Search

Background: Biomarker measurements improve the phenotyping of patients with severe uncontrolled asthma (SUA) and predict therapeutic responses. The use of biomarkers in asthma, however, remains underused. Objective: To test the hypothesis that biomarker measurements of patients with SUA remain markedly underused and contributes to asthma morbidity and oral corticosteroid use. Methods: Leveraging claims data linked to electronic health record data, we calculated biomarker use by providers treating patients with SUA from January 2017 to August 2020. Results: From 3.6 million clients, 3817 had a primary diagnosis of asthma; most were between 50 and 60 years old. Also, 63.2% were female patients; those under ages 10 years were primarily boys. Of the 728 patients who reported race, 69.9% were white and 21.8% were African American. Of the 840 who reported ethnicity, 14% were Latinx. A predetermined definition of SUA identified 348 patients with SUA. In a nested sample of 151 patients with SUA, 43% were managed by primary care physicians (PCP), 4% by specialists, and 49.7% by both. Of this sample, 61.5% had a measurement of serum eosinophils, 9.9% total immunoglobulin E values, and 9.3% radioallergosorbent skin tests; 38% received no tests, whereas 9.9% had more than one. Specialists ordered a biomarker test 4.6 times more often than did PCPs, whereas PCPs ordered 70% of the prednisone prescriptions for recurrent asthma exacerbations. Conclusion: Specialists were more likely to order biomarkers than were PCPs. Patients managed exclusively by PCPs were more likely prescribed oral prednisone. Real-world evidence shows that biomarkers are infrequently used to characterize patients with SUA, especially among patients exclusively managed by PCPs. Programs that encouraged biomarker use may improve SUA management and oral corticosteroid burden.

BACKGROUND: Chronic vulvar pain is a prevalent but often misdiagnosed and undertreated condition that adversely impacts quality of life. A large proportion of women report not seeking care for chronic vulvar pain, but little is known about the factors that underlie care-seeking decisions. MATERIALS AND METHODS: We used a large, population-based survey of women aged 18–40 years to assess a history of chronic vulvar burning, pain on contact, or itching that had lasted ≥3 months. The survey also captured demographic characteristics and comorbidities. Women were asked if they had ever sought care for their chronic vulvar condition. Demographic characteristics and comorbidities were evaluated across pain categories and by care-seeking behaviors. RESULTS: A higher proportion of women who described their pain as burning only and both burning and pain on contact had sought care for their pain (69.2% and 85.2%, respectively) compared with pain on contact only (41.8%). Women who described their pain as pain on contact only were also less likely to see multiple providers and to have ever received treatment for their pain. Care seekers were more likely to be married, have a college education, have a normal body mass index, and have multiple gynecologic comorbidities. CONCLUSIONS: Our study suggests that care-seeking behavior varies by pain type. Less than half of women who characterized their pain as pain on contact had sought medical care. Those who did seek care reported seeing fewer providers than those who experienced burning. Providers may wish to proactively ask patients about pain on contact.

The cornerstone of management in patients with acute promyelocytic leukemia (APL) is early diagnosis and prompt initiation of treatment with an all-trans retinoic acid (ATRA)-based regimen. Identification of the t(15;17)(PML-RARA) chromosomal translocation through conventional cytogenetics fluorescence in-situ hybridization (FISH) or detection of the promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) fusion through RT-PCR represent the current standard of care for diagnosing APL. However, about 1–2% of patients with APL have a variant translocation involving other fusion partners with RARα besides PML. These patients present a unique diagnostic and clinical challenge in that conventional cytogenetics in addition to FISH and/or RT-PCR for PML-RARα may fail to identify these clinically relevant genetic lesions leading to an inappropriate diagnosis and treatment. We present two cases of patients who had APL with variant translocations whose bone marrow specimens were sent to the University of Michigan for enrollment in the MI-ONCOSEQ study (HUM00067928) after standard testing failed to identify PML-RARα or t(15;17) despite a phenotypic concern for this diagnosis. In these two patients, whole exome and transcriptome profiling via the MI-ONCOSEQ platform identified a PRKAR1A-RARα fusion in one patient and ZBTB16-RARα fusion in another patient. These cases illustrate the utility of whole exome and transcriptome profiling in diagnosing variant translocations in patients in whom there is a high clinical suspicion for APL based on hematopathology review.

Novel treatment strategies have shifted the treatment landscape for patients with diffuse large B-cell lymphoma, particularly for those with relapsed/refractory disease. However, uncertainty remains regarding the therapeutic value of these novel agents compared to existing salvage chemotherapy regimens. In addition, the high cost associated with these agents puts both patients and health systems at risk of financial toxicity, further complicating their use. The development of clinical pathways incorporating oncology stewardship principles are necessary in order to maximize value-based care. This comprehensive review assesses the efficacy and safety data available for novel treatment options in relapsed/refractory diffuse large B-cell lymphoma and applies stewardship principles to evaluate their optimal place in therapy, with the aim of optimizing safe, effective, and financially responsible patient care.

AAV-mediated gene therapy is a promising approach for treating genetic hearing loss. Replacement or editing of the Tmc1 gene, encoding hair cell mechanosensory ion channels, is effective for hearing restoration in mice with some limitations. Efficient rescue of outer hair cell function and lack of hearing recovery with later-stage treatment remain issues to be solved. Exogenous genes delivered with the adeno-associated virus (AAV)9-PHP.B capsid via the utricle transduce both inner and outer hair cells of the mouse cochlea with high efficacy. Here, we demonstrate that AAV9-PHP.B gene therapy can promote hair cell survival and successfully rescues hearing in three distinct mouse models of hearing loss. Tmc1 replacement with AAV9-PHP.B in a Tmc1 knockout mouse rescues hearing and promotes hair cell survival with equal efficacy in inner and outer hair cells. The same treatment in a recessive Tmc1 hearing-loss model, Baringo, partially recovers hearing even with later-stage treatment. Finally, dual delivery of Streptococcus pyogenes Cas9 (SpCas9) and guide RNA (gRNA) in separate AAV9-PHP.B vectors selectively disrupts a dominant Tmc1 allele and preserves hearing in Beethoven mice, a model of dominant, progressive hearing loss. Tmc1-targeted gene therapies using single or dual AAV9-PHP.B vectors offer potent and versatile approaches for treating dominant and recessive deafness.

Malaria and malnutrition remain primary causes of morbidity and mortality among children younger than 5 years in Africa. Studies investigating the association between malnutrition and subsequent malaria outcomes are inconsistent. We studied the effects of malnutrition on incidence and prevalence of malaria parasitemia in data from a cohort studied in the 1990s. Data came from the Asembo Bay cohort study, which collected malaria and health information on children from 1992 to 1996 in western Kenya. Infants were enrolled at birth and followed up until loss to follow-up, death, end of study, or 5 years old. Anthropometric measures and blood specimens were obtained monthly. Nutritional exposures included categorized Z-scores for height-for-age, weight-for-age, and weight-for-height. Febrile parasitemia and afebrile parasitemia were assessed with thick and thin blood films. Multiply imputed and weighted multinomial generalized estimating equation models estimated odds ratios (OR) for the association between exposures and outcomes. The sample included 1,182 children aged 0–30 months who contributed 18,028 follow-up visits. There was no significant association between malnutrition and either incident febrile parasitemia or prevalent febrile parasitemia. Prevalence ORs for afebrile parasitemia increased from 1.07 (95% CI: 0.89, 1.29) to 1.35 (1.03, 1.76) as stunting severity increased from mild to severe, and from 1.16 (1.02, 1.33) to 1.35 (1.09, 1.66) as underweight increased from mild to moderate. Stunting and underweight did not show a significant association with subsequent febrile parasitemia infections, but they did show a modest association with subsequent afebrile parasitemia. Consideration should be given to testing malnourished children for malaria, even if they present without fever.

