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OBJECTIVE To compare the prospective risk of stillbirth between women with and without a stillbirth in their first pregnancy. METHODS We conducted a cohort study using perinatal data from Finland, Malta, and Scotland. Women who had at least two singleton deliveries were included. The exposed and unexposed cohorts comprised women with a stillbirth and live birth in their first pregnancy, respectively. The risk of stillbirth in any subsequent pregnancy was assessed using a Cox proportional hazards model. Time-to-event analyses were conducted to investigate whether first pregnancy outcome had an effect on time to or the number of pregnancies preceding subsequent stillbirth. RESULTS The pooled data set included 1,064,564 women, 6,288 (0.59%) with a stillbirth and 1,058,276 with a live birth in a first pregnancy. Compared with women with a live birth, women with a stillbirth in the first pregnancy were more likely to have a subsequent stillbirth (adjusted hazard ratio [aHR] 2.25, 95% CI 1.86-2.72). For women with more than two pregnancies, the difference in risk of subsequent stillbirth between the two groups increased with the number of subsequent pregnancies. Maternal age younger than 25 years or 40 years and older, smoking, low socioeconomic status, not having a partner, pre-existing diabetes, preeclampsia, placental abruption, or delivery of a growth-restricted neonate in a first pregnancy were independently associated with subsequent stillbirth. Compared with women with a live birth in the first pregnancy, women with a stillbirth were more likely to have another pregnancy within 1 year. The absolute risk of stillbirth in a subsequent pregnancy for women with stillbirth and live birth in a first pregnancy were 2.5% and 0.5%, respectively. CONCLUSION Compared with women with a live birth in a first pregnancy, women with a stillbirth have a higher risk of subsequent stillbirth irrespective of the number and sequence of the pregnancies. Despite high relative risk, the absolute risk of recurrence was low.

Action observation (AO) and motor imagery (MI) have been used separately across different populations to alleviate movement impairment. Recently these two forms of covert motor simulation have been combined (combined action observation and motor imagery; AOMI), resulting in greater neurophysiological activity in the motor system, and more favourable behavioural outcomes when compared to independent AO and MI. This review aims to outline how some of the neural deficits associated with developmental coordination disorder (DCD) are evident during AO and MI, and highlight how these motor simulation techniques have been used independently to improve motor skill learning in children in this population. The growing body of evidence indicating that AOMI is superior to the independent use of either AO and MI is then synthesised and discussed in the context of children with DCD. To conclude, recommendations to optimise the delivery of AOMI for children with DCD are provided and future avenues for research are highlighted.

Fc γ receptor IIB (FcγRIIB) is an inhibitory molecule capable of reducing antibody immunotherapy efficacy. We hypothesized its expression could confer resistance in patients with diffuse large B-cell lymphoma (DLBCL) treated with anti-CD20 monoclonal antibody (mAb) chemoimmunotherapy, with outcomes varying depending on mAb (rituximab [R]/obinutuzumab [G]) because of different mechanisms of action. We evaluated correlates between FCGR2B messenger RNA and/or FcγRIIB protein expression and outcomes in 3 de novo DLBCL discovery cohorts treated with R plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) reported by Arthur, Schmitz, and Reddy, and R-CHOP/G-CHOP-treated patients in the GOYA trial (NCT01287741). In the discovery cohorts, higher FCGR2B expression was associated with significantly shorter progression-free survival (PFS; Arthur: hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.01-1.19; P = .0360; Schmitz: HR, 1.13; 95% CI, 1.02-1.26; P = .0243). Similar results were observed in GOYA with R-CHOP (HR, 1.26; 95% CI, 1.00-1.58; P = .0455), but not G-CHOP (HR, 0.91; 95% CI, 0.69-1.20; P = .50). A nonsignificant trend that high FCGR2B expression favored G-CHOP over R-CHOP was observed (HR, 0.67; 95% CI, 0.44-1.02; P = .0622); however, low FCGR2B expression favored R-CHOP (HR, 1.58; 95% CI, 1.00-2.50; P = .0503). In Arthur and GOYA, FCGR2B expression was associated with tumor FcγRIIB expression; correlating with shorter PFS for R-CHOP (HR, 2.17; 95% CI, 1.04-4.50; P = .0378), but not G-CHOP (HR, 1.37; 95% CI, 0.66-2.87; P = .3997). This effect was independent of established prognostic biomarkers. High FcγRIIB/FCGR2B expression has prognostic value in R-treated patients with DLBCL and may confer differential responsiveness to R-CHOP/G-CHOP.

BACKGROUND Nearly 1-in-10 trauma patients in the United States are readmitted within 30 days of discharge, with a median hospital cost of more than $8,000 per readmission. There are national efforts to reduce readmissions in trauma care, but we do not yet understand which are potentially preventable. Our study aims to quantify the potentially preventable readmissions (PPRs) in trauma care to serve as the anchor point for ongoing efforts to curb hospital readmissions and ultimately, bring preventable readmissions to zero. METHODS We identified inpatient hospitalizations after trauma and readmissions within 90 days in the 2017 National Readmissions Database (NRD). Potentially preventable readmissions were defined as the Agency for Healthcare Research and Quality-defined Ambulatory Care Sensitive Conditions, in addition to superficial surgical site infection, acute kidney injury/acute renal failure, and aspiration pneumonitis. Mean costs for these admissions were calculated using the NRD. A multivariable logistic regression model was used to characterize the relationship between patient characteristics and PPR. RESULTS A total of 1,320,083 patients were admitted for trauma care in the 2017 NRD, and 137,854 (10.4%) were readmitted within 90 days of discharge. Of these readmissions, 22.7% were potentially preventable. The mean cost was $10,001/PPR, resulting in $313,802,278 in cost to the US health care system. Of readmitted trauma patients younger than 65 years, Medicaid or Medicare patients had 2.7-fold increased odds of PPRs compared with privately insured patients. Patients of any age with congestive heart failure had 2.9 times increased odds of PPR, those with chronic obstructive pulmonary disease or complicated diabetes mellitus had 1.8 times increased odds, and those with chronic kidney disease had 1.7 times increased odds. Furthermore, as the days from discharge increased, the proportion of readmissions due to PPRs increased. CONCLUSION One-in-five trauma readmissions are potentially preventable, which account for more than $300 million annually in health care costs. Improved access to postdischarge ambulatory care may be key to minimizing PPRs, especially for those with certain comorbidities. LEVEL OF EVIDENCE Economic and value-based evaluations, level II.

Background While much of trauma care is rightly focused on improving inpatient survival, the ultimate goal of recovery is to help patients return to their daily lives after injury. Although the overwhelming majority of trauma patients in the United States survive to hospital discharge, little is known nationally regarding the postdischarge economic burden of injuries among trauma survivors. Methods We used the National Health Interview Survey from 2008 to 2017 to identify working-age trauma patients, aged 18 to 64 years, who sustained injuries requiring hospitalization. We used propensity score matching to identify noninjured respondents. Our primary outcome measure was postinjury return to work among trauma patients. Our secondary outcomes included measures of food insecurity, medical debt, accessibility and affordability of health care, and disability. Results A nationally weighted sample of 319,580 working-age trauma patients were identified. Of these patients, 51.7% were employed at the time of injury, and 58.9% of them had returned to work at the time of interview, at a median of 47 days postdischarge. Higher rates of returning to work were associated with shorter length of hospital stay, higher education level, and private health insurance. Injury was associated with food insecurity at an adjusted odds ratio (aOR) of 1.8 (95% confidence interval, 1.40-2.37), with difficulty affording health care at aOR of 1.6 (1.00-2.47), with medical debt at aOR of 2.6 (2.11-3.20), and with foregoing care due to cost at aOR of 2.0 (1.52-2.63). Working-age trauma patients had disability at an aOR of 17.6 (12.93-24.05). Conclusion The postdischarge burden of injury among working-age US trauma survivors is profound-patients report significant limitations in employment, financial security, disability, and functional independence. A better understanding of the long-term impact of injury is necessary to design the interventions needed to optimize postinjury recovery so that trauma survivors can lead productive and fulfilling lives after injury. Level of evidence Economic & Value-Based Evaluations, level II; Prognostic, level II.

