Frequency of and predictors for withholding patient safety concerns among oncology staff: a survey study.

Speaking up about patient safety is vital to avoid errors reaching the patient and to improve a culture of safety. This study investigated the prevalence of non-speaking up despite concerns for safety and aimed to identify predictors for withholding voice among healthcare professionals (HCPs) in oncology. A self-administered questionnaire assessed safety concerns, speaking up beliefs and behaviours among nurses and doctors from nine oncology departments. Multiple regression analysis was used to identify predictors for withholding safety concerns. A total of 1013 HCPs returned the completed survey (response rate 65%). Safety concerns were common among responders. Fifty-four per cent reported to recognise their colleagues making potentially harmful errors at least sometimes. A majority of responders reported at least some episodes of withholding concerns about patient safety. Thirty-seven per cent said they remained silent at least once when they had information that might have helped prevent an incident. Respondents believed that a high level of interpersonal, communication and coping skills are necessary to speak up about patient safety issues at their workplace. Higher levels of perceived advocacy for patient safety and psychological safety significantly decreased the frequency of withholding voice. Remaining silent about safety concerns is a common phenomenon in oncology. Improved strategies are needed to support staff in effective communication and make cancer care safer.

Active surveillance for rheumatic heart disease in endemic regions: a systematic review and meta-analysis of prevalence among children and adolescents

BACKGROUND Rheumatic heart disease accounts for up to 250 000 premature deaths every year worldwide and can be regarded as a physical manifestation of poverty and social inequality. We aimed to estimate the prevalence of rheumatic heart disease in endemic countries as assessed by different screening modalities and as a function of age. METHODS We searched Medline, Embase, the Latin American and Caribbean System on Health Sciences Information, African Journals Online, and the Cochrane Database of Systematic Reviews for population-based studies published between Jan 1, 1993, and June 30, 2014, that reported on prevalence of rheumatic heart disease among children and adolescents (≥5 years to <18 years). We assessed prevalence of clinically silent and clinically manifest rheumatic heart disease in random effects meta-analyses according to screening modality and geographical region. We assessed the association between social inequality and rheumatic heart disease with the Gini coefficient. We used Poisson regression to analyse the effect of age on prevalence of rheumatic heart disease and estimated the incidence of rheumatic heart disease from prevalence data. FINDINGS We included 37 populations in the systematic review and meta-analysis. The pooled prevalence of rheumatic heart disease detected by cardiac auscultation was 2·9 per 1000 people (95% CI 1·7-5·0) and by echocardiography it was 12·9 per 1000 people (8·9-18·6), with substantial heterogeneity between individual reports for both screening modalities (I(2)=99·0% and 94·9%, respectively). We noted an association between social inequality expressed by the Gini coefficient and prevalence of rheumatic heart disease (p=0·0002). The prevalence of clinically silent rheumatic heart disease (21·1 per 1000 people, 95% CI 14·1-31·4) was about seven to eight times higher than that of clinically manifest disease (2·7 per 1000 people, 1·6-4·4). Prevalence progressively increased with advancing age, from 4·7 per 1000 people (95% CI 0·0-11·2) at age 5 years to 21·0 per 1000 people (6·8-35·1) at 16 years. The estimated incidence was 1·6 per 1000 people (0·8-2·3) and remained constant across age categories (range 2·5, 95% CI 1·3-3·7 in 5-year-old children to 1·7, 0·0-5·1 in 15-year-old adolescents). We noted no sex-related differences in prevalence (p=0·829). INTERPRETATION We found a high prevalence of rheumatic heart disease in endemic countries. Although a reduction in social inequalities represents the cornerstone of community-based prevention, the importance of early detection of silent rheumatic heart disease remains to be further assessed. FUNDING UBS Optimus Foundation.