Background: Toileting behaviors are increasingly recognized as factors potentially contributing to development of lower urinary tract symptoms (LUTS). Objectives: To examine adult women's toileting behaviors and LUTS across age and race/ethnicity groups and relationships between toileting behaviors and LUTS. Design: Planned secondary analysis of questionnaire data collected in a focus group study on bladder health. Settings: Questionnaires were completed at the conclusion of focus groups conducted in community settings affiliated with seven research centers across the United States. Participants: Community-living women regardless of LUTS status. Methods: Forty-four focus groups were conducted with 360 adolescent and adult cisgender women. After each focus group, participants completed questionnaires to assess toileting behaviors (Toileting Behaviors-Women's Elimination Behaviors Scale (TB-WEB)) and their experience of LUTS (Lower Urinary Tract Symptom Tool), This analysis includes quantitative data from the subgroup of 316 participants who completed the questionnaires. Results: Participants ranged in age from 18 to 93 years (Mean= 50.2 years). A significant effect for age was found for delayed voiding behavior, reported by 76.5% of women ages 18–25 years and 21.9% of those 75+ years (p

Background: We recently introduced the myocardial-ischemic-injury-index (MI3), a machine learning algorithm that predicts the likelihood of myocardial infarction in patients with suspected acute coronary syndrome. Whether this algorithm performs well in routine clinical practice or predicts subsequent events is unknown.Methods: MI3 was validated in a prespecified exploratory analysis from a multi-centre randomised trial that included consecutive patients with suspected acute coronary syndrome undergoing serial high-sensitivity cardiac troponin I measurement. Patients with ST-segment elevation myocardial infarction were excluded. MI3 incorporates age, sex, and two troponin measurements to compute a value (0-100) reflecting an individual’s likelihood of myocardial infarction during the index visit and estimates diagnostic performance metrics at the computed score. Model performance for an index diagnosis of myocardial infarction, and for subsequent myocardial infarction or cardiovascular death at one year was determined using previously defined low- and high-probability MI3 thresholds (1·6 and 49·7, respectively). Findings: In total, 20,761 patients (64±16 years, 46% women) were included of whom 3,272 (15·8%) had myocardial infarction. MI3 had an area under the receiver-operating-characteristic curve of 0·949 (95% confidence interval 0·946-0·952) identifying 12,983 (62·5%) patients as low-probability (sensitivity 99·3% [99·0-99·6%], negative predictive value 99·8% [99·8-99·9%]), and 2,961 (14·3%) as high-probability (specificity 95·0% [94·6-95·3%], positive predictive value 70·4% [68·7-72·0%]). At one year, subsequent myocardial infarction or cardiovascular death occurred more often in high-probability compared to low-probability patients (17·6% [520/2,961] versus 1·5% [197/12,983], PInterpretation: In consecutive patients undergoing serial cardiac troponin measurement for suspected acute coronary syndrome, the MI3 algorithm accurately estimates the likelihood of myocardial infarction and predicts subsequent adverse cardiovascular events.

BackgroundThe biological mechanisms involved in SARS-CoV-2 infection are only partially understood. Thus we explored the plasma metabolome of patients infected with SARS-CoV-2 to search for diagnostic and/or prognostic biomarkers and to improve the knowledge of metabolic disturbance in this infection.Materials and Methods We analyzed the plasma metabolome of 55 patients infected with SARS-CoV-2 and 45 controls by LC-HRMS at the time of diagnosis (D0). We first evaluated the ability to predict the diagnosis from the metabotype at D0 in an independent population. Next, we assessed the feasibility of predicting the disease evolution at the 7th and 15th day.ResultsPlasma metabolome allowed us to generate a discriminant multivariate model to predict the diagnosis of SARS-CoV-2 in an independent population (accuracy>74%, sensitivity, specificity>75%). We identified the role of the cytosine and tryptophan-nicotinamide pathways in this discrimination. However, metabolomic exploration modestly explained the disease evolution.DiscussionHere, we present the first metabolomic study in SARS-CoV-2 patients which showed a high reliable prediction of early diagnosis. We have highlighted the role of the tryptophan-nicotinamide pathway clearly linked to inflammatory signals and microbiota, and the involvement of cytosine, previously described as a coordinator of cell metabolism in SARS-CoV-2. These findings could open new therapeutic perspectives as indirect targets.

BackgroundPediatric and adult high-grade glioma (HGG) frequently harbor PDGFRA alterations. We hypothesized that co-treatment with everolimus may improve the efficacy of dasatinib in PDGFRα-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib.MethodsDose response, synergism studies, P-gp inhibition and pharmacokinetic studies were performed on in vitro and in vivo human and mouse models of HGG. Six patients with recurrent PDGFRα-driven glioma were treated with dasatinib and everolimus.ResultsDasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a variety of PDGFRA alterations. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents, with reduction in mTOR signaling that persists after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended survival of PPK tumor bearing mice. Pediatric patients (n=6) with glioma tolerated this combination without significant adverse events. Recurrent patients (n=4) demonstrated median overall survival of 8.5 months.ConclusionEfficacy of dasatinib treatment of PDGFRα-driven HGG is improved with everolimus and suggests a promising route for improving targeted therapy for this patient population.Trial RegistrationClinicalTrials.gov NCT03352427FundingThe authors thank the patients and their families for participation in this study. CK is supported by NIH/NINDS K08-NS099427-01, the University of Michigan Chad Carr Pediatric Brain Tumor Center, the Chad Tough Foundation, Hyundai Hope on Wheels, Catching up With Jack, Prayers from Maria Foundation, U CAN-CER VIVE FOUNDATION, Morgan Behen Golf Classic, and the DIPG Collaborative. The PEDS-MIONCOSEQ study was supported by grant 1UM1HG006508 from the National Institutes of Health Clinical Sequencing Exploratory Research Award (PI: Arul Chinnaiyan).

International audience; We assessed bone mineral density (BMD) in a cohort of human immunodeficiency virus (HIV)-positive patients after a median of 11 years of combination antiretroviral therapy (cART) and evaluated the respective role of HIV infection and antiretroviral drugs (ARVs). A cross-sectional study of 162 participants (131 male) from the ANRS-C08 cohort was performed with bone dual-energy X-ray absorptiometry (DXA) scans and renal assessment. The window of exposure to ARVs was defined as an exposure of more than six cumulative months during the last 3 years before the DXA evaluation to account for a cumulative exposure that could affect bone remodeling. The association with low BMD (Z-score < -2) was assessed by a multiple logistic regression model. The study population was 50 years (median), hepatitis C virus (HCV) (18%), and hepatitis B virus (HBV) (8%) coinfection with HIV-RNA

Background and objective When patients seek to discontinue buprenorphine (BUP) treatment, monthly injectable extended-release naltrexone (XR-NTX) may help them avoid relapse. The efficacy of low ascending doses of oral NTX vs placebo for patients transitioning from BUP to XR-NTX is evaluated in this study. Methods In a phase 3, hybrid residential/outpatient study, clinically stable participants with opioid use disorder (N = 101), receiving BUP for more than or equal to 3 months and seeking antagonist treatment, were randomized (1:1) to 7 residential days of descending doses of BUP and low ascending doses of oral NTX (NTX/BUP, n = 50) or placebo (PBO-N/BUP, n = 51). Both groups received standing ancillary medications and psychoeducational counseling. Following negative naloxone challenge, participants received XR-NTX (day 8). The primary endpoint was the proportion of participants who received and tolerated XR-NTX. Results There was no statistical difference between groups for participants receiving a first dose of XR-NTX: 68.6% (NTX/BUP) vs 76.0% (PBO-N/BUP; P = .407). The mean number of days with peak Clinical Opiate Withdrawal Scale (COWS) score less than or equal to 12 during the treatment period (days 1-7) was similar for NTX/BUP and PBO-N/BUP groups (5.8 vs 6.3; P = .511). Opioid withdrawal symptoms during XR-NTX induction and post-XR-NTX observation period (days 8-11) were mild and similar between groups (mean peak COWS score: NTX/BUP, 5.1 vs PBO-N/BUP, 5.4; P = .464). Adverse events were mostly mild/moderate. Conclusions and scientific significance Low ascending doses of oral NTX did not increase induction rates onto XR-NTX compared with placebo. The overall rate of successful induction across treatment groups supports a brief BUP taper with standing ancillary medications as a well-tolerated approach for patients seeking transition from BUP to XR-NTX. (Am J Addict 2020;00:00-00).

