Predicting flow cytometry crossmatch results from single-antigen bead testing.

The aim of this study was to devise an algorithm that would predict flow cytometry crossmatch (FCXM) results using single-antigen bead (SAB) mean fluorescent intensity (MFI) levels using samples received through the National External Quality Assurance Scheme (NEQAS) 2B external proficiency testing scheme between 2019 and 2023. A total of 159 serum samples were retrospectively screened using LABScreen Single Antigen Class I and II (SAB), and 40 peripheral blood samples were human leucocyte antigen (HLA) typed with LABType SSO. Donor-specific antibodies were identified for each cell-serum combination tested, and cumulative MFI values were calculated for each test before correlating the screening result with the consensus crossmatch results for this scheme. HLA Class I MFIs were combined to predict the T cell crossmatch. For the B cell crossmatch prediction, two options were considered: (i) HLA Class II MFI values alone and (ii) HLA Class I + Class II MFIs. Receiver operating characteristic analysis was carried out to identify the combined MFI threshold that predicted NEQAS consensus results with the greatest sensitivity and specificity. HLA Class I combined MFI >5000 predicted T cell crossmatch results with 96% sensitivity, 100% specificity, 100% positive predictive value (PPV) and 92% negative predictive value (NPV). For B cell results, HLA Class I + Class II combined MFIs >11,000 gave the best model, showing 97% sensitivity, 82% specificity, 96% PPV and 85% NPV. However, for samples with only HLA Class II sensitization, combined MFIs >13,000 improved the B cell crossmatch predictions: 92% sensitivity, 95% specificity, 96% PPV and 91% NPV. Using this model, combined MFI can be used to predict the immunological risk posed by donor-specific antibodies when it is not possible to carry out an FCXM.

Chromatin bridges, not micronuclei, activate cGAS after drug-induced mitotic errors in human cells.

Mitotic errors can activate cyclic GMP-AMP synthase (cGAS) and induce type I interferon (IFN) signaling. Current models propose that chromosome segregation errors generate micronuclei whose rupture activates cGAS. We used a panel of antimitotic drugs to perturb mitosis in human fibroblasts and measured abnormal nuclear morphologies, cGAS localization, and IFN signaling in the subsequent interphase. Micronuclei consistently recruited cGAS without activating it. Instead, IFN signaling correlated with formation of cGAS-coated chromatin bridges that were selectively generated by microtubule stabilizers and MPS1 inhibitors. cGAS activation by chromatin bridges was suppressed by drugs that prevented cytokinesis. We confirmed cGAS activation by chromatin bridges in cancer lines that are unable to secrete IFN by measuring paracrine transfer of 2'3'-cGAMP to fibroblasts, and in mouse cells. We propose that cGAS is selectively activated by self-chromatin when it is stretched in chromatin bridges. Immunosurveillance of cells that fail mitosis, and antitumor actions of taxanes and MPS1 inhibitors, may depend on this effect.

Coronary artery dilation in non-hospitalised children with asymptomatic or mild COVID-19.

INTRODUCTION: Infection with Sars-CoV-2 is known to cause cardiac injury and coronary artery changes in moderate to severe acute COVID-19 and post-acute multisystem inflammatory syndrome in children (MIS-C). However, little is known about the potential for cardiac involvement, in particular coronary artery dilation, in asymptomatic or mild cases of COVID-19. METHODS: A retrospective review of children ≤ 18 years of age with a history of asymptomatic or mild COVID-19 disease who underwent echocardiography after Sars-CoV-2 infection is conducted. Patients were excluded if they had been hospitalised for COVID-19/MIS-C or had a history of cardiac disease that could affect coronary artery dimension. Coronary artery dilation was defined as the Boston Z-score greater than 2.0. RESULTS: One hundred and fifty-seven patients met inclusion criteria with a mean age of 9.4 years (+/- 5.4 years). Eighty-four (54%) patients were identified as having COVID-19 through positive antibody testing. All patients underwent electrocardiogram and echocardiogram as part of their cardiology evaluation. One hundred and thirty-five (86%) patients had a normal evaluation or only a minor variant on electrocardiogram, while 22 patients had abnormalities on echocardiogram, 4 of which demonstrated coronary artery dilation based on the Boston Z-score. CONCLUSIONS: Much of the literature for post-infectious screening and follow-up focuses on patients with a history of moderate to severe COVID-19 disease, emphasising the need for surveillance for the potential development of myocarditis. In this study, 4 out of 157 (2.5%) children with a history of asymptomatic or mild COVID-19 disease without MIS-C were found to have some degree of coronary artery dilation. The significance of this finding currently remains unknown.