Youth at-risk for HIV are also at-risk for mental health disorders and psychiatric hospitalization. Understanding the association between engagement in HIV prevention, concurrent risk behaviors, and psychiatric hospitalization may lead to improvements in integrated prevention and mental health treatment efforts. Youth at-risk for HIV, aged 14-24 years old, predominantly Black/African American and Latinx (75%) were recruited through youth-serving clinics and community sites in Los Angeles (n = 839) and New Orleans (n = 647). We compared youth with and without histories of psychiatric hospitalization on engagement in HIV prevention, concurrent risk behaviors, and demographic characteristics. We examined predictors of hospitalization using multiple imputations for missing data. Hospitalized youth (30%) were more involved in HIV programs, but were less likely to use PrEP/PEP or condoms than non-hospitalized youth. The odds of hospitalization were higher for transgender/gender nonconforming youth relative to cisgender youth; the OR was increased after adjustment for concurrent risk behaviors. Hospitalization was associated with homelessness, trauma, incarceration, substance use, and involvement in substance abuse treatment programs. There is a continuing need to integrate the diagnosis and treatment of mental health disorders into HIV prevention programs to better address multiple challenges faced by vulnerable youth.

Background and Aims There remains a historical misconception that inflammatory bowel disease [IBD] patients are underweight. However, recent data suggest rates of obesity in IBD parallel to those of the general population. The impact obesity has on the natural history of IBD is unclear. We aimed to determine obesity rates at the time of IBD diagnosis in a population-based cohort of ulcerative colitis [UC] patients. Methods Chart review was performed on patients diagnosed with UC over 1970–2010. Data were collected on demographics, body mass index [BMI], disease characteristics, IBD-specific hospitalisations, intestinal resection, and corticosteroid use. The proportion of patients who were obese at the time of their diagnosis was evaluated over time, and survival free of IBD-related complications was assessed using Kaplan-Meier survival analysis. Results A total of 417 adults were diagnosed with UC over 1970–2010, 55.4% of whom were classified as either overweight [34.8%] or obese [20.6%]. The prevalence of obesity increased 2–3-fold over the 40-year study period. Obese patients had a 72% increased risk of hospitalisation (hazard ratio [HR],1.72; 95% confidence interval [CI], 1.10–2.71; p = 0.018) when compared with normal weight patients. Additionally, with each incremental increase in BMI by 1 kg/m2, the risk of hospitalisation increased by 5% [HR,1.05; 95% CI, 1.01–1.08; p = 0.008] and risk of corticosteroid use increased by 2.6% [HR,1.026; 95% CI, 1.00–1.05; p = 0.05]. Conclusions The prevalence of obesity in the UC population is increasing and may have negative prognostic implications, specifically regarding risk of future hospitalisation and corticosteroid use. Additional prospective studies are necessary to more clearly define these associations.

Purpose Radiation therapy (RT) is the standard treatment for patients with inoperable skin malignancies of the head and neck region (H&N), and as adjuvant treatment post surgery in patients at high risk for local or regional recurrence. This study reports clinical outcomes of intensity-modulated proton therapy (IMPT) for these malignancies. Materials and Methods We retrospectively reviewed cases involving 47 patients with H&N malignancies of the skin (squamous cell, basal cell, melanoma, Merkel cell, angiosarcoma, other) who underwent IMPT for curative intent between July 2016 and July 2019. Overall survival was estimated via Kaplan-Meier analysis, and oncologic outcomes were reported as cumulative incidence with death as a competing risk. Results The 2-year estimated local recurrence rate, regional recurrence rate, local regional recurrence rate, distant metastasis rate, and overall survival were 11.1% (95% confidence interval [CI], 4.1%-30.3%), 4.4% (95% CI, 1.1%-17.4%), 15.5% (95% CI, 7%-34.3%), 23.4% (95% CI, 5.8%-95.5%), and 87.2% (95% CI, 75.7%-100%), respectively. No patient was reported to have a grade 3 or higher adverse event during the last week of treatment or at the 3-month follow-up visit. Conclusion IMPT is safe and effective in the treatment of skin malignancies of the H&N.

BACKGROUND Emergency general surgery (EGS) is a high-volume and high-risk surgical service. Interhospital variation in EGS outcomes exists, but there is disagreement in the literature as to whether hospital admission volume affects in-hospital mortality. Scotland collects high-quality data on all admitted patients, whether managed operatively or nonoperatively. Our aim was to determine the relationship between hospital admission volume and in-hospital mortality of EGS patients in Scotland. Second, to investigate whether surgeon admission volume affects mortality. METHODS This national population-level cohort study included EGS patients aged 16 years and older, who were admitted to a Scottish hospital between 2014 and 2018 (inclusive). A logistic regression model was created, with in-hospital mortality as the dependent variable, and admission volume of hospital per year as a continuous covariate of interest, adjusted for age, sex, comorbidity, deprivation, surgeon admission volume, surgeon operative rate, transfer status, diagnosis, and operation category. RESULTS There were 376,076 admissions to 25 hospitals, which met our inclusion criteria. The EGS hospital admission rate per year had no effect on in-hospital mortality (odds ratio [OR], 1.000; 95% confidence interval [CI], 1.000-1.000). Higher average surgeon monthly admission volume increased the odds of in-hospital mortality (>35 admissions: OR, 1.139; 95% CI, 1.038-1.250; 25-35 admissions: OR, 1.091; 95% CI, 1.004-1.185

Background U.S. physicians lack training in caring for patients with obesity. For family medicine, the newly developed Obesity Medicine Education Collaborative (OMEC) competencies provide an opportunity to compare current training with widely accepted standards. We aimed to evaluate the current state of obesity training in family medicine residency programs. Methods We conducted a study consisting of a cross-sectional survey of U.S. family medicine residency program leaders. A total of 735 directors (including associate/assistant directors) from 472 family medicine residency programs identified from the American Academy of Family Physicians public directory were invited via postal mail to complete an online survey in 2018. Results Seventy-seven program leaders completed surveys (16% response rate). Sixty-four percent of programs offered training on prevention of obesity and 83% provided training on management of patients with obesity; however, 39% of programs surveyed reported not teaching an approach to obesity management that integrates clinical and community systems as partners, or doing so very little. Topics such as behavioral aspects of obesity (52%), physical activity (44%), and nutritional aspects of obesity (36%) were the most widely covered (to a great extent) by residency programs. In contrast, very few programs extensively covered pharmacological treatment of obesity (10%) and weight stigma and discrimination (14%). Most respondents perceived obesity-related training as very important; 65% of the respondents indicated that expanding obesity education was a high or medium priority for their programs. Lack of room in the curriculum and lack of faculty expertise were reported as the greatest barriers to obesity education during residency. Only 21% of the respondents perceived their residents as very prepared to manage patients with obesity at the end of the residency training. Conclusion Family medicine residency programs are currently incorporating recommended teaching to address OMEC competencies to a variable degree, with some topic areas moderately well represented and others poorly represented such as pharmacotherapy and weight stigma. Very few program directors report their family medicine residents are adequately prepared to manage patients with obesity at the completion of their training. The OMEC competencies could serve as a basis for systematic obesity training in family medicine residency programs.