Postnatal Notch1 activation induces T‑cell malignancy in conditional and inducible mouse models

The Notch1 signaling pathway is essential for hematopoietic development. However, the effects of postnatal activation of Notch1 signaling on hematopoietic system is not yet fully understood. We previously generated ZEG‑IC‑Notch1 transgenic mice that have a floxed β‑geo/stop signal between a CMV promoter and intracellular domain of Notch1 (IC‑Notch1). Constitutively active IC‑Notch1 is silent until the introduction of Cre recombinase. In this study, endothelial/hematopoietic specific expression of IC‑Notch1 in double transgenic ZEG‑IC‑Notch1/Tie2‑Cre embryos induced embryonic lethality at E9.5 with defects in vascular system but not in hematopoietic system. Inducible IC‑Notch1 expression in adult mice was achieved by using tetracycline regulated Cre system. The ZEG‑IC‑Notch1/Tie2‑tTA/tet‑O‑Cre triple transgenic mice survived embryonic development when maintained on tetracycline. Post‑natal withdrawal of tetracycline induced expression of IC‑Notch1 transgene in hematopoietic cells of adult mice. The triple transgenic mice displayed extensive T‑cell infiltration in multiple organs and T‑cell malignancy of lymph nodes. In addition, the protein levels of p53 and alternative reading frame (ARF) were decreased in lymphoma‑like neoplasms from the triple transgenic mice while their mRNA expression remained unchanged, suggesting that IC‑Notch1 might repress ARF‑p53 pathway by a post‑transcriptional mechanism. This study demonstrated that activation of constitutive Notch1 signaling after embryonic development alters adult hematopoiesis and induces T‑cell malignancy.

Violence-related PTSD and neural activation when seeing emotionally charged male-female interactions.

Post-traumatic stress disorder (PTSD) is a disorder that involves impaired regulation of the fear response to traumatic reminders. This study tested how women with male-perpetrated interpersonal violence-related PTSD (IPV-PTSD) differed in their brain activation from healthy controls (HC) when exposed to scenes of male-female interaction of differing emotional content. Sixteen women with symptoms of IPV-PTSD and 19 HC participated in this study. During magnetic resonance imaging, participants watched a stimulus protocol of 23 different 20 s silent epochs of male-female interactions taken from feature films, which were neutral, menacing or prosocial. IPV-PTSD participants compared with HC showed (i) greater dorsomedial prefrontal cortex (dmPFC) and dorsolateral prefrontal cortex (dlPFC) activation in response to menacing vs prosocial scenes and (ii) greater anterior cingulate cortex (ACC), right hippocampus activation and lower ventromedial prefrontal cortex (vmPFC) activty in response to emotional vs neutral scenes. The fact that IPV-PTSD participants compared with HC showed lower activity of the ventral ACC during emotionally charged scenes regardless of the valence of the scenes suggests that impaired social perception among IPV-PTSD patients transcends menacing contexts and generalizes to a wider variety of emotionally charged male-female interactions.

Reconsidering the logic of World Federation of Neurosurgical Societies grading in patients with severe subarachnoid hemorrhage.

OBJECT Current data show a favorable outcome in up to 50% of patients with World Federation of Neurosurgical Societies (WFNS) Grade V subarachnoid hemorrhage (SAH) and a rather poor prediction of worst cases. Thus, the usefulness of the current WFNS grading system for identifying the worst scenarios for clinical studies and for making treatment decisions is limited. One reason for this lack of differentiation is the use of "negative" or "silent" diagnostic signs as part of the WFNS Grade V definition. The authors therefore reevaluated the WFNS scale by using "positive" clinical signs and the logic of the Glasgow Coma Scale as a progressive herniation score. METHODS The authors performed a retrospective analysis of 182 patients with SAH who had poor grades on the WFNS scale. Patients were graded according to the original WFNS scale and additionally according to a modified classification, the WFNS herniation (hWFNS) scale (Grade IV, no clinical signs of herniation; Grade V, clinical signs of herniation). The prediction of poor outcome was compared between these two grading systems. RESULTS The positive predictive values of Grade V for poor outcome were 74.3% (OR 3.79, 95% CI 1.94-7.54) for WFNS Grade V and 85.7% (OR 8.27, 95% CI 3.78-19.47) for hWFNS Grade V. With respect to mortality, the positive predictive values were 68.3% (OR 3.9, 95% CI 2.01-7.69) for WFNS Grade V and 77.9% (OR 6.22, 95% CI 3.07-13.14) for hWFNS Grade V. CONCLUSIONS Limiting WFNS Grade V to the positive clinical signs of the Glasgow Coma Scale such as flexion, extension, and pupillary abnormalities instead of including "no motor response" increases the prediction of mortality and poor outcome in patients with severe SAH.

