Fatigue and vigilance in medical experts detecting breast cancer.

An abundance of laboratory-based experiments has described a vigilance decrement of reducing accuracy to detect targets with time on task, but there are few real-world studies, none of which have previously controlled the environment to control for bias. We describe accuracy in clinical practice for 360 experts who examined >1 million women's mammograms for signs of cancer, whilst controlling for potential biases. The vigilance decrement pattern was not observed. Instead, test accuracy improved over time, through a reduction in false alarms and an increase in speed, with no significant change in sensitivity. The multiple-decision model explains why experts miss targets in low prevalence settings through a change in decision threshold and search quit threshold and propose it should be adapted to explain these observed patterns of accuracy with time on task. What is typically thought of as standard and robust research findings in controlled laboratory settings may not directly apply to real-world environments and instead large, controlled studies in relevant environments are needed.

Optimised Multi-Channel Transcranial Direct Current Stimulation (MtDCS) Reveals Differential Involvement of the Right-Ventrolateral Prefrontal Cortex (rVLPFC) and Insular Complex in those Predisposed to Aberrant Experiences.

Research has shown a prominent role for cortical hyperexcitability underlying aberrant perceptions, hallucinations, and distortions in human conscious experience - even in neurotypical groups. The rVLPFC has been identified as an important structure in mediating cognitive affective states / feeling conscious states. The current study examined the involvement of the rVLPFC in mediating cognitive affective states in those predisposed to aberrant experiences in the neurotypical population. Participants completed two trait-based measures: (i) the Cortical Hyperexcitability Index_II (CHi_II, a proxy measure of cortical hyperexcitability) and (ii) two factors from the Cambridge Depersonalisation Scale (CDS). An optimised 7-channel MtDCS montage for stimulation conditions (Anodal, Cathodal and Sham) was created targeting the rVLPFC in a single-blind study. At the end of each stimulation session, participants completed a body-threat task (BTAB) while skin conductance responses (SCRs) and psychological responses were recorded. Participants with signs of increasing cortical hyperexcitability showed significant suppression of SCRs in the Cathodal stimulation relative to the Anodal and sSham conditions. Those high on the trait-based measures of depersonalisation-like experiences failed to show reliable effects. Collectively, the findings suggest that baseline brain states can mediate the effects of neurostimulation which would be missed via sample level averaging and without appropriate measures for stratifying individual differences.

Outcome of primary mediastinal large B-cell lymphoma using R-CHOP: impact of a PET-adapted approach.

Cure rates for primary mediastinal large B-cell lymphoma (PMBCL) have improved with the integration of rituximab. However, the type of primary therapy and role of radiotherapy (RT) remains ill-defined. Herein, we evaluated the outcome of PMBCL primarily treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and the impact of an end-of-treatment (EOT) 18F-fluorodeoxyglucose positron emission tomography (PET) scan to guide consolidative RT. Patients ≥18 years of age with PMBCL treated with curative intent rituximab-chemotherapy were identified. Prior to 2005, patients were recommended to receive R-CHOP + RT (RT era). Beginning in 2005, EOT PET was used to guide RT and only those with a PET-positive scan received RT (PET era). In total, 159 patients were identified, 94% were treated with R-CHOP and 44% received RT (78% in RT era, 28% in PET era). The 5-year time to progression (TTP) and overall survival (OS) for the entire cohort were 80% and 89%, respectively, similar across treatment eras. Overall, 10% had refractory disease. In total, 113 patients had an EOT PET scan: 63% negative and 37% positive with a 5-year TTP of 90% vs 71% and 5-year OS of 97% vs 88%, respectively. For those with Deauville (D)-scored PET scans (n = 103), the 5-year TTP for PET-negative cases by Deauville criteria (D1-D3, DX) was 91%, with inferior outcomes for D5 vs D4 (5-year TTP 33% vs 87%, P = .0002). Outcomes for PMBCL treated with RCHOP are favorable and use of a PET-adapted approach reduces RT in the majority of patients. A small proportion have refractory disease and may benefit from an alternate treatment.

Pregnancy outcomes in the omalizumab pregnancy registry and a disease-matched comparator cohort.

