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Abstract Despite the availability of efficacious direct-acting antiviral (DAA) therapy, the number of people infected with hepatitis C virus (HCV) continues to rise, and HCV remains a leading cause of liver-related morbidity, liver transplantation, and mortality. We developed and validated machine learning (ML) algorithms to predict DAA treatment failure. Using the HCV-TARGET registry of adults who initiated all-oral DAA treatment, we developed elastic net (EN), random forest (RF), gradient boosting machine (GBM), and feedforward neural network (FNN) ML algorithms. Model performances were compared with multivariable logistic regression (MLR) by assessing C statistics and other prediction evaluation metrics. Among 6525 HCV-infected adults, 308 patients (4.7%) experienced DAA treatment failure. ML models performed similarly in predicting DAA treatment failure (C statistic [95% CI]: EN, 0.74 [0.69–0.79]; RF, 0.74 [0.69–0.80]; GBM, 0.72 [0.67–0.78]; FNN, 0.75 [0.70–0.80]), and all 4 outperformed MLR (C statistic [95% CI]: 0.51 [0.46–0.57]), and EN used the fewest predictors (n = 27). With Youden index, the EN had 58.4% sensitivity and 77.8% specificity, and nine patients were needed to evaluate to identify 1 DAA treatment failure. Over 60% treatment failure were classified in top three risk decile subgroups. EN-identified predictors included male sex, treatment 1.2 g/dL, advanced liver disease, and use of tobacco, alcohol, or vitamins. Addressing modifiable factors of DAA treatment failure may reduce the burden of retreatment. Machine learning algorithms have the potential to inform public health policies regarding curative treatment of HCV.

Abstract Background Poor cardiorespiratory fitness (CRF) is a cardinal feature of post‐treatment primary lung cancer. The most effective exercise therapy regimen to improve CRF has not been determined. Methods In this parallel‐group factorial randomized controlled trial, lung cancer survivors with poor CRF (below age–sex sedentary values) were randomly allocated to receive 48 consecutive supervised sessions thrice weekly of (i) aerobic training (AT)—cycle ergometry at 55% to >95% of peak oxygen consumption (VO2peak); (ii) resistance training (RT)—lower and upper extremity exercises at 50–85% of maximal strength; (iii) combination training (CT)—AT plus RT; or (iv) stretching attention control (AC) for 16 weeks. The primary endpoint was change in CRF (VO2peak, mL O2·kg−1·min−1). Secondary endpoints were body composition, muscle strength, patient‐reported outcomes, tolerability (relative dose intensity of exercise), and safety. Analysis of covariance determined change in primary and secondary endpoints from baseline to post‐intervention (Week 17) with adjustment for baseline values of the endpoint and other relevant clinical covariates. Results Ninety patients (65 ± 9 years; 66% female) were randomized (AT, n = 24; RT, n = 23; CT, n = 20; and AC, n = 23) of the planned n = 160. No serious adverse events were observed. For the overall cohort, the lost‐to‐follow‐up rate was 10%. Mean attendance was ≥75% in all groups. In intention‐to‐treat analysis, VO2peak increased 1.1 mL O2·kg−1·min−1 [95% confidence interval (CI): 0.0, 2.2, P = 0.04] and 1.4 mL O2·kg−1·min−1 (95% CI: 0.2, 2.5, P = 0.02) in AT and CT, respectively, compared with AC. There was no difference in VO2peak change between RT and AC (−0.1 mL O2·kg−1·min−1, 95% CI: −1.2, 1.0, P = 0.88). Favourable improvements in maximal strength and body composition were observed in RT and CT groups compared with AT and AC groups (Ps

Introduction: Anatomical resection—often by lobectomy—is the standard of care for patients with early stage NSCLC. With increased diagnosis, survival, and prevalence of persons with early stage NSCLC, the incidence of second primary NSCLC, and consequently, the need for contralateral lobectomy for a metachronous cancer, is increasing. Perioperative outcomes after contralateral lobectomy are unknown. Methods: Among patients who underwent contralateral lobectomy for second primary NSCLC during 1995 to 2020, we evaluated 90-day mortality and major morbidity (Clavien-Dindo grades 3–5) rates and their association with clinicopathologic variables, including the year of contralateral lobectomy and duration between lobectomies. Results: A total of 98 patients underwent contralateral lobectomy for second primary NSCLC; 51 during an early time period (1995–2009) and 47 from a late time period (2010–2020). There were five mortalities and 23 patients with major morbidities after contralateral lobectomy; both rates decreased in 2010 to 2020 compared with 1995 to 2009 (mortality 10%–0%, major morbidity 35%–11%). Major morbidity was associated with an interval of less than 1 year between lobectomies, a diffusing capacity of the lung for carbon monoxide

We model how docked bikeshare can improve transit accessibility in two Los Angeles neighborhoods. We measure the fraction of study area population within 5- and 10-minute walk/bike commutes from high frequency transit (≤ 10-minute morning peak headway). We show that bikeshare can increase the number of residents within 5-minutes / 10-minutes of high frequency transit by 12% / 13% (deploying 74 docked bikeshare stations) and by 42% / 66% (deploying 296 bikeshare stations.) The results for within the 5-minute travel time are robust to siting specification changes, while the 10-minute results are more sensitive to specification.

