Sutter Health

This is the seventh in a series of eight articles analysing the gap between research and practice Series editors: Andrew Haines and Anna Donald Despite the considerable amount of money spent on clinical research relatively little attention has been paid to ensuring that the findings of research are implemented in routine clinical practice.1 There are many different types of intervention that can be used to promote behavioural change among healthcare professionals and the implementation of research findings. Disentangling the effects of intervention from the influence of contextual factors is difficult when interpreting the results of individual trials of behavioural change.2 Nevertheless, systematic reviews of rigorous studies provide the best evidence of the effectiveness of different strategies for promoting behavioural change. 3 4 In this paper we examine systematic reviews of different strategies for the dissemination and implementation of research findings to identify evidence of the effectiveness of different strategies and to assess the quality of the systematic reviews. #### Summary points Systematic reviews of rigorous studies provide the best evidence on the effectiveness of different strategies to promote the implementation of research findings Passive dissemination of information is generally ineffective It seems necessary to use specific strategies to encourage implementation of research based recommendations and to ensure changes in practice Further research on the relative effectiveness and efficiency of different strategies is required We searched Medline records dating from 1966 to June 1995 using a strategy developed in collaboration with the NHS Centre for Reviews and Dissemination. The search identified 1139 references. No reviews from the Cochrane Effective Practice and Organisation of Care Review Group4 had been published during this time. In addition, we searched the Database of Abstracts of Research Effectiveness (DARE) (http://www.york.ac.uk/inst/crd) but did not identify any other review meeting the inclusion criteria. We searched for any review …

PURPOSE: The immunomodulatory effect of lenvatinib (a multikinase inhibitor) on tumor microenvironments may contribute to antitumor activity when combined with programmed death receptor-1 (PD-1) signaling inhibitors in hepatocellular carcinoma (HCC). We report results from a phase Ib study of lenvatinib plus pembrolizumab (an anti-PD-1 antibody) in unresectable HCC (uHCC). PATIENTS AND METHODS: In this open-label multicenter study, patients with uHCC received lenvatinib (bodyweight ≥ 60 kg, 12 mg; < 60 kg, 8 mg) orally daily and pembrolizumab 200 mg intravenously on day 1 of a 21-day cycle. The study included a dose-limiting toxicity (DLT) phase and an expansion phase (first-line patients). Primary objectives were safety/tolerability (DLT phase), and objective response rate (ORR) and duration of response (DOR) by modified RECIST (mRECIST) and RECIST version 1.1 (v1.1) per independent imaging review (IIR; expansion phase). RESULTS: A total of 104 patients were enrolled. No DLTs were reported (n = 6) in the DLT phase; 100 patients (expansion phase; included n = 2 from DLT phase) had received no prior systemic therapy and had Barcelona Clinic Liver Cancer stage B (n = 29) or C disease (n = 71). At data cutoff, 37% of patients remained on treatment. Median duration of follow-up was 10.6 months (95% CI, 9.2 to 11.5 months). Confirmed ORRs by IIR were 46.0% (95% CI, 36.0% to 56.3%) per mRECIST and 36.0% (95% CI, 26.6% to 46.2%) per RECIST v1.1. Median DORs by IIR were 8.6 months (95% CI, 6.9 months to not estimable [NE]) per mRECIST and 12.6 months (95% CI, 6.9 months to NE) per RECIST v1.1. Median progression-free survival by IIR was 9.3 months per mRECIST and 8.6 months per RECIST v1.1. Median overall survival was 22 months. Grade ≥ 3 treatment-related adverse events occurred in 67% (grade 5, 3%) of patients. No new safety signals were identified. CONCLUSION: Lenvatinib plus pembrolizumab has promising antitumor activity in uHCC. Toxicities were manageable, with no unexpected safety signals.