BACKGROUND: The Observational Study of the Use and Safety of Xolair (omalizumab) during Pregnancy (EXPECT) pregnancy registry was a prospective observational study established in 2006 to evaluate perinatal outcomes in pregnant women exposed to omalizumab and their infants. OBJECTIVE: This analysis compares EXPECT outcomes with those from a disease-matched population of pregnant women not treated with omalizumab. Data from a substudy of platelet counts among newborns are also presented. METHODS: The EXPECT study enrolled 250 women with asthma exposed to omalizumab during pregnancy. The disease-matched external comparator cohort of women with moderate-to-severe asthma (n = 1153), termed the Quebec External Comparator Cohort (QECC), was created by using data from health care databases in Quebec, Canada. Outcome estimates were age adjusted based on the maternal age distribution of the EXPECT study. RESULTS: Among singleton infants in the EXPECT study, the prevalence of major congenital anomalies was 8.1%, which was similar to the 8.9% seen in the QECC. In the EXPECT study 99.1% of pregnancies resulted in live births, which was similar to 99.3% in the QECC. Premature birth was identified in 15.0% of EXPECT infants and 11.3% in the QECC. Small for gestational age was identified in 9.7% of EXPECT infants and 15.8% in the QECC. CONCLUSION: There was no evidence of an increased risk of major congenital anomalies among pregnant women exposed to omalizumab compared with a disease-matched unexposed cohort. Given the observational nature of this registry, however, an absence of increased risk with omalizumab cannot be definitively established.

Validation of a simplified international prognostic score (IPS-3) in patients with advanced-stage classic Hodgkin lymphoma.

A novel prognostic score (IPS-3), comprised of only three of the seven IPS-7 indicators (age ≥45, stage IV, haemoglobin <105 g/l), was recently proposed as a simplified model for advanced-stage classic Hodgkin lymphoma (cHL). We aimed to validate this model in advanced-stage cHL patients treated with doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) in British Columbia. The estimated five-year freedom from progression (FFP) for scores of 0, 1, 2 and 3 were very similar to the original report at 84%, 76%, 72% and 68% respectively. The IPS-3 score is highly reproducible in this independent dataset and its simplicity makes it appealing for everyday clinical practice.

Seen this scene? Scene recognition in the reaction-time Concealed Information Test.

Detecting a suspect's recognition of a crime scene (e.g., a burgled room or a location visited for criminal activity) can be of great value during criminal investigations. Although it is established that the Reaction-Time Concealed Information Test (RT-CIT) can determine whether a suspect recognizes crime-related objects, no research has tested whether this capability extends to the recognition of scenes. In Experiment 1, participants were given an autobiographic scene-based RT-CIT. In Experiment 2, participants watched a mock crime video before completing an RT-CIT that included both scenes and objects. In Experiment 3, participants completed an autobiographic scene-based RT-CIT, with half instructed to perform a physical countermeasure. Overall, the findings showed that an equivalent RT-CIT effect can be found with both scene and object stimuli and that RT-CITs may not be susceptible to physical countermeasure strategies, thereby increasing its real-world applicability.

Women's occupational exposure to polycyclic aromatic hydrocarbons and risk of breast cancer.

OBJECTIVE: To estimate the association between occupational polycyclic aromatic hydrocarbon (PAH) exposure and female breast cancer. METHODS: Lifetime work histories for 1130 cases and 1169 controls from British Columbia and Ontario (Canada) were assessed for PAH exposure using a job-exposure matrix based on compliance measurements obtained during US Occupational Safety and Health Administration workplace safety inspections. RESULTS: Exposure to any level of PAHs was associated with an increased risk of breast cancer (OR=1.32, 95% CI: 1.10 to 1.59), as was duration at high PAH exposure (for >7.4 years: OR=1.45, 95% CI: 1.10 to 1.91; ptrend=0.01), compared with women who were never exposed. Increased risk of breast cancer was most strongly associated with prolonged duration at high occupational PAH exposure among women with a family history of breast cancer (for >7.4 years: OR=2.79, 95% CI: 1.25 to 6.24; ptrend<0.01). CONCLUSIONS: Our study suggests that prolonged occupational exposure to PAH may increase breast cancer risk, especially among women with a family history of breast cancer.

The depersonalized brain: New evidence supporting a distinction between depersonalization and derealization from discrete patterns of autonomic suppression observed in a non-clinical sample.