Abstract Background Metastasis directed therapy (MDT) for patients with oligometastatic disease is associated with improvements in progression free survival (PFS) and overall survival (OS) compared to systemic therapy alone. Additionally, within a prostate-cancer-specific cohort, MDT is able to forestall initiation of androgen deprivation therapy (ADT) in men with hormone-sensitive, oligometastatic prostate cancer (HSOPCa) compared to observation. While MDT appears to be safe and effective in HSOPCa, a large percentage of men will eventually have disease recurrence. Patterns of failure in HSOPCa demonstrate patients tend to have recurrence in the bone following MDT, raising the question of sub-clinically-apparent osseous disease. Radium-223 dichloride is a radiopharmaceutical with structural similarity to calcium, allowing it to be taken up by bone where it emits alpha particles, and therefore might have utility in the treatment of micrometastatic osseous disease. Therefore, the primary goal of the phase II RAVENS trial is to evaluate the efficacy of MDT + radium-223 dichloride in prolonging progression free survival in men with HSOPCa. Methods Patients with HSOPCa and 3 or less metastases with at least 1 bone metastasis will be randomized 1:1 to stereotactic ablative radiation (SABR, also known as stereotactic body radiation therapy (SBRT)) alone vs SABR + radium-223 dichloride with a minimization algorithm to balance assignment by institution, primary intervention, prior hormonal therapy, and PSA doubling time. SABR is delivered in one to five fractions and patients in the SABR + radium-223 dichloride arm will receive six infusions of radium-223 dichloride at four-week intervals. The primary end point is progression free survival. The secondary clinical endpoints include toxicity and quality of life assessments, local control at 12 months, locoregional progression, time to distant progression, time to new metastasis, and duration of response. Discussion The RAVENS trial will be the first described phase II, non-blinded, randomized study to compare SABR +/− radium-223 dichloride in patients with HSOPCa and 3 or less metastases with at least one bone metastasis. The primary hypothesis is that SABR + radium-223 dichloride will increase median progression-free survival from 10 months in the SABR arm to 20 months in the SABR + radium-223 dichloride arm. Trial registrations Clinicaltrials.gov. Identifier: NCT04037358 . Date of Registration: July 30, 2019. Date of First Participant Enrolled: August 9, 2019. Date of Last Approved Amendment: October 16, 2019. Protocol Version: Version 5.

Introduction: The Evidence-Based Care of the Elderly Health Guide is a clinical guide with cross-references for care recommendations. This guide is an innovative adaptation of the Rourke Baby Record to support elderly care. In 2003, the guide was published with an endorsement from the Health Care-of-the-Elderly Committee of the College of Family Physicians of Canada. Since then, physicians have used the guide as a checklist and a monitoring tool for care to elderly patients. Objective: We will update the 2003 Care-of-the-Elderly Health Guide with current published evidence-based recommendations. Methods: This was a mixed methods study consisting of (1) the creation of a list of topics and corresponding guidelines or recommendations, (2) two focus group discussions among family physicians (n = 12) to validate the list for relevance to practice, and (3) a modified Delphi technique in a group of ten experts in Care of the Elderly and geriatrics to attain consensus on whether the guidelines/recommendations represent best practice and be included. Results: The initial list contained 43 topics relevant to family practice, citing 49 published guidelines or recommendations. The focus group participants found the list of topics and guidelines potentially useful in clinical practice and emphasized the need for user-friendliness and clinical applicability. In the first online survey of the modified Delphi technique, 93% (63/66) of the references attained consensus that these represented standards of care. The other references (3/66) attained consensus in the second online survey. The final list contained 47 topics, citing 66 references. Conclusion: The Care-of-the-Elderly Health Guide is a quick reference to geriatric care, reviewed for relevance by family physicians and a panel of experts. The Guide is intended to be used in primary care practice.