OBJECTIVE: Decades-old, common ICU practices including deep sedation, immobilization, and limited family access are being challenged. We endeavoured to evaluate the relationship between ABCDEF bundle performance and patient-centered outcomes in critical care. DESIGN: Prospective, multicenter, cohort study from a national quality improvement collaborative. SETTING: 68 academic, community, and federal ICUs collected data during a 20-month period. PATIENTS: 15,226 adults with at least one ICU day. INTERVENTIONS: We defined ABCDEF bundle performance (our main exposure) in two ways: 1) complete performance (patient received every eligible bundle element on any given day) and 2) proportional performance (percentage of eligible bundle elements performed on any given day). We explored the association between complete and proportional ABCDEF bundle performance and three sets of outcomes: patient-related (mortality, ICU and hospital discharge), symptom-related (mechanical ventilation, coma, delirium, pain, restraint use), and system-related (ICU readmission, discharge destination). All models were adjusted for a minimum of 18 a priori determined potential confounders. MEASUREMENTS AND RESULTS: Complete ABCDEF bundle performance was associated with lower likelihood of seven outcomes: hospital death within 7 days (adjusted hazard ratio, 0.32; CI, 0.17-0.62), next-day mechanical ventilation (adjusted odds ratio [AOR], 0.28; CI, 0.22-0.36), coma (AOR, 0.35; CI, 0.22-0.56), delirium (AOR, 0.60; CI, 0.49-0.72), physical restraint use (AOR, 0.37; CI, 0.30-0.46), ICU readmission (AOR, 0.54; CI, 0.37-0.79), and discharge to a facility other than home (AOR, 0.64; CI, 0.51-0.80). There was a consistent dose-response relationship between higher proportional bundle performance and improvements in each of the above-mentioned clinical outcomes (all p < 0.002). Significant pain was more frequently reported as bundle performance proportionally increased (p = 0.0001). CONCLUSIONS: ABCDEF bundle performance showed significant and clinically meaningful improvements in outcomes including survival, mechanical ventilation use, coma, delirium, restraint-free care, ICU readmissions, and post-ICU discharge disposition.

Objective: We explored whether use of deep learning to model temporal relations among events in electronic health records (EHRs) would improve model performance in predicting initial diagnosis of heart failure (HF) compared to conventional methods that ignore temporality. Materials and Methods: Data were from a health system's EHR on 3884 incident HF cases and 28 903 controls, identified as primary care patients, between May 16, 2000, and May 23, 2013. Recurrent neural network (RNN) models using gated recurrent units (GRUs) were adapted to detect relations among time-stamped events (eg, disease diagnosis, medication orders, procedure orders, etc.) with a 12- to 18-month observation window of cases and controls. Model performance metrics were compared to regularized logistic regression, neural network, support vector machine, and K-nearest neighbor classifier approaches. Results: Using a 12-month observation window, the area under the curve (AUC) for the RNN model was 0.777, compared to AUCs for logistic regression (0.747), multilayer perceptron (MLP) with 1 hidden layer (0.765), support vector machine (SVM) (0.743), and K-nearest neighbor (KNN) (0.730). When using an 18-month observation window, the AUC for the RNN model increased to 0.883 and was significantly higher than the 0.834 AUC for the best of the baseline methods (MLP). Conclusion: Deep learning models adapted to leverage temporal relations appear to improve performance of models for detection of incident heart failure with a short observation window of 12-18 months.

Accuracy and interpretability are two dominant features of successful\npredictive models. Typically, a choice must be made in favor of complex black\nbox models such as recurrent neural networks (RNN) for accuracy versus less\naccurate but more interpretable traditional models such as logistic regression.\nThis tradeoff poses challenges in medicine where both accuracy and\ninterpretability are important. We addressed this challenge by developing the\nREverse Time AttentIoN model (RETAIN) for application to Electronic Health\nRecords (EHR) data. RETAIN achieves high accuracy while remaining clinically\ninterpretable and is based on a two-level neural attention model that detects\ninfluential past visits and significant clinical variables within those visits\n(e.g. key diagnoses). RETAIN mimics physician practice by attending the EHR\ndata in a reverse time order so that recent clinical visits are likely to\nreceive higher attention. RETAIN was tested on a large health system EHR\ndataset with 14 million visits completed by 263K patients over an 8 year period\nand demonstrated predictive accuracy and computational scalability comparable\nto state-of-the-art methods such as RNN, and ease of interpretability\ncomparable to traditional models.\n