Purpose: This work evaluated the use and type of dietary supplements and home monitoring for nonneovascular age-related macular degeneration (AMD), as well as the prevalence of genetic testing among patients with AMD. Methods: A cross-sectional study was conducted of 129 participants older than 50 years who completed self-administered questionnaires regarding usage and type of dietary supplements and home monitoring, as well as the participants’ use of genetic testing for AMD. Results: Of 91 participants with AMD, 83 (91.2%) took vitamins, including 55 (60.4%) who used an Age-Related Eye Disease Study (AREDS) or AREDS2 formulation. Of 38 without AMD, 31 (81.6%) took vitamins (difference from participants with AMD = 9.6% [95% CI, 0%-23.2%]), including 2 on an AREDS formulation. Among 82 participants with AMD who were AREDS candidates (intermediate or advanced AMD in 1 or both eyes), 51 (62.2%; 95% CI, 51.7%-72.7%) took an AREDS or AREDS2 formulation, and 31 (37.8%) did not (5 were unsure). Additionally, 50 (61.0%; 95% CI, 50.4%-71.6%) AREDS candidates did some type of home monitoring. Only 1 (1.2%; 95% CI, 0%-3.6%) underwent genetic testing for AMD. Among 9 with AMD who were not AREDS candidates, 4 (44.4%) used an AREDS formulation, 4 (44.4%) did not, and 1 (11.1%) was unsure; only 1 (11.1%) of these 9 performed home monitoring. Conclusions: Despite similar results from past surveys and AREDS2 data supporting supplement use in 2013 and home monitoring in 2014, these findings suggest about one-third of AREDS candidates do not do so, providing further support for improving education regarding appropriate supplement and home monitoring usage. Genetic testing for AMD also appears infrequent.

Consolidative radiation therapy (RT) for advanced-stage diffuse large B-cell lymphoma (DLBCL) remains controversial, with routine practice continuing to include RT in patients with initial bulky disease or residual masses. Positron emission tomography (PET)-computed tomography is a sensitive modality for detecting the presence of residual disease at the end of treatment (EOT). A PET-guided approach to selectively administering RT has been the policy in British Columbia since 2005. Patients with advanced-stage DLBCL diagnosed from 1 January 2005 to 1 March 2017 and treated with at least 6 cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab), who underwent EOT PET, were included in this analysis. Those with complete metabolic response (PET-negative [PET-NEG]) were observed; those with PET-positive (PET-POS) scans were offered consolidative RT, when feasible. Of the patient records reviewed, 723 were identified, with median follow-up of 4.3 years: 517 (72%) were PET-NEG; 206 (28%) were PET-POS. Time to progression (TTP) and overall survival (OS) at 3 years were 83% vs 56% and 87% vs 64%, in patients with PET-NEG and PET-POS scans, respectively. PET-POS patients with nonprogressing disease treated with consolidative RT (109 and 206; 53%) had outcomes approaching those of PET-NEG patients, with 3-year estimates of 76% and 80% for TTP and OS. PET-NEG patients who had bulky disease (≥10 cm) at diagnosis had outcomes indistinguishable from those without bulk, despite the omission of RT. These data suggest that patients with advanced-stage DLBCL who are PET-NEG at EOT and receive no RT have excellent outcomes. 18F-fluorodeoxyglucose-PET can reliably guide selective administration of consolidative RT, even in patients with initially bulky disease.

ObjectiveCognitive–behavioural therapy (CBT) has been shown to be effective in the management of chronic widespread pain (CWP); we now test whether it can prevent onset among adults at high risk.MethodsA population-based randomised controlled prevention trial, with recruitment through UK general practices. A mailed screening questionnaire identified adults at high risk of CWP. Participants received either usual care (UC) or a short course of telephone CBT (tCBT). The primary outcome was CWP onset at 12 months assessed by mailed questionnaire. There were seven secondary outcomes including quality of life (EuroQol Questionnaire-five dimensions-five levels/EQ-5D-5L) used as part of a health economic assessment.Results996 participants were randomised and included in the intention-to-treat analysis of which 825 provided primary outcome data. The median age of participants was 59 years; 59% were women. At 12 months there was no difference in the onset of CWP (tCBT: 18.0% vs UC: 17.5%; OR 1.05; 95% CI 0.75 to 1.48). Participants who received tCBT were more likely to report better quality of life (EQ-5D-5L utility score mean difference 0.024 (95% CI 0.009 to 0.040)); and had 0.023 (95% CI 0.007 to 0.039) more quality-adjusted life-years at an additional cost of £42.30 (95% CI −£451.19 to £597.90), yielding an incremental cost-effectiveness ratio of £1828. Most secondary outcomes showed significant benefit for the intervention.ConclusionsA short course of tCBT did not prevent onset of CWP in adults at high risk, but improved quality of life and was cost-effective. A low-cost, short-duration intervention benefits persons at risk of CWP.Trial registration numberClinicalTrials.gov Registry (NCT02668003).

Patients with screened detected colorectal cancer (CRC) have a better survival than patients referred with symptoms. This may be because of cancers being identified in a younger population and at an earlier stage. In this study, we assess whether screened detected CRC has an improved outcome after controlling for key pathological and patient factors known to influence prognosis.This is a cohort study of all CRC patients diagnosed in NHS Grampian. Patients aged 51-75 years old between June 2007 and July 2017 were included. Data were obtained from a prospectively maintained regional pathology database and outcomes from ISD records. All-cause mortality rates at 1 and 5 years were examined. A Cox proportional hazards regression model was used to estimate the effect of screening status, age, gender, Duke stage, tumour location, extramural venous invasion (EMVI) status and lymph node ratio (LNR) on overall survival.Of 1618 CRC cases, 449 (27.8%) were screened and 1169 (72.2%) were symptomatic. Screened CRC patients had improved survival compared to non-screened CRC at 1 year (88.9% vs 83.9% p 0.001) and 5-years (42.5% vs 36.2%; p 0.001). On multivariable analysis of patients who had no neoadjuvant therapy (n = 1272), screening had better survival (HR 0.57; 95% CI 0.44-0.74; p 0.001). EMVI (HR 2.22; CI 1.76 to 2.79; p 0.001) and tumour location were found to affect outcome.Patients referred through screening had improved survival compared with symptomatic patients. Further research could be targeted to determine if screened CRC cases are pathologically different to symptomatic cancers or if the screening cohort is inherently more healthy.