Purpose Studies have noted a link between radiation dose to the heart and overall survival (OS) for patients with lung cancer treated with chemoradiation. The purpose of this study was to characterize pre- to posttreatment cardiac metabolic changes using fluorodeoxyglucose/positron emission tomography (FDG-PET) images and to evaluate whether changes in cardiac metabolism predict for OS. Methods and Materials Thirty-nine patients enrolled in a functional avoidance prospective study who had undergone pre- and postchemoradiation FDG-PET imaging were evaluated. For each patient, the pretreatment and posttreatment PET/CTs were rigidly registered to the planning CT, dose, and structure set. PET-based metabolic dose-response was assessed by comparing pretreatment to posttreatment mean standardized uptake values (SUVmean) in the heart as a function of dose-bin. OS analysis was performed by comparing SUVmean changes for patients who were alive or had died at last follow-up and by using a multivariate model to assess whether pre- to posttreatment SUVmean changes were a predictor of OS. Results The dose-response curve revealed increasing changes in SUV as a function of cardiac dose with an average SUVmean increase of 1.7% per 10 Gy. Patients were followed for a median of 437 days (range, 201-1131 days). SUVmean change was significantly predictive of OS on multivariate analysis with a hazard ratio of 0.541 (95% confidence intervals, 0.312-0.937). Patients alive at follow-up had an average increase of 17.2% in cardiac SUVmean while patients that died had an average decrease in SUVmean decrease of 13.5% (P = .048). Conclusions Our data demonstrated that posttreatment SUV changes in the heart were significant indicators of dose-response and predictors of OS. The present work is hypothesis generating and must be validated in an independent cohort. If validated, our data show the potential for cardiac metabolic changes to be an early predictor for clinical outcomes.

Purpose Many radiation oncology programs use Step 1 score metrics as a surrogate for intelligence and success to screen applicants. The impact of this practice on radiation oncology applicant pool diversity is unknown. Methods and Materials Electronic Residency Application Service applications submitted to our institution between 2015 and 2018 match cycles were reviewed. Sex, age, race/ethnicity, and Step 1 scores were collected. Groupings by characteristics were sex (female vs male), age ≤30 versus >30 years, and race/ethnicity by underrepresented minority (URM) versus non-URM status. URMs were defined as Black/African American, Hispanic, Native American/Alaskan Native, and Hawaiian/Pacific Islander. Step 1 scores were divided based on scores of 220 and 240. The association between applicant demographics and Step 1 scores was assessed using proportional odds logistic regression for ordinal outcomes. Results Eight hundred ten applicants with Step 1 scores ranging from 188 to 275 were collected, representing nearly 90% of all applicants during the 2015 to 2018 Electronic Residency Application Service cycles. Twenty-nine percent were female, 29% were >30 years of age, and 10% were URMs. Increasing Step 1 score requirements disproportionately decreased representation of applicants who were female versus male at 240 (–51% vs –31%), >30 versus ≤30 years old at 220 (–28% vs –6%) and 240 (–55% vs –26%), and URMs versus non-URMs at 220 (–34% vs –9%) and 240 (–61% vs –34%). On analysis, Step 1 score requirements had a statistically significantly impact on applicant distributions based on sex, age, and URM status (P Conclusions Overemphasis of Step 1 scores may reduce the diversity of the radiation oncology applicant pool. Further evaluation of practices that counter the stated American Society of Clinical Oncology, American Society of Radiation Oncology, and American College of Radiology diversity missions should be pursued to improve understanding of barriers and biases.

Background: Hormonal contraceptive use is common among reproductive-aged women, but research evaluating its etiological relationship to vulvodynia remains mixed. We sought to evaluate this association and examine the potential for bias due to care-seeking behavior. Materials and Methods: We conducted a case–control study of women recruited from a large health care network database from 2008 to 2011. Of 26,455 eligible respondents, 1168 met the case definition for chronic vulvar pain (CVP). We matched each case to three controls by age and used conditional logistic regression to calculate odds ratios (ORs) for prior hormonal contraception (HC) use and CVP, stratifying cases by whether or not they sought care for their vulvar pain. We also simulated the influence of potential biases due to care seeking, using parameters based on this dataset. Results: HC users had higher odds of CVP (adjusted OR = 2.6, 95% confidence interval [CI]: 2.2–3.2). Effect estimates were stronger when cases were restricted to care seekers (adjusted OR = 2.9, 95% CI: 2.2–3.7). Effect estimates decreased slightly as time increased between HC initiation and pain onset. Our simulations suggested that effect estimates may be spuriously strengthened when cases are restricted to care-seeking women, but controls are recruited from the general population. Conclusions: Our results suggest an association between antecedent HC use and CVP that is potentially spuriously strengthened in case–control studies when cases are restricted to care seekers but controls are not.

OBJECTIVE The aim of the study was to evaluate the association between vulvodynia and thymic function. MATERIALS AND METHODS In this case-control study of 200 clinically confirmed cases of vulvodynia and 205 general population controls residing in the Minneapolis/Saint Paul metropolitan area, we used DNA extracted from whole blood to measure levels of signal joint T-cell receptor excision circles (sjTRECs), a measure of thymic output. We used logistic regression to evaluate the association between vulvodynia and thymic function. RESULTS In 405 participants (aged 18-40 years), we observed an association between decreasing thymic function and increasing age. Women with vulvodynia had a steeper decline in sjTREC values across age categories compared with women without vulvodynia. In addition, at younger ages, women with vulvodynia had higher sjTREC values compared with women without vulvodynia. In older women, those with vulvodynia had lower sjTREC than those without vulvodynia. When accounting for recency of vulvar pain onset, women with a shorter time since pain onset had higher thymic function compared with women with a longer time since vulvar pain onset. CONCLUSIONS These findings suggest that at younger ages, women with vulvodynia have higher thymic output and a more precipitous decline of thymic function than those without vulvodynia. It also seems that a strong immune inflammatory response is present proximate to the onset of vulvar pain and may wane subsequently over time.

Background Approximately 11% of 18–25 year-olds report thoughts of suicide. Additionally, suicide is the second leading cause of death in college student populations. We sought to evaluate the relationship between diagnosed mental health conditions and current symptoms of depression and/or anxiety and suicidality in the past year. Methods Healthy Minds Study (HMS) 2018-2019 data from 38,757 college students were analyzed. The PHQ-9, GAD-7, and prior mental health condition diagnoses were used to create a suicidality severity index and we determined how these associations varied by race/ethnicity, gender, and sexual orientation. We also assessed non-suicidal self-injury (NSSI) outcomes in the past year. Results Students with both a mental health condition diagnosis and current moderate/severe symptoms of depression and/or anxiety had a higher prevalence of NSSI, 10 times the odds (95% CI 9.4-11.5) of suicide ideation, 28 times the odds (95% CI 23.8-33.1) of suicide ideation, with planning or attempt, and 47 times the odds (95% CI 31.1-71.4) of suicide ideation, with planning and attempt, compared to students with none/minimal depression and/or anxiety symptoms and no mental health condition diagnosis. Limitations We could not clinically confirm depression or anxiety diagnoses nor infer causality of associations in this cross-sectional study. Future longitudinal studies are needed to establish temporality. Conclusions Mental health condition diagnoses and moderate/severe symptoms of depression and/or anxiety were strongly associated with suicidality among college students. These findings identify potential opportunities to further understand and address the mental health needs of college students.