BACKGROUND: Reducing hepatitis B virus (HBV) replication to minimal levels is emerging as a key therapeutic goal for chronic hepatitis B. METHODS: In this double-blind, phase 3 trial, 1370 patients with chronic hepatitis B were randomly assigned to receive 600 mg of telbivudine or 100 mg of lamivudine once daily. The primary efficacy end point was noninferiority of telbivudine to lamivudine for therapeutic response (i.e., a reduction in serum HBV DNA levels to fewer than 5 log10 copies per milliliter, along with loss of hepatitis B e antigen [HBeAg] or normalization of alanine aminotransferase levels). Secondary efficacy measures included histologic response, changes in serum HBV DNA levels, and HBeAg responses. RESULTS: At week 52, a significantly higher proportion of HBeAg-positive patients receiving telbivudine than of those receiving lamivudine had a therapeutic response (75.3% vs. 67.0%, P=0.005) or a histologic response (64.7% vs. 56.3%, P=0.01); telbivudine also was not inferior to lamivudine for these end points in HBeAg-negative patients. In HBeAg-positive and HBeAg-negative patients, telbivudine was superior to lamivudine with respect to the mean reduction in the number of copies of HBV DNA from baseline, the proportion of patients with a reduction in HBV DNA to levels undetectable by polymerase-chain-reaction assay, and development of resistance to the drug. Elevated creatine kinase levels were more common in patients who received telbivudine, whereas elevated alanine aminotransferase and aspartate aminotransferase levels were more common in those who received lamivudine. CONCLUSIONS: Among patients with HBeAg-positive chronic hepatitis B, the rates of therapeutic and histologic response at 1 year were significantly higher in patients treated with telbivudine than in patients treated with lamivudine. In both the HBeAg-negative and the HBeAg-positive groups, telbivudine demonstrated greater HBV DNA suppression with less resistance than did lamivudine. (ClinicalTrials.gov number, NCT00057265 [ClinicalTrials.gov].).

IMPORTANCE: Germline mutations in BRCA1 and BRCA2 are relatively common in women with ovarian, fallopian tube, and peritoneal carcinoma (OC) causing a greatly increased lifetime risk of these cancers, but the frequency and relevance of inherited mutations in other genes is less well characterized. OBJECTIVE: To determine the frequency and importance of germline mutations in cancer-associated genes in OC. DESIGN, SETTING, AND PARTICIPANTS: A study population of 1915 woman with OC and available germline DNA were identified from the University of Washington (UW) gynecologic tissue bank (n = 570) and from Gynecologic Oncology Group (GOG) phase III clinical trials 218 (n = 788) and 262 (n = 557). Patients were enrolled at diagnosis and were not selected for age or family history. Germline DNA was sequenced from women with OC using a targeted capture and multiplex sequencing assay. MAIN OUTCOMES AND MEASURES: Mutation frequencies in OC were compared with the National Heart, Lung, and Blood Institute GO Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC). Clinical characteristics and survival were assessed by mutation status. RESULTS: Overall, the median (range) age at diagnosis was 60 (28-91) years in patients recruited from UW and 61 (23-87) years in patients recruited from the GOG trials. A higher number of black women were recruited from the GOG trials (4.3% vs 1.4%; P = .009); but in patients recruited from UW, there was a higher proportion of fallopian tube carcinomas (13.3% vs 5.7%; P < .001); stage I and II disease (14.6% vs 0% [GOG trials were restricted to advanced-stage cancer]); and nonserous carcinomas (29.9% vs 13.1%, P < .001). Of 1915 patients, 280 (15%) had mutations in BRCA1 (n = 182), or BRCA2 (n = 98), and 8 (0.4%) had mutations in DNA mismatch repair genes. Mutations in BRIP1 (n = 26), RAD51C (n = 11), RAD51D (n = 11), PALB2 (n = 12), and BARD1 (n = 4) were significantly more common in patients with OC than in the ESP or ExAC, present in 3.3%. Race, histologic subtype, and disease site were not predictive of mutation frequency. Patients with a BRCA2 mutation from the GOG trials had longer progression-free survival (hazard ratio [HR], 0.60; 95% CI, 0.45-0.79; P < .001) and overall survival (HR, 0.39; 95% CI, 0.25-0.60; P < .001) compared with those without mutations. CONCLUSIONS AND RELEVANCE: Of 1915 patients with OC, 347 (18%) carried pathogenic germline mutations in genes associated with OC risk. PALB2 and BARD1 are suspected OC genes and together with established OC genes (BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH2, MLH1, PMS2, and MSH6) bring the total number of genes suspected to cause hereditary OC to 11.

accuracy, data needs, interpretability) of GRAM to various methods including the recurrent neural network (RNN) in two sequential diagnoses prediction tasks and one heart failure prediction task. Compared to the basic RNN, GRAM achieved 10% higher accuracy for predicting diseases rarely observed in the training data and 3% improved area under the ROC curve for predicting heart failure using an order of magnitude less training data. Additionally, unlike other methods, the medical concept representations learned by GRAM are well aligned with the medical ontology. Finally, GRAM exhibits intuitive attention behaviors by adaptively generalizing to higher level concepts when facing data insufficiency at the lower level concepts.