Unit cohesion during deployment and post-deployment mental health: is cohesion an individual- or unit-level buffer for combat-exposed soldiers?

BACKGROUND: Unit cohesion may protect service member mental health by mitigating effects of combat exposure; however, questions remain about the origins of potential stress-buffering effects. We examined buffering effects associated with two forms of unit cohesion (peer-oriented horizontal cohesion and subordinate-leader vertical cohesion) defined as either individual-level or aggregated unit-level variables. METHODS: Longitudinal survey data from US Army soldiers who deployed to Afghanistan in 2012 were analyzed using mixed-effects regression. Models evaluated individual- and unit-level interaction effects of combat exposure and cohesion during deployment on symptoms of post-traumatic stress disorder (PTSD), depression, and suicidal ideation reported at 3 months post-deployment (model n's = 6684 to 6826). Given the small effective sample size (k = 89), the significance of unit-level interactions was evaluated at a 90% confidence level. RESULTS: At the individual-level, buffering effects of horizontal cohesion were found for PTSD symptoms [B = -0.11, 95% CI (-0.18 to -0.04), p < 0.01] and depressive symptoms [B = -0.06, 95% CI (-0.10 to -0.01), p < 0.05]; while a buffering effect of vertical cohesion was observed for PTSD symptoms only [B = -0.03, 95% CI (-0.06 to -0.0001), p < 0.05]. At the unit-level, buffering effects of horizontal (but not vertical) cohesion were observed for PTSD symptoms [B = -0.91, 90% CI (-1.70 to -0.11), p = 0.06], depressive symptoms [B = -0.83, 90% CI (-1.24 to -0.41), p < 0.01], and suicidal ideation [B = -0.32, 90% CI (-0.62 to -0.01), p = 0.08]. CONCLUSIONS: Policies and interventions that enhance horizontal cohesion may protect combat-exposed units against post-deployment mental health problems. Efforts to support individual soldiers who report low levels of horizontal or vertical cohesion may also yield mental health benefits.

An early evaluation of the HISTO SPOT® AB ID Class I & II test in cardiothoracic transplant patients.

The HISTO SPOT® AB ID assay (BAG Diagnostics GmbH) is a novel single antigen HLA Class I & II antibody definition test used with the MR.SPOT® processor. We compared this assay with Luminex® -based assays to assess its potential application in defining unacceptable antigens for transplantation in patients awaiting transplants with cardiothoracic organs. A cohort of 40 sensitized cardiothoracic patients were identified, and one sample was selected from each patient. The required screening was based on the patients' antibody profiles (Class I, n = 17, Class II, n = 11, Class I & II, n = 12). Samples were screened with LABScreen™ Single Antigen (SAg), LIFECODES® LSA™, HISTO SPOT® AB ID, and an acid modified LABScreen™ SAg test for detecting antibodies against denatured HLA. Results indicated that HISTO SPOT® AB ID had reduced sensitivity (68% for Class I; 69% for Class II). When compared to LABScreen™ and LIFECODES® , HISTO SPOT® AB ID failed to detect Luminex® -defined antibodies with median fluorescence intensity (MFI) ranging from 1114 to 24,489. The HISTO SPOT® AB ID panel used in the study had reduced antigen representation compared with Luminex® -based assays which further compromised its capacity for antibody detection and definition. Further work is needed to evaluate the clinical relevance of these differences between the performance of HISTO SPOT® and Luminex® -based methods.

Coronary Artery Dilation in an Asymptomatic Pediatric Patient with COVID19 Antibodies.

We describe a 16-year-old asymptomatic male who presented with coronary artery dilation (z score + 2.3) identified on echo performed solely for presence of COVID-19 antibodies. This case raises the question of whether cardiac screening should be considered for all patients with a history of COVID-19.

The Deconditioning Effect of the COVID-19 Pandemic on Unaffected Healthy Children.

