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PURPOSE Patients with malignant pleural mesothelioma, a rapidly progressing malignancy with a median survival time of 6 to 9 months, have previously responded poorly to chemotherapy. We conducted a phase III trial to determine whether treatment with pemetrexed and cisplatin results in survival time superior to that achieved with cisplatin alone. PATIENTS AND METHODS Chemotherapy-naive patients who were not eligible for curative surgery were randomly assigned to receive pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1, or cisplatin 75 mg/m2 on day 1. Both regimens were given intravenously every 21 days. RESULTS A total of 456 patients were assigned: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and eight never received therapy. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm ( P = .020, two-sided log-rank test). The hazard ratio for death of patients in the pemetrexed/cisplatin arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months ( P = .001). Response rates were 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm ( P < .0001). After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm. CONCLUSION Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant pleural mesothelioma. Addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time.

Abstract. Background: Coronavirus disease 2019 (COVID-19) threatens people's physical and mental health, globally, and it may even trigger suicide ideation and suicidal behavior. Aims: We aimed to examine the impact of COVID-19 on suicide risk by sampling Chinese Weibo users and analyzing their social media messages. Method: We predicted the probability of suicide (including hopelessness, suicidal ideation, negative self-evaluation, and hostility) of Weibo users in order to assess the changes in suicide probability at different times. Repeated-measures ANOVA was performed to examine the differences in suicide probability in different regions during different periods. Results: There was no significant difference in suicide probability between profoundly infected areas (PIAs) and less infected areas (LIAs) before the outbreak of COVID-19. LIAs had an increase in hopelessness during the COVID-19 growth period, while hopelessness and hostility in PIA increased during the COVID-19 decline period, indicating potential suicide probability. Limitations: Results should be interpreted with caution, and cross-cultural research may be considered in the future. Conclusion: COVID-19 has a dynamic impact on suicide probability. Using data from online social networks may help to understand the impact pattern of COVID-19 on people's suicide probability.

OBJECTIVE The aim of glioblastoma surgery is to maximize the extent of resection while preserving functional integrity. Standards are lacking for surgical decision-making, and previous studies indicate treatment variations. These shortcomings reflect the need to evaluate larger populations from different care teams. In this study, the authors used probability maps to quantify and compare surgical decision-making throughout the brain by 12 neurosurgical teams for patients with glioblastoma. METHODS The study included all adult patients who underwent first-time glioblastoma surgery in 2012–2013 and were treated by 1 of the 12 participating neurosurgical teams. Voxel-wise probability maps of tumor location, biopsy, and resection were constructed for each team to identify and compare patient treatment variations. Brain regions with different biopsy and resection results between teams were identified and analyzed for patient functional outcome and survival. RESULTS The study cohort consisted of 1087 patients, of whom 363 underwent a biopsy and 724 a resection. Biopsy and resection decisions were generally comparable between teams, providing benchmarks for probability maps of resections and biopsies for glioblastoma. Differences in biopsy rates were identified for the right superior frontal gyrus and indicated variation in biopsy decisions. Differences in resection rates were identified for the left superior parietal lobule, indicating variations in resection decisions. CONCLUSIONS Probability maps of glioblastoma surgery enabled capture of clinical practice decisions and indicated that teams generally agreed on which region to biopsy or to resect. However, treatment variations reflecting clinical dilemmas were observed and pinpointed by using the probability maps, which could therefore be useful for quality-of-care discussions between surgical teams for patients with glioblastoma.

Contains fulltext : 244552.pdf (Publisher’s version ) (Open Access) BACKGROUND: Histology restricted genetic predisposition testing of ovarian carcinoma patients is a topic of debate as the prevalence of BRCA1/2 pathogenic variants (PVs) in various histological subtypes is ambiguous. Our primary aim was to investigate the proportion of germline BRCA1/2 PVs per histological subtype. Additionally, we evaluated (i) proportion of somatic BRCA1/2 PVs and (ii) proportion of germline PVs in other ovarian carcinoma risk genes. METHODS: PubMed, EMBASE and Web of Science were systematically searched and we included all studies reporting germline BRCA1/2 PVs per histological subtype. Pooled proportions were calculated using a random-effects meta-analysis model. Subsets of studies were used for secondary analyses. RESULTS: Twenty-eight studies were identified. The overall estimated proportion of germline BRCA1/2 PVs was 16.8% (95% CI 14.6 to 19.2). Presence differed substantially among patients with varying histological subtypes of OC; proportions being highest in high-grade serous (22.2%, 95% CI 19.6 to 25.0) and lowest in clear cell (3.0%, 95% CI 1.6 to 5.6) and mucinous (2.5%, 95% CI 0.6 to 9.6) carcinomas. Somatic BRCA1/2 PVs were present with total estimated proportion of 6.0% (95% CI 5.0 to 7.3), based on a smaller subset of studies. Germline PVs in BRIP1, RAD51C, RAD51D, PALB2, and ATM were present in approximately 3%, based on a subset of nine studies. CONCLUSION: Germline BRCA1/2 PVs are most frequently identified in high-grade serous ovarian carcinoma patients, but are also detected in patients having ovarian carcinomas of other histological subtypes. Limiting genetic predisposition testing to high-grade serous ovarian carcinoma patients will likely be insufficient to identify all patients with a germline PV.

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Background. Up to now, an accurate nomogram to predict the lung metastasis probability in Ewing sarcoma (ES) at initial diagnosis is lacking. Our objective was to construct and validate a nomogram for the prediction of lung metastasis in ES patients. Methods. A total of 1157 patients with ES from the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively collected. The predictors of lung metastasis were identified via the least absolute shrinkage and selection operator (LASSO) and multivariate logistic analysis. The discrimination and calibration of the nomogram were validated by receiver operating characteristic (ROC) curve and calibration curve. Decision curve analysis (DCA) was used to evaluate the clinical usefulness and net benefits of the prediction model. Results. Factors including age, tumor size, primary site, tumor extension, and other site metastasis were identified as the ultimate predictors for the nomogram. The calibration curves for the training and validation cohorts both revealed good agreement, and the Hosmer&ndash, Lemeshow test identified that the model was well fitted (p &gt, 0.05). In addition, the area under the ROC curve (AUC) values in the training and validation cohorts were 0.732 (95% confidence interval, CI: 0.607&ndash, 0.808) and 0.741 (95% CI: 0.602&ndash, 0.856), respectively, indicating good predictive discrimination. The DCA showed that when the predictive metastasis probability was between 1% and 90%, the nomogram could provide clinical usefulness and net benefit. Conclusion. The nomogram constructed and validated by us could provide a convenient and effective tool for clinicians that can improve prediction of the probability of lung metastasis in patients with ES at initial diagnosis.

Background and purpose We aimed to determine the risk factors for radiation-induced brain injury (RIBI 1 ) after carbon ion radiotherapy (CIRT) to predict their probabilities in long-term survivors. Materials and methods We evaluated 104 patients with head, neck, and skull base tumors who underwent CIRT in a regimen of 32 fractions and were followed up for at least 24 months. RIBI was assessed using the Common Terminology Criteria for Adverse Events. Results The median follow-up period was 45.5 months; 19 (18.3 %) patients developed grade ≥2 RIBI. The maximal absolute dose covering 5 mL of the brain (D5ml) was the only significant risk factor for grade ≥2 RIBI in the multivariate logistic regression analysis (p = 0.001). The tolerance doses of D5ml for the 5% and 50% probabilities of developing grade ≥2 RIBI were estimated to be 55.4 Gy (relative biological effectiveness [RBE]) and 68.4 Gy (RBE) by a logistic model, respectively. Conclusion D5ml was most significantly associated with grade ≥2 RIBI and may enable the prediction of its probability.

Aim To determine the long-term probability of remission without antiepileptic treatment of common epileptic syndromes and of children without a specific syndromic diagnosis. Patients and methods All children less than 14 years old with 2 or more unprovoked seizures seen at our hospital between June 1, 1994, and March 1, 2011 (n = 680), were included and prospectively followed up until August 15, 2020. Syndromic diagnosis was made retrospectively but blinded to subsequent evolution, employing the data available at 6 months after diagnosis and under predefined operational criteria. Results The Kaplan-Meier estimate of the probability of achieving a remission period of at least 5 years, with neither seizures nor antiepileptic treatment at 14 years was 97% for well-defined childhood epilepsy with centrotemporal spikes, 82% for uncertain childhood epilepsy with centrotemporal spikes, 85% for well-defined Panayiotopoulos syndrome, 88% for uncertain Panayiotopoulos syndrome, 93% for nonfamilial self-limited infantile epilepsy, 100% for familial self-limited infantile epilepsy, 86% for absence epilepsy, 6% for juvenile myoclonic epilepsy, 71% for cryptogenic West syndrome, 72% for patients with no associated neurologic deficits and no specific syndromic diagnosis, 65% for symptomatic West syndrome, and 40% for patients with associated neurologic deficits and no specific syndromic diagnosis. Conclusions The study results highlight the long-term outcomes of the main epileptic syndromes and also of the patients with no syndromic diagnosis.