PURPOSE: To develop an evidence-based clinical practice guideline to assist in clinical decision making for patients with advanced hepatocellular carcinoma (HCC). METHODS: ASCO convened an Expert Panel to conduct a systematic review of published phase III randomized controlled trials (2007-2020) on systemic therapy for advanced HCC and provide recommended care options for this patient population. RESULTS: Nine phase III randomized controlled trials met the inclusion criteria. RECOMMENDATIONS: Atezolizumab + bevacizumab (atezo + bev) may be offered as first-line treatment of most patients with advanced HCC, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1, and following management of esophageal varices, when present, according to institutional guidelines. Where there are contraindications to atezolizumab and/or bevacizumab, tyrosine kinase inhibitors sorafenib or lenvatinib may be offered as first-line treatment of patients with advanced HCC, Child-Pugh class A liver disease, and ECOG PS 0-1. Following first-line treatment with atezo + bev, and until better data are available, second-line therapy with a tyrosine kinase inhibitor may be recommended for appropriate candidates. Following first-line therapy with sorafenib or lenvatinib, second-line therapy options for appropriate candidates include cabozantinib, regorafenib for patients who previously tolerated sorafenib, or ramucirumab (for patients with α-fetoprotein ≥ 400 ng/mL), or atezo + bev where patients did not have access to this option as first-line therapy. Pembrolizumab or nivolumab are also reasonable options for appropriate patients following sorafenib or lenvatinib. Consideration of nivolumab + ipilimumab as an option for second-line therapy and third-line therapy is discussed. Further guidance on choosing between therapy options is included within the guideline. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

The use and functionality of electronic health records (EHRs) have increased rapidly in the past decade. Although the primary purpose of EHRs is clinical, researchers have used them to conduct epidemiologic investigations, ranging from cross-sectional studies within a given hospital to longitudinal studies on geographically distributed patients. Herein, we describe EHRs, examine their use in population health research, and compare them with traditional epidemiologic methods. We describe diverse research applications that benefit from the large sample sizes and generalizable patient populations afforded by EHRs. These have included reevaluation of prior findings, a range of diseases and subgroups, environmental and social epidemiology, stigmatized conditions, predictive modeling, and evaluation of natural experiments. Although studies using primary data collection methods may have more reliable data and better population retention, EHR-based studies are less expensive and require less time to complete. Future EHR epidemiology with enhanced collection of social/behavior measures, linkage with vital records, and integration of emerging technologies such as personal sensing could improve clinical care and population health.

As the novel coronavirus disease (COVID-19) pandemic spreads throughout the United States, evidence is mounting that racial and ethnic minorities and socioeconomically disadvantaged groups are bearing a disproportionate burden of illness and death. We conducted a retrospective cohort analysis of COVID-19 patients at Sutter Health, a large integrated health system in northern California, to measure potential disparities. We used Sutter's integrated electronic health record to identify adults with suspected and confirmed COVID-19, and we used multivariable logistic regression to assess risk of hospitalization, adjusting for known risk factors, such as race/ethnicity, sex, age, health, and socioeconomic variables. We analyzed 1,052 confirmed cases of COVID-19 from the period January 1-April 8, 2020. Among our findings, we observed that compared with non-Hispanic white patients, non-Hispanic African American patients had 2.7 times the odds of hospitalization, after adjustment for age, sex, comorbidities, and income. We explore possible explanations for this, including societal factors that either result in barriers to timely access to care or create circumstances in which patients view delaying care as the most sensible option. Our study provides real-world evidence of racial and ethnic disparities in the presentation of COVID-19.