The COVID-19 pandemic has had devastating direct consequences on the health of affected patients. It has also had a significant impact on the ability of unaffected children to be physically active. We evaluated the effect of deconditioning from social distancing and school shutdowns implemented during the COVID-19 pandemic on the cardiovascular fitness of healthy unaffected children. This is a single-center, retrospective case-control study performed in an urban tertiary referral center. A cohort of 10 healthy children that underwent cardiopulmonary exercise testing after COVID-19 hospital restrictions were lifted was compared to a matched cohort before COVID-19-related shutdowns on school and after-school activities. Comparisons of oxygen uptake (VO2) max and VO2 at anaerobic threshold between the pre- and post-COVID-19 cohorts were done. The VO2 max in the post-COVID cohort was significantly lower than in the pre-COVID cohort (39.1 vs. 44.7, p = 0.031). Only one out of ten patients had a higher VO2 max when compared to their matched pre-COVID control and was also the only patient with a documented history of participation in varsity-type athletics. The percentile of predicted VO2 was significantly lower in the post-COVID cohort (95% vs. 105%, p = 0.042). This study for the first time documented a significant measurable decline in physical fitness of healthy children as a result of the COVID-19 pandemic and its associated restrictions. Measures need to be identified that encourage and facilitate regular exercise in children in a way that are not solely dependent on school and organized after-school activities.

Epipericardial Fat Pad Necrosis-A Rare Cause of Chest Pain in an Adolescent.

ABSTRACT: Epipericardial fat necrosis is a rare cause of acute pleuritic chest pain reported in approximately 40 cases. This diagnosis mimics a myocardial infarction, pulmonary embolism, or pericarditis; however, the cardiac enzymes and electrocardiogram are usually normal. We present the first reported case of epipericardial fat necrosis in an adolescent.

Intergroup Randomized Phase III Study of Postoperative Oxaliplatin, 5-Fluorouracil, and Leucovorin Versus Oxaliplatin, 5-Fluorouracil, Leucovorin, and Bevacizumab for Patients with Stage II or III Rectal Cancer Receiving Preoperative Chemoradiation: A Trial of the ECOG-ACRIN Research Group (E5204).

BACKGROUND: The addition of bevacizumab to chemotherapy improved outcomes for patients with metastatic colon cancer. E5204 was designed to test whether the addition of bevacizumab to mFOLFOX6, following neoadjuvant chemoradiation and definitive surgery, could improve overall survival (OS) in patients with stage II/III adenocarcinoma of the rectum. SUBJECTS, MATERIALS, AND METHODS: Patients with stage II/III rectal cancer who had completed neoadjuvant 5-fluorouracil-based chemoradiation and had undergone complete resection were enrolled. Patients were randomized to mFOLFOX6 (Arm A) or mFOLFOX6 with bevacizumab (Arm B) administered every 2 weeks for 12 cycles. RESULTS: E5204 registered only 355 patients (17% of planned accrual goal) as it was terminated prematurely owing to poor accrual. At a median follow-up of 72 months, there was no difference in 5-year overall survival (88.3% vs. 83.7%) or 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. The rate of treatment-related grade ≥ 3 adverse events (AEs) was 68.8% on Arm A and 70.7% on Arm B. Arm B had a higher proportion of patients who discontinued therapy early as a result of AEs and patient withdrawal than did Arm A (32.4% vs. 21.5%, p = .029).The most common grade 3-4 treatment-related AEs were neutropenia, leukopenia, neuropathy, diarrhea (without prior colostomy), and fatigue. CONCLUSION: At 17% of its planned accrual, E5204 did not meet its primary endpoint. The addition of bevacizumab to FOLFOX6 in the adjuvant setting did not significantly improve OS in patients with stage II/III rectal cancer. IMPLICATIONS FOR PRACTICE: At 17% of its planned accrual, E5204 was terminated early owing to poor accrual. At a median follow-up of 72 months, there was no significant difference in 5-year overall survival (88.3% vs. 83.7%) or in 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. Despite significant advances in the treatment of rectal cancer, especially in improving local control rates, the risk of distant metastases and the need to further improve quality of life remain a challenge. Strategies combining novel agents with chemoradiation to improve both distant and local control are needed.

Frontline brentuximab vedotin in combination with dacarbazine or bendamustine in patients aged ≥60 years with HL.