Adeno-associated virus (AAV)-mediated gene therapy is a novel treatment promising to reduce morbidity associated with hemophilia. Although multiple clinical trials continue to evaluate efficacy and safety, limited cost-effectiveness data have been published. This study compared the potential cost-effectiveness of AAV-mediated factor IX (FIX)-Padua gene therapy for patients with severe hemophilia B in the United States vs on-demand FIX replacement and primary FIX prophylaxis, using either standard or extended half-life FIX products. A microsimulation Markov model was constructed, and transition probabilities between health states and utilities were informed by using published data. Costs were aggregated by using a microcosting approach. A time horizon from 18 years old until death, from the perspective of a third-party payer in the United States, was conducted. Gene therapy was more cost-effective than both alternatives considering a $150 000/quality-adjusted life-year threshold. The price for gene therapy was assumed to be $2 000 000 in the base case scenario; however, one of the 1-way sensitivity analyses was conducted by using observed manufacturing, administration, and 5-year follow-up costs of $87 198 for AAV-mediated gene therapy vector as derived from the manufacturing facility and clinical practice at St Jude Children’s Research Hospital. One-way sensitivity analyses revealed 10 of 102 scenarios in which gene therapy was not cost-effective compared with alternative treatments. Notably, gene therapy remained cost-effective in a hypothetical scenario in which we estimated that the discounted factor concentrate price was 20% of the wholesale acquisition cost in the United States. Probabilistic sensitivity analysis estimated gene therapy to be cost-effective at 92% of simulations considering a $150 000/quality-adjusted life-year threshold. In conclusion, based on detailed simulation inputs and assumptions, gene therapy was more cost-effective than on-demand treatment and prophylaxis for patients with severe hemophilia B.

This study proposes the comprehensive index of biomarker (CIB), based on the consistency of a biomarker in case control (Youden index, J) and cohort studies (Crc), to evaluate biomarker efficacy. CIB was calculated as the mean of J and Crc. Analysis of the effect of sensitivity and specificity on CIB and ROC analysis of CIB were performed in simulated and actual datasets. J and CIB had similar values for high-probability events (say probability was 0.50), but there was a significant difference between J and CIB for low-probability events (say probability was 0.05). Therefore, as the subjects considered for diagnosis are usually symptomatic, the occurrence of a disease can be assumed to be a high-probability event. In contrast, as the subjects considered in screening for a disease are usually healthy and asymptomatic, the occurrence of a disease is assumed to be a low-probability event. Although J is the common index used to evaluate the diagnostic effectiveness, unfortunately, the J value is significantly larger than CIB value in a low-probability event, showing overestimation for screening purpose. CIB could have more potential than J for determining the screening efficacy of a biomarker. The efficacy of a biomarker could differ for diagnostic, screening, predictive, and prognostic purposes, and it would be better to evaluate the efficacy of biomarkers for specific systems or contexts.

Informative, participatory clinical decision-making needs to combine both skills and expertise as well as current scientific evidence. The flood of digital information makes it difficult in everyday clinical practice to keep up to date with the latest publications. This article provides assistance for coping with this problem. A basic understanding of prior and posterior probabilities as well as systematic error (bias) makes it easier to weigh up the benefits and risks, e.g. of a (surgical) intervention compared to a nonsurgical treatment. Randomized controlled trials (RCT, with all modern modifications) deliver undistorted results but in orthopedic and trauma surgery can lead to a heavily selected nonrepresentative sample and the results must be confirmed or refuted by further, independent RCTs. Large-scale observational data (e.g. from registries) can be modelled in a quasi-experimental manner and accompany RCTs in health technology assessment.Für eine informierte, partizipative ärztliche Entscheidungsfindung müssen Sie neben Ihrem Erfahrungswissen aktuelle wissenschaftliche Daten berücksichtigen. Die digitale Informationsflut macht es im klinischen Alltag allerdings schwer, immer auf dem Stand des Wissens zu bleiben. Der Beitrag bietet einige Hilfen an, wie mit diesem Problem umgegangen werden kann. Ein grundlegendes Verständnis über Vor- und Nachwahrscheinlichkeiten sowie systematische Fehler (Bias) erleichtert die Abwägung zwischen Nutzen und Risiko z. B. einer (chirurgischen) Intervention im Vergleich zu einer nichtoperativen Therapie. Randomisierte Studien („randomized controlled trials“, RCT, mit allen modernen Modifikationen) liefern unverzerrte Ergebnisse, führen in Orthopädie und Unfallchirurgie evtl. zu einer stark selektierten, nichtrepräsentativen Stichprobe, und ihre Resultate müssen durch weitere, unabhängige RCT bestätigt oder widerlegt werden. Große beobachtende Datenmengen (z. B. aus Registern) können quasiexperimentell modelliert werden und RCT in der Gesundheitstechnologiebewertung flankieren.

The geographical overlaps of malaria parasites and Salmonella spp. can lead to co-infection of these two pathogens, especially in the tropics where malaria is endemic. Moreover, few literatures suggested that malaria infection was associated with Salmonella bacteremia. Therefore, this study quantified pooled prevalence of typhoidal/non-typhoidal Salmonella (NTS) and probability of typhoidal/NTS and malaria co-infection among febrile patients. The systematic review protocol was registered at PROSPERO (CRD42021252322). Studies on co-infection of typhoidal/NTS and malaria were searched in PubMed, Scopus, and Web of Science. The risk of bias of the included studies was assessed using the checklist for analytical cross-sectional studies developed by the Joanna Briggs Institute. Meta-analyses on the following criteria were performed: (1) pooled prevalence of typhoidal/NTS and malaria co-infection among febrile patients, (2) pooled prevalence of typhoidal/NTS among malaria patients, (3) pooled prevalence of malaria infections among patients with Salmonella spp. infection, and (4) probability of typhoidal/NTS and malaria co-infection among febrile patients. Additionally, the case fatality rate and mean difference of malarial parasitemia between typhoidal/NTS and malaria co-infection and Plasmodium monoinfection were also determined. The subgroup analyses of typhoidal/NTS, regions (Africa and Asia), countries, time (publication year), characteristics of participants, and diagnostic tests for identifying Salmonella spp. were also conducted. A sensitivity test was performed to determine the robustness of the study outcomes. Publication bias among the included studies was evaluated using the funnel plot and Egger’s test. All analyses were performed using Stata version 15 (StataCorp LLC, Texas, USA) with a p-value 2, 99.4%; 2971/17,720 cases) and 1% (95% CI 1–1%; I2, 89.9%; 252/29,081 cases) using the Widal test and culture methods for identifying Salmonella spp., respectively. The pooled prevalence rates of typhoidal/NTS infection among patients with malaria were 31% (95% CI 23–39%; I2, 99.5%; 3202/19,208 cases) and 3% (95% CI 2–3%; I2, 86.8%; 407/40,426 cases) using the Widal test and culture methods for identifying Salmonella spp., respectively. The pooled prevalence rates of malaria infection among patients with typhoidal/NTS were 17% (95% CI 6–29%; I2, 33.3%; 13/75 cases) and 43% (95% CI 32–53%; I2, 89.1%; 287/736 cases), respectively. Malaria infection was associated with typhoidal/NTS in children aged 2, 73.9%; 3188/43,212 cases). The case fatality rate in patients with malaria and NTS co-infections was 16% (95% CI 9–24%; I2, 89.1%; 18/103 cases). From the view of the present study, the inappropriate use of the Widal test for Salmonella spp. diagnosis can overestimate the prevalence of typhoidal/NTS and malaria co-infections. Malaria infection associated with typhoidal/NTS in children and the high case fatality rates among few patients with co-infections were highlighted. Future prospective longitudinal studies using the appropriate and confirmatory dsiagnosis for Salmonella spp. infections are highly recommended to ensure the real prevalence of co-infection and highlight the outcome of co-infection for providing adequate treatment in febrile patients who live in areas where malaria is endemic, such as tropical Africa and India.

BACKGROUND A decrease in glutathione (GSH) levels is considered one of the earliest biochemical changes in Parkinson's disease (PD). OBJECTIVE The authors explored the potential role of plasma GSH as a risk/susceptibility biomarker for prodromal PD (pPD) by examining its longitudinal associations with pPD probability trajectories. METHODS A total of 405 community-dwelling participants (median age [interquartile range] = 73.2 [7.41] years) without clinical features of parkinsonism were followed for a mean (standard deviation) of 3.0 (0.9) years. RESULTS A 1 μmol/L increase in plasma GSH was associated with 0.4% (95% confidence interval [CI], 0.1%-0.7%; P = 0.017) less increase in pPD probability for 1 year of follow-up. Compared with participants in the lowest GSH tertile, participants in the highest GSH tertile had a 12.9% (95% CI, 22.4%-2.2%; P = 0.020) slower rate of increase of pPD probability for 1 year of follow-up. CONCLUSION Plasma GSH was associated with pPD probability trajectories; therefore, it might assist in the identification of individuals who are likely to reach the threshold for pPD diagnosis more rapidly. © 2021 International Parkinson and Movement Disorder Society.