Background: In diffuse large B-cell lymphoma (DLBCL), the presence of MYC and BCL2 and/or BCL6 translocations, so-called double-hit lymphoma (DH), has been associated with an aggressive clinical course. Recently, it was reported that gene expression profiling (GEP) could also identify cases with the biological and clinical characteristics of DH lymphoma, including some without the requisite translocations (DHITsig-positive cases)1. The purpose of this study was to develop a molecular subtyping schema for germinal center B-cell type (GCB) DLBCL using genomic studies such as fluorescence in situ hybridization (FISH) cytogenetic analysis, GEP, and mutation analysis to risk-stratify patients with GCB DLBCL. Method and Results: We performed a detailed genomic analysis of 87 cases of de novo GCB DLBCL to identify characteristics that are associated with survival in those treated with R-CHOP. The cases were extensively characterized by combining the results of immunohistochemistry, cell-of-origin GEP (Nanostring), DH GEP (DLBCL90)1, FISH cytogenetic analysis for DH lymphoma, copy number analysis (CNA), and targeted deep sequencing using a custom mutation panel of 334 genes. These studies were used to divide the cases into four groups. GCB1: DHITsig-positive with TP53 inactivation (DHIT+TP53): DLBCL with TP53 mutations and/or deletions has a poor prognosis in patients treated with R-CHOP. We found 7 cases (8% of all cases) of GCB DLBCL that were DHITsig-pos with TP53 abnormalities. By FISH analysis, two cases had a triple-hit (TH), one was DH with MYC/BCL2, and 2 cases had a MYC translocation only. Cases in GCB1 had the worst overall survival (OS; Hazard Ratio (HR)=9.2, P=0.0018) and shortest progression-free survival (PFS; HR=6.1, P=0.002) compared to other groups (Figures 1 A/B). However, cases with TP53 abnormalities that were DHITsig-neg did not have the same poor survival. GCB2: DHITsig-positive (DHITsig-pos): The other 8 cases (9%) who were DHITsig-pos from the DBLCL90 GEP but lacked TP53 abnormalities showed a predilection (88%) for having an EZH2 mutation and/or BCL2 translocation (EZB of Schmitz et al2). These cases also had a high frequency of MYC mutations (63%) but lacked mutations in SGK1 and had a low frequency of mutations in linker histone genes (e.g. HIST1H1E). By FISH analysis, 3 cases were DH lymphoma with MYC/BCL2, 2 cases were TH lymphoma, and 1 case had a MYC translocation only. Typically DHITsig-pos cases have a poor OS when compared to DHITsig-neg cases1, however this group demonstrated good survival in our study, after removing the cases with TP53 abnormalities. GCB3: DHITsig-negative and EZH2 mutation and/or BCL2 translocation (EZB-like): We had 28 cases (32%) that were DHITsig-neg and had an EZH2 mutation and/or BCL2 translocation. These were categorized as EZB-like with some overlapping features with the DLBCL in Cluster 3 of Chapuy et al3. The survival of this group was intermediate compared to the other groups (Figures 1A/B). GCB4: DHITsig-negative and not EZB-like (GCB Other): The largest group of cases (51%) were DHITsig-neg and lacked EZH2 mutations and BCL2 translocations. These cases had frequent mutations in SGK1 (16%) and histone modifying genes (50%), as well as TET2 mutations (25%). These cases have similarities to Cluster 4 of Chapuy et al3 and the ST2 group from Wright et al4. The survival of this group was excellent (Figures 1 A/B). These groups were validated in an independent cohort of 188 cases of GCB DLBCL4 (Figures 1 C/D). Conclusions: We have identified four distinct biologic subgroups of GCB DLBCL with different survival rates, and with similarities to the genomic classifications from recent large retrospective studies of DLBCL. Patients with the DH signature but no abnormalities of TP53 (GCB2), and those lacking EZH2 mutation and BCL2 translocation (GCB4), had an excellent prognosis. However, patients with an EZB-like profile (GCB3) had an intermediate prognosis, whereas those with TP53 inactivation combined with the DH signature (GCB1) had an extremely poor prognosis. We propose this as a practical schema to risk-stratify patients with GCB DLBCL. This schema provides a promising new approach to identify high-risk patients for new and innovative therapies. Figure 1 Disclosures Herrera: AstraZeneca: Research Funding; Karyopharm: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; Pharmacyclics: Research Funding. Zain:Kyowa Kirlin: Research Funding; Mundai Pharma: Research Funding; Seattle Genetics: Research Funding. Popplewell:Pfizer: Research Funding; Novartis: Research Funding; Roche: Research Funding. Kwak:Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; CJ Healthcare: Consultancy; Sellas Life Sciences Grp: Consultancy; Enzychem Life Sciences: Membership on an entity's Board of Directors or advisory committees; Antigenics: Other: equity; InnoLifes, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pepromene Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Xeme Biopharma/Theratest: Other: equity; Celltrion, Inc.: Consultancy. Scott:NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Roche/Genentech: Research Funding; Celgene: Consultancy; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy, Research Funding.

Background Transcranial magnetic stimulation (TMS) is an effective treatment for major depressive disorder (MDD). The rest time between pulse trains is the inter-train interval (ITI). Since 2016, some TMS clinicians have adopted a stimulation protocol with shorter ITIs than were used in regulatory clinical trials. Objective To contrast treatment outcomes with the Standard TMS protocol (38.5 min per session) and the “Dash” protocol, which, at the shortest ITI, has a session duration of 18.75 minutes. Methods Registry data were collected at 103 practice sites. Of 7,759 participants, 5,010 were included in an intent-to-treat (ITT) sample, defined as a primary MDD diagnosis, age ≥ 18, and completion of the PHQ-9 before TMS and with at least one PHQ-9 assessment after baseline. Completers (N=3,814) were responders or had received ≥ 20 sessions and had an end of acute treatment PHQ-9 assessment. Within the ITT sample, 613 patients were treated with the Standard NeuroStar 38-minute protocol and 1,493 patients with the new Dash protocol. CGI-S ratings were obtained in smaller samples. Treatment outcomes were also examined in subgroups considered Completers, as well as the subgroups who met criteria for Full Adherence to the Standard or Dash protocol parameters. Results In the ITT, Completer, and Fully Adherent samples, response (58-72%) and remission (28-53%) rates were notably high across PHQ-9 and CGI-S ratings. The Standard and Dash protocols did not differ in number of treatment sessions, and both manifested strong antidepressant effects. Conclusions The Standard and Dash protocols did not meaningfully differ in efficacy.

Background Depression in children presents a significant health burden to society and often co-exists with chronic illnesses, such as human immunodeficiency virus (HIV). Research has demonstrated that 10–37% of children and adolescents living with HIV also suffer from depression. Low-and-middle income countries (LMICs) shoulder a disproportionate burden of HIV among other health challenges, but reliable estimates of co-morbid depression are lacking in these settings. Prior studies in Rwanda, a LMIC of 12 million people in East Africa, found that 25% of children living with HIV met criteria for depression. Though depression may negatively affect adherence to HIV treatment among children and adolescents, most LMICs fail to routinely screen children for mental health problems due to a shortage of trained health care providers. While some screening tools exist, they can be costly to implement in resource-constrained settings and are often lacking a contextual appropriateness. Methods Relying on international guidelines for diagnosing depression, Rwandan health experts developed a freely available, open-access Child Depression Screening Tool (CDST). To validate this tool in Rwanda, a sample of 296 children with a known diagnosis of HIV between ages 7–14 years were recruited as study participants. In addition to completing the CDST, all participants were evaluated by a mental health professional using a structured clinical interview. The validity of the CDST was assessed in terms of sensitivity, specificity, and a receiver operating characteristic (ROC) curve. Results This analysis found that depression continues to be a co-morbid condition among children living with HIV in Rwanda. For identifying these at-risk children, the CDST had a sensitivity of 88.1% and specificity of 96.5% in identifying risk for depression among children living with HIV at a cutoff score of 6 points. This corresponded with an area under the ROC curve of 92.3%. Conclusions This study provides evidence that the CDST is a valid tool for screening depression among children affected by HIV in a resource-constrained setting. As an open-access and freely available tool in LMICs, the CDST can allow any health practitioner to identify children at risk of depression and refer them in a timely manner to more specialized mental health services. Future work can show if and how this tool has the potential to be useful in screening depression in children suffering from other chronic illnesses.

OBJECTIVE To determine if initial American Board of Surgery certification in general surgery is associated with better risk-adjusted patient outcomes for Medicare patients undergoing partial colectomy by an early career surgeon. BACKGROUND Board certification is a voluntary commitment to professionalism, continued learning, and delivery of high-quality patient care. Not all surgeons are certified, and some have questioned the value of certification due to limited evidence that board-certified surgeons have better patient outcomes. In response, we examined the outcomes of certified versus noncertified early career general surgeons. METHODS We identified Medicare patients who underwent a partial colectomy between 2008 and 2016 and were operated on by a non-subspecialty trained surgeon within their first 5 years of practice. Surgeon certification status was determined using the American Board of Surgery data. Generalized linear mixed models were used to control for patient-, procedure-, and hospital-level effects. Primary outcomes were the occurrence of severe complications and occurrence of death within 30 days. RESULTS We identified 69,325 patients who underwent a partial colectomy by an early career general surgeon. The adjusted rate of severe complications after partial colectomy by certified (n = 4239) versus noncertified (n = 191) early-career general surgeons was 9.1% versus 10.7% (odds ratio 0.83, P = 0.03). Adjusted mortality rate for certified versus noncertified early-career general surgeons was 4.9% versus 6.1% (odds ratio 0.79, P = 0.01). CONCLUSION Patients undergoing partial colectomy by an early career general surgeon have decreased odds of severe complications and death when their surgeon is board certified.