Depersonalization and Derealization are characterised by feelings of detachment from one's bodily self/surroundings and a general emotional numbness. We explored predisposition to trait-based experiences of depersonalization/derealization-type experiences and autonomic arousal toward simulated body-threats, which were delivered to the participant's own body (i.e. Self) and when observed being delivered to another individual (i.e. Other). Ninety participants took part in an "Implied Body-Threat Illusion" task (Dewe, Watson, & Braithwaite, 2016) and autonomic arousal was recorded via standardised skin conductance responses and finger temperature. Autonomic suppression in response to threats delivered to the Self correlated with increases in trait-based depersonalization-type experiences. In contrast, autonomic suppression for threats delivered to Others correlated with trait-based derealization-like experiences. Body-temperature and anticipatory arousal did not correlate reliably with predisposition to depersonalization- or derealization-type experiences. The theoretical implications of these findings are discussed in terms of a fronto-limbic autonomic suppression mechanism.

Where the item still rules supreme: Time-based selection, enumeration, pre-attentive processing and the target template?

I propose that there remains a central role for the item (or its equivalent) in a wider range of search and search-related tasks/functions than might be conveyed by the article. I consider the functional relationship between the framework and some aspects of previous theories, and suggest some challenges that the new framework might encounter.

Is the ANS linked to mathematics performance?

Leibovich et al. argue persuasively that researchers should not assume that approximate number system (ANS) tasks harness an innate sense of number. However, some studies have reported a causal link between ANS tasks and mathematics performance, implicating the ANS in the development of numerical skills. Here we report a p-curve analysis, which indicates that these experimental studies do not contain evidential value.

Sedentary work and the risk of breast cancer in premenopausal and postmenopausal women: a pooled analysis of two case-control studies.

OBJECTIVES: There is limited research on the association between sedentary behaviour and breast cancer risk, particularly whether sedentary behaviour is differentially associated with premenopausal and postmenopausal breast cancer. We pooled data from 2 case-control studies from Australia and Canada to investigate this association. METHODS: This pooled analysis included 1762 incident breast cancer cases and 2532 controls. Participants in both studies completed a lifetime occupational history and self-rated occupational physical activity level. A job-exposure matrix (JEM) was also applied to job titles to assess sedentary work. Logistic regression analyses (6 pooled and 12 study-specific) were conducted to estimate associations between both self-reported and JEM-assessed sedentary work and breast cancer risk among premenopausal and postmenopausal women. RESULTS: No association was observed in the 6 pooled analyses, and 10 of the study-specific analyses also showed null results. 2 study-specific analyses provided inconsistent and contradictory results, with 1 showing statistically significant increased risk of breast cancer for self-reported sedentary work among premenopausal women cancer in the Canadian study, and the other a non-significant inverse association between JEM-assessed sedentary work and breast cancer risk among postmenopausal women in the Australian study. CONCLUSIONS: While a suggestion of increased risk was seen for premenopausal women in the Canadian study when using the self-reported measure, overall this pooled study does not provide evidence that sedentary work is associated with breast cancer risk.

Uncomfortably numb: new evidence for suppressed emotional reactivity in response to body-threats in those predisposed to sub-clinical dissociative experiences.

INTRODUCTION: Depersonalisation and derealisation disorders refer to feelings of detachment and dissociation from one's "self" or surroundings. A reduced sense of self (or "presence") and emotional "numbness" is thought to be mediated by aberrant emotional processing due to biases in self-referent multi-sensory integration. This emotional "numbing" is often accompanied by suppressed autonomic arousal to emotionally salient stimuli. METHODS: 118 participants completed the Cambridge Depersonalisation scale [Sierra, & Berrios, 2000. The Cambridge Depersonalisation Scale: A new instrument for the measurement of depersonalisation. Psychiatry Research, 93, 153-164)] as an index of dissociative anomalous experience. Participants took part in a novel "Implied Body-Threat Illusion" task; a pantomimed injection procedure conducted directly onto their real body (hand). Objective psychophysiological data were recorded via standardised threat-related skin conductance responses and finger temperature measures. RESULTS: Individuals predisposed to depersonalisation/derealisation revealed suppressed skin conductance responses towards the pantomimed body-threat. Although the task revealed a reliable reduction in finger temperature as a fear response, this reduction was not reliably associated with measures of dissociative experience. CONCLUSIONS: The present findings significantly extend previous research by revealing emotional suppression via a more direct body-threat task, even for sub-clinical groups. The findings are discussed within probabilistic and predictive coding frameworks of multi-sensory integration underlying a coherent sense of self.

The Cortical Hyperexcitability Index (CHi): a new measure for quantifying correlates of visually driven cortical hyperexcitability.