As a reaction to the pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), a multitude of clinical trials for the treatment of SARS‐CoV‐2 or the resulting corona disease 2019 (COVID‐19) are globally at various stages from planning to completion. Although some attempts were made to standardize study designs, this was hindered by the ferocity of the pandemic and the need to set up clinical trials quickly. We take the view that a successful treatment of COVID‐19 patients (i) increases the probability of a recovery or improvement within a certain time interval, say 28 days; (ii) aims to expedite favorable events within this time frame; and (iii) does not increase mortality over this time period. On this background, we discuss the choice of endpoint and its analysis. Furthermore, we consider consequences of this choice for other design aspects including sample size and power and provide some guidance on the application of adaptive designs in this particular context.

Purpose: Osteoradionecrosis (ORN) of the mandible represents a severe, debilitating complication of radiation therapy (RT) for head and neck cancer (HNC). At present, no normal tissue complication probability (NTCP) models for risk of ORN exist. The aim of this study was to develop a multivariable clinical/dose-based NTCP model for the prediction of ORN any grade (ORNI-IV) and grade IV (ORNIV) after RT (+/- chemotherapy) in patients with HNC.Methods and Materials: Included patients with HNC were treated with (chemo-)RT between 2005 and 2015. Mandible bone radiation dose-volume parameters and clinical variables (ie, age, sex, tumor site, pre-RT dental extractions, chemotherapy history, postoperative RT, and smoking status) were considered as potential predictors. The patient cohort was randomly divided into a training (70%) and independent test (30%) cohort. Bootstrapped forward variable selection was performed in the training cohort to select the predictors for the NTCP models. Final NTCP model(s) were validated on the holdback test subset.Results: Of 1259 included patients with HNC, 13.7% (n = 173 patients) developed any grade ORN (ORNI-IV primary endpoint) and 5% (n = 65) ORNIV (secondary endpoint). All dose and volume parameters of the mandible bone were significantly associated with the development of ORN in univariable models. Multivariable analyses identified D30% and pre-RT dental extraction as independent predictors for both ORNI-IV and ORNIV best-performing NTCP models with an area under the curve (AUC) of 0.78 (AUCvalidation = 0.75 [0.69-0.82]) and 0.81 (AUCvalidation = 0.82 [0.74-0.89]), respectively.Conclusions: This study presented NTCP models based on mandible bone D30% and pre-RT dental extraction that predict ORNI-IV and ORNIV (ie, needing invasive surgical intervention) after HNC RT. Our results suggest that less than 30% of the mandible should receive a dose of 35 Gy or more for an ORNI-IV risk lower than 5%. These NTCP models can improve ORN prevention and management by identifying patients at risk of ORN. (C) 2021 The Author(s). Published by Elsevier Inc.

Background The randomized, double-blind, phase 3 ASPECT-NP trial evaluated the efficacy of 3 g of ceftolozane/tazobactam (C/T) versus 1 g of meropenem infused every 8 h for 8 to 14 days for treatment of adults with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). We assessed the probability of target attainment and compared efficacy outcomes from ASPECT-NP in participants with augmented renal clearance (ARC) versus those with normal renal function. Methods Baseline renal function was categorized as normal renal function (creatinine clearance 80–130 mL/min) or ARC (creatinine clearance > 130 mL/min). Population pharmacokinetic models informed Monte Carlo simulations to assess probability of target attainment in plasma and pulmonary epithelial lining fluid. Outcomes included 28-day all-cause mortality and clinical cure and per-participant microbiologic cure rates at the test-of-cure visit. Results A > 99% and > 80% probability of target attainment was demonstrated for ceftolozane and tazobactam, respectively, in simulated plasma and epithelial lining fluid. Within treatment arms, 28-day all-cause mortality rates in participants with normal renal function (C/T, n = 131; meropenem, n = 123) and ARC (C/T, n = 96; meropenem, n = 113) were comparable (data comparisons presented as rate; treatment difference [95% CI]) (C/T: normal renal function, 17.6%; ARC, 17.7%; 0.2 [− 9.6 to 10.6]; meropenem: normal renal function, 20.3%; ARC, 17.7%; − 2.6 [− 12.6 to 7.5]). Clinical cure rates at test-of-cure were also comparable across renal function groups within treatment arms (C/T: normal renal function, 57.3%; ARC, 59.4%; − 2.1 [− 14.8 to 10.8]; meropenem: normal renal function, 59.3%; ARC, 57.5%; 1.8 [− 10.6 to 14.2]). Per-participant microbiologic cure rates at test-of-cure were consistent across renal function groups within treatment arms (C/T: normal renal function, 72.2% [n/N = 70/97]; ARC, 71.4% [n/N = 55/77]; 0.7 [− 12.4 to 14.2]; meropenem: normal renal function, 75.0% [n/N = 66/88]; ARC, 70.0% [n/N = 49/70]; 5.0 [− 8.7 to 19.0]). Conclusions C/T and meropenem resulted in 28-day all-cause mortality, clinical cure, and microbiologic cure rates that were comparable between participants with ARC or normal renal function. In conjunction with high probability of target attainment, these results confirm that C/T (3 g) every 8 h is appropriate in patients with HABP/VABP and ARC. Trial registration ClinicalTrials.gov identifier: NCT02070757, registered February 25, 2014; EudraCT: 2012-002862-11.

In Italy, an HLA-matched unrelated donor is currently the primary donor when a HLA matched sibling is not found for allogeneic haematopoietic stem cell transplantation (HSCT). Better outcomes for transplantation require optimal matching between donor and recipient at least at the HLA-A, -B, -C, and -DRB1 loci; therefore, the availability of HLA-matched unrelated donors is important. The enormous HLA polymorphism has always necessitated registries with a large number of individuals in order to be able to provide well-matched donors to a substantial percentage of patients. In order to increase the efficiency of the Italian Bone Marrow Donor Registry (IBMDR) in providing Italian patients with a suitable donor, the probability of finding an HLA-A, -B, -C, and -DRB1 allele-matched (8/8) or a single mismatch unrelated donor (7/8) was estimated in this study according to IBMDR size. Using a biostatistical approach based on HLA haplotype frequencies of more than 100,000 Italian donors enrolled in the IBMDR and HLA-typed at high-resolution level, the probability of finding an 8/8 HLA-matched donor was 23.8%; 33.4%; and 41.4% in simulated registry sizes of 200,000; 500,000; and 1,000,000 donors; respectively. More than 2 million recruited donors are needed to increase the likelihood of identifying an HLA 8/8 matched donor for 50% of Italian patients. If one single mismatch at HLA I class loci was accepted, the probability of finding a 7/8 HLA-matched donor was 62.8%; 73.7%; and 80.3% in 200,000 donors; 500,000; and 1,000,000 donors; respectively. Using the regional haplotype frequencies of IBMDR donors, the probability of recruiting a donor with a new HLA phenotype, in the different Italian regions, was also calculated. Our findings are highly relevant in estimating the optimal size of the national registry, in planning a cost-effective strategy for donor recruitment in Italy, and determining the regional priority setting of recruitment activity in order to increase the phenotypic variability of IBMDR as well as its efficiency.

Choking/strangulation during sex is prevalent among young adults in the United States. We examined associations between having ever been choked and participants' current mental health symptoms (e.g., feeling depressed, anxious, sad, lonely) in the prior 30 days and in the prior year. Participants were 4352 randomly sampled undergraduates who completed a confidential online survey and reported lifetime partnered sexual activity. 33.6% of women and 6.0% of men reported having been choked more than five times. After adjusting for demographic characteristics, having been choked remained significantly associated with all four mental health outcomes, except for overwhelming anxiety among men.