Background Emergency general surgery (EGS) encompasses a heterogeneous population of acutely ill patients, and standardized methods for determining disease severity are essential for comparative effectiveness research and quality improvement initiatives. The American Association for the Surgery of Trauma (AAST) has developed a grading system for the anatomic severity of 16 EGS conditions; however, little is known regarding how well these AAST EGS grades can be approximated by diagnosis codes in administrative databases. Methods We identified adults admitted for 16 common EGS conditions in the 2012 to 2017q3 National Inpatient Sample. Disease severity strata were assigned using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis codes based on AAST EGS anatomic severity grades. We evaluated whether assigned EGS severity (multiple strata or dichotomized into less versus more complex) were associated with in-hospital mortality, complications, length of stay, discharge disposition, and costs. Analyses were adjusted for age, sex, comorbidities, hospital traits, geography, and year. Results We identified 10,886,822 EGS admissions. The number of anatomic severity strata derived from ICD-9/10-CM codes varied by EGS condition and by year. Four conditions mapped to four strata across all years. Two conditions mapped to four strata with ICD-9-CM codes but only two or three strata with ICD-10-CM codes. Others mapped to three or fewer strata. When dichotomized into less versus more complex disease, patients with more complex disease had worse outcomes across all 16 conditions. The addition of multiple strata beyond a binary measure of complex disease, however, showed inconsistent results. Conclusion Classification of common EGS conditions according to anatomic severity is feasible with International Classification of Diseases codes. No condition mapped to five distinct severity grades, and the relationship between increasing grade and outcomes was not consistent across conditions. However, a standardized measure of severity, even if just dichotomized into less versus more complex, can inform ongoing efforts aimed at optimizing outcomes for EGS patients across the nation. Level of evidence Prognostic, level III.

PURPOSE Examine the ability of PCORnet data resources to investigate molecular-guided cancer treatment. PATIENTS AND METHODS Patients (N = 86,154) had single primary solid tumors (diagnosed 2013-2017) from hospital oncology registries linked to the PCORnet Common Data Model (CDM) at 11 medical institutions. Molecular and anatomic test procedures and oral and infused therapies were identified with Current Procedural Terminology (CPT) and Healthcare Common Procedure Coding System (HCPCS) codes, RxNorm Concept Unique Identifier, and National Drug Codes from CDM tables. Chart review (2 institutions, n = 213) for advanced colorectal cancer and Medicare claims linkages (7 institutions, n = 1,731) for breast cancer explored options for increasing electronic data capture. RESULTS Molecular testing prevalence detected via analyte-specific molecular CPT/HCPCS codes was 5.5% (n = 4,784); for the nonspecific anatomic pathology codes, for which only some testing is performed to guide therapy selection, it was an additional 44.8% (n = 38,610). Molecular-guided therapy prevalence was 5% (n = 4,289). Testing and treatment were most common with stage IV disease and varied across cancer types and study institutions (testing, 0%-10.4%; treatment, 0.8%-8.4%). Therapy-concordant test results were found in charts for all 36 treated patients with colorectal cancer at the 2 institutions, 3 (8.3%) of whom received treatment outside the institution. Breast cancer Medicare claims linkage increased rates of identified testing from 62.7%-98.9% and treatment from 3.9%-8.2%. CONCLUSION Although a minority of patients received molecular-guided therapies, the majority had testing that could guide cancer treatment. Claims data extended electronic data capture for therapies and test orders but often was uninformative for types of test ordered. Test results continue to require text data curation from narrative pathology reports.

PurposeTo evaluate longitudinal quantitative ischaemic and vasculature parameters, including ischaemic index, vessel area, length and geodesic distance in sickle cell retinopathy (SCR) on ultra-widefield fluorescein angiography (UWFA).MethodsOptimal UWFA images from two longitudinal timepoints of 74 eyes from 45 patients with SCR were aligned and a common region of interest was determined. A deep-learning augmented ischaemia and vascular segmentation platform was used for feature extraction. Geodesic distance maps demonstrating the shortest distance within the vascular masks from the centre of the optic disc were created. Ischaemic index, vessel area, vessel length and geodesic distance were measured. Paired t-test and linear mixed effect model analysis were performed.ResultsOverall, 25 (44 eyes) patients with HbSS, 14 (19 eyes) with HbSC, 6 (11 eyes) with HbSthal and other genotypes were included. Mean age was 40.1±11.0 years. Mean time interval between two UWFA studies was 23.0±15.1 months (range: 3–71.3). Mean panretinal ischaemic index increased from 10.0±7.2% to 10.9±7.3% (pConclusionLongitudinal ischaemic index and retinal vascular parameter measurements demonstrate statistically significant progression in SCR. The clinical significance of these relatively small magnitude changes remains unclear but may provide insights into the progression of retinal ischaemia in SCR.

BACKGROUND Patients are at a high risk for developing venous thromboembolism (VTE) following traumatic injury. We examined the relationship between timing of initiation of pharmacologic prophylaxis with VTE complications. METHODS Trauma quality collaborative data from 34 American College of Surgeons Committee on Trauma-verified levels I and II trauma centers were analyzed. Patients were excluded if they were on anticoagulant therapy at the time of injury, had hospitalization

Measuring heterogeneity of dengue illness is necessary to define suitable endpoints in dengue vaccine and therapeutic trials and will help clarify behavioral responses to illness. To quantify heterogeneity in dengue illness, including milder cases, we developed the Dengue Illness Perceptions Response (IPR) survey, which captured detailed symptom data, including intensity, duration, and character, and change in routine activities caused by illness. During 2016-2019, we collected IPR data daily during the acute phase of illness for 79 persons with a positive reverse transcription PCR result for dengue virus RNA. Most participants had mild ambulatory disease. However, we measured substantial heterogeneity in illness experience, symptom duration, and maximum reported intensity of individual symptoms. Symptom intensity was a more valuable predicter of major activity change during dengue illness than symptom presence or absence alone. These data suggest that the IPR measures clinically useful heterogeneity in dengue illness experience and its relation to altered human behavior.

Background During their work on the cerebrospinal fluid (CSF) circulatory system of human nerves and brain, the authors applied imaging and tissue techniques that complemented basic anatomical dissection. Objectives The authors sought to show how integrating fluorescent imaging and basic immunohistochemistry (IHC) with facial anatomy can address current problems in aesthetic surgery. Methods The authors developed an algorithm and a set of principles from their work on the CSF circulatory system and applied these to 3 problems in aesthetic surgery: the functional anatomy of the vermilion-cutaneous junction; chemosis; and the functional anatomy of periosteal fixation. Results Integrating fluorescent imaging and IHC with anatomical dissection characterizes structural and functional anatomy. Fluorescent imaging helps to identify and locate easily missed structures. IHC defines cell type and function. The vermilion-cutaneous junction is defined by a major lymphatic vessel. Lymphatic flow from the medial limbus to the lateral canthus suggests the etiology of chemosis. Periosteal sites of fixation prevent shear where dural CSF vessels drain directly to subcutaneous lymphatics. Conclusions Integrating anatomical dissection with fluorescent imaging and basic IHC characterizes structural and functional anatomy and helps to better understand many problems encountered in aesthetic surgery.