Conserved sequences and cell-specific DNase I hypersensitive sites upstream from the co-ordinately expressed alpha I- and alpha II-globin genes of Xenopus laevis

The globin gene family of Xenopus laevis comprises pairs of closely related genes that are arranged in two clusters, each pair of genes being co-ordinately and stage-specifically expressed. To get information on putative regulatory elements, we compared the DNA sequences and the chromatin conformation 5' to the co-ordinately expressed adult alpha-globin genes. Sequence analysis revealed a relatively conserved region from the cap site up to position -289, and further upstream seven distinct boxes of homology, separated by more diverged sequences or deletions/insertions. The homology boxes comprise 22 to 194 base-pairs showing 78 to 95% homology. Analysis of chromatin conformation showed that DNase I preferentially cuts the upstream region of both genes at similar positions, 5' to the T-A-T-A and the C-C-A-A-T boxes, only in chromatin of adult erythroblasts and erythrocytes, where adult globin genes are expressed, but not in chromatin of adult liver cells or larval erythrocytes, where these genes are silent. This suggests that cell- and stage-specific activation of these genes coincides with specific changes in chromatin conformation within the proximal upstream region. No difference was found in the nucleotide sequence within the DNase I hypersensitive region proximal to the adult alpha 1-globin gene in DNA from embryonic cells, in which this gene is inactive, and adult erythrocytes, expressing this gene.

Antithrombotic therapy in TAVI patients: changing concepts.

The clinical and demographic characteristics of patients undergoing TAVI pose unique challenges for developing and implementing optimal antithrombotic therapy. Ischaemic and bleeding events in the periprocedural period and months after TAVI still remain a relevant concern to be faced with optimised antithrombotic therapy. Moreover, the antiplatelet and anticoagulant pharmacopeia has evolved significantly in recent years with new drugs and multiple possible combinations. Dual antiplatelet therapy (DAPT) is currently recommended after TAVI with oral anticoagulation (OAC) restricted for specific indications. However, atrial fibrillation (which is often clinically silent and unrecognised) is common after the procedure and embolic material often thrombin-rich. Recent evidence has therefore questioned this approach, suggesting that DAPT may be futile compared with aspirin alone and that OAC could be a relevant alternative. Future randomised and appropriately powered trials comparing different regimens of antithrombotic therapy, including new antiplatelet and anticoagulant agents, are warranted to increase the available evidence on this topic and create appropriate recommendations for this frail population. Meanwhile, it remains rational to adhere to current guidelines, with routine DAPT and recourse to OAC when specifically indicated, whilst always tailoring therapy on the basis of individual bleeding and thromboembolic risk.

Acute Cytomegalovirus Hepatitis in an Immunocompetent Host as a Reason for Upper Right Abdominal Pain

Cytomegalovirus infections are widely distributed with a seroprevalence of up to 100%. The majority of the cases take a silent course or deal with unspecific clinical symptoms. Complications in immunocompetent patients are rare but may affect the liver and lead up to an acute organ failure. In this case report, we describe a 35-year-old immunocompetent female with an acute cytomegalovirus infection presenting as acute hepatitis with ongoing upper right abdominal pain after cholecystectomy. Upper right abdominal pain is a common symptom with a wide range of differential diagnoses. If common reasons can be excluded, we want to sensitize for cytomegalovirus infection as a minor differential diagnosis even in immunocompetent patients.