INTRODUCTION: Aberrations of visual experience, including visual hallucinations and visual distortions, are known to be associated with increased cortical hyperexcitability. As a consequence, the presence, intensity and frequency of certain experiences may well be indicative of an underlying increase in cortical hyperexcitability. METHODS: The current study presents a new proxy measure of cortical hyperexcitability, the Cortical Hyperexcitability Index (CHi). Two hundred and fifty healthy participants completed the CHi with the results subjected to exploratory factor analysis (EFA). RESULTS: The EFA revealed a three-factor model as the most parsimonious solution. The three factors were defined as: (1) heightened visual sensitivity and discomfort; (2) negative aura-type visual aberrations; and (3) positive aura-type visual aberrations. The identification of three factors suggests that multiple mechanisms underlie the notion of cortical hyperexcitability, providing researchers with new and greater precision in delineating these underlying features. CONCLUSIONS: The factorial structure of the CHi and the increased precision could aid the interpretation of findings from neuroscientific (i.e., brain imaging/stimulation) examinations of cortical processes underlying aberrant perceptions across a host of clinical, neurological and pathological conditions. As a consequence, the CHi is a useful and comprehensive proxy measure of cortical hyperexcitability with considerable scientific and clinical utility.

Statistical Modeling of Occupational Exposure to Polycyclic Aromatic Hydrocarbons Using OSHA Data.

Polycyclic aromatic hydrocarbons (PAHs) are a group of pollutants with multiple variants classified as carcinogenic. The Occupational Safety and Health Administration (OSHA) provided access to two PAH exposure databanks of United States workplace compliance testing data collected between 1979 and 2010. Mixed-effects logistic models were used to predict the exceedance fraction (EF), i.e., the probability of exceeding OSHA's Permissible Exposure Limit (PEL = 0.2 mg/m3) for PAHs based on industry and occupation. Measurements of coal tar pitch volatiles were used as a surrogate for PAHs. Time, databank, occupation, and industry were included as fixed-effects while an identifier for the compliance inspection number was included as a random effect. Analyses involved 2,509 full-shift personal measurements. Results showed that the majority of industries had an estimated EF < 0.5, although several industries, including Standardized Industry Classification codes 1623 (Water, Sewer, Pipeline, and Communication and Powerline Construction), 1711 (Plumbing, Heating, and Air-Conditioning), 2824 (Manmade Organic Fibres), 3496 (Misc. Fabricated Wire products), and 5812 (Eating Places), and Major group's 13 (Oil and Gas Extraction) and 30 (Rubber and Miscellaneous Plastic Products), were estimated to have more than an 80% likelihood of exceeding the PEL. There was an inverse temporal trend of exceeding the PEL, with lower risk in most recent years, albeit not statistically significant. Similar results were shown when incorporating occupation, but varied depending on the occupation as the majority of industries predicted at the administrative level, e.g., managers, had an estimated EF < 0.5 while at the minimally skilled/laborer level there was a substantial increase in the estimated EF. These statistical models allow the prediction of PAH exposure risk through individual occupational histories and will be used to create a job-exposure matrix for use in a population-based case-control study exploring PAH exposure and breast cancer risk.

Cytochrome P450 3A and P-glycoprotein drug-drug interactions with voclosporin.

AIMS: Voclosporin is a novel calcineurin inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. Pharmacokinetic drug interactions between voclosporin and a CYP3A inhibitor, inducer and substrate and a P-glycoprotein inhibitor and substrate were evaluated. METHODS: Voclosporin 0.4 mg kg(-1) was administered to 24 subjects in each of five studies, as follows: every 12 h (Q12H) alone and concomitantly with ketoconazole 400 mg once daily (QD); single dose before and single dose after rifampin 600 mg QD; Q12H where midazolam 7.5 mg was administered as a single dose alone before voclosporin and with last the dose of voclosporin; Q12H alone and concomitantly with verapamil 80 mg every 8 h; and Q12H with digoxin 0.25 mg QD. The noncompartmental pharmacokinetic parameters maximal concentration (Cmax ) and area under the concentration-time curve (AUC) were obtained, and geometric least squares mean ratios and 90% confidence intervals were evaluated. RESULTS: Ketoconazole increased voclosporin Cmax (6.4-fold) and AUC (18-fold); rifampin reduced voclosporin AUC (0.9-fold); voclosporin did not change exposure of midazolam or α-hydroxy-midazolam; verapamil increased voclosporin Cmax (2.1-fold) and AUC (2.7-fold); and voclosporin increased digoxin Cmax (0.5-fold), AUC (0.25-fold) and urinary excretion (0.2-fold). CONCLUSIONS: Administration of voclosporin concomitantly with strong inhibitors and inducers of CYP3A resulted in increased and decreased exposures, respectively, and should be considered contraindicated. Drug-drug interactions involving voclosporin and CYP3A substrates are not expected. Administration of voclosporin concomitantly with inhibitors and substrates of P-glycoprotein resulted in increased voclosporin and substrate exposures, respectively. Appropriate concentration and safety monitoring is recommended with co-administration of voclosporin and P-glycoprotein substrates and inhibitors.

