseason to ensure recovery of physiological state and to set up a productive offseason.

Quantification of measurable residual disease using duplex sequencing in adults with acute myeloid leukemia.

The presence of measurable residual disease (MRD) is strongly associated with treatment outcomes in acute myeloid leukemia (AML). Despite the correlation with clinical outcomes, MRD assessment has yet to be standardized or routinely incorporated into clinical trials and discrepancies have been observed between different techniques for MRD assessment. In 62 patients with AML, aged 18-60 years, in first complete remission after intensive induction therapy on the randomized phase III SWOG-S0106 clinical trial (clinicaltrials gov. Identifier: NCT00085709), MRD detection by centralized, high-quality multiparametric flow cytometry was compared with a 29-gene panel utilizing duplex sequencing (DS), an ultrasensitive next-generation sequencing method that generates double-stranded consensus sequences to reduce false positive errors. MRD as defined by DS was observed in 22 (35%) patients and was strongly associated with higher rates of relapse (68% vs. 13%; hazard ratio [HR] =8.8; 95% confidence interval [CI]: 3.2-24.5; P<0.001) and decreased survival (32% vs. 82%; HR=5.6; 95% CI: 2.3-13.8; P<0.001) at 5 years. DS MRD strongly outperformed multiparametric flow cytometry MRD, which was observed in ten (16%) patients and marginally associated with higher rates of relapse (50% vs. 30%; HR=2.4; 95% CI: 0.9-6.7; P=0.087) and decreased survival (40% vs. 68%; HR=2.5; 95% CI: 1.0-6.3; P=0.059) at 5 years. Furthermore, the prognostic significance of DS MRD status at the time of remission for subsequent relapse was similar on both randomized arms of the trial. These findings suggest that next-generation sequencing-based AML MRD testing is a powerful tool that could be developed for use in patient management and for early anti-leukemic treatment assessment in clinical trials.

Papillary Hemangioma Harbors Somatic GNA11 and GNAQ Mutations.

Papillary hemangioma (PH) is a small, primarily dermal lesion occurring predominantly in the head and neck in both children and adults. Its signature characteristics are dilated thin-walled channels containing papillary clusters of mainly capillary-sized vessels and endothelial cytoplasmic eosinophilic inclusions. Given certain histopathologic similarities to congenital hemangioma which harbor mutations in GNAQ and GNA11 , we investigated whether similar mutations are present in PH. Seven PH specimens were studied. All presented in the first 4 years of life, with one being noted at birth. With the exception of one lesion, all were in the head and neck. Lesions were bluish and ranged in size from 0.5 to 2.8 cm. Four samples had GNA11 p.Q209L and 3 had GNAQ p.Q209L missense mutations. Mutations in GNA11 and GNAQ are associated with other types of somatic vascular lesions including capillary malformation, congenital hemangioma, anastomosing hemangioma, thrombotic anastomosing hemangioma, and hepatic small cell neoplasm. Shared mutations in GNA11 and GNAQ may account for some overlapping clinical and pathologic features in these entities, perhaps explicable by the timing of the mutation or influence of the germline phenotype.

A randomized phase III study of standard versus high-dose cytarabine with or without vorinostat for AML.

Prior experience indicated that use of higher doses of cytarabine during induction for acute myeloid leukemia (AML) with a histone deacetylase inhibitor resulted in high response rates. S1203 was a randomized multicenter trial for previously untreated patients aged 18-60 with AML which compared daunorubicin and cytarabine (DA), idarubicin with higher dose cytarabine (IA) and IA with vorinostat (IA + V). The primary endpoint was event free survival (EFS). 738 patients were randomized: 261 to each DA and IA arms and 216 to the IA + V arm. 96, 456, and 150 patients had favorable-, intermediate-, and unfavorable-risk cytogenetics, respectively. 152 were NPM1 and 158 FLT3 mutated. The overall remission rate was 77.5% including 62.5% CR and 15.0% CRi. No differences in remission, EFS, or overall survival were observed among the 3 arms except for the favorable cytogenetics subset who had improved outcomes with DA and postremission high dose cytarabine. A trend towards increased toxicity was observed with the IA and IA + V arms. The use of higher dose cytarabine during induction therapy in younger patients with AML, with or without vorinostat, does not result in improved outcomes. (Funded by the US National Institutes of Health and others, ClinicalTrials.gov number, NCT01802333.).

Effects of Minimal-Equipment Resistance Training and Blood Flow Restriction on Military-Relevant Performance Outcomes.