Patients aged ≥60 years with treatment-naive Hodgkin lymphoma (HL) have few treatment options and inferior survival due to treatment-related toxicities and comorbidities. This phase 2, nonrandomized, open-label study evaluated brentuximab vedotin (BV) monotherapy (results previously reported), BV plus dacarbazine (DTIC), and BV plus bendamustine. Patients had classical HL and were ineligible for or declined frontline chemotherapy. Twenty-two patients received 1.8 mg/kg BV and 375 mg/m2 DTIC for up to 12 cycles, and 20 more patients received 1.8 mg/kg BV plus 90 or 70 mg/m2 bendamustine for up to 6 cycles (dose reduced due to toxicity). Subsequent BV monotherapy was allowed. Approximately 30 patients were to receive BV plus bendamustine; however, the incidence of serious adverse events (65%) and 2 deaths on study led to discontinuation of bendamustine and cessation of enrollment. Most patients had stage III/IV disease, and approximately half had ≥3 comorbidities or were impaired in ≥1 aspect that significantly interfered with quality of life. For BV plus DTIC, the objective response rate (ORR) was 100% and the complete remission (CR) rate was 62%. To date, the median progression-free survival (PFS) is 17.9 months. For BV plus bendamustine, the ORR was 100% and the CR rate was 88%. Neither the median PFS nor overall survival was reached. For elderly patients with HL, BV plus DTIC may be a frontline option based on tolerability and response duration. Despite activity, BV plus bendamustine is not a tolerable regimen in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01716806.

Drug Use Mediates the Relationship Between Depressive Symptoms and Adherence to ART Among Recently Incarcerated People Living with HIV.

Depression is a known risk factor for antiretroviral therapy (ART) non-adherence, but little is known about the mechanisms explaining this relationship. Identifying these mechanisms among people living with HIV (PLHIV) after release from prison is particularly important, as individuals during this critical period are at high risk for both depression and poor ART adherence. 347 PLHIV recently released from prison in North Carolina and Texas were included in analyses to assess mediation of the relationship between depressive symptoms at 2 weeks post-release and ART adherence (assessed by unannounced telephone pill counts) at weeks 9-21 post-release by the hypothesized explanatory mechanisms of alcohol use, drug use, adherence self-efficacy, and adherence motivation (measured at weeks 6 and 14 post-release). Indirect effects were estimated using structural equation models with maximum likelihood estimation and bootstrapped confidence intervals. On average, participants achieved 79% ART adherence. The indirect effect of depression on adherence through drug use was statistically significant; greater symptoms of depression were associated with greater drug use, which was in turn associated with lower adherence. Lower adherence self-efficacy was associated with depressive symptoms, but not with adherence. Depression screening and targeted mental health and substance use services for depressed individuals at risk of substance use constitute important steps to promote adherence to ART after prison release.

Antiretroviral Adherence Following Prison Release in a Randomized Trial of the imPACT Intervention to Maintain Suppression of HIV Viremia.

Many people living with HIV (PLWH) pass through correctional facilities each year, a large proportion of whom do not maintain viral suppression following release. We examined the effects of imPACT, an intervention designed to promote post-release viral suppression, on antiretroviral therapy (ART) adherence. PLWH awaiting release from prisons in two southern states were randomized to imPACT (consisting of motivational interviewing, care linkage coordination, and text message medication reminders) versus standard care (SC). ART adherence, measured by unannounced monthly telephone pill counts, was compared between study arms over 6 months post-release. Of 381 participants eligible for post-release follow-up, 302 (79%) completed ≥ 1 of 6 possible pill counts (median: 4; IQR 1-6). Average adherence over follow-up was 80.3% (95% CI 77.5, 83.1) and 81.0% (78.3, 83.6) of expected doses taken in the imPACT and SC arms, respectively. There was no difference between arms when accounting for missing data using multiple imputation (mean difference = - 0.2 percentage points [- 3.7, 3.3]), controlling for study site and week of follow-up. Of the 936 (40.9%) pill counts that were missed, 212 (22.7%) were due to re-incarceration. Those who missed pill counts for any reason were more likely to be unsuppressed, suggesting that they had lower adherence. However, missingness was balanced between arms. Among PLWH released from prison, ART adherence averaged > 80% in both study arms over 6 months-a level higher than seen with most other chronic diseases. However, missing data may have led to an overestimate of adherence. Factors independent of the intervention influence ART adherence in this population and should be identified to inform future targeted interventions.

Self-reported antiretroviral therapy adherence and viral load in criminal justice-involved populations.

