Impaired contextual modulation of memories in PTSD: an fMRI and psychophysiological study of extinction retention and fear renewal

Post-traumatic stress disorder (PTSD) patients display pervasive fear memories, expressed indiscriminately. Proposed mechanisms include enhanced fear learning and impaired extinction or extinction recall. Documented extinction recall deficits and failure to use safety signals could result from general failure to use contextual information, a hippocampus-dependent process. This can be probed by adding a renewal phase to standard conditioning and extinction paradigms. Human subjects with PTSD and combat controls were conditioned (skin conductance response), extinguished, and tested for extinction retention and renewal in a scanner (fMRI). Fear conditioning (light paired with shock) occurred in one context, followed by extinction in another, to create danger and safety contexts. The next day, the extinguished conditioned stimulus (CS+E) was re-presented to assess extinction recall (safety context) and fear renewal (danger context). PTSD patients showed impaired extinction recall, with increased skin conductance and heightened amygdala activity to the extinguished CS+ in the safety context. However, they also showed impaired fear renewal; in the danger context, they had less skin conductance response to CS+E and lower activity in amygdala and ventral-medial prefrontal cortex compared with combat controls. Control subjects displayed appropriate contextual modulation of memory recall, with extinction (safety) memory prevailing in the safety context, and fear memory prevailing in the danger context. PTSD patients could not use safety context to sustain suppression of extinguished fear memory, but they also less effectively used danger context to enhance fear. They did not display globally enhanced fear expression, but rather showed a globally diminished capacity to use contextual information to modulate fear expression

Known and unknown requirements in healthcare

We report experience in requirements elicitation of domain knowledge from experts in clinical and cognitive neurosciences. The elicitation target was a causal model for early signs of dementia indicated by changes in user behaviour and errors apparent in logs of computer activity. A Delphi-style process consisting of workshops with experts followed by a questionnaire was adopted. The paper describes how the elicitation process had to be adapted to deal with problems encountered in terminology and limited consensus among the experts. In spite of the difficulties encountered, a partial causal model of user behavioural pathologies and errors was elicited. This informed requirements for configuring data- and text-mining tools to search for the specific data patterns. Lessons learned for elicitation from experts are presented, and the implications for requirements are discussed as “unknown unknowns”, as well as configuration requirements for directing data-/text-mining tools towards refining awareness requirements in healthcare applications

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer

When do ecosystem services depend on rare species?

Conservation aims to preserve species and ecosystem services. If rare species contribute little to ecosystem services, yet are those most in need of preservation, tradeoffs may exist for these contrasting objectives. However, little attention has focused on identifying how, when, and where rare species contribute to ecosystem services and at what scales. Here, we review distinct ways that ecosystem services can positively depend on the presence, abundance, disproportionate contribution or, counterintuitively, the scarcity of rare species. By contrast, ecosystem services are less likely to depend on rare species that do not have a unique role in any service or become abundant enough to contribute substantially. We propose a research agenda to identify when rare species may contribute significantly to services

From PIM1 to PI3Kδ via GSK3β: Target Hopping through the Kinome

Selective inhibitors of phosphoinositide 3-kinase delta are of interest for the treatment of inflammatory diseases. Initial optimization of a 3-substituted indazole hit compound targeting the kinase PIM1 focused on improving selectivity over GSK3β through consideration of differences in the ATP binding pockets. Continued kinase cross-screening showed PI3Kδ activity in a series of 4,6-disubstituted indazole compounds, and subsequent structure–activity relationship exploration led to the discovery of an indole-containing lead compound as a potent PI3Kδ inhibitor with selectivity over the other PI3K isoforms

A Multicenter Prospective Analysis of Pediatric Trauma Activation Criteria Routinely Used in Addition to the Six Criteria of the American College of Surgeons

BACKGROUND The American College of Surgeons has defined six minimum activation criteria (ACS-6) for the highest level of trauma activations at trauma centers. The verification criteria also allow for the inclusion of additional criteria at the institution’s discretion. The purpose of this prospective multicenter study was to evaluate the ACS-6 as well as commonly used activation criteria to evaluate overtriage and undertriage rates for pediatric trauma team activation. METHODS Data were prospectively collected at nine pediatric trauma centers to examine 29 commonly used activation criteria. Patients meeting any of these criteria were evaluated for the use of high-level trauma resuscitation resources according to an expert consensus list. Patients requiring a resource but not meeting any activation criteria were included to evaluate undertriage rates. RESULTS During the 1-year study, a total of 656 patients were enrolled with a mean age of 8 years, a median Injury Severity Score of 14, and mortality of 11%. Using all criteria, 55% of patients would have been overtriaged and 9% would have been undertriaged. If only the ACS-6 were used, 24% of patients would have been overtriaged and 16% would have been undertriaged. Among activation criteria with more than 10 patients, those most predictive of using a high-level resource were a gunshot wound to the abdomen (92%), blood given before arrival (83%), traumatic arrest (83%), tachycardia/poor perfusion (83%), and age-appropriate hypotension (77%). The addition of tachycardia/poor perfusion and pretrauma center resuscitation with greater than 40 mL/kg results in eight criteria with an overtriage of 39% and an undertriage of 10.5%. CONCLUSION The ACS-6 provides a reliable overtriage or undertriage rate for pediatric patients. The inclusion of two additional criteria can further improve these rates while maintianing a simplified triage list for children. LEVEL OF EVIDENCE Therapeutic study, level III