Introduction: Stereotactic ablative radiotherapy (SABR) can achieve good local control for metastatic adrenal lesions. Magnetic resonance (MR)-guidance with daily on-table plan adaptation can augment the delivery of SABR with greater dose certainty. The goal of this study was to quantify the potential clinical benefit MR-guided daily-adaptive adrenal SABR using the normal tissue complication probability (NTCP) framework. Methods: Patients treated with adrenal MR-guided SABR at a single institution were retrospectively reviewed. Lyman-Kutcher-Burman NTCP models were used to calculate the NTCP of upper abdominal organs-at-risk (OARs) at simulation and both before and after daily on-table plan adaptation. Differences in OAR NTCPs were assessed using signed-rank tests. Potential predictors of the benefits of adaptation were assessed by linear regression. Results: Fifty-two adrenal MR-guided SABR courses were analyzed. The baseline simulation plan underestimated the absolute stomach NTCP by 10.0% on average (95% confidence interval: 4.7–15.2%, p < 0.001). Daily on-table adaptation lowered absolute NTCP by 8.7% (4.2–13.2%, p < 0.001). The most significant predictor of the benefits of adaptation was lesion laterality (p = 0.018), with left-sided lesions benefitting more (13.3% [6.3–20.4%], p < 0.001) than right-sided lesions (2.1% [−1.6–5.7%], p = 0.25). Sensitivity analyses did not change the statistical significance of the findings. Conclusion: NTCP analysis revealed that patients with left adrenal tumors were more likely to benefit from MR-guided daily on-table adaptive SABR using current dose/fractionation regimens due to reductions in predicted gastric toxicity. Right-sided adrenal lesions may be considered for dose escalation due to low predicted NTCP.

Background The COVID-19 pandemic has required new treatment paradigms to limit exposures and optimize hospital resources, including the use of neoadjuvant endocrine therapy (NAET) as bridging therapy for HR+/HER2-invasive tumors and DCIS. While this approach has been used in locally advanced disease, it is unclear how it may affect outcomes in resectable HR+/HER2- tumors. Methods Women ≥18 years diagnosed with in situ (Tis) or non-metastatic HR+/HER2- breast cancer from March-May 2019 and 2020 were included. Fisher’s exact test and two-sample t test were used to compare baseline characteristics and surgical outcomes between strata. Sub-analysis was performed between patients who received primary surgery vs a bridging NAET approach. Results Despite similar clinical characteristics, patients in 2019 were more likely to have a surgery-first approach (75% vs 42%, P-value = .0007), receive surgery sooner (22 vs 29 days, P-value < .001), and within 60 days from diagnosis date (100% vs 85%, P-value = .0301). Neoadjuvant endocrine therapy was a more prevalent approach in 2020 (48% vs 7%, P-value < .0001). Rates of clinical to pathologic up-staging remained consistent across primary surgery vs bridging NAET subgroups ( P-value = .9253). Discussion Pandemic-driven treatment protocols provide a unique opportunity to assess the utility of bridging endocrine therapy for resectable HR+/HER2- tumors. Differences in clinical and pathologic staging were similar across groups and did not appear to be affected by receipt of NAET. Our limited cohort demonstrates this strategic therapeutic avenue can optimize health care utilization and may be a reasonable approach when delaying surgery is preferred.

STUDY QUESTION Does the probability of a live birth after fresh IVF/ICSI cycles with autologous oocytes differ in early onset female cancer survivors compared to their siblings? SUMMARY ANSWER The probability of a live birth was similar in female cancer survivors and siblings after four fresh IVF/ICSI cycles. WHAT IS KNOWN ALREADY Fertility preservation strategies are rapidly being developed to help female cancer patients who wish to have children later. However, there are only a few studies available on fertility treatments and following live births in female cancer survivors before fertility preservation strategies became available. In one of them, the probability of a live birth was reduced after assisted reproductive technology with autologous oocytes in cancer survivors compared to siblings. STUDY DESIGN, SIZE, DURATION In this retrospective, register-based study, data from Finnish registers on cancer, birth and prescribed medications were merged to identify 8944 female cancer survivors (diagnosed with cancer between 1953 and 2012 at the age of 0–40 years) and 9848 female siblings of survivors eligible for IVF/ICSI treatments between January 1993 and December 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS Fresh IVF/ICSI cycles and following live birth rates (LBRs) within 22–48 weeks in cancer survivors and siblings at the age of 20–41 years were identified. A binomial regression model with log-link function was used to calculate risk ratio (RR) for live births after fresh IVF/ICSI cycles in survivors compared to siblings, adjusting for attained age and calendar time. A Poisson regression model was used to estimate incidence rate ratios (IRRs) for an IVF/ICSI treatment, as well as overall live births, including both pregnancies after fertility treatments and spontaneous pregnancies, in survivors compared to siblings. MAIN RESULTS AND THE ROLE OF CHANCE We observed an overall decreased LBR, irrespective of IVF/ICSI treatments, in cancer survivors compared to siblings (IRR 0.68, 95% CI 0.64–0.71). All in all, 179 (2.0%) survivors and 230 (2.3%) siblings were prescribed fertility drugs for IVF/ICSI treatments (IRR 0.72, 95% CI 0.62–0.84). For the first fresh IVF/ICSI cycle, the LBR was 17.2% among survivors and 15.7% among siblings (RR 1.13, 95% CI 0.72–1.87). The mean LBR after four fresh IVF/ICSI cycles was not statistically different in survivors compared to siblings. LIMITATIONS, REASONS FOR CAUTION In this study, only IVF/ICSI treatments with autologous oocytes were included. The probability of a live birth after a frozen embryo transfer or oocyte donation could not be evaluated in this study. Information on miscarriages, extrauterine pregnancies or termination of pregnancies was not available. WIDER IMPLICATIONS OF THE FINDINGS For those early onset cancer survivors, who received IVF/ICSI treatments, the probability of live birth was not different from siblings who received IVF/ICSI treatments. However, an overall decreased LBR, irrespective of IVF/ICSI treatments, was observed in cancer survivors compared to siblings, indicating that cancer survivors receiving IVF/ICSI treatments in our study consisted of a selected group with at least a moderate ovarian reserve. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by a grant from the Cancer Foundation (Finland) (grant number 130079) and by a grant from LähiTapiola. The authors have no potential conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

Purpose The extent of lymphadenectomy and clinical features influence the risk of occult nodes in node-negative prostate cancer. We derived a simple estimation model for the negative predictive value (npv) of histopathologically node-negative prostate cancer patients (pN0) to guide adjuvant treatment. Methods Approximations of sensitivities in detecting lymph node metastasis from current publications depending on the number of removed lymph nodes were used for a theoretical deduction of a simplified formulation of npv assuming a false node positivity of 0. Results A theoretical formula of npv = p(N0IpN0) = (100 − prevalence) / (100 − sensitivity × prevalence) was calculated (sensitivity and preoperative prevalence in %). Depending on the number of removed lymph nodes (nLN), the sensitivity of pN0-staged prostate cancer was derived for three sensitivity levels accordingly: sensitivity = f(nLN) = 9 × nLN /100 for 0 ≤ nLN ≤ 8 and f(nLN) = (nLN + 70) /100 for 9 ≤ nLN ≤ 29 and f(nLN) = 1 for nLN ≥ 30. Conclusion We developed a theoretical formula for estimation of the npv in pN0-staged prostate cancer patients. It is a sine qua non to use the formula in a clinically experienced context before deciding to electively irradiate pelvic lymph nodes or to intensify adjuvant systemic treatment.

Objectives To elaborate an ECG-based nomogram estimating the probability to detect cardiac involvement by cardiac magnetic resonance (CMR) in Fabry Disease (FD). Methods 119 FD patients and 26 healthy controls underwent ECG and CMR. Test (n = 88, 60%) and validation cohorts (n = 57, 40%) were randomly derived. Cardiac involvement was defined as the presence of low myocardial T1 value, a CMR-surrogate of myocardial glycosphingolipid storage. ECG changes associated with low T1 value were identified in the test cohort, included in the nomogram and then tested in the validation cohort. Results Sokolow-Lyon index (AUC = 0.769), ratio between P-wave and PR-segment durations (Pwave/PRsegment) (AUC = 0.778), QRS duration (AUC = 0.703), QT (AUC = 0.769) duration were independently associated with the presence of low T1 on CMR at multivariate analysis. An ECG-based nomogram including these four parameters was accurate in identifying patients with CMR evidence of glycosphingolipid storage (c-index of the derived-nomogram = 0.90 in the test group; 0.81 in the validation group). Conclusion We propose a practical ECG-based nomogram accurately estimating the probability to detect low T1 values by CMR in FD patients. The application of this tool in clinical practice could improve early detection of FD cardiac involvement.

Aim: The purpose of the study is the development and evaluation of the informativeness of the author’s 3D nephrometric score application to predict the probability of intraoperative and postoperative complications in kidney operations. Material and methods: The study includes 264 patients who underwent surgical treatment of renal tumors, before that CT and 3D modeling were carried out. All patients underwent an analysis of the surgical intervention complexity on the C-index, PADUA, R.E.N.A.L., and developed 3D nephrometric score. To determine the set of variables that allow to classify patients, the method of discriminant analysis was used to predict the nature, volume of blood loss, duration of ischemia, and the number of complications. The sensitivity and specificity of the predictors were estimated with the help of ROC analysis. Results: Indicators have been established to classify patients according to the probability of complications, the amount of blood loss and the duration of ischemia during surgery for kidney cancer. We have created linear models that predict the development of bleeding during surgery, the volume of blood loss of more than 200 ml and the duration of ischemia more than 20 min, as well as the likelihood of complications using discriminant functions. The proposed author’s nephrometric score exceeds the capabilities of C-index, PADUA, R.E.N.A.L in many ways in blood loss and time of ischemia predicting, which allows us to recommend it for the assessment of resectability in kidney operations.