Introduction:The World Health Organization (WHO; Geneva, Switzerland) recommends lay first responder (LFR) programs as a first step toward establishing formal Emergency Medical Services (EMS) in low- and middle-income countries (LMICs) to address injury. There is a scarcity of research investigating LFR program development in predominantly rural settings of LMICs.Study Objective:A pilot LFR program was launched and assessed over 12 months to investigate the feasibility of leveraging pre-existing transportation providers to scale up prehospital emergency care in rural, low-resource settings of LMICs.Methods:An LFR program was established in rural Chad to evaluate curriculum efficacy, using a validated 15-question pre-/post-test to measure participant knowledge improvement. Pre-/post-test score distributions were compared using a Wilcoxon Signed-Rank test. For test evaluation, each pre-test question was mapped to its corresponding post-test analog and compared using McNemar’s Chi-Squared Test to examine knowledge acquisition on a by-question basis. Longitudinal prehospital care was evaluated with incident reports, while program cost was tracked using a one-way sensitivity analysis. Qualitative follow-up surveys and semi-interviews were conducted at 12 months, with initial participants and randomly sampled motorcycle taxi drivers, and used a constructivist grounded theory approach to understand the factors motivating continued voluntary participation to inform future program continuity. The consolidated criteria for reporting qualitative research (COREQ) checklist was used to guide design, analysis, and reporting the qualitative results.Results:A total of 108 motorcycle taxi participants demonstrated significant knowledge improvement (P Conclusion:Lay first responder programs appear feasible and cost-effective in rural LMIC settings. Participants demonstrate significant knowledge acquisition, and after 12 months of providing emergency care, report sustained voluntary participation due to social and financial benefits, suggesting sustainability and scalability of LFR programs in low-resource settings.

Background We sought to compare the dysplasia detection rate of high-definition white light endoscopy (HDWLE) with that of chromoendoscopy in patients with long-standing inflammatory bowel disease (IBD). Methods This is a retrospective observational cohort of patients with IBD who underwent surveillance colonoscopy between October 1, 2016 and September 30, 2017. We assessed the association between dysplasia detection and multiple variables. Results A total of 808 unique colonoscopies were performed, of which 150 (18.6%) included chromoendoscopy. Primary sclerosing cholangitis was a comorbid diagnosis in 24.5% of patients. The performing endoscopist was an IBD specialist with 37.1% of patients and had >10 years’ experience with 64.9% of patients. Prior dysplasia had been seen in 245 (30.3%) patients: 102 (68.0%) and 143 (22.0%) among patients who had chromoendoscopy and HDWLE, respectively. Dysplasia in polyps was found in 129 procedures (15.1%). Among patients who had chromoendoscopy and HDWLE, polypoid dysplasia was identified in 50 (33.0%) and 79 (12.0%) patients, respectively, P < 0.01. Dysplasia in random biopsies was found in 39 patients (4.8%): 15 (10%) who had chromoendoscopy and 24 (3.6%) who had HDWLE (P < 0.001). On multivariate analysis, patient and disease characteristics significantly associated with an increased odds for polypoid dysplasia included older age at diagnosis (odds ratio [OR] = 1.3 per 10 years; 95% confidence interval [CI], 1.07-1.60), having an IBD physician endoscopist (OR = 1.6; 95% CI, 1.01-2.67), having an endoscopist with less than 10 years’ experience (OR = 1.8; 95% CI (1.16-2.89), and prior random dysplasia (OR = 4.2; 95% CI (1.93-9.17). Concomitant primary sclerosing cholangitis was significantly associated with random dysplasia (OR = 2.3; 95% CI, 1.02-5.07). After multivariate analysis adjusting for these variables, chromoendoscopy was no more likely to identify dysplasia than was HDWLE. Conclusions Chromoendoscopy and HDWLE had a similar diagnostic yield for dysplasia detection in patients with chronic IBD-colitis after adjusting for multiple known risk factors.

Purpose Electrocardiogram-gated computed tomography with coronary angiography can be used for cardiac substructure sparing (CSS) optimization, which identifies and improves avoidance of cardiac substructures when treating with intensity modulated radiotherapy (IMRT). We investigated whether intensity modulated proton therapy (IMPT) would further reduce dose to cardiac substructures for patients with mediastinal lymphoma. Patients and Methods Twenty-one patients with mediastinal lymphoma were enrolled and underwent electrocardiogram-gated computed tomography angiography during or shortly after simulation for radiotherapy planning. Thirteen patients with delineated cardiac substructures underwent comparative planning with both IMPT and IMRT. Plans were normalized for equivalent (95%) target volume coverage for treatment comparison. Results Thirteen patients met criteria for this study. The median size of the mediastinal lymphadenopathy was 7.9 cm at the greatest diameter. Compared with IMRT-CSS, IMPT-CSS significantly reduced mean dose to all cardiac substructures, including 3 coronary arteries and 4 cardiac valves. Use of IMPT significantly reduced average whole-heart dose from 9.6 to 4.9 Gy (P Conclusions For patients with mediastinal lymphoma, IMPT-CSS treatment planning significantly reduced radiation dose to cardiac substructures. The significant improvements outlined in this study for proton therapy suggest possible clinical improvement in alignment with previous analyses of CSS optimization.

How old is too old? In vivo engraftment of human peripheral blood stem cells cryopreserved for up to 18 years - implications for clinical transplantation and stability programs

Purpose Patients with myopia are at increased risk for the development of glaucoma. The inability to correct for axial length on spectral-domain (SD) OCT translates into lower signal strength and scan reliability in patients with high axial myopia. We evaluated the effectiveness of a contact lens to increase the signal strength and to assess optic nerve dimensions and nerve fiber layer (NFL) thickness using SD OCT in patients with glaucoma or who are glaucoma suspects with high axial myopia. Design Single-center, prospective, interventional study. Participants Patients with axial lengths of more than 25.5 mm with a diagnosis of glaucoma or glaucoma suspect. Methods The optic nerve cube 200×200 scan using the Cirrus SD OCT 400 (Carl Zeiss Meditec, Inc., Dublin, CA) was carried out first without the use of a contact lens and then repeated with placement of the contact lens to correct for the spherical equivalent of the refractive error. Main Outcome Measures The primary outcome measure was the change in the average NFL thickness before and after use of the contact lens. Secondary outcome measures included the changes in cup volume, disc area, and rim area on OCT. Results Twelve patients were recruited (20 eyes); the average axial length was 27.06 mm, and the average signal strength interval increased by 1.73 (P = 0.001). With the use of a contact lens, the average NFL thickness was significantly thicker. None of the changes in the secondary outcome measures were significant: rim area, cup volume, or disc area. Conclusions Based on our data, the use of a contact lens statistically improved the signal strength and average NFL thickness of the SD OCT scan. The ability to capture the perimeter of the optic disc accurately can be limited in the setting of peripapillary atrophy, which was present in all but 2 participants. Future studies with a larger number of participants and a wider range of axial myopia to discern if contact lens correction has a greater effect on the highest axial lengths are needed.

Background As neoadjuvant therapy of borderline resectable pancreatic cancer (BRPC) is becoming more widely used, better indicators of progression are needed to help guide therapeutic decisions. Materials and Methods A retrospective review was performed on all patients with BRPC who received 24 weeks of neoadjuvant chemotherapy. Patients with chemotoxicity or medical comorbidities limiting treatment completion and nonexpressors of carbohydrate antigen 19-9 (CA19-9) were excluded. Serum CA19-9 response was analyzed as a predictor of disease progression, recurrence, and survival. Results One hundred four patients were included; 39 (37%) progressed on treatment (18 local and 21 distant) and 65 (63%) were resected (68% R0). Multivariate logistic regression analysis determined that the percent decrease in CA19-9 from baseline to minimum value (odds ratio [OR] 0.947, p ≤ .0001) and the percent increase from minimum value to final restaging CA19-9 (OR 1.030, p ≤ .0001) were predictive of progression. A receiver operating characteristics curve analysis determined cutoff values predictive of progression, which were used to create four prognostic groups. CA19-9 responses were categorized as follows: (1) always normal (n = 6); (2) poor response (n = 31); (3) unsustained response (n = 19); and (4) sustained response (n = 48). Median overall survival for Groups 1–4 was 58, 16, 20, and 38 months, respectively (p ≤ .0001). Conclusion Patients with initially elevated CA19-9 levels who do not have a decline to a sustained low level are at risk for progression, recurrence, and poor survival. Alternative treatment strategies prior to an attempt at curative resection should be considered in this cohort.