PURPOSE: Panobinostat, an orally bioavailable pan-HDAC inhibitor, has demonstrated potent activity in multiple malignancies, including pediatric brain tumors such as DIPG, with increased activity against H3K27M mutant cell lines. Given limited evidence regarding the CNS penetration of panobinostat, we sought to characterize its BBB penetration in a murine model. METHODS: Panobinostat 15 mg/kg was administered IV to 12 CD-1 female mice. At specified time points, mice were euthanized, blood samples were collected, and brains were removed. LC–MS was performed to quantify panobinostat concentrations. C(max) and AUC were estimated and correlated with previously published pharmacokinetic analyses and reports of IC-50 values in DIPG cell lines. RESULTS: Mean panobinostat plasma concentrations (ng/mL) were 27.3 ± 2.5 at 1 h, 7.56 ± 1.8 at 2 h, 1.48 ± 0.56 at 4 h, and 2.33 ± 1.18 at 7 h. Mean panobinostat brain concentrations (ng/g) were 60.5 ± 6.1 at 1 h, 42.9 ± 5.4 at 2 h, 33.2 ± 6.1 at 4 h, and 28.1 ± 4.3 at 7 h. Brain-to-plasma ratio at 1 h was 2.22 and the brain to plasma AUC ratio was 2.63. Based on the published human pharmacokinetic data, the anticipated C(max) in humans is expected to be significantly higher than the IC-50 identified in DIPG models. CONCLUSION: It is expected that panobinostat would be effective in CNS tumors where the IC-50 is in the low nanomolar range. Thus, our data demonstrate panobinostat crosses the BBB and achieves concentrations above the IC-50 for DIPG and other brain tumors and should be explored further for clinical efficacy.

Supplemental Digital Content is available in the text., Background: High-sensitivity cardiac troponin assays enable myocardial infarction to be ruled out earlier, but the safety and efficacy of this approach is uncertain. We investigated whether an early rule-out pathway is safe and effective for patients with suspected acute coronary syndrome. Methods: We performed a stepped-wedge cluster randomized controlled trial in the emergency departments of 7 acute care hospitals in Scotland. Consecutive patients presenting with suspected acute coronary syndrome between December 2014 and December 2016 were included. Sites were randomized to implement an early rule-out pathway where myocardial infarction was excluded if high-sensitivity cardiac troponin I concentrations were

Extended-release formulations of naltrexone have emerged as effective treatment options for opioid use disorder. This post-hoc analysis examined the temporal relationship between episodes of opioid use and subsequent dropout in a placebo-controlled trial of extended-release injection naltrexone (XR-NTX) to draw inferences about the mechanism by which extended blockade of opioid receptors translates into clinical effectiveness.This was a 24-week multiple-site, double-blind, randomized trial of monthly XR-NTX versus placebo injections. We analyzed time to dropout from treatment using survival analysis with an extended Cox model as a function of treatment (XR-NTX versus placebo) and with weekly urine drug test (UDT) results for opioids at each week as a time-dependent covariate.Thirteen addiction treatment programs in Russia, 2008-09.A total of 250 adults with opioid use disorder who had completed in-patient detoxification.XR-NTX injection or placebo injection every 4 weeks with weekly clinic visits and biweekly counseling.Urine toxicology for opioids measured weekly and week of dropout from treatment.The Cox model yielded a significant interaction of time-dependent urine toxicology by treatment (P = 0.024). Among patients receiving placebo, a positive UDT in a given week increased the risk for dropout from treatment in the subsequent week [hazard ratio (HR) = 6.25; 95% confidence interval (CI) = 3.6-10.0], whereas among patients receiving XR-NTX, a positive UDT result showed no significant effect on risk for dropout (HR = 1.67; 95% CI = 0.6-4.5). The proportion of patients who completed all 24 weeks without any positive UDT result was 31% on XR-NTX compared with 20% on placebo (P = 0.051).Extended-release injection naltrexone was effective at reducing the risk of dropout from opioid use disorder treatment after an episode of opioid use. Just under a third of patients (31%) on XR-NTX had no opioid-positive urine tests across the trial, but the hypothesis that this would differ from placebo (20%) was not confirmed.

Objective To determine whether routine blood glucose assessment of patients admitted to hospital from emergency departments (EDs) results in higher rates of new diagnoses of diabetes and documentation of follow-up plans. Design, setting Cluster randomised trial in 18 New South Wales public district and tertiary hospitals, 31 May 2011 - 31 December 2012; outcomes follow-up to 31 March 2016. Participants Patients aged 18 years or more admitted to hospital from EDs. Intervention Routine blood glucose assessment at control and intervention hospitals; automatic requests for glycated haemoglobin (HbA1c ) assessment and notification of diabetes services about patients at intervention hospitals with blood glucose levels of 14 mmol/L or more. Main outcome measure New diagnoses of diabetes and documented follow-up plans for patients with admission blood glucose levels of 14 mmol/L or more. Results Blood glucose was measured in 133 837 patients admitted to hospital from an ED. The numbers of new diabetes diagnoses with documented follow-up plans for patients with blood glucose levels of 14 mmol/L or more were similar in intervention (83/506 patients, 16%) and control hospitals (73/278, 26%; adjusted odds ratio [aOR], 0.83; 95% CI 0.42-1.7; P = 0.61), as were new diabetes diagnoses with or without plans (intervention, 157/506, 31%; control, 86/278, 31%; aOR, 1.51; 95% CI, 0.83-2.80; P = 0.18). 30-day re-admission (31% v 22%; aOR, 1.34; 95% CI, 0.86-2.09; P = 0.21) and post-hospital mortality rates (24% v 22%; aOR, 1.07; 95% CI, 0.74-1.55; P = 0.72) were also similar for patients in intervention and control hospitals. Conclusion Glucose and HbA1c screening of patients admitted to hospital from EDs does not alone increase detection of previously unidentified diabetes. Adequate resourcing and effective management pathways for patients with newly detected hyperglycaemia and diabetes are needed. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12611001007921.

OBJECTIVES Delays from surgery to adjuvant radiation therapy (aRT) are associated with poorer prognosis in multiple neoplasms. Presently, no data exist for Merkel cell carcinoma (MCC). The authors sought to assess the time interval from surgery to aRT and effect on outcomes in MCC. MATERIALS AND METHODS The National Cancer Database was queried for histologically confirmed nonmetastatic MCC status post resection and aRT diagnosed between 2004 and 2015 who received aRT within 24 weeks of surgery. Kaplan-Meier analysis assessed univariate overall survival (OS); multivariable Cox proportional hazards modeling assessed multivariate OS; χ and logistic regression assessed differences in baseline characteristics and predictors of delayed aRT. RESULTS Of 5952 patients meeting criteria, 13% commenced aRT within 4 weeks, 48% between 4 and 7 weeks, 23% between 8 and 11 weeks, 11% between 12 and 15 weeks, and 6% between 16 and 24 weeks. There were no differences in OS on the basis of the surgery-aRT interval (P=0.99). Predictors of worse OS on the multivariate analysis included advanced age, greater comorbidities, male sex, lower regional income, earlier year of diagnosis, more advanced tumor and nodal staging, positive margins, head and neck location, and treatment at community facilities (P

Preclinical evidence and data from a proof-of-concept study in healthy volunteers suggest that samidorphan, an opioid antagonist, mitigates weight gain associated with olanzapine. This study prospectively compared combination therapy of olanzapine plus either samidorphan or placebo for the treatment of schizophrenia.This was an international, multicenter, randomized phase 2 study of olanzapine plus samidorphan in patients with schizophrenia. The study had a 1-week open-label olanzapine lead-in period followed by a 12-week double-blind treatment phase in which patients were randomly assigned in a 1:1:1:1 ratio to receive olanzapine plus placebo (N=75) or olanzapine plus 5 mg (N=80), 10 mg (N=86), or 20 mg (N=68) of samidorphan. The primary aims were to confirm that the antipsychotic efficacy of olanzapine plus samidorphan was comparable to olanzapine plus placebo, to assess the effect of combining olanzapine with samidorphan on olanzapine-induced weight gain, and to assess the overall safety and tolerability of olanzapine plus samidorphan.Antipsychotic efficacy, as assessed by total score on the Positive and Negative Syndrome Scale (PANSS), was equivalent across all treatment groups. Treatment with olanzapine plus samidorphan resulted in a statistically significant lower weight gain (37% lower weight gain compared with olanzapine plus placebo). The least square mean percent change from baseline in body weight was 4.1% (2.9 kg) for the olanzapine plus placebo group and 2.6% (1.9 kg) for the olanzapine plus samidorphan group (2.8% [2.1 kg] for the 5 mg group, 2.1% [1.5 kg] for the 10 mg group, and 2.9% [2.2 kg] for the 20 mg group). Adverse events reported at a frequency ≥5% in any of the olanzapine plus samidorphan groups and occurring at a rate ≥2 times greater than in the olanzapine plus placebo group were somnolence, sedation, dizziness, and constipation. Other safety measures were comparable between the olanzapine plus samidorphan groups and the olanzapine plus placebo group.The antipsychotic efficacy of olanzapine plus samidorphan was equivalent to that of olanzapine plus placebo, and olanzapine plus samidorphan was associated with clinically meaningful and statistically significant mitigation of weight gain compared with olanzapine plus placebo. Olanzapine plus samidorphan was generally well tolerated, with a safety profile similar to olanzapine plus placebo.