Beyond crosswalks: reliability of exposure assessment following automated coding of free-text job descriptions for occupational epidemiology.

Epidemiologists typically collect narrative descriptions of occupational histories because these are less prone than self-reported exposures to recall bias of exposure to a specific hazard. However, the task of coding these narratives can be daunting and prohibitively time-consuming in some settings. The aim of this manuscript is to evaluate the performance of a computer algorithm to translate the narrative description of occupational codes into standard classification of jobs (2010 Standard Occupational Classification) in an epidemiological context. The fundamental question we address is whether exposure assignment resulting from manual (presumed gold standard) coding of the narratives is materially different from that arising from the application of automated coding. We pursued our work through three motivating examples: assessment of physical demands in Women's Health Initiative observational study, evaluation of predictors of exposure to coal tar pitch volatiles in the US Occupational Safety and Health Administration's (OSHA) Integrated Management Information System, and assessment of exposure to agents known to cause occupational asthma in a pregnancy cohort. In these diverse settings, we demonstrate that automated coding of occupations results in assignment of exposures that are in reasonable agreement with results that can be obtained through manual coding. The correlation between physical demand scores based on manual and automated job classification schemes was reasonable (r = 0.5). The agreement between predictive probability of exceeding the OSHA's permissible exposure level for polycyclic aromatic hydrocarbons, using coal tar pitch volatiles as a surrogate, based on manual and automated coding of jobs was modest (Kendall rank correlation = 0.29). In the case of binary assignment of exposure to asthmagens, we observed that fair to excellent agreement in classifications can be reached, depending on presence of ambiguity in assigned job classification (κ = 0.5-0.8). Thus, the success of automated coding appears to depend on the setting and type of exposure that is being assessed. Our overall recommendation is that automated translation of short narrative descriptions of jobs for exposure assessment is feasible in some settings and essential for large cohorts, especially if combined with manual coding to both assess reliability of coding and to further refine the coding algorithm.

How should human-driven and autonomous vehicles behave at a zebra crossing? Determining acceptable stopping distances and setting-off times.

Autonomous vehicles (AVs) offer a range of substantial safety and mobility benefits. However, successful deployment of AVs will involve interacting with other road users, such as pedestrians and other human-driven vehicles. While previous research has focused on factors that influence perceptions of AVs, less work has addressed how specific interactions with other road users influence acceptability from multiple perspectives. Accordingly, we conducted six studies examining how vehicles, either human-driven or autonomous, should behave at a zebra crossing in terms of stopping distance from the crossing, how long a vehicle should wait before setting off, and the influence of traffic context. Using computer-generated videos we found that: the optimal stopping distance was just before the stop line; participants were generally accepting of a vehicle that waited until a pedestrian had fully cleared the crossing before setting off, and sometime earlier; the presence of other vehicles, context and observer viewpoint can affect judgements of vehicle behaviour; autonomous vehicles were judged more harshly than human drivers with learner drivers judged less harshly in some circumstances, and that vehicle size appeared to have little influence over the acceptability of vehicle behaviours. The results are important for informing the design of autonomous vehicle manoeuvres from the viewpoints of vehicle occupants and other road users.

A regional interdependence model of musculoskeletal dysfunction: research, mechanisms, and clinical implications.

The term 'regional interdependence' or RI has recently been introduced into the vernacular of physical therapy and rehabilitation literature as a clinical model of musculoskeletal assessment and intervention. The underlying premise of this model is that seemingly unrelated impairments in remote anatomical regions of the body may contribute to and be associated with a patient's primary report of symptoms. The clinical implication of this premise is that interventions directed at one region of the body will often have effects at remote and seeming unrelated areas. The formalized concept of RI is relatively new and was originally derived in an inductive manner from a variety of earlier publications and clinical observations. However, recent literature has provided additional support to the concept. The primary purpose of this article will be to further refine the operational definition for the concept of RI, examine supporting literature, discuss possible clinically relevant mechanisms, and conclude with a discussion of the implications of these findings on clinical practice and research.