BACKGROUND: Self-reported antiretroviral therapy (ART) adherence measures that are associated with plasma viral load (VL) are valuable to clinicians and researchers, but are rarely examined among groups vulnerable to dropping out of care. One-seventh of all those living with HIV pass through incarceration annually and criminal-justice (CJ) involved people living with HIV (PLH) are vulnerable to falling out of care. We examined the association of self-reported ART adherence with VL in a criminal-justice sample compared to a routine-care sample. METHODS: Samples: We examined data from a multisite collaboration of studies addressing the continuum of HIV care among CjJ involved persons in the Seek, Test, Treat, and Retain cohort. Data pooled from seven CJ- studies (n = 414) were examined and compared with the routine-care sample from the Centers for AIDS Research Network of Integrated Clinical Systems' seven sites (n = 11,698). MEASURES: In both samples, data on self-reported percent ART doses taken were collected via the visual analogue scale adherence measure. Viral load data were obtained by blood-draw. ANALYSIS: We examined the associations of adherence with VL in both cohorts using mixed effects linear regression of log-VL, and mixed effects logistic regression of binary VL (≥ 200 copies/mL) outcomes. Interactions by CD4 count and self-reported health status were also tested. RESULTS: Among the CJ sample, the coefficient for log-VL was - 0.31 (95% CI = - 0.43, - 0.18; P < 0.01) and that in the routine-care sample was - 0.42 (95% CI = - 0.45, - 0.38; P < 0.01). For the logistic regression of binary detectable VL on 10% increments of adherence we found the coefficient was - 0.26 (95% CI = - 0.37, - 0.14; P < 0.01) and in the routine-care sample it was - 0.38 (95% CI = - 0.41, - 0.35; P < 0.01). There was no significant interaction by CD4 count level in the CJ sample, but there was in the routine-care sample. Conversely, there was a significant interaction by self-reported health status level in the criminal-justice sample, but not in the routine-care sample. CONCLUSIONS: The visual analogue scale is valid and useful to measure ART adherence, supporting treatment for CJ- involved PLH vulnerable to falling out of care. Research should examine adherence and VL in additional populations.

Treatment Retention Satisfaction, and Therapeutic Progress for Justice-Involved Individuals Referred to Community-Based Medication-Assisted Treatment.

Background: Limited research has examined factors associated with medication-assisted treatment for justice-involved individuals. Objectives: The current study used a mixed-method design to examine the influence of client- and counselor-level factors on 90-day treatment retention, satisfaction, and progress for justice-involved individuals referred to medication-assisted treatment. Methods: The effects of co-occurring disorders (i.e., psychiatric symptoms, anxiety, depression), social functioning (i.e., social support, self-esteem), substance use severity, and treatment motivation on treatment retention, treatment satisfaction, and treatment progress while controlling for counselor-level variance were assessed through multilevel modeling. Results: Fewer co-occurring disorders and more social support were related to greater treatment satisfaction and progress. A higher level of treatment motivation was associated with greater treatment progress. Mediation of treatment satisfaction on the relationship between client-level factors and treatment progress also was tested. Depression was negatively associated with treatment satisfaction, which in turn led to lower ratings of treatment progress. Social support was positively correlated with treatment satisfaction, which in turn was positively correlated with treatment progress. The association of client substance use severity with treatment retention differed between counselors, so did the association of co-occurring disorders and treatment motivation with treatment satisfaction. Qualitative analyses that were derived from counselors' perception of factors relating to recovery success underscored the importance of integrated interventions, social support, treatment motivation, and therapeutic alliance, and their associations with treatment outcomes. Conclusions/Importance: The current findings highlight the importance of integrated treatment services, collaborating with community corrections, and teaching clients strategies for dealing with deviant peers as to facilitating recovery.

Perceived Wellness Associated With Practice and Competition in National Collegiate Athletic Association Division I Football Players.