Introduction Vulvodynia is a debilitating, chronic vulvar pain condition. Community-based case-control studies have consistently shown associations between early-life chronic stressors and vulvodynia onset. Aim We examined rumination as a specific stress response involved in the psychobiological mechanism of vulvodynia. Methods A psychosocial survey with questions specific to early-life traumatic events and rumination were administered to 185 matched case-control pairs of women with and without vulvodynia. Conditional logistic regression was used to examine associations between rumination constructs (ie, total rumination, emotion-focused, instrumental, and searching for meaning) and vulvodynia onset. Conditional logistic regression was also used to determine whether these associations depended on early-life stressors (ie, severity of childhood abuse and of self-reported antecedent traumatic events). Age at interview, antecedent pain disorders, any childhood abuse, and antecedent psychiatric morbidity were included as covariates. Main Outcome Measures We estimated the odds of rumination in relation to the onset of vulvodynia within a community-based and clinically confirmed sample of women with and without vulvodynia. Results Vulvodynia was associated with the highest tertile of emotion-focused (odds ratio [OR] = 2.1; 95% CI = 1.2, 3.2) and instrumental (OR = 2.1; 95% CI = 1.1, 4.0) rumination. These associations were attenuated after additional adjustment for antecedent psychiatric morbidity. Among women who reported rumination about early-life stressors before vulvar pain in cases or matched reference age in control subjects, those with vulvodynia were >2 times more likely to report the highest tertile of total rumination (OR = 2.3; 95% CI = 1.1, 5.0) compared with those without vulvodynia. Clinical Implications Healthcare providers may be able to identify subsets of women who could benefit from preventive measures before the development of vulvodynia. Strength & Limitations This is the first study to use a community-based and clinically confirmed sample of women with and without vulvodynia to examine the associations between rumination about early-life trauma and the onset of vulvodynia. However, as with all retrospective studies, the reporting of information (eg, traumatic events) was subject to recall bias and misclassification. Conclusion Our findings indicate that a prolonged cognitive stress response (ie, rumination) may be 1 important mechanism by which early-life chronic stressors contribute to the onset vulvodynia. Prospective studies are recommended to examine whether and how cognitive, affective, and physiological components of prolonged stress responses interact to influence the development of vulvodynia. Understanding both the psychobiological and behavioral mechanisms may help in addressing and treating individuals to potentially reverse the development of vulvodynia.

Background Acute leukemia with mixed-phenotype blasts is associated with poor outcomes. There are no standard treatment regimens. Due to disease heterogeneity, controversy exists over whether an AML-based, ALL-based, or a combined (hybrid) AML/ALL-based regimen is most appropriate. Materials and Methods We conducted a single-center, retrospective case series review of patients with acute leukemia with mixed phenotype blasts as described by the European Group for Immunological Characterization of Leukemia (EGIL) or the 2008 WHO classification. Patients were treated from November 2014 and December 2019 with the combination chemotherapy regimen FLAG-idarubicin-vincristine-prednisone with or without rituximab. Outcomes included induction response, time to transplant, time to relapse, overall survival, time to neutrophil or platelet recovery, infection, and duration of hospitalization. Results The median age was 68 years (range 21−77). Six patients (87.5 %) had unfavorable/complex cytogenetics. All patients achieved a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi). Estimated 1-year overall survival was 85.7 %. There were no deaths during induction, with a 22 day median duration of hospitalization for induction. Conclusion The combination of FLAG, idarubicin, vincristine, and prednisone (FLAG-VIPR) demonstrated favorable induction responses in a disease state with historically poor outcomes and should be studied in a prospective clinical trial.

A combination of olanzapine and the opioid receptor antagonist samidorphan is under development for the treatment of schizophrenia and bipolar I disorder. The single-tablet combination treatment is intended to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. In this phase 3 double-blind trial, the authors evaluated the weight profile of combined olanzapine/samidorphan compared with olanzapine in patients with schizophrenia.Adults (ages 18‒55 years) with schizophrenia were randomly assigned to receive either combination treatment with olanzapine and samidorphan or olanzapine treatment for 24 weeks. Primary endpoints were percent change from baseline in body weight and proportion of patients with ≥10% weight gain at week 24. The key secondary endpoint was the proportion of patients with ≥7% weight gain. Waist circumference and fasting metabolic laboratory parameters were also measured.Of 561 patients who underwent randomization (olanzapine/samidorphan combination, N=280; olanzapine, N=281), 538 had at least one postbaseline weight assessment. At week 24, the least squares mean percent weight change from baseline was 4.21% (SE=0.68) in the olanzapine/samidorphan group and 6.59% (SE=0.67) in the olanzapine group (the difference of -2.38% [SE=0.76] was significant). Significantly fewer patients in the olanzapine/samidorphan combination group compared with the olanzapine group had weight gain ≥10% (17.8% and 29.8%, respectively; number needed to treat [NNT]=7.29; odds ratio=0.50) and weight gain ≥7% (27.5% and 42.7%, respectively; NNT=6.29; odds ratio=0.50). Increases in waist circumference were smaller in the olanzapine/samidorphan combination group compared with the olanzapine group. Schizophrenia symptom improvement was similar between treatment groups. Adverse events (in ≥10% of the groups) in the olanzapine/samidorphan and olanzapine groups included weight gain (24.8% and 36.2%), somnolence (21.2% and 18.1%), dry mouth (12.8% and 8.0%), and increased appetite (10.9% and 12.3%). Metabolic changes were small and similar between treatments.Olanzapine/samidorphan combination treatment was associated with significantly less weight gain and smaller increases in waist circumference than olanzapine and was well tolerated. The antipsychotic efficacy of the combination treatment was similar to that of olanzapine monotherapy.

Vulvodynia affects about 8% of women, many of whom report a negative impact on their ability to have sexually satisfying relationships. In this study, we examined predictors of sexual satisfaction in 207 women with clinically confirmed vulvodynia. We adapted a model examining resilience in chronic pain patients originally developed by Sturgeon and Zautra (2010) to include resilience factors (communication with partner about sexual health, coping strategies) and vulnerable factors (abuse history, pain intensity, rumination). These variables were regressed onto sexual satisfaction. In the full model, only emotion-based rumination was predictive of sexual satisfaction. Thus, focusing on emotion-based rumination in clinical intervention may improve sexual satisfaction.

OBJECTIVES: To examine whether the school toilet environment at age 13, including bullying at toilets, is associated with female lower urinary tract symptoms (LUTS) at ages 13 and 19, as little is known about the association among school toilet environment, voiding behaviors, and LUTS in adolescent girls.METHODS: The sample comprised 3962 female participants from the Avon Longitudinal Study of Parents and Children. At age 13, participants reported on 7 school toilet environment characteristics and a range of LUTS items. At age 19, participants completed the Bristol Female Lower Urinary Tract Symptoms questionnaire.RESULTS: All toilet environmental factors were associated with at least 1 LUTS outcome at age 13. Holding behavior was associated with all school toilet environmental factors, with odds ratios ranging from 1.36 (95% confidence interval [CI]: 1.05, 1.76) for dirty toilets to 2.38 (95% CI: 1.60, 3.52) for feeling bullied at toilets. Bullying was associated with all daytime LUTS symptoms and nocturia; odds ratios ranged from 1.60 (95% CI: 1.04, 2.07) for nocturia to 2.90 (95% CI: 1.77, 4.75) for urgency. Associations between age 13 school toilets and age 19 LUTS were in the same direction as age 13 LUTS.CONCLUSION: This is the first examination of associations between school toilets and LUTS. Toileting environments were cross-sectionally associated with LUTS in adolescent girls. While further work is needed to determine whether these associations are causal, school toilet environments are modifiable and thus a promising target for LUTS prevention.