Prevalence of Subclinical Rheumatic Heart Disease in Eastern Nepal

Importance: Although rheumatic heart disease has been nearly eradicated in high-income countries, 3 in 4 children grow up in parts of the world where it is still endemic. Objectives: To determine the prevalence of clinically silent and manifest rheumatic heart disease as a function of age, sex, and socioeconomic status and to estimate age-specific incidence. Design, Setting, and Participants: In this school-based cross-sectional study with cluster sampling, 26 schools in the Sunsari district in Eastern Nepal with 5467 eligible children 5 to 15 years of age were randomly selected from 595 registered schools. After exclusion of 289 children, 5178 children were enrolled in the present study from December 12, 2012, through September 12, 2014. Data analysis was performed from October 1, 2014, to April 15, 2015. Exposures: Demographic and socioeconomic characteristics were acquired in a standardized interview by means of a questionnaire customized to the age of the children. A focused medical history was followed by a brief physical examination. Cardiac auscultation and transthoracic echocardiography were performed by 2 independent physicians. Main Outcomes and Measures: Rheumatic heart disease according to the World Heart Federation criteria. Results: The median age of the 5178 children enrolled in the study was 10 years (interquartile range, 8-13 years), and 2503 (48.3%) were female. The prevalence of borderline or definite rheumatic heart disease was 10.2 (95% CI, 7.5-13.0) per 1000 children and increased with advancing age from 5.5 (95% CI, 3.5-7.5) per 1000 children 5 years of age to 16.0 (95% CI, 14.9-17.0) in children 15 years of age, whereas the mean incidence remained stable at 1.1 per 1000 children per year. Children with rheumatic heart disease were older than children without rheumatic heart disease (median age [interquartile range], 11 [9-14] years vs 10 [8-13] years; P = .03), more commonly female (34 [64.2%] vs 2469 [48.2%]; P = .02), and more frequently went to governmental schools (40 [75.5%] vs 2792 [54.5%]; P = .002). Silent disease (n = 44) was 5 times more common than manifest disease (n = 9). Conclusions and Relevance: Rheumatic heart disease affects 1 in 100 schoolchildren in Eastern Nepal, is primarily clinically silent, and may be more common among girls. The overall prevalence and the ratio of manifest to subclinical disease increase with advancing age, whereas the incidence remains stable at 1.1 per 1000 children per year. Early detection of silent disease may help prevent progression to severe valvular damage.

Protective efficacy and safety of liver stage attenuated malaria parasites

During the clinically silent liver stage of a Plasmodium infection the parasite replicates from a single sporozoite into thousands of merozoites. Infection of humans and rodents with large numbers of sporozoites that arrest their development within the liver can cause sterile protection from subsequent infections. Disruption of genes essential for liver stage development of rodent malaria parasites has yielded a number of attenuated parasite strains. A key question to this end is how increased attenuation relates to vaccine efficacy. Here, we generated rodent malaria parasite lines that arrest during liver stage development and probed the impact of multiple gene deletions on attenuation and protective efficacy. In contrast to P. berghei strain ANKA LISP2(-) or uis3(-) single knockout parasites, which occasionally caused breakthrough infections, the double mutant lacking both genes was completely attenuated even when high numbers of sporozoites were administered. However, different vaccination protocols showed that LISP2(-) parasites protected better than uis3(-) and double mutants. Hence, deletion of several genes can yield increased safety but might come at the cost of protective efficacy.

Interference by the intracellular parasite Theileria parva with T-cell signal transduction pathways induces transformation and protection against apoptosis

The intracellular parasite Theileria parva transforms bovine T-lymphocytes, inducing uncontrolled proliferation. Upon infection, cells cease to require antigenic stimulation and exogenous growth factors to proliferate. Earlier studies have shown that pathways triggered via stimulation of the T-cell receptor are silent in transformed cells. This is reflected by a lack of phosphorylation of key signalling molecules and the fact that proliferation is not inhibited by immunosuppressants such as cyclosporin and ascomycin that target calcineurin. This suggests that the parasite bypasses the normal T-cells activation pathways to induce proliferation. Among the MAP-kinase pathways, ERK and p38 are silent, and only Jun N-terminal kinase is activated. This appears to suffice to induce constitutive activation of the transcription factor AP-1. More recently, it could be shown that the presence of the parasite in the host cell cytoplasm also induces constitutive activation of NF-kappaB, a transcription factor involved in proliferation and protection against apoptosis. Activation is effectuated by parasite-induced degradation of IkappaBs, the cytoplasmic inhibitors which sequester NF-kappaB in the cytoplasm. NF-kappaB activation is resistant to the antioxidant N-acetyl cysteine and a range of other reagents, suggesting that activation might occur in an unorthodox manner. Studies using inhibitors and dominant negative mutants demonstrate that the parasite activates a NF-kappaB-dependent anti-apoptotic mechanism that protects the transformed cell form spontaneous apoptosis and is essential for maintaining the transformed state of the parasitised cell.