Background: Several studies have reported that abdominal fat and muscle changes occur in diabetic patients. However, there are few studies about such changes among prediabetic patients. In this study, we evaluated the differences in abdominal fat and muscles based on abdominopelvic computed tomography in prediabetic and diabetic subjects compared to normal subjects.Methods: We performed a cross-sectional study using health examination data from March 2014 to June 2019 at Ulsan University Hospital and classified subjects into normal, prediabetic, and diabetic groups. We analyzed the body mass index corrected area of intra-abdominal components among the three groups using inverse probability treatment weighting (IPTW) analysis.Results: Overall, 8,030 subjects were enrolled; 5,137 (64.0%), 2,364 (29.4%), and 529 (6.6%) subjects were included in the normal, prediabetic, and diabetic groups, respectively. After IPTW adjustment of baseline characteristics, there were significant differences in log visceral adipose tissue index (VATI; 1.22±0.64 cm2/[kg/m2] vs. 1.30±0.63 cm2/[kg/m2] vs. 1.47±0.64 cm2/[kg/m2], P

Purpose This study aimed to investigate factors, which influence the content of circulating tumor DNA (ctDNA). Methods 398 serial plasma samples were collected within 1–7 consecutive days from patients with EGFR-mutated lung cancer (n = 13), RAS/RAF-mutated colorectal cancer (n = 54) and BRAF-mutated melanoma (n = 17), who presented with measurable tumor disease. The amount of ctDNA was determined by ddPCR. Results Among 82 patients, who donated 2–6 serial plasma samples, 42 subjects were classified as ctDNA-positive; only 22% cases were mutation-positive across all consecutive tests, while 24/82 (29%) patients showed presence of mutated ctDNA in some but not all blood draws. Subjects with progressing tumors had higher probability of being detected ctDNA-positive as compared to patients, who responded to therapy or had stable disease (39/55 (71%) vs. 4/24 (17%); p = 0.0001). Our study failed to reveal the impact of the time of the day, recent meal or prior physical exercise on the results of ctDNA testing. Conclusions Presence of ctDNA in plasma is particularly characteristic for patients, who experience clinical progression of tumor disease. Consecutive plasma tests may occasionally provide discordant data; thus, the repetition of analysis may be advised in certain cases in order to ensure the validity of negative ctDNA result.

Objective This study aimed to develop and internally validate risk prediction models for predicting groin wound surgical site infections (SSIs) following arterial intervention and to evaluate the utility of existing risk prediction models for this outcome. Methods Data from the Groin wound Infection after Vascular Exposure (GIVE) multicentre cohort study were used. The GIVE study prospectively enrolled 1 039 consecutive patients undergoing an arterial procedure through 1 339 groin incisions. An overall SSI rate of 8.6% per groin incision, and a deep/organ space SSI rate of 3.8%, were reported. Eight independent predictors of all SSIs, and four independent predictors of deep/organ space SSIs were included in the development and internal validation of two risk prediction models. A systematic search of the literature was conducted to identify relevant risk prediction models for their evaluation. Results The “GIVE SSI risk prediction model” (“GIVE SSI model”) and the “GIVE deep/organ space SSI risk prediction model” (“deep SSI model”) had adequate discrimination (C statistic 0.735 and 0.720, respectively). Three other groin incision SSI risk prediction models were identified; both GIVE risk prediction models significantly outperformed these other risk models in this cohort (C statistic 0.618 – 0.629; p Conclusion Two models were created and internally validated that performed acceptably in predicting “all” and “deep” groin SSIs, outperforming current existing risk prediction models in this cohort. Future studies should aim to externally validate the GIVE models.

Health events emerge from host, community, environment, and pathogen factors—forecasting epidemics is a complex task. We describe an exploratory analysis to identify economic risk factors that could aid epidemic risk assessment. A line list was constructed using the World Health Organization Disease Outbreak News (2016–2018) and economic indicators from the World Bank. Poisson regression employing forward imputations was used to establish relationships with the frequency with which countries reported public health events. Economic indicators demonstrated strong performance appropriate for further assessment in surveillance programming. In our analysis, three economic indicators were significantly associated to event reporting: how much the country’s urban population changed, its average forest area, and a novel economic indicator we developed that assessed how much the gross domestic product changed per capita. Other economic indicators performed less well: changes in total, female, urban, and rural population sizes; population density; net migration; change in per cent forest area; total forest area; and another novel indicator, change in percent of trade as a fraction of the total economy. We then undertook a further analysis of the start of the current COVID-19 pandemic that revealed similar associations, but confounding by global disease burden is likely. Continued development of forecasting approaches capturing information relevant to whole-of-society factors (e.g., economic factors as assessed in our study) could improve the risk management process through earlier hazard identification and inform strategic decision processes in multisectoral strategies to preventing, detecting, and responding to pandemic-threat events.

Prior research has described women's experiences with exercise-induced orgasm (EIO). However, little is known about men's experiences with EIO, the population prevalence of EIO, or the association of EIO with other kinds of orgasm. Using U.S. probability survey data, the objectives of the present research were to: (1) describe the lifetime prevalence of exercise-induced orgasm (EIO) and sleep orgasm; (2) assess respondents' age at first experience of EIO as well as the type of exercise connected with their first EIO; (3) examine associations between lifetime EIO experience and orgasm at respondents' most recent partnered sexual event; and (4) examine associations between lifetime EIO experience and sleep orgasms. Data were from the 2014 National Survey of Sexual Health and Behavior (1012 men and 1083 women, ages 14 years and older). About 9% of respondents reported having ever experienced exercise-induced orgasm. More men than women reported having experienced orgasm during sleep at least once in their lifetime (66.3% men, 41.8% women). The mean age for women's first EIO was significantly older than men (22.8 years women, 16.8 years men). Respondents described a wide range of exercises as associated with their first EIO (i.e., climbing ropes, abdominal exercise, yoga). Lifetime EIO experience was associated with lifetime sleep orgasms but not with event-level orgasm during partnered sex. Implications related to understanding orgasm and recommendations for clinicians and sex educators are discussed.

BACKGROUND AND PURPOSE: Several modifiable lifestyle factors have been associated with the onset and health outcomes of multiple sclerosis (MS), including clinically significant fatigue. A combined lifestyle score approach represents one method of assessing their relationship with clinical outcomes. The aim was to examine the association of two lifestyle scores with clinically significant fatigue and change thereof over 2.5 years' follow-up using inverse probability treatment weighting (IPTW). METHODS: Data on sociodemographic, lifestyle, and clinical characteristics surveyed from an international cohort of people with MS at baseline and at 2.5-year follow-up were used. Fatigue was defined by the Fatigue Severity Scale (FSS >5) and healthy lifestyle by the Healthy Lifestyle Index Score (HLIS) and the Smoking, Nutrition, Alcohol Consumption and Physical Activity (SNAP) score. Analyses were by IPTW accounting for age, sex, MS type, disability, treated comorbidity number, immunomodulatory medication use, prescription antifatigue medication use, and ongoing relapse symptoms. RESULTS: In total, 1268 participants completed the FSS at both time points; approximately 62% had fatigue. Using doubly robust IPTW, high (>11/20) HLIS (odds ratio [OR] 0.90, 95% confidence interval [CI] 0.81-0.98) and high (>3/5) SNAP (OR 0.82, 95% CI 0.73-0.90) were each associated with lower risk of fatigue at follow-up. Evaluating change in fatigue, a higher SNAP score was associated with a lower risk of fatigue (OR 0.89, 95% CI 0.80-0.97) but the score for HLIS did not reach statistical significance (OR 0.93, 95% CI 0.85-1.01). CONCLUSION: These results suggest a robust role for key lifestyle factors in preventing clinically significant fatigue and may represent a place for lifestyle modification in improving clinical outcomes in MS.

A goal of rehabilitation after stroke is to promote pre-stroke levels of arm use for every day, frequently bimanual, functional activities. We reasoned that, after a stroke, the choice to use one or both hands for bimanual tasks might depend not only on residual motor capacity, but also the specialized demands imposed by the task on the paretic hand. To capture spontaneous, task-specific choices, we covertly observed 50 pre-stroke right-handed chronic stroke survivors (25 each of left, LHD, and right-hemisphere damage, RHD) and 11 age-similar control adults and recorded their hand use strategies for two pairs of bimanual tasks with distinct demands: one with greater precision requirements (photo-album tasks), and another with greater stabilization requirements (letter-envelope tasks). The primary outcome was the choice to use one or both hands. Logistic regression was used to test the two hypotheses that the probability of choosing a bimanual strategy would be greater in those with less severe motor impairment and also in those with LHD. When collapsed across the four tasks, we found support for these hypotheses. Notably, however, the influence of these factors on bimanual choice varied based on task demands. For the photo–album pair, the probability of a bimanual strategy was greater for those with LHD compared to RHD, regardless of the degree of motor impairment. For the letter–envelope pair, we found a significant interaction between impairment and side of lesion in determining the likelihood of choosing both hands. Therefore, the manner in which side of lesion moderates the effect of impairment on hand use depends on the task.