Objective Alcohol use disorder (AUD) is a common comorbidity of schizophrenia. No effective pharmacologic treatment is available for both disorders to date. Methods In a phase 2, double-blind study, patients with schizophrenia and AUD experiencing ≥ 10 drinking and ≥ 2 heavy-drinking days in the previous month and recent (≤ 6 mo) disease symptom exacerbation were recruited between June 2014 and March 2017. DSM-IV-TR and DSM-5 criteria were used to assign the diagnoses of schizophrenia and AUD, respectively. After a 6-week lead-in period, 234 eligible patients were randomized (1:1) to olanzapine + 10 mg samidorphan tablets (OLZ/SAM) or olanzapine + placebo tablets (olanzapine) for 36-60 weeks of treatment. The primary outcome of time to the first event of exacerbation of disease symptoms (EEDS) was evaluated using the log rank test for treatment comparison, and the Cox proportional-hazards model was used to estimate hazard ratio. Safety was assessed as adverse events and laboratory measures. Results No significant difference was observed between groups in the time to first EEDS (hazard ratio = 0.91; 95% CI, 0.53-1.56; P = .746). Patients treated with OLZ/SAM vs olanzapine had numerically lower rates in 6 of 8 criteria to evaluate EEDS. Change from baseline in percentage of heavy-drinking days during the double-blind treatment period was similar in OLZ/SAM- vs olanzapine-treated patients. OLZ/SAM was generally well tolerated with a safety profile similar to olanzapine. Conclusions OLZ/SAM was not superior to olanzapine in the time to EEDS and was well tolerated in patients with schizophrenia and AUD. Further research is needed to identify effective treatments for this difficult-to-treat population. Trial registrations ClinicalTrials.gov identifier: NCT02161718; EudraCT number: 2014-001211-39 ​.

Background Lymphatic filariasis (LF) is widely endemic in Cote d’Ivoire, and elimination as public health problem (EPHP) is based on annual mass drug administration (MDA) using ivermectin and albendazole. To guide EPHP efforts, we evaluated Wuchereria bancrofti infection indices among humans, and mosquito vectors after four rounds of MDA in four cross-border health districts of Cote d’Ivoire. Methodology We monitored people and mosquitoes for W. bancrofti infections in the cross-border health districts of Aboisso, Blolequin, Odienne and Ouangolodougou, Cote d’Ivoire. W. bancrofti circulating filarial antigen (CFA) was identified using filariasis test strips, and antigen-positive individuals were screened for microfilaremia. Moreover, filarial mosquito vectors were sampled using window exit traps and pyrethrum sprays, and identified morphologically at species level. Anopheles gambiae s.l. and Culex quinquefasciatus females were analyzed for W. bancrofti infection using polymerase chain reaction (PCR) technique. Principal findings Overall, we found a substantial decline in W. bancrofti infection indices after four rounds of MDA compared to pre-MDA baseline data. CFA prevalence fell from 3.38–5.50% during pre-MDA to 0.00–1.53% after MDA interventions. No subjects had detectable levels of CFA in Ouangolodougou. Moreover, post-MDA CFA prevalence was very low, and below the 1% elimination threshold in Aboisso (0.19%) and Odienne (0.49%). Conversely, CFA prevalence remained above 1% in Blolequin (1.53%). W. bancrofti microfilariae (Mf) were not found in Aboisso, Blolequin, and Ouangolodougou, except for Odienne with low prevalence (0.16%; n = 613) and microfilaremia of 32.0 Mf/mL. No An. gambiae s.l. and Cx. quinquefasciatus pools were infected with W. bancrofti in Blolequin and Ouangolodougou, while they exhibited low infection rates in Aboisso (1% and 0.07%), and Odienne (0.08% and 0.08%), respectively. Conclusions In cross-border areas of Cote d’Ivoire, LF infection indices in humans and mosquito vectors substantially declined after four rounds of MDA. CFA prevalence fell under the World Health Organization (WHO)-established threshold (1%) in Aboisso, Ouangolodougou and Odienne. Moreover, W. bancrofti prevalence in mosquitoes was lower than WHO-established threshold (2%) in all areas. This might suggest the interruption of W. bancrofti transmission, and possible MDA cessation. However, a formal transmission assessment survey (TAS) and molecular xenomonitoring in mosquito vectors should be implemented before eventual MDA cessation. However, MDA should pursue in Blolequin where W. bancrofti infection prevalence remained above 1%. Our results provided important ramifications for LF control efforts towards EPHP in Cote d’Ivoire.

Withaferin A (WFA), a withanolide derived from medicinal plant Withania somnifera, possesses anti-tumorigenic and immunomodulatory activities against various cancer cells. However, the role of WFA in myocardial ischemia reperfusion (MI/R) injury remains unclear. In the present study, we determined whether WFA may regulate cardiac ischemia reperfusion injury and elucidate the underlying mechanisms. We demonstrated that WFA enhanced H9c2 cells survival ability against simulated ischemia/reperfusion (SI/R) or hydrogen peroxide (H2O2)-induced cell apoptosis. In addition, the enhanced oxidative stress induced by SI/R was inhibited by WFA. Among the multiple antioxidant molecules determined, antioxidants SOD2, SOD3, Prdx-1 was obviously upregulated by WFA. When Akt inhibitor IV was administrated, WFA's suppression effect on oxidative stress was obviously abolished. Additional experiments demonstrated that WFA successfully inhibited H2O2 induced upregulation of SOD2, SOD3, and Prdx-1, ameliorated cardiomyocyte caspase-3 activity via an Akt dependent manner. Collectively, these results support the therapeutic potential of WFA against cardiac ischemia reperfusion injury and highlight the application of WFA in cardiovascular diseases holding great promise for the future.

Antipsychotic medications are associated with weight gain and adverse metabolic effects that complicate the treatment and management of schizophrenia. Olanzapine (OLZ) in particular is associated with significant weight gain and adverse metabolic effects. The present Phase 1, proof of concept, multicenter, randomized, double-blind, placebo-controlled study investigated the safety and effect on weight of a combination of OLZ (10mg) and the opioid modulator samidorphan (SAM; 5mg) in comparison to OLZ alone in healthy, male normal weight volunteers. Altogether, 106 male subjects with stable body weight and BMI 18-25kg/m2 were randomized to OLZ alone, OLZ+SAM, SAM alone, or placebo in a 2:2:1:1 ratio. The primary efficacy endpoint, mean (SD) body weight change from baseline to last assessment in the 3-week treatment period, was significantly less for OLZ+SAM vs. OLZ alone subjects [+2.2 (1.4) kg vs. +3.1 (1.9) kg; respectively; p=0.02]. In contrast, there was no significant difference in weight from baseline for either SAM or placebo [+0.1 (1.0) kg and +0.8 (1.4) kg, respectively]; p=0.09. Overall, OLZ+SAM compared to OLZ alone had similar safety and tolerability. In addition, less nausea was observed in subjects given OLZ+SAM compared to SAM alone. Thus, OLZ+SAM may offer effective treatment of schizophrenia with less weight gain and metabolic risk. Additional research exploring additional doses over longer durations in psychiatric populations is warranted.

Background and Aims Extended-release naltrexone (XR-NTX), a μ-opioid receptor antagonist for prevention of relapse to opioid dependence, has demonstrated efficacy compared with placebo and comparative effectiveness with buprenorphine-naloxone. We report outcomes for XR-NTX in Vivitrol's Cost and Treatment Outcomes Registry. Design Observational, open-label, single-arm, multicenter registry assessing baseline characteristics and clinical and health-related quality-of-life outcomes associated with XR-NTX treatment in clinical practice. Setting 32 US treatment centers from 2011 to 2013. Participants Patients with opioid dependence who were prescribed XR-NTX treatment and then enrolled in the registry. Measurements Monthly visits were evaluated for the full population and for patient subgroups retrospectively, defined by injection number, focusing on the period between baseline and month 6 (1-, 2/3-, or 6-XR-NTX). Findings Of 403 enrolled patients, 395 were analyzed. Most patients (n=349) received outpatient care. On average, patients received 5 injections (median 3; range 1-25). The median number of injections administered within 6 months was higher in patients who at baseline were employed (3 vs 2 unemployed, P=0.02) or had private insurance (5 vs 2 self-payment, P=0.005; vs 2 state-funded, P

Background Patients with melanoma brain metastases (MBM) have been excluded from trials evaluating immunotherapy in melanoma. As such, immunotherapy's role in MBM is poorly understood, particularly in combination with radiotherapy. Methods The National Cancer Database was queried for patients with MBM receiving brain radiotherapy. They were classified according to immunotherapy receipt. Multivariate Cox regression was performed to identify factors associated with survival. Results Among 1287 patients, 185 received immunotherapy. Factors associated with improved survival included younger age, academic facility, lower extracranial disease burden, stereotactic radiotherapy, chemotherapy, and immunotherapy. Conclusions Adding immunotherapy to radiotherapy for MBM is associated with improved survival.