ABSTRACT: Cintineo, HP, Chandler, AJ, Mastrofini, GF, Lints, BS, McFadden, BA, and Arent, SM. Effects of minimal-equipment resistance training and blood flow restriction on military-relevant performance outcomes. J Strength Cond Res 38(1): 55-65, 2024-This study compared minimal-equipment resistance training (RT) with and without blood flow restriction (BFR) to traditional-equipment RT on performance and body composition changes over 6 weeks. Reserve officers' training corps cadets and midshipmen (N = 54, 40.7% female) were randomized into traditional-equipment RT (TRAD), minimal-equipment RT (MIN), or minimal-equipment RT with BFR (MIN + BFR). Performance and body composition were assessed pretraining and post-training, and measures of intensity and workload were evaluated throughout. Performance assessments included the army combat fitness test (ACFT), countermovement vertical jump, 3RM bench press, and V̇O2max; body composition measures included body fat percentage, fat-free mass, and muscle and tendon thickness. All groups trained 4 days per week after a full-body routine. Data were analyzed by mixed-effects models (α = 0.05). Group-by-time interactions for 3RM deadlift and 3RM bench press (p < 0.004) showed larger improvements for TRAD compared with MIN and MIN + BFR. Time main effects for all other performance variables, body fat percentage, fat-free mass, and muscle thickness (p ≤ 0.035) indicated improvements in all groups. A group-by-time interaction for blood lactate (p < 0.001) and group main effects for heart rate (p < 0.001) and workload variables (p < 0.008) indicated higher intensity and workload for MIN and MIN + BFR compared with TRAD. A sex-by-time interaction for 3RM deadlift (p = 0.008) and sex-by-group-by-time interaction for 3RM bench press (p = 0.018) were also found. Minimal-equipment RT improved performance and body composition, although strength improvements were greater with traditional equipment. Minimal-equipment RT and minimal-equipment RT with BFR exhibited higher exertion levels than TRAD, although adaptations were similar. Overall, individuals can improve performance and body composition using portable, field-expedient RT equipment.

From a decentralized clinical trial to a decentralized and clinical-trial-in-a-box platform: Towards patient-centric and equitable trials.

Background/Objective: Despite the intuitive attractiveness of bringing research to participants rather than making them come to central study sites, widespread decentralized enrollment has not been common in clinical trials. Methods: The need for clinical research in the context of the COVID-19 pandemic, along with innovations in technology, led us to use a decentralized trial approach in our Phase 2 COVID-19 trial. We used real-time acquisition and transmission of health-related data using home-based monitoring devices and mobile applications to assess outcomes. This approach not only avoids spreading COVID-19 but it also can support inclusion of participants in more diverse socioeconomic circumstances and in rural settings. Results: Our team developed and deployed a decentralized trial platform to support patient engagement and adverse event reporting. Clinicians, engineers, and informaticians on our research team developed a Clinical-Trial-in-a-Box tool to optimally collect and analyze data from multiple decentralized platforms. Conclusion: Applying the decentralized model in Long COVID, using digital health technology and personal devices integrated with our telehealth platform, we share the lessons learned from our work, along with challenges and future possibilities.

Leveraging the Expertise of the CTSA Program to Increase the Impact and Efficiency of Clinical Trials.

Importance: Multicenter clinical trials play a critical role in the translational processes that enable new treatments to reach all people and improve public health. However, conducting multicenter randomized clinical trials (mRCT) presents challenges. The Trial Innovation Network (TIN), established in 2016 to partner with the Clinical and Translational Science Award (CTSA) Consortium of academic medical institutions in the implementation of mRCTs, consists of 3 Trial Innovation Centers (TICs) and 1 Recruitment Innovation Center (RIC). This unique partnership has aimed to address critical roadblocks that impede the design and conduct of mRCTs, in expectation of accelerating the translation of novel interventions to clinical practice. The TIN's challenges and achievements are described in this article, along with examples of innovative resources and processes that may serve as useful models for other clinical trial networks providing operational and recruitment support. Observations: The TIN has successfully integrated more than 60 CTSA institution program hubs into a functional network for mRCT implementation and optimization. A unique support system for investigators has been created that includes the development and deployment of novel tools, operational and recruitment services, consultation models, and rapid communication pathways designed to reduce delays in trial start-up, enhance recruitment, improve engagement of diverse research participants and communities, and streamline processes that improve the quality, efficiency, and conduct of mRCTs. These resources and processes span the clinical trial spectrum and enable the TICs and RIC to serve as coordinating centers, data centers, and recruitment specialists to assist trials across the National Institutes of Health and other agencies. The TIN's impact has been demonstrated through its response to both historical operational challenges and emerging public health emergencies, including the national opioid public health crisis and the COVID-19 pandemic. Conclusions and Relevance: The TIN has worked to reduce barriers to implementing mRCTs and to improve mRCT processes and operations by providing needed clinical trial infrastructure and resources to CTSA investigators. These resources have been instrumental in more quickly and efficiently translating research discoveries into beneficial patient treatments.