Repeated presentation of a stimulus leads to reductions in measures of neural responses. This phenomenon, termed repetition suppression (RS), has recently been conceptualized using models based on predictive coding, which describe RS as due to expectations that are weighted toward recently-seen stimuli. To evaluate these models, researchers have manipulated the likelihood of stimulus repetition within experiments. They have reported findings that are inconsistent across hemodynamic and electrophysiological measures, and difficult to interpret as clear support or refutation of predictive coding models. We instead investigated a different type of expectation effect that is apparent in stimulus repetition experiments: the difference in one’s ability to predict the identity of repeated, compared to unrepeated, stimuli. In previous experiments that presented pairs of repeated or alternating images, once participants had seen the first stimulus image in a pair, they could form specific expectations about the repeated stimulus image. However they could not form such expectations for the alternating image, which was often randomly chosen from a large stimulus set. To assess the contribution of stimulus predictability effects to previously observed RS, we measured BOLD signals while presenting pairs of repeated and alternating faces. This was done in contexts whereby stimuli in alternating trials were either i.) predictable through statistically learned associations between pairs of stimuli or ii.) chosen randomly and therefore unpredictable. We found that RS in the right FFA was much larger in trials with unpredictable compared to predictable alternating faces. This was primarily due to unpredictable alternating stimuli evoking larger BOLD signals than predictable alternating stimuli. We show that imbalances in stimulus predictability across repeated and alternating trials can greatly inflate measures of RS, or even mimic RS effects. Our findings also indicate that stimulus-specific expectations, as described by predictive coding models, may account for a sizeable portion of observed RS effects.

Adaptive designs are gaining popularity in early phase clinical trials because they enable investigators to change the course of a study in response to accumulating data. We propose a novel design to simultaneously monitor several endpoints. These include efficacy, futility, toxicity and other outcomes in early phase, single-arm studies. We construct a recursive relationship to compute the exact probabilities of stopping for any combination of endpoints without the need for simulation, given pre-specified decision rules. The proposed design is flexible in the number and timing of interim analyses. A R Shiny app with user-friendly web interface has been created to facilitate the implementation of the proposed design.

INTRODUCTION The American Academy of Orthopaedic Surgeons (AAOS) Annual Meeting provides an opportunity for clinicians to attain the most recent advancements in the orthopaedic field. However, the most recent study analyzing publication rates from the 2001 Annual Meeting determined that only 49% of the podium and poster abstracts were eventually published. The purpose of this study was to determine the publication rate, likelihood of publication based on the presentation format, and time to publication for abstracts presented at the 2014 to 2017 AAOS Annual Meetings. METHODS We did a comprehensive search of PubMed and Google Scholar to determine whether abstracts presented in the podium, poster, and scientific exhibit formats from the 2014 to 2017 AAOS Annual Meetings were published in a peer-reviewed journal. Abstract title, authors, and keywords were used to query for publication status and date of publication. RESULTS We analyzed 5,902 abstracts from the 2014 to 2017 AAOS Annual Meetings. The overall publication rate for podium and poster presentations was 69.9%, with individual publication rates at 73.0% and 65.1%, respectively. A higher likelihood of publication in the podium format was noted with odds ratio 1.45 (P < 0.0001). Scientific exhibits displayed a publication rate of 46.9%. Most publications in all formats occurred within 2 years. CONCLUSION A large increase was noted in the quality of research being presented at the AAOS Annual Meeting. With 69.9% of podium and poster presentations from the 2014 to 2017 Annual Meetings being published in a peer-reviewed journal, clinicians can use the data presented as an up-to-date, adjunct source of guidance for their clinical practices.

Background There has been no study systematically assessing the causal effects of putative modifiable risk factors on lung cancer. In this study, we aimed to construct a modifiable risk factors atlas of lung cancer by using the two‐sample Mendelian randomization framework. Methods We included 46 modifiable risk factors identified in previous studies. Traits with p‐value smaller than 0.05 were considered as suggestive risk factors. While the Bonferroni corrected p‐value for significant risk factors was set to be 8.33 × 10−4. Results In this two‐sample Mendelian randomization analysis, we found that higher socioeconomic status was significantly correlated with lower risk of lung cancer, including years of schooling, college or university degree, and household income. While cigarettes smoked per day, time spent watching TV, polyunsaturated fatty acids, docosapentaenoic acid, eicosapentaenoic acid, and arachidonic acid in blood were significantly associated with higher risk of lung cancer. Suggestive risk factors for lung cancer were found to be serum vitamin A1, copper in blood, docosahexaenoic acid in blood, and body fat percentage. Conclusions This study provided the first Mendelian randomization assessment of the causality between previously reported risk factors and lung cancer risk. Several modifiable targets, concerning socioeconomic status, lifestyle, dietary, and obesity, should be taken into consideration for the development of primary prevention strategies for lung cancer., With the utilization of Mendelian randomization analysis, we provided the evidence for the relationship between previously reported risk factors and lung cancer from the aspect of causation. We identified several modifiable targets for primary prevention of lung cancer, concerning socioeconomic status, lifestyle, dietary and obesity. ​

Objectives Accurate estimation of the risk of SARS‐CoV‐2 infection based on bedside data alone has importance to emergency department (ED) operations and throughput. The 13‐item CORC (COVID [or coronavirus] Rule‐out Criteria) rule had good overall diagnostic accuracy in retrospective derivation and validation. The objective of this study was to prospectively test the inter‐rater reliability and diagnostic accuracy of the CORC score and rule (score ≤ 0 negative, > 0 positive) and compare the CORC rule performance with physician gestalt. Methods This noninterventional study was conducted at an urban academic ED from February 2021 to March 2021. Two practitioners were approached by research coordinators and asked to independently complete a form capturing the CORC criteria for their shared patient and their gestalt binary prediction of the SARS‐CoV‐2 test result and confidence (0%–100%). The criterion standard for SARS‐CoV‐2 was from reverse transcriptase polymerase chain reaction performed on a nasopharyngeal swab. The primary analysis was from weighted Cohen's kappa and likelihood ratios (LRs). Results For 928 patients, agreement between observers was good for the total CORC score, κ = 0.613 (95% confidence interval [CI] = 0.579–0.646), and for the CORC rule, κ = 0.644 (95% CI = 0.591–0.697). The agreement for clinician gestalt binary determination of SARs‐CoV‐2 status was κ = 0.534 (95% CI = 0.437–0.632) with median confidence of 76% (first–third quartile = 66–88.5). For 425 patients who had the criterion standard, a negative CORC rule (both observers scored CORC < 0), the sensitivity was 88%, and specificity was 51%, with a negative LR (LR−) of 0.24 (95% CI = 0.10–0.50). Among patients with a mean CORC score of >4, the prevalence of a positive SARS‐CoV‐2 test was 58% (95% CI = 28%–85%) and positive LR was 13.1 (95% CI = 4.5–37.2). Clinician gestalt demonstrated a sensitivity of 51% and specificity of 86% with a LR− of 0.57 (95% CI = 0.39–0.74). Conclusion In this prospective study, the CORC score and rule demonstrated good inter‐rater reliability and reproducible diagnostic accuracy for estimating the pretest probability of SARs‐CoV‐2 infection.

Introduction: This study performed a path analysis to uncover the behavioral pathways (from contributing factors, pre-crash actions to injury severities) in bicycle-motor vehicle crashes. Method: The analysis investigated more than 7,000 bicycle-motor vehicle crashes in North Carolina between 2007 and 2014. Pre-crash actions discussed in this study are actions of cyclists and motorists prior to the event of a crash, including “bicyclist failed to yield,” “motorist failed to yield,” “bicyclist overtaking motorist,” and “motorist overtaking bicyclist.” Results: Model results show significant correlates of pre-crash actions and bicyclist injury severity. For example, young bicyclists (18 years old or younger) are 23.5% more likely to fail to yield to motor traffic prior to the event of a crash than elder bicyclists. The “bicyclist failed to yield” action is associated with increased bicyclist injury severity than other actions, as this behavior is associated with an increase of 5.88 percentage points in probability of a bicyclist being at least evidently injured. The path analysis can highlight contributing factors related to risky pre-crash actions that lead to severe injuries. For example, bicyclists traveling on regular vehicle travel lanes are found to be more likely to involve the “bicyclist failed to yield” action, which resulted in a total 44.38% (7.04% direct effect + 37.34% indirect effect) higher likelihood of evident or severe injuries. The path analysis can also identify factors (e.g., intersection) that are not directly but indirectly correlated with injury severity through pre-crash actions. Practical Applications: This study offers a methodological framework to quantify the behavioral pathways in bicycle-motor vehicle crashes. The findings are useful for cycling safety improvements from the perspective of bicyclist behavior, such as the educational program for cyclists.