BACKGROUND: The strikingly higher prevalence of migraine in females compared with males is one of the hallmarks of migraine. A large global body of evidence exists on the sex differences in the prevalence of migraine with female to male ratios ranging from 2:1 to 3:1 and peaking in midlife. Some data are available on sex differences in associated symptoms, headache-related disability and impairment, and healthcare resource utilization in migraine. Few data are available on corresponding sex differences in probable migraine (PM) and other severe headache (ie, nonmigraine-spectrum severe headache). Gaining a clear understanding of sex differences in a range of severe headache disorders may help differentiate the range of headache types. Herein, we compare sexes on prevalence and a range of clinical variables for migraine, PM, and other severe headache in a large sample from the US population. METHODS: This study analyzed data from the 2004 American Migraine Prevalence and Prevention Study. Total and demographic-stratified sex-specific, prevalence estimates of headache subtypes (migraine, PM, and other severe headache) are reported. Log-binomial models are used to calculate sex-specific adjusted prevalence ratios and 95% confidence intervals for each across demographic strata. A smoothed sex prevalence ratio (female to male) figure is presented for migraine and PM. RESULTS: One hundred sixty-two thousand seven hundred fifty-six individuals aged 12 and older responded to the 2004 American Migraine Prevalence and Prevention Study survey (64.9% response rate). Twenty-eight thousand two hundred sixty-one (17.4%) reported "severe headache" in the preceding year (23.5% of females and 10.6% of males), 11.8% met International Classification of Headache Disorders-2 criteria for migraine (17.3% of females and 5.7% of males), 4.6% met criteria for PM (5.3% of females and 3.9% of males), and 1.0% were categorized with other severe headache (0.9% of females and 1.0% of males). Sex differences were observed in the prevalence of migraine and PM, but not for other severe headache. Adjusted female to male prevalence ratios ranged from 1.48 to 3.25 across the lifetime for migraine and from 1.22 to 1.53 for PM. Sex differences were also observed in associated symptomology, aura, headache-related disability, healthcare resource utilization, and diagnosis for migraine and PM. Despite higher rates of migraine diagnosis by a healthcare professional, females with migraine were less likely than males to be using preventive pharmacologic treatment for headache. CONCLUSIONS: In this large, US population sample, both migraine and PM were more common among females, but a sex difference was not observed in the prevalence of other severe headache. The sex difference in migraine and PM held true across age and for most other sociodemographic variables with the exception of race for PM. Females with migraine and PM had higher rates of most migraine symptoms, aura, greater associated impairment, and higher healthcare resource utilization than males. Corresponding sex differences were not observed among individuals with other severe headache on the majority of these comparisons. Results suggest that PM is part of the migraine spectrum whereas other severe headache types are not. Results also substantiate existing literature on sex differences in primary headaches and extend results to additional headache types and related factors.

PURPOSE: Perirectal spacing, whereby biomaterials are placed between the prostate and rectum, shows promise in reducing rectal dose during prostate cancer radiation therapy. A prospective multicenter randomized controlled pivotal trial was performed to assess outcomes following absorbable spacer (SpaceOAR system) implantation. METHODS AND MATERIALS: Overall, 222 patients with clinical stage T1 or T2 prostate cancer underwent computed tomography (CT) and magnetic resonance imaging (MRI) scans for treatment planning, followed with fiducial marker placement, and were randomized to receive spacer injection or no injection (control). Patients received postprocedure CT and MRI planning scans and underwent image guided intensity modulated radiation therapy (79.2 Gy in 1.8-Gy fractions). Spacer safety and impact on rectal irradiation, toxicity, and quality of life were assessed throughout 15 months. RESULTS: Spacer application was rated as "easy" or "very easy" 98.7% of the time, with a 99% hydrogel placement success rate. Perirectal spaces were 12.6 ± 3.9 mm and 1.6 ± 2.0 mm in the spacer and control groups, respectively. There were no device-related adverse events, rectal perforations, serious bleeding, or infections within either group. Pre-to postspacer plans had a significant reduction in mean rectal V70 (12.4% to 3.3%, P<.0001). Overall acute rectal adverse event rates were similar between groups, with fewer spacer patients experiencing rectal pain (P=.02). A significant reduction in late (3-15 months) rectal toxicity severity in the spacer group was observed (P=.04), with a 2.0% and 7.0% late rectal toxicity incidence in the spacer and control groups, respectively. There was no late rectal toxicity greater than grade 1 in the spacer group. At 15 months 11.6% and 21.4% of spacer and control patients, respectively, experienced 10-point declines in bowel quality of life. MRI scans at 12 months verified spacer absorption. CONCLUSIONS: Spacer application was well tolerated. Increased perirectal space reduced rectal irradiation, reduced rectal toxicity severity, and decreased rates of patients experiencing declines in bowel quality of life. The spacer appears to be an effective tool, potentially enabling advanced prostate RT protocols.