Background Relapsed/refractory acute myeloid leukemia (AML) confers a poor prognosis, and there is no single standard of care first-line salvage regimen. FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) is a common salvage regimen with a favorable toxicity and efficacy profile in poor-risk AML. Materials and Methods We conducted a single-center, retrospective analysis of first relapse/primary refractory patients with AML that received salvage chemotherapy from January 2009 to July 2019. We propensity-score matched patients 1:1 (based on age at diagnosis, cytogenetic risk group, Charlson comorbidity index, de novo vs. secondary AML, and whether or not they received an allogeneic stem cell transplant in first complete remission) into 2 groups, FLAG (Group 1) or non-FLAG (Group 2) as first-line salvage regimen, with 66 patients in each group. The primary endpoint was overall response rate (complete response and complete response with incomplete hematologic recovery). Results The median patient age was 59 years (range, 19-80 years). Patients treated with FLAG had a higher overall response rate (complete response/complete response with incomplete hematologic recovery) (71.2% vs. 50.0%; odds ratio, 2.47; 95% confidence interval [CI], 1.21-5.08; P = .013), longer event-free survival (8.9 vs. 2.1 months; hazard ratio [HR], 0.58; 95% CI, 0.39-0.86; P = .005), and longer overall survival (14.2 vs. 5.9 months; HR, 0.62; 95% CI, 0.41-0.93; P = .019). Patients who received FLAG had a shorter median duration of neutropenia (22 vs. 34 days; HR, 0.43; 95% CI, 0.29-0.64; P Conclusion This analysis supports the FLAG regimen as an effective and well-tolerated salvage therapy for patients with relapsed/refractory AML.

Purpose Allogeneic hematopoietic cell transplant recipients undergo myelosuppressive chemotherapy to allow engraftment of stem cells and are at particularly high risk for bacterial infections and adverse outcomes. Patients undergoing hematopoietic cell transplant are at increased risk for healthcare-associated infections, including infections with multidrug-resistant pathogens. Cefepime is a commonly prescribed antibiotic for empiric therapy in hematopoietic cell transplant patients, but there is minimal data describing cefepime resistance rates, risk factors for resistance, and clinical outcomes associated with cefepime-resistant infections. Methods Adult (≥18 years old) allogeneic hematopoietic cell transplant recipients with a culture positive for a gram-negative rod between January 2010 and January 2016 were spilt into two groups: cefepime susceptible and cefepime nonsusceptible . The primary objective of this study was to identify risk factors for cefepime nonsusceptible through multivariable logistic regression. Results A total of 107 patients were included (27 cefepime nonsusceptible, 80 cefepime-susceptible), yielding a 25.2% nonsusceptibility rate. Multivariable analysis yielded age >60 years old, Klebsiella spp. infection, Acinetobacter spp. infection, healthcare exposures within 90 days, acute gastrointestinal graft-vs-host-disease, and chronic graft-vs-host-disease at multiple locations as significant risk factors for cefepime nonsusceptible. The receiver operating characteristic area under the curve of the model was 0.851. Thirty-day all-cause mortality (29.6% versus 16.3%, p = 0.13) and length of hospitalization (19 versus 12.5 days, p = 0.0650) were numerically higher in the cefepime nonsusceptible group. Conclusions Hematopoietic cell transplant patients with acute gastrointestinal graft versus host disease, extensive chronic graft-vs-host-disease, advanced age, previous healthcare exposures, or infections with Klebsiella and Acinetobacter are at increased risk for cefepime nonsusceptible. Patients infected with cefepime nonsusceptible pathogens may have higher rates of mortality and length of hospitalization.

OBJECTIVES The role of radiotherapy (RT) in locally advanced pancreatic cancer (LAPC) is uncertain. This study examines patterns of care and survival outcomes of LAPC undergoing chemotherapy alone versus chemotherapy plus RT (C + RT). METHODS The National Cancer Database was queried for nonmetastatic LAPC patients who received chemotherapy alone or C + RT. RESULTS Of the 13,695 patients included, 5306 underwent chemotherapy alone and 4971, C + RT. Use of C + RT declined from 2003 to 2011 (73%-53%), whereas chemotherapy alone increased. Of those receiving RT, rates of intensity-modulated radiotherapy (IMRT) increased (27%-72%), whereas 3-dimensional (3D) RT decreased (73%-28%). Unadjusted 1-year overall survival (OS) was longer for versus chemotherapy (45.6% vs 38.7%), as was 2-year OS (12.9% vs 11.9%) (hazard ratio, 0.88; 0.85-0.91; P < 0.001). Under multivariate analysis, C + RT was associated with improved OS (hazard ratio, 0.84; 0.81-0.87; P < 0.001). On subgroup analysis comparing C + IMRT, C + 3D RT, and chemotherapy alone, 1-year OS was 49.1%, 45.1%, and 38.7%, and 2-year OS was 13.1%, 11.6%, and 11.9% accordingly. CONCLUSIONS Utilization of RT in LAPC is decreasing, whereas chemotherapy alone is increasing. Of patients undergoing RT, rates of IMRT are increasing. Whereas C + IMRT appeared to be associated with improved OS compared with chemotherapy alone, 3D RT was not.

Posaconazole is the prophylactic antifungal of choice for patients with haematological malignancies at high risk of invasive fungal infections (IFIs). Studies have demonstrated that subtherapeutic concentrations of posaconazole are associated with breakthrough fungal infections and specific risk factors for subtherapeutic troughs associated with the suspension formulation have been identified. However, these risk factors have not been evaluated in a large patient population with the recently approved tablet formulation.To determine the risk factors for subtherapeutic posaconazole troughs associated with the tablet formulation in patients receiving posaconazole as IFI prophylaxis.From 1 February 2013 to 31 March 2015 all posaconazole serum trough concentrations were evaluated. A total of 157 patients receiving posaconazole tablet for prophylaxis during induction therapy for haematological malignancies and allogeneic stem cell transplant recipients with graft-versus-host disease were included for analysis.Overall, 28 patients (18%) had subtherapeutic troughs (700 ng/mL). Patients were more likely to have subtherapeutic troughs if they had diarrhoea (n = 24; 83%) (P 0.001), were receiving a proton pump inhibitor (n = 27; 93%) (P = 0.016) and weighed90 kg (n = 14; 48%) (P = 0.047).While the posaconazole tablet has provided more consistent therapeutic concentrations when compared with the suspension there may still be a role for therapeutic drug monitoring (TDM). These results may guide us to a specific population in which TDM is necessary to identify subtherapeutic troughs.