Background Considering the high morbidity and mortality of lung cancer and the high incidence of pulmonary nodules, clearly distinguishing benign from malignant lung nodules at an early stage is of great significance. However, determining the kind of lung nodule which is more prone to lung cancer remains a problem worldwide. Methods A total of 480 patients with pulmonary nodule data were collected from Shandong, China. We assessed the clinical characteristics and computed tomography (CT) imaging features among pulmonary nodules in patients who had undergone video‐assisted thoracoscopic surgery (VATS) lobectomy from 2013 to 2018. Preliminary selection of features was based on a statistical analysis using SPSS. We used WEKA to assess the machine learning models using its multiple algorithms and selected the best decision tree model using its optimization algorithm. Results The combination of decision tree and logistics regression optimized the decision tree without affecting its AUC. The decision tree structure showed that lobulation was the most important feature, followed by spiculation, vessel convergence sign, nodule type, satellite nodule, nodule size and age of patient. Conclusions Our study shows that decision tree analyses can be applied to screen individuals for early lung cancer with CT. Our decision tree provides a new way to help clinicians establish a logical diagnosis by a stepwise progression method, but still needs to be validated for prospective trials in a larger patient population., Considering the high morbidity and mortality of lung cancer and the high incidence of pulmonary nodules, it is of great significance to clearly distinguish between benign and malignant lung nodules at early stages. However, what kind of lung nodules are more prone to lung cancer is still a worldwide problem. In this study, 458 cases with pulmonary nodules data were collected from Shandong, China. We assessed the clinical characteristics and low‐dose computed tomography (LDCT) imaging features among pulmonary nodules in patients who had undergone video‐assisted thoracoscopic surgery (VATS) lobectomy from 2013 to 2018 to determine the machine learning models using multiple algorithms and select the best decision tree model. Our study shows that decision tree analyses can be applied to screen individuals for early lung cancer with CT. Our decision tree provides a new way to help clinicians establish a logical diagnosis by a stepwise progression method, but still needs to be validated for prospective trials in a larger patient population.

Background: Disclosing prognostic information is necessary to enable patients to make well-informed treatment decisions. OncologIQ is a prognostic model that predicts the overall survival (OS) probability in patients with head and neck squamous cell carcinoma (HNSCC). We aimed to externally validate and update the model with new prognostic factors and translate it to a clinically useful tool. Methods: A consecutive retrospective sample of 2189 patients eligible for curative treatment of a primary HNSCC were selected. Discriminative performance was determined using the C-statistic. Results: External validation showed systematic underestimation of OS in the new population, and reasonable discrimination (C-statistic 0.67). Adding smoking, pack years, BMI, weight loss, WHO performance, socioeconomic status, and p16 positivity to the recalibrated multivariable model, improved the internally validated C-statistic to 0.71. The model showed minor optimism and was translated in an online tool (www.oncologiq.nl). Conclusions: The updated model enables personalized patient counseling during treatment decision consultations.

PURPOSE: Stereotactic body radiation therapy (SBRT) has emerged as a viable reirradiation strategy for locally recurrent previously-irradiated head and neck cancer. Doses in the literature have varied, which challenges clinical application of SBRT as well as clinical trial design. MATERIAL & METHODS: A working group was formed through the American Association of Physicists in Medicine to study tumor control probabilities for SBRT in head and neck cancer. We herein present a systematic review of the available literature addressing the dose/volume data for tumor control probability with SBRT in patients with locally recurrent previously-irradiated head and neck cancer. Dose-response models are generated that present tumor control probability as a function of dose. RESULTS: Data from more than 300 cases in 8 publications suggest that there is a dose-response relationship, with superior local control and possibly improved overall survival for doses of 35 to 45 Gy (in 5 fractions) compared with

Background D-dimer levels below a well-defined cut-off level enable to safely rule out VTE in patients with a low or intermediate pre-test probability (PTP), as the test negative predictive value (NPV) was high. As ageing is associated with increased D-dimer levels, the question was raised of the usefulness of their measurement to rule out VTE in elderly patients. Various attempts were made in the recent years to address that issue, particularly the use of age-adjusted cut-off values calculated by multiplying the patient's age by 10, in patients aged over 50. Aim of that study The aim of the study was to validate such a strategy, and to evaluate its economic impact in unselected outpatients referred to the emergency departments of 5 French centres (2 university hospitals, and 3 general hospitals). Patients, Materials and Methods After exclusion of those on anticoagulant treatment at the time of the diagnosis (n=23), a total of 1255 consecutive patients with a non-high PTP of VTE were included in the study. The same standardized procedure was used in the 5 centres, i.e. D-dimer measurement in patients with a non-high PTP, and imaging techniques (usually computed pulmonary angiography in case of suspected PE and Doppler ultrasonography in case of suspected DVT) only when D-dimer was above the cut-off level. D-dimer was evaluated using the same latex-based fully automated assay (HemosIL D-dimer HS500 assay, Instrumentation Laboratory). Test results were expressed in ng/mL fibrinogen equivalent units (FEU), and the traditional cut-off level for VTE exclusion was 500 ng/mL. Results VTE was diagnosed in 105 patients of the 1255 included patients (8.4%): 88 patients were diagnosed out of the 1082 patients referred for suspected PE and 27 out the 173 referred for suspected DVT. D-dimer levels were above 500 ng/mL in all patients with VTE and in 521 of the 1150 patients without VTE (45.3%). The test NPV was 100% as well as its sensitivity. If the overall test specificity was 54.7%, it significantly decreased in an age-dependent manner over 70 years, related to a high percentage of increased D-dimer levels in elderly patients, particularly in those above 80 years. Using age-adjusted cut-off levels, calculated by multiplying the patient's age by 10, induced a significantly improvement in test specificity, particularly in very old patients with an overall NPV=60.2% vs. 54.7% using the fixed cut-off value. The overall NPV remained high (99.9%), even if a 78 y-old female with a low PTP of PE would have been misdiagnosed as her D-dimer level (540 ng/mL) was above 500 ng/mL but below the age-adjusted cut-off value. Such an improvement in test performance was found both in patients with suspected PE and DVT (Table). As this increase in test specificity would have led to exclude VTE in a higher percentage of patients in the studied population, we evaluated the cost-effectiveness of that strategy, taking into account the local cost of D-dimer testing, angiography and Doppler US (16.20, 58.72, and 75.60 Euros respectively). In the case of suspected PE, the economic impact of the proposed diagnosis strategy was a decreased of 6.9% of total costs (45,023.4 vs. 48,356.4 Euros). In the case of DVT, the overall saving was 5.1% (9,909 vs. 10,438.2 Euros). If such an analysis was used in the US, where angiography and Doppler US were more expensive (648 and 226 US$ respectively), and D-dimer less costly (14 US$), the cost savings would have been even higher (-11.0% for PE, and -6.3% for DVT). Conclusions The use age-adjusted cut-off levels for D-dimer, in patients aged over 50 years old, leaded to a significant increase in the test specificity, but correlatively to slightly decreased NPV and sensitivity, as some patients with D-dimer levels above 500 ng/mL but below the age-adjusted cut-off value could be misdiagnosed. However such a strategy was found to be safe in our studied populations, as the NPV remained high (99.9%), and cost-effective. Table Table. Disclosures No relevant conflicts of interest to declare.

We developed a confidence interval-(CI) assessing model in multivariable normal tissue complication probability (NTCP) modeling for predicting radiation-induced liver disease (RILD) in primary liver cancer patients using clinical and dosimetric data. Both the mean NTCP and difference in the mean NTCP (ΔNTCP) between two treatment plans of different radiotherapy modalities were further evaluated and their CIs were assessed. Clinical data were retrospectively reviewed in 322 patients with hepatocellular carcinoma (n = 215) and intrahepatic cholangiocarcinoma (n = 107) treated with photon therapy. Dose–volume histograms of normal liver were reduced to mean liver dose (MLD) based on the fraction size-adjusted equivalent uniform dose. The most predictive variables were used to build the model based on multivariable logistic regression analysis with bootstrapping. Internal validation was performed using the cross-validation leave-one-out method. Both the mean NTCP and the mean ΔNTCP with 95% CIs were calculated from computationally generated multivariate random sets of NTCP model parameters using variance–covariance matrix information. RILD occurred in 108/322 patients (33.5%). The NTCP model with three clinical and one dosimetric parameter (tumor type, Child–Pugh class, hepatitis infection status and MLD) was most predictive, with an area under the receiver operative characteristics curve (AUC) of 0.79 (95% CI 0.74–0.84). In eight clinical subgroups based on the three clinical parameters, both the mean NTCP and the mean ΔNTCP with 95% CIs were able to be estimated computationally. The multivariable NTCP model with the assessment of 95% CIs has potential to improve the reliability of the NTCP model-based approach to select the appropriate radiotherapy modality for each patient.