Background Compared to other perioperative complications, failure to rescue (i.e., death after suffering a complication) is highest after perioperative myocardial infarction (a myocardial infarction that occurs intraoperatively or within 30 days after surgery). The purpose of this study was to identify patient and surgical risk factors for failure to rescue in patients who have had a perioperative myocardial infarction. Methods Individuals who experienced a perioperative myocardial infarction after noncardiac surgery between 2012 and 2016 were identified from the American College of Surgeons (Chicago, Illinois) National Surgical Quality Improvement Program database. Multivariable logistic regression was used to identify risk factors for failure to rescue. Subgroup and sensitivity analyses evaluated the robustness of primary findings. Results The authors identified 1,307,884 individuals who had intermediate to high-risk noncardiac surgery. A total of 8,923 (0.68%) individuals had a perioperative myocardial infarction, of which 1,726 (19.3%) experienced failure to rescue. Strongest associations (adjusted odds ratio greater than 1.5) were age 85 yr or older (2.52 [95% CI, 2.05 to 3.09] vs. age younger than 65 yr), underweight body mass index (1.53 [95% CI, 1.17 to 2.01] vs. normal body mass index), American Society of Anesthesiologists class IV (1.76 [95% CI, 1.33 to 2.31] vs. class I or II) and class V (3.48 [95% CI, 2.20 to 5.48] vs. class I or II), and presence of: ascites (1.81 [95% CI, 1.15 to 2.87]), disseminated cancer (1.54 [95% CI, 1.18 to 2.00]), systemic inflammatory response syndrome (1.55 [95% CI, 1.26 to 1.90]), sepsis (1.75 [95% CI, 1.39 to 2.20]), septic shock (1.79 [95% CI, 1.34 to 2.37]), and dyspnea at rest (1.94 [95% CI, 1.32 to 2.86]). Patients who had emergency surgery, high-risk procedures, and postoperative complications were at higher risk of failure to rescue. Conclusions Routinely identified patient and surgical factors predict risk of failure to rescue after perioperative myocardial infarction. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

INTRODUCTION: Induction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)-ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients. METHODS: In this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal. RESULTS: In total, 36 patients were treated (a 450-mg cohort [n=14] and a 300-mg cohort [n=22]). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval [CI]: 35.9-99.6) in the 450-mg cohort and 60% (95% CI: 26.2-87.8) in the 300-mg cohort. Among ALKI-pretreated patients, the ORR was 50% (95% CI: 15.7-84.3) in the 450-mg cohort and 25% (95% CI: 5.5-57.2) in the 300-mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% of patients [95% CI: 35.1-87.2] had confirmed responses as compared with those with negative PD-L1 staining (31% [95% CI: 11.0-58.7]). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of patients in the 450-mg and 300-mg cohorts, respectively; no grade 4 rash was reported. CONCLUSION: Ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent. ispartof: Journal of Thoracic Oncology vol:15 issue:3 pages:392-403 ispartof: location:United States status: published

Background and purpose Pulmonary hypertension (PH) secondary to chronic lung disease (World Health Organization Group 3 PH) is deadly, with lung transplant being the only available long-term treatment option. Myeloid-derived cells are known to affect progression of both pulmonary fibrosis and PH, although the mechanism of action is unknown. Therefore, we investigated the effect of myeloid cell proliferation induced by emergency myelopoiesis on development of PH and therapy directed against programmed death-ligand 1 (PD-L1), expressed by myeloid cells in prevention of pulmonary vascular remodelling. Experimental approach LysM.Cre-DTR ("mDTR") mice were injected with bleomycin (0.018 U·g-1 , i.p.) while receiving either vehicle or diphtheria toxin (DT; 100 ng, i.p.) to induce severe PH. Approximately 4 weeks after initiation of bleomycin protocol, right ventricular pressure measurements were performed and tissue samples collected for histologic assessment. In a separate experiment, DT-treated mice were given anti-PD-L1 antibody (αPD-L1; 500 μg, i.p.) preventive treatment before bleomycin administration. Key results Mice undergoing induction of emergency myelopoiesis displayed more severe PH, right ventricular remodelling and pulmonary vascular muscularization compared to controls, without a change in lung fibrosis. This worsening of PH was associated with increased pulmonary myeloid-derived suppressor cell (MDSC), particularly polymorphonuclear MDSC (PMN-MDSC). Treatment with αPD-L1 normalized pulmonary pressures. PD-L1 expression was likewise found to be elevated on circulating PMN-MDSC from patients with interstitial lung disease and PH. Conclusions and implications PD-L1 is a viable therapeutic target in PH, acting through a signalling axis involving MDSC. Linked articles This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc.

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Up-regulation of BCL2 in cases of diffuse large B-cell lymphoma (DLBCL) can confer treatment resistance. Quantitative immunofluorescence (QIF) histology allows objective quantification of protein-based biomarkers. We investigated the utility of QIF for evaluating BCL2 as a biomarker in DLBCL by quantifying BCL2 selectively in CD20-expressing lymphoma cells in biopsy samples from 116 cases of DLBCL in two cohorts one of which consisted of relapsed/refractory cases from a clinical trial. BCL2 protein by QIF correlated with BCL2 mRNA abundance and was associated with both translocation and copy number gain of the BCL2 gene. Elevated BCL2 protein expression by QIF, but not immunohistochemistry or mRNA quantification, was associated with inferior overall and relapse-free survival in the relapsed/refractory cohort. QIF is an effective means of quantifying BCL2 protein objectively in routine cancer biopsy specimens and shows promise for identifying relapsed/refractory DLBCL patients at risk of inferior outcomes after salvage therapy.

The role of extracorporeal membrane oxygenation in the adult patient population still is evolving. Technologic advancements have improved the ability to provide extracorporeal life support. The miniaturization and durability of these systems have made extracorporeal membrane oxygenation more convenient and mobile than ever. Because of these improvements, its use has increased steadily. The indications for use also have diversified. In this review, the authors provide a panoramic view of extracorporeal membrane oxygenation to provide a foundation of knowledge for anesthesiologists.

Purpose Ileal Pouch-Anal Anastomosis (IPAA) is the standard of care for children requiring surgical treatment of severe colitis or polyposis syndromes. This study aims is to investigate the sexual function and fertility in women after undergoing childhood IPAA. Methods A prospectively maintained colon and rectal database of consenting patients was queried from January 1980 to October 2015. We included all females that replied to at least 1 survey between the ages of 20 and 45 years that had undergone IPAA younger than 20 years of age. Results Two hundred females met inclusion criteria, whereas 149 women replied to the sexual function questions. Ulcerative colitis was diagnosed in 122 (83%) patients, with the remainder having polyposis. Seven patients had a laparoscopic proctectomy. Only 2 patients had a pelvic infection, whereas 21 had intestinal obstruction postoperatively. A severely restricted sex life was reported in 6 (5%) patients. Of the 93 (62%) women who attempted pregnancy, 68 (73%) became pregnant. Median age of pregnancy and IPAA was 34 (range 22–45) and 17 years (range 9–20), respectively. Medical intervention to assist fertilization was required in 14/68. A total of 29 women reported problems during pregnancy with 58/68 (88%) giving birth to a live baby. Elective termination was reported in 2/68 surveys. Vaginal delivery occurred in 26/58 mothers with 27/58 planned and 9/58 unplanned cesarean sections. Age at IPAA, diagnosis, procedure type, pelvic infection, and obstruction were not associated with decreased fertility. All 7 patients operated laparoscopically have become pregnant. Change in pouch function after delivery was reported in 20/68 (32%, 5 missing) surveys. Conclusions 73% of women who desired children become pregnant, and 88% had a successful delivery after pediatric IPAA. Only 5% reported severely restricted sexual function. Changes in pouch function occurred with pregnancy and persisted in 1/3 after delivery. Minimally invasive techniques may improve fertility rates but equire continued follow-up. Level of evidence Level IV. Type of study Observational study.