Wellman, AD, Coad, SC, Flynn, PJ, Siam, TK, and McLellan, CP. Perceived wellness associated with practice and competition in National Collegiate Athletic Association Division I football players. J Strength Cond Res 33(1): 112-124, 2019-This study assessed the influence of movement demands resulting from weekly practice sessions and games, on perceived wellness measurements taken postgame (Sunday) and 48 hours pregame (Thursday) throughout the in-season period in National Collegiate Athletic Association (NCAA) Division I football players. Thirty players were monitored using global positioning system receivers (OptimEye S5; Catapult Innovations) during 12 games and 24 in-season practices. Movement variables included low-intensity distance, medium-intensity distance, high-intensity distance, sprint distance, total distance, player load, and acceleration and deceleration distance. Perceived wellness, including fatigue, soreness, sleep quality and quantity, stress, and mood, was examined using a questionnaire on a 1-5 Likert scale. Multilevel mixed linear regressions determined the differential effects of movement metrics on perceived wellness. Post hoc tests were conducted to evaluate the pairwise differentials of movement and significance for wellness ratings. Notable findings included significantly (p ≤ 0.05) less player load, low-intensity distance, medium-intensity distance, high-intensity distance, total distance, and acceleration and deceleration distance at all intensities, in those reporting more favorable (4-5) ratings of perceived fatigue and soreness on Sunday. Conversely, individuals reporting more favorable Sunday-perceived stress ratings demonstrated significantly (p ≤ 0.05) higher player load, low-intensity and medium-intensity distance, total distance, low-intensity and medium-intensity deceleration distance, and acceleration distance at all intensities than individuals reporting less favorable (1-2) perceived stress ratings. Data from this study provide a novel investigation of perceived wellness associated with college football practice and competition. Results support the use of wellness questionnaires for monitoring perceived wellness in NCAA Division I college football players.

Comparison of Preseason and In-Season Practice and Game Loads in National Collegiate Athletic Association Division I Football Players.

Wellman, AD, Coad, SC, Flynn, PJ, Siam, TK, and McLellan, CP. A Comparison of preseason and in-season practice and game loads in NCAA Division I football players. J Strength Cond Res 33(4): 1020-1027, 2019-The aim of this study was to quantify the individual practice and game loads throughout the National Collegiate Athletic Association (NCAA) Division I football season to determine whether significant differences exist between the practice loads associated with the preseason training camp and those undertaken during the in-season period. Thirty-one NCAA Division I football players were monitored using the global positioning system and triaxial accelerometer (IA) (MinimaxX S5; Catapult Innovations, Melbourne, Australia) during 22 preseason practices, 36 in-season practices, and 12 competitions. The season was divided into 4 distinct phases for data analysis: preseason week 1 (preseason 1), preseason week 2 (preseason 2), preseason week 3 (preseason 3), and 12 in-season weeks. Individual IA data sets represented players from every offensive and defensive position group Wide Receiver (WR: n = 5), Offensive Line (OL: n = 4), Running Back (RB: n = 4), Quarterback (QB: n = 2), Tight End (TE: n = 3), Defensive Line (DL: n = 4), Linebacker (LB: n = 4), Defensive Back (DB: n = 5). Data were set at the practice level, where an observation for each player's maximum player load (PLMax) or mean player load (PLMean) from each training camp phase was referenced against each player's respective PL from each game, Tuesday, Wednesday, or Thursday practice session. Notable results included significantly (p ≤ 0.05) greater PLMax values attributed to preseason 1 compared with PL resulting from all in-season practices, and significantly (p ≤ 0.05) higher cumulative PL reported for preseason 1, 2, and 3 compared with every in-season week. Data from this study augment our understanding of the practice demands experienced by NCAA Division I college football players, and provide scope for the improvement of preseason practice design and physical conditioning strategies for coaches seeking to optimize performance.

Heterogeneity in the psychiatric presentation of behavioural variant frontotemporal dementia (bvFTD).

OBJECTIVE: This article describes how the onset of bvFTD can be heralded by psychiatric symptoms. METHOD: Case reports are described with reference to the relevant literature review. RESULTS: Three patients were admitted with psychiatric symptoms, including depression, mania, psychosis and catatonia. Two had been previously diagnosed with a psychiatric disorder. All three were diagnosed with probable bvFTD. CONCLUSION: bvFTD is an important differential diagnosis to consider when patients present with atypical psychiatric symptoms.

Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572.

BACKGROUND: Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. METHODS: Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)-naive patients and patients who progressed after prior VEGFi. RESULTS: The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients. CONCLUSIONS: The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63. © 2018 American Cancer Society.

Effectiveness of echocardiography simulation training for paediatric cardiology fellows in CHD.

Simulation is used in many aspects of medical training but less so for echocardiography instruction in paediatric cardiology. We report our experience with the introduction of simulator-based echocardiography training at Weill Cornell Medicine for paediatric cardiology fellows of the New York-Presbyterian Hospital of Columbia University and Weill Cornell Medicine. Knowledge of CHD and echocardiographic performance improved following simulation-based training. Simulator training in echocardiography can be an effective addition to standard training for paediatric cardiology trainees.