OBJECTIVES: To track compliance by an interprofessional team with the Awakening and Breathing Coordination, Choice of drugs, Delirium monitoring and management, Early mobility, and Family engagement (ABCDEF) bundle in implementing the Pain, Agitation, and Delirium guidelines. The aim was to study the association between ABCDEF bundle compliance and outcomes including hospital survival and delirium-free and coma-free days in community hospitals. DESIGN: A prospective cohort quality improvement initiative involving ICU patients. SETTING: Seven community hospitals within California's Sutter Health System. PATIENTS: Ventilated and nonventilated general medical and surgical ICU patients enrolled between January 1, 2014, and December 31, 2014. MEASUREMENTS AND MAIN RESULTS: Total and partial bundle compliance were measured daily. Random effects regression was used to determine the association between ABCDEF bundle compliance accounting for total compliance (all or none) or for partial compliance ("dose" or number of bundle elements used) and outcomes of hospital survival and delirium-free and coma-free days, after adjusting for age, severity of illness, and presence of mechanical ventilation. Of 6,064 patients, a total of 586 (9.7%) died before hospital discharge. For every 10% increase in total bundle compliance, patients had a 7% higher odds of hospital survival (odds ratio, 1.07; 95% CI, 1.04-1.11; p < 0.001). Likewise, for every 10% increase in partial bundle compliance, patients had a 15% higher hospital survival (odds ratio, 1.15; 95% CI, 1.09-1.22; p < 0.001). These results were even more striking (12% and 23% higher odds of survival per 10% increase in bundle compliance, respectively, p < 0.001) in a sensitivity analysis removing ICU patients identified as receiving palliative care. Patients experienced more days alive and free of delirium and coma with both total bundle compliance (incident rate ratio, 1.02; 95% CI, 1.01-1.04; p = 0.004) and partial bundle compliance (incident rate ratio, 1.15; 95% CI, 1.09-1.22; p < 0.001). CONCLUSIONS: The evidence-based ABCDEF bundle was successfully implemented in seven community hospital ICUs using an interprofessional team model to operationalize the Pain, Agitation, and Delirium guidelines. Higher bundle compliance was independently associated with improved survival and more days free of delirium and coma after adjusting for age, severity of illness, and presence of mechanical ventilation.

Importance: Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed. Objective: To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma. Design, Setting, and Participants: This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021. Interventions: The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies. Main Outcomes and Measures: The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials. Results: A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03). Conclusions and Relevance: In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone. Trial Registration: ClinicalTrials.gov Identifier: NCT00045968.

Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson's disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson's disease.

Time spent by physicians is a key resource in health care delivery. This study used data captured by the access time stamp functionality of an electronic health record (EHR) to examine physician work effort. This is a potentially powerful, yet unobtrusive, way to study physicians' use of time. We used data on physicians' time allocation patterns captured by over thirty-one million EHR transactions in the period 2011-14 recorded by 471 primary care physicians, who collectively worked on 765,129 patients' EHRs. Our results suggest that the physicians logged an average of 3.08 hours on office visits and 3.17 hours on desktop medicine each day. Desktop medicine consists of activities such as communicating with patients through a secure patient portal, responding to patients' online requests for prescription refills or medical advice, ordering tests, sending staff messages, and reviewing test results. Over time, log records from physicians showed a decline in the time allocated to face-to-face visits, accompanied by an increase in time allocated to desktop medicine. Staffing and scheduling in the physician's office, as well as provider payment models for primary care practice, should account for these desktop medicine efforts.

PURPOSE: To investigate the association of soccer heading with subclinical evidence of traumatic brain injury. MATERIALS AND METHODS: With institutional review board approval and compliance with HIPAA guidelines, 37 amateur soccer players (mean age, 30.9 years; 78% [29] men, 22% [eight] women) gave written informed consent and completed a questionnaire to quantify heading in the prior 12 months and lifetime concussions. Diffusion-tensor magnetic resonance (MR) imaging at 3.0 T was performed (32 directions; b value, 800 sec/mm(2); 2 × 2 × 2-mm voxels). Cognitive function was measured by using a computerized battery of tests. Voxelwise linear regression (heading vs fractional anisotropy [FA]) was applied to identify significant regional associations. FA at each location and cognition were tested for a nonlinear relationship to heading by using an inverse logit model that incorporated demographic covariates and history of concussion. RESULTS: Participants had headed 32-5400 times (median, 432 times) over the previous year. Heading was associated with lower FA at three locations in temporo-occipital white matter with a threshold that varied according to location (885-1550 headings per year) (P < .00001). Lower levels of FA were also associated with poorer memory scores (P < .00001), with a threshold of 1800 headings per year. Lifetime concussion history and demographic features were not significantly associated with either FA or cognitive performance. CONCLUSION: Heading is associated with abnormal white matter microstructure and with poorer neurocognitive performance. This relationship is not explained by a history of concussion.