Purpose Stereotactic body radiation therapy (SBRT) and stereotactic ablative body radiation therapy is being increasingly used for pancreatic cancer (PCa), particularly in patients with locally advanced and borderline resectable disease. A wide variety of dose fractionation schemes have been reported in the literature. This HyTEC review uses tumor control probability models to evaluate the comparative effectiveness of the various SBRT treatment regimens used in the treatment of patients with localized PCa. Methods and Materials A PubMed search was performed to review the published literature on the use of hypofractionated SBRT (usually in 1-5 fractions) for PCa in various clinical scenarios (eg, preoperative [neoadjuvant], borderline resectable, and locally advanced PCa). The linear quadratic model with α/β= 10 Gy was used to address differences in fractionation. Logistic tumor control probability models were generated using maximum likelihood parameter fitting. Results After converting to 3-fraction equivalent doses, the pooled reported data and associated models suggests that 1-year local control (LC) without surgery is ≈79% to 86% after the equivalent of 30 to 36 Gy in 3 fractions, showing a dose response in the range of 25 to 36 Gy, and decreasing to less than 70% 1-year LC at doses below 24 Gy in 3 fractions. The 33 Gy in 5 fraction regimen (Alliance A021501) corresponds to 28.2 Gy in 3 fractions, for which the HyTEC pooled model had 77% 1-year LC without surgery. Above an equivalent dose of 28 Gy in 3 fractions, with margin-negative resection the 1-year LC exceeded 90%. Conclusions Pooled analyses of reported tumor control probabilities for commonly used SBRT dose-fractionation schedules for PCa suggests a dose response. These findings should be viewed with caution given the challenges and limitations of this review. Additional data are needed to better understand the dose or fractionation-response of SBRT for PCa.

Purpose: This study was conducted to evaluate the effectiveness of primary tumor resection (PTR) in asymptomatic colorectal cancer (CRC) patients with unresectable metastases using the inverse probability of treatment weighting (IPTW) method to minimize selection bias.Methods: We selected 146 patients diagnosed with stage IV CRC with unresectable metastasis between 2001 and 2018 from our institutional database. In a multivariate logistic regression model using the patients’ baseline covariates associated with PTR, we applied the IPTW method based on a propensity score and performed a weighted Cox proportional regression analysis to estimate survival according to PTR.Results: Upfront PTR was performed in 98 patients, and no significant differences in baseline factors were detected. The upweighted median survival of the PTR group was 18 months and that of the non-PTR group was 15 months (P = 0.15). After applying the IPTW, the PTR was still insignificant in the univariate Cox regression (hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.5–1.21). However, in the multivariate weighted Cox regression with adjustment for other covariates, the PTR showed a significantly decreased risk of cancer-related death (HR, 0.61; 95% CI, 0.40–0.94).Conclusion: In this study, we showed that asymptomatic CRC patients with unresectable metastases could gain a survival benefit from upfront PTR by analysis with the IPTW method. However, randomized controlled trials are mandatory.

The American Society of Hematology and American College of Chest Physicians heparin-induced thrombocytopenia guidelines recommend calculation of a pretest probability score prior to performing laboratory testing, and the 4Ts score is commonly used. Inter-rater agreement of the 4Ts score has been evaluated, but limited data are available regarding the reliability of the 4Ts score when performed by nonexpert clinicians. The purpose of this study was to Compare 4Ts scores calculated by medical teams to an expert. A single-center observational study was conducted in patients evaluated for heparin-induced thrombocytopenia over 24 months. The primary outcome was difference in mean 4Ts score calculated by the medical team compared with an expert. Secondary outcomes included inter-rater agreement in risk category assignment and the negative predictive value (NPV) of the 4Ts score. The mean total 4Ts score was significantly higher when calculated by the medical team compared with expert (4.16 ± 1.41 versus 3.42 ± 1.53; P < 0.001). There was slight agreement in risk category assignment (Cohen κ coefficient = 0.164; P = 0.005). The NPV of the 4Ts score was 0.949 (95% confidence interval 0.891-1.000) when calculated by the medical team and 0.927 (95% confidence interval 0.869-0.984) when calculated by expert. Total 4Ts scores calculated by the medical team were significantly higher with only slight inter-rater agreement compared with expert. The NPV of the 4Ts score when calculated by nonexperts may be lower than previously reported. The recommendation to forgo laboratory testing for low 4Ts score patients may need to be revisited.

Background Analyses of the effectiveness of infectious disease control interventions often rely on dynamic transmission models to simulate intervention effects. We aim to understand how the choice of network or compartmental model can influence estimates of intervention effectiveness in the short and long term for an endemic disease with susceptible and infected states in which infection, once contracted, is lifelong. Methods We consider 4 disease models with different permutations of socially connected network versus unstructured contact (mass-action mixing) model and heterogeneous versus homogeneous disease risk. The models have susceptible and infected populations calibrated to the same long-term equilibrium disease prevalence. We consider a simple intervention with varying levels of coverage and efficacy that reduces transmission probabilities. We measure the rate of prevalence decline over the first 365 d after the intervention, long-term equilibrium prevalence, and long-term effective reproduction ratio at equilibrium. Results Prevalence declined up to 10% faster in homogeneous risk models than heterogeneous risk models. When the disease was not eradicated, the long-term equilibrium disease prevalence was higher in mass-action mixing models than in network models by 40% or more. This difference in long-term equilibrium prevalence between network versus mass-action mixing models was greater than that of heterogeneous versus homogeneous risk models (less than 30%); network models tended to have higher effective reproduction ratios than mass-action mixing models for given combinations of intervention coverage and efficacy. Conclusions For interventions with high efficacy and coverage, mass-action mixing models could provide a sufficient estimate of effectiveness, whereas for interventions with low efficacy and coverage, or interventions in which outcomes are measured over short time horizons, predictions from network and mass-action models diverge, highlighting the importance of sensitivity analyses on model structure. Highlights • We calibrate 4 models—socially connected network versus unstructured contact (mass-action mixing) model and heterogeneous versus homogeneous disease risk—to 10% preintervention disease prevalence. • We measure the short- and long-term intervention effectiveness of all models using the rate of prevalence decline, long-term equilibrium disease prevalence, and effective reproduction ratio. • Generally, in the short term, prevalence declined faster in the homogeneous risk models than in the heterogeneous risk models. • Generally, in the long term, equilibrium disease prevalence was higher in the mass-action mixing models than in the network models, and the effective reproduction ratio was higher in network models than in the mass-action mixing models.

Everyday clinical decisions are based on “statistically” significant or non-significant results, with an exaggerated credit given to statistics. This is due to the interesting dichotomy that statistics respond to: to perform a surgery or not, to give a treatment or not. However, statistics rely on the law of probability and cannot provide definite judgments. This manuscript aims to highlight the statistical flaws in clinical practice from a simple perspective for surgeons.

Background: The optimal choice of endoscopic method between endoscopic sphincterotomy (EST), endoscopic papillary large balloon dilation (EPLBD), and EST plus EPLBD (endoscopic sphincterotomy and l...

OBJECTIVE Decisions in glioblastoma surgery are often guided by presumed eloquence of the tumor location. The authors introduce the “expected residual tumor volume” (eRV) and the “expected resectability index” (eRI) based on previous decisions aggregated in resection probability maps. The diagnostic accuracy of eRV and eRI to predict biopsy decisions, resectability, functional outcome, and survival was determined. METHODS Consecutive patients with first-time glioblastoma surgery in 2012–2013 were included from 12 hospitals. The eRV was calculated from the preoperative MR images of each patient using a resection probability map, and the eRI was derived from the tumor volume. As reference, Sawaya’s tumor location eloquence grades (EGs) were classified. Resectability was measured as observed extent of resection (EOR) and residual volume, and functional outcome as change in Karnofsky Performance Scale score. Receiver operating characteristic curves and multivariable logistic regression were applied. RESULTS Of 915 patients, 674 (74%) underwent a resection with a median EOR of 97%, functional improvement in 71 (8%), functional decline in 78 (9%), and median survival of 12.8 months. The eRI and eRV identified biopsies and EORs of at least 80%, 90%, or 98% better than EG. The eRV and eRI predicted observed residual volumes under 10, 5, and 1 ml better than EG. The eRV, eRI, and EG had low diagnostic accuracy for functional outcome changes. Higher eRV and lower eRI were strongly associated with shorter survival, independent of known prognostic factors. CONCLUSIONS The eRV and eRI predict biopsy decisions, resectability, and survival better than eloquence grading and may be useful preoperative indices to support surgical decisions.