Asparaginase is commonly de-emphasized/omitted in adult acute lymphoblastic leukemia regimens due to poor tolerability, including hepatotoxicity (HTX). Adult patients (n = 100) given induction therapy containing pegylated asparaginase (PEG) from January 2008 to February 2016 were evaluated for HTX. Sixteen patients met criteria for HTX (direct bilirubin >3 g/dL). A multivariable model identified body surface area >2m2 (OR 7.40; 95% CI: 1.73–31.61, p = .007), albumin

Radiotherapy (RT) to the primary nasopharyngeal tumor is frequently offered to patients with metastatic nasopharyngeal carcinoma (mNPC). However, only limited data exist to support RT in this setting. We used the National Cancer Database (NCDB) to evaluate outcomes for mNPC patients receiving chemotherapy with and without local RT.The NCDB was queried for patients with mNPC with synchronous metastatic disease at diagnosis who received chemotherapy. Overall survival (OS) was analyzed using the Kaplan-Meier method, Cox proportional hazards models, and propensity score-matched analyses.From 2004 to 2013, 718 cases were identified (39% chemotherapy-alone, 61% chemotherapy+RT). At a median follow-up of 4.4years, RT was associated with improved survival on univariate analysis (median OS 21.4 vs 15.5months; 5-year OS 28% vs 10%; p0.001) and multivariate analyses (HR, 0.61; CI, 0.51-0.74; p0.001). Propensity score analysis with matched baseline characteristics demonstrated a similar OS advantage with RT (HR, 0.68; CI, 0.55-0.84; p0.001). The benefits of RT remained consistent in models controlling for single vs multi-organ metastases and anatomic sites of metastatic involvement. RT dose was an independent prognostic factor as both a continuous and categorical variable, with OS benefits observed among patients receiving ≥50Gy. Long-term survival of10years was only observed in the RT cohort.This analysis supports strategies incorporating local RT with chemotherapy for mNPC. Prospective trials evaluating RT integration for mNPC are warranted.

ObjectiveAripiprazole lauroxil (AL) is a long-acting injectable atypical antipsychotic that was evaluated for the treatment of schizophrenia in a randomized, placebo-controlled, Phase 3 study. Here, we present exploratory analyses of supportive efficacy endpoints.MethodsPatients experiencing an acute exacerbation of schizophrenia received AL 441 mg intramuscularly (IM), AL 882 mg IM, or matching placebo IM monthly. Supportive endpoints included changes from baseline at subsequent time points in Clinical Global Impression-Severity (CGI-S) scale score; Positive and Negative Syndrome Scale (PANSS) Total score; PANSS Positive, Negative, and General Psychopathology subscale scores; PANSS Marder factors (post hoc); and PANSS responder rate. Overall response rate, based on PANSS Total score and Clinical Global Impression–Improvement (CGI-I) scale score, was also analyzed.ResultsOf 622 patients who were randomized, 596 had ≥1 post-baseline PANSS score. Patients were markedly ill at baseline (mean PANSS Total scores 92–94). Compared with placebo, CGI-S scores; PANSS Positive, Negative, and General Psychopathology subscale scores; and PANSS Marder factors were all significantly (pConclusionAL demonstrated robust efficacy on CGI-S score, PANSS subscale scores, PANSS Marder factors, and response rates. Study limitations included use of a fixed dose for initial oral aripiprazole and fixed monthly AL doses without the option to individualize the oral initiation dosing or injection frequency for efficacy, tolerability, or safety.

Summary Background Alcohol dependence is often untreated. Although abstinence is often the aim of treatment, many drinkers prefer drinking reduction goals. Therefore, if supported by evidence of benefit, drinking reduction goals could broaden the appeal of treatment. Regulatory agencies are considering non-abstinent outcomes as efficacy indicators in clinical trials, including reduction in WHO drinking risk levels—very high, high, moderate, and low—defined in terms of mean ethanol consumption (in grams) per day. We aimed to study the relationship between reductions in WHO drinking risk levels and subsequent reduction in the risk of alcohol dependence. Methods In this population-based cohort study, we included data from 22 005 drinkers who were interviewed in 2001–02 (Wave 1) and re-interviewed 3 years later (2004–05; Wave 2) in the US National Epidemiologic Survey on Alcohol and Related Conditions. Alcohol consumption (WHO drinking risk levels) and alcohol dependence (at least three of seven DSM-IV criteria in the previous 12 months) were assessed at both waves. We used logistic regression to test the relationship between change in WHO drinking risk levels between Waves 1 and 2, and alcohol dependence at Wave 2. Findings At Wave 1, 2·5% (weighted proportion) of the respondents were very-high-risk drinkers, 2·5% were high-risk drinkers, 4·8% were moderate-risk drinkers, and most (90·2%) were low-risk drinkers. Reduction in WHO drinking risk level predicted significantly lower odds of alcohol dependence at Wave 2, particularly among very-high-risk drinkers (adjusted odds ratios 0·27 [95% CI 0·18–0·41] for reduction by one level, 0·17 [0·10–0·27] for two levels, and 0·07 [0·05–0·10] for three levels) and high-risk drinkers (0·64 [0·54–0·75] for one level and 0·12 [0·09–0·15] for two levels), and among those with alcohol dependence at Wave 1 (0·29 [0·15–0·57] for one level, 0·06 [0·04–0·10] for two levels, and 0·04 [0·03–0·06] for three levels in very-high-risk drinkers). Interpretation Our results support the use of reductions in WHO drinking risk levels as an efficacy outcome in clinical trials. Because these risk levels can be readily translated into standard drink equivalents per day of different countries, the WHO risk levels could also be used internationally to guide treatment goals and clinical recommendations on drinking reduction. Funding US National Institute on Alcohol Abuse and Alcoholism, New York State Psychiatric Institute, the Alcohol Clinical Trials Initiative.

Prospective studies have shown during the years preceding and following menopause, also known as "menopause transition", that midlife women are at higher risk for developing first-onset major depressive disorder (MDD). The biological factors associated with risk and resilience in this population are, however, largely unknown. Considering the growing body of evidence suggesting that inflammation, oxidative stress, and brain-derived neurotrophic factor (BDNF) are associated with the pathophysiology of MDD, we investigated serum levels of protein carbonyl, lipid peroxidation (thiobarbituric acid reactive substances-TBARS), thiol group content, BDNF, 3-nitrotyrosine, and heat shock protein 70 (HSP70) in a longitudinal cohort of first-onset MDD. One hundred and forty-eight women from the Harvard Study of Moods and Cycles, a prospective study of midlife women monitored throughout the transition to menopause, were studied. Within- and between-groups analyses of these peripheral markers were conducted in 37 women who developed and 111 women that did not develop MDD during the 3-year follow-up period. In women who developed MDD, HSP70 and 3-nitrotyrosine were elevated at baseline, whereas TBARS were elevated 6 months prior to development of MDD, as compared to those who did not develop MDD. Within-group analyses showed that HSP70, 3-nitrotyrosine, and BDNF decreased over time, whereas protein carbonyl was elevated only at 12 months prior to development of MDD. In women who did not develop MDD, HSP70 and thiol decreased over time. The development of MDD in midlife women may be associated with a systemic cascade of pro-oxidative and pro-inflammatory events including increased HSP70, 3-nitrotyrosine, protein carbonyl, and lipid peroxidation and decreased BDNF.

Objectives Healthcare professionals (HCPs) with opioid dependence are at risk for relapse and death, particularly in the first year of recovery; however, maintenance treatment with opioid agonists is controversial in this safety-sensitive group. We evaluated long-term safety, tolerability, and treatment outcomes of injectable, intramuscular, extended-release naltrexone (XR-NTX) in opioid-dependent HCPs. Methods This single-arm, multisite, open-label study was conducted in opioid-dependent HCPs who had been detoxified from opioids for at least 2 weeks. Subjects received monthly XR-NTX injections for up to 24 months, combined with counseling via intensive outpatient substance abuse treatment programs. Assessments included monthly urine opioid drug tests and routine safety assessments, along with a trimonthly short form (36) Health Survey, opioid craving questionnaire, and Treatment Satisfaction Questionnaire for Medication. Results Of 49 opioid-dependent HCPs screened, 38 enrolled and received at least 1 XR-NTX injection. Most were female (n = 31) and nurses or nursing assistants (n = 30). More than half (n = 21; 55.3%) received at least 12 injections. Seven discontinued due to adverse events (3 anxiety, 2 headache, 1 injection-site mass, 1 derealization). None experienced relapses to opioid dependence necessitating detoxification, overdose, or death during treatment. At 24 months, mean opioid craving fell by 45.2%, and short form (36) mental component scores improved by 31.1% from baseline and approached normal levels. Of 22 unemployed subjects at baseline, 45.5% improved employment status at 24 months. Conclusions Long-term (2 years) XR-NTX was associated with no new safety concerns, and, compared with shorter-term studies in the general population, similar or better rates of retention, opioid-negative urines, opioid craving reduction, mental health functional quality of life improvement, and re-employment.