PURPOSE Reducing radiation treatment dose could improve the quality of life (QOL) of patients with good-risk human papillomavirus–associated oropharyngeal squamous cell carcinoma (OPSCC). Whether reduced-dose radiation produces disease control and QOL equivalent to standard chemoradiation is not proven. PATIENTS AND METHODS In this randomized, phase II trial, patients with p16-positive, T1-T2 N1-N2b M0, or T3 N0-N2b M0 OPSCC (7th edition staging) with ≤ 10 pack-years of smoking received 60 Gy of intensity-modulated radiation therapy (IMRT) over 6 weeks with concurrent weekly cisplatin (C) or 60 Gy IMRT over 5 weeks. To be considered for a phase III study, an arm had to achieve a 2-year progression-free survival (PFS) rate superior to a historical control rate of 85% and a 1-year mean composite score ≥ 60 on the MD Anderson Dysphagia Inventory (MDADI). RESULTS Three hundred six patients were randomly assigned and eligible. Two-year PFS for IMRT + C was 90.5% rejecting the null hypothesis of 2-year PFS ≤ 85% ( P = .04). For IMRT, 2-year PFS was 87.6% ( P = .23). One-year MDADI mean scores were 85.30 and 81.76 for IMRT + C and IMRT, respectively. Two-year overall survival rates were 96.7% for IMRT + C and 97.3% for IMRT. Acute adverse events (AEs) were defined as those occurring within 180 days from the end of treatment. There were more grade 3-4 acute AEs for IMRT + C (79.6% v 52.4%; P &lt; .001). Rates of grade 3-4 late AEs were 21.3% and 18.1% ( P = .56). CONCLUSION The IMRT + C arm met both prespecified end points justifying advancement to a phase III study. Higher rates of grade ≥ 3 acute AEs were reported in the IMRT + C arm.

PURPOSE: Pegylated recombinant human hyaluronidase (PEGPH20) degrades hyaluronan (HA) and, in combination with chemotherapy, prolongs survival in preclinical models. The activity of PEGPH20 with modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) was evaluated in patients with metastatic pancreatic cancer (mPC). MATERIALS AND METHODS: Patients had untreated mPC, a performance status of 0 to 1, and adequate organ function. Tumor HA status was not required for eligibility. After a phase Ib dose-finding study of mFOLFIRINOX plus PEGPH20, the phase II open-label study randomly assigned patients (1:1) to the combination arm or to mFOLFIRINOX alone (n = 138). The primary end point was overall survival (OS). RESULTS: PEGPH20 dosages of 3 µg/kg every 2 weeks were more tolerable than twice-weekly dosages used in the phase I study, so 3 µg/kg every 2 weeks was the phase II dosage. An amendment instituted enoxaparin prophylaxis in the PEGPH20 combination arm as a result of increased thromboembolic (TE) events. The planned interim futility analysis when 35 deaths (of 103 analyzable patients) occurred resulted in an OS hazard ratio (HR) of 2.07 that favored the control arm, and the study was closed to accrual. The treatment-related grade 3 to 4 toxicity was significantly increased in the PEGPH20 combination arm relative to control (odds ratio, 2.7; 95% CI, 1.1 to 7.1). The median OS in the mFOLFIRINOX arm was 14.4 months (95% CI, 10.1 to 15.7 months) versus 7.7 months (95% CI, 4.6 to 9.3 months) in the PEGPH20 combination arm. CONCLUSION: Addition of PEGPH20 to mFOLFIRINOX seems to be detrimental in patients unselected for tumor HA status. This combination caused increased toxicity (mostly GI and TE events) and resulted in decreased treatment duration compared with mFOLFIRINOX alone. The median OS in the mFOLFIRINOX control arm (14.4 months) is, to our knowledge, the longest yet reported and can be considered for patients with good PS.