Introduction: Given the concern for cardiopulmonary toxicity in patients with NSCLC undergoing postoperative radiation therapy (PORT), the purpose of this study was to evaluate the association between heart dose and overall survival (OS) in patients undergoing PORT with modern techniques. Methods: This is a retrospective study of consecutive patients with NSCLC treated with PORT between May 2004 and January 2017. Clinical records were reviewed and radiation dose distributions were analyzed for association with OS. Results: A total of 284 patients were analyzed. At the time of surgery, most patients had pathologic American Joint Committee on Cancer seventh edition stage III disease (91.2 %) and received either preoperative or adjuvant chemotherapy (92.3 %). Most patients underwent a lobectomy (81.3 %) and had R0 (80.6 %) or R1 (19.4 %) resection. PORT was delivered with a median radiation dose of 54 Gy, and 70.4 % of patients were treated with intensity-modulated radiation therapy. Dosimetric variables across a large range of doses to the heart were highly significant (p < 0.05) for OS. The volume of the heart receiving 8 Gy (HV8) was the most significant dosimetric variable (p < 0.001), and the median HV8 was 35.5 %. The median OS was 33.2 versus 53.6 months (p < 0.005) for patients with HV8 above or below 35.5 %, respectively. On multivariable analysis accounting for other potential prognostic confounders, HV8 remained highly significant (p < 0.001). Conclusions: The data reveal a strong correlation between increasing heart dose and OS in patients with NSCLC undergoing PORT. Taken together with the recently presented LungART trial, lowering heart dose in PORT patients may help to decrease the risk of morbidity and mortality and improve the therapeutic ratio of PORT.

Background/Aims: Paraneoplastic dermatoses are skin disorders that are associated with malignancy. Anaplastic large T-cell lymphoma (ALTCL) has rarely been associated with paraneoplastic skin manifestations such as gangrenous foot ulcers and erythroderma. Methods: We describe a case of ALTCL presenting as a large annular skin rash. The clinical picture, course, and treatment will be discussed along with current hypotheses on the mechanism of paraneoplastic syndromes. Results: Skin manifestations in ALTCL most commonly arise in two distinct ways; either as primary cutaneous lymphoma manifestation or as systemic disease with secondary metastasis. Less commonly, systemic disease causes skin manifestations secondary to a paraneoplastic process without infiltration of malignant cells. This is thought to be mediated by an immunologic reaction to tumor antigen or the result of cytokines and other inflammatory markers produced by the tumor itself. Conclusion: Paraneoplastic dermatoses could be the initial presentations of systemic lymphoma. Knowledge about their association with anaplastic large-cell lymphoma may help with timely diagnosis. In a patient with unexplained dermatosis associated with B symptoms who is unresponsive to topic treatment, an investigation for systemic lymphoma workup is warranted.

We report a case of a small-cell variant of anaplastic large-cell lymphoma, with an unusual clinical presentation mimicking sepsis and a fulminant clinic course, in a 48-year-old Caucasian female. In this report, we discuss the diagnostic challenge, histopathologic features, and unique cytogenetic features of this case, in order to raise awareness of this rare presentation and emphasize the importance of meticulous peripheral smear examination and early bone marrow evaluation.

The thymus is a critical organ for the development of the adaptive immune system and thymic epithelial tumors (TETs; thymomas and thymic carcinomas) are often associated with auto-immune paraneoplastic conditions. However, the immunobiology of TETs is not well described. An evaluation of the tumor microenvironment, with particular focus on expression of immunotherapeutic targets, may facilitate and prioritize development of immunotherapy strategies for patients with TETs.Tumor tissues from 23 patients with WHO Type B2/B3 thymoma (n = 12) and thymic carcinoma (n = 11) were identified and clinical outcomes were annotated. The expression of membranous PD-L1 on tumor cells, CD3+ and CD8+ tumor infiltrating lymphocytes (TILs), co-stimulatory (CD137, GITR, ICOS), and co-inhibitory immune checkpoint molecules (PD-1, CTLA-4, TIM-3) were assessed semi-quantitatively using immunohistochemistry.PD-L1 positivity (≥ 25% of tumor membrane expression) was frequent in TETs (15/23, 65%), more common in thymomas compared to thymic carcinomas (p

The damage sustained by rigidly-clamped square steel plates when subjected to close-proximity underwater explosions has been investigated. The test specimens consisted of plates 0.76 mm and 1.21 mm thick made of either ASTM A1008 mild steel or 350 WT structural-grade steel with a low-temperature notch-toughness requirement. The explosively-loaded area of the plates was square, with dimensions of 254 mm X 254 mm. High-explosive charges from 1.1 g to 50 g were used at different standoff distances to obtain different shock strengths and bubble collapse intensities. Although the main impulsive load on the plate was due to the shock impact, because the standoff distances were less than twice the maximum free-field bubble radius, a strong interaction between the detonation product bubble and the target plate caused a rapid water jet to impinge on the plate, resulting in additional loading and damage. As a result, four main regimes of loading and damage were identified: a) holing/petaling due to shock loading, b) edge tearing due to shock loading only, c) edge tearing due to the cumulative loading from shock and bubble collapse, and d) large deformation due to shock and bubble collapse loading. The damage mechanisms and dynamic response of the plates were measured using dynamic displacement sensors, pressure gauges, and high-speed video. A fracture analysis was performed on the damaged plates to analyze the mechanisms of failure. Finally, finite-element analysis using a failure criterion based on normalized shear stress and effective strain has been used to examine the failure limits.