To compare the severity of macular vascular changes in children with sickle cell disease (SCD) vs age- and race-matched controls.Cross-sectional study.Children (18 years old) with HbSS and HbS variant (HbSC and HbS thalassemia) genotypes, and their age- and race-matched controls, were recruited between January 2017 and December 2018. All subjects underwent optical coherence tomography angiography (OCTA) scans centered on the fovea and temporal macula. Retinal thickness, superficial capillary plexus (SCP) and deep capillary plexus (DCP) vessel density (VD), and foveal avascular zone (FAZ) size were measured and compared between HbSS and HbS variant vs controls.Thirty-four HbSS, 34 HbS variant (Goldberg staging 0-3 for SCD eyes), and 24 control eyes (total 48 children, aged 5-17 years) were included. Total VD (3-mm ETDRS circle) was lower in HbS variant eyes than in controls for both the SCP (42.9% vs 47.7%, P = .02) and DCP (47.4% vs 52.6%, P = .01). In HbSS eyes, VD was lower in the DCP (47.7%, P = .008) but not in the SCP (45.5%, P = .5), compared to controls. A higher proportion of HbSS (n = 18, 55%) than HbS variant eyes (n = 9, 26%) had pathologic areas of retinal thinning associated with SCP and DCP flow loss (P = .03). However, retinal thickness measurements and FAZ size did not differ between either HbSS or HbS variant group vs controls.Children with SCD have similar retinal thickness but less dense vasculature on OCTA compared to age and race-matched controls, suggesting that microvascular insult may precede structural thinning.

OBJECTIVE: To evaluate the effects of gaining access to Medicare on key financial outcomes for surgical patients. SUMMARY BACKGROUND DATA: Surgical care poses a significant financial burden, especially among patients with insufficient financial risk protection. Medicare may mitigate the risk of these adverse circumstances, but the impact of Medicare eligibility on surgical patients remains poorly understood. METHODS: Regression discontinuity analysis of national, cross-sectional survey and cost data from the 2008–2018 National Health Interview Survey (NHIS) and Medical Expenditure Panel Survey (MEPS). Patients were between the ages of 57–72 with surgery in the past 12 months. The primary outcomes were the presence of medical debt, delay/deferment of care due to cost, total annual out-of-pocket (OOP) costs, and experiencing catastrophic health expenditures (CHE). RESULTS: Among 45,982,243 NHIS patients, Medicare eligibility was associated with a 6.6 percentage-point decrease (95%CI: −9.0% to −4.3) in being uninsured (>99% relative reduction), 7.6 percentage-point decrease (24% relative reduction) in having medical debt (95%CI: −14.1% to −1.1%), and 4.9 percentage-point decrease (95%CI: −9.4% to −0.4%) in deferrals/delays in medical care due to cost (28% relative reduction). Among 33,084,967 MEPS patients, annual OOP spending decreased by $1,199 per patient (95%CI: −$1,633 to −$765), a 33% relative reduction, and CHE decreased by 7.3 percentage points (95%CI: −13.6% to −0.1%), a 55% relative reduction. CONCLUSIONS: Medicare may reduce the economic burden of healthcare spending and delays in care for older adult surgical patients. These findings have important implications for policy discussions regarding changing insurance eligibility thresholds for the older adult population.

The objective of this study was to evaluate the distribution and prognostic impact of a broad range of molecular attributes in a large cohort of immunocompetent patients with primary central nervous system lymphoma (PCNSL) by using tissue microarray. Patients diagnosed with PCNSL were initially identified in the BC Cancer Lymphoid Cancer clinical and pathology databases. Tissue microarrays were constructed by using archival formalin-fixed paraffin-embedded diagnostic biopsy tissue. Immunohistochemistry and fluorescent in situ hybridization studies were performed. A total of 115 patients with PCNSL with diffuse large B-cell lymphoma (DLBCL) histology were identified. The majority of cases (≥75%) had a non–germinal center B-cell phenotype according to immunohistochemistry algorithms, but cell of origin did not affect progression-free or overall survival. MYC (40%), BCL2 (75%), and programmed death-ligand 1 (29%) protein expression were common, but their corresponding gene rearrangements were rare (≤1% each), suggesting that alternate mechanisms were driving expression. There were no dual rearrangements involving MYC and BCL2. Only 22% of cases had membranous expression of major histocompatibility complex class II, suggesting a mechanism for escape from immune surveillance. Epstein-Barr virus–encoded RNA was positive in 1 immunocompetent patient. BCL6 protein expression (77%) and BCL6 rearrangements (31%) were frequent; the latter was the only factor associated with a poor prognosis in the overall cohort and in the subgroup of 52 patients treated with high-dose methotrexate–based regimens. This large population-based study shows that prominent molecular features of PCNSL are unique and different from those of systemic DLBCL. These results may better inform drug development in PCNSL.

Introduction Laparoscopic (LHR) and open (OHR) inguinal hernia repairs are both used to treat primary herniae. This study analyses the rates of operation for recurrence after laparoscopic and open inguinal hernia repair, at a population level, while considering competing risks, such as death and other operative interventions. Methods This is a population cohort study in Scotland. All adult patients who had a primary inguinal hernia repair in Scotland between 01/04/1996 and 01/01/2015 were included. The main outcome was recurrent operations. Cumulative incidence functions (CIF) were calculated for competing risks of death. A cox proportional hazards regression model was used to control for confounders of age, gender, bilateral herniae, deprivation and year of procedure. Results Of 88,590 patients, there were 10,145 LHR and 78,445 OHR. Recurrent operations were required in 1397 (1.8%) OHR and 362 (3.6%). LHR had greater hazard of recurrence than OHR (HR 1.83, 95% CI 1.61–2.08, p p p = 0.04) and having a bilateral index operation (HR 2.53, 95% CI 2.22–2.88, p Conclusions LHR is becoming more popular in Scotland over the past 2 decades. However, when other key confounding factors are controlled, it is associated with a higher recurrence rate.

BACKGROUND: Hundreds of thousands of individuals visit the emergency department (ED) every year, with many visits occurring following alcohol misuse. Parent-child relationship factors are associated with alcohol-related outcomes. For example, offspring choice to self-disclose information about their lives to parents, rather than parents actively soliciting this information, is associated with substance use. However, it is unclear whether self-disclosure uniquely predicts alcohol-related outcomes in a young adult ED sample. METHODS: Data were collected from young adults (age 18-30 years) visiting an ED for a traumatic injury (n=79). Participants were about 24.4 years old, majority male (53.7%), and Caucasian (76%; 24% African-American). A bifactor model within a structural equation model tested unique effects of self-disclosure on age at first drink, propensity for risky drinking, and likelihood of consuming substances prior to ED visit, over and above parental solicitation and a general factor and gender. RESULTS: Those who shared more information with their caregivers reported an older age at first drink, lower propensity for risky drinking and lower propensity to consume substances prior to their ED visit. CONCLUSIONS: These findings suggest that self-disclosure may be a unique risk factor in the initiation of alcohol use, development of problem use, and consequences following use.