Emergency Ultrasound Unveils Intermediate-High Risk Saddle Pulmonary Embolism with Extensive Bilateral Clot Burden, Masquerading as Micturition Syncope: A Case Report.

BACKGROUND: Isolated syncope as the manifestation of pulmonary embolism (PE) is a rare and diagnostically challenging presentation that often leads to delayed or missed diagnosis, increasing morbidity and mortality. In spite of emphasizing cardiovascular etiologies of syncope, current guidelines offer essentially no guidance in establishing a diagnostic workup for PE in these patients. By performing bedside echocardiography, emergency physicians can accurately identify concerning features suggestive of PE in patients with syncope. CASE REPORT: A 78-year-old man, receiving ertapenem via a peripherally inserted central catheter for treatment of extended spectrum ß-lactamase urinary tract infection, presented to the emergency department for isolated syncope with collapse while urinating. Arriving asymptomatic with normal vital signs and a benign physical examination, a presumptive diagnosis of micturition syncope was made. However, subtle vital sign changes on reassessment prompted performance of a point-of-care echocardiogram, which revealed signs of right heart strain. A computed tomography angiogram confirmed a saddle PE with extensive bilateral clot burden. Catheter-directed thrombectomy was performed via interventional radiology, with successful removal of pulmonary emboli. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Pulmonary embolism presenting as isolated syncope represents a daunting diagnostic dilemma, as emergency physicians may not consider it, or anchor on more benign etiologies of syncope. Although lacking sufficient sensitivity to rule out PE, point-of-care echocardiography to evaluate for signs of right heart strain can quickly and effectively point toward the diagnosis, while also assessing for other emergent cardiovascular causes of syncope. Given the lack of evidence-based guidance concerning PE presenting as syncope, bedside echocardiography should be highly considered as a part of the emergency physician's diagnostic workup, especially in patients with abnormal vital signs.

LSD1/KDM1A is essential for neural stem cell differentiation in mice.

The proper regulation of neural stem cell differentiation is required for the proper specification of the central nervous system. Here we investigated the function of the H3K4me1/2 demethylase LSD1/KDM1A during neural stem differentiation in mice. Conditional deletion of LSD1 in nestin- positive neural stem cells results in 100% perinatal lethality after birth with severe motor coordination deficits, retarded growth and defects in brain morphology. Despite these severe defects, motor neuron progenitors and the initial motor neuron population are specified normally and motor neurons with normal morphology can be cultured from these mice in vitro. However, motor neurons cultured from mice lacking LSD1 in neural stem cells continue to inappropriately maintain critical neural stem cell proteins. Taken together these results suggest that, as in other mouse stem cell populations, LSD1 is required to deactivate the stem cell program to enable normal neural stem cell differentiation. However, unlike in other mouse stem cell populations, the inappropriate maintenance of the stem cell program during neural stem cell differentiation may compromise neuronal function rather than neuronal specification.

Exploring motivations for participating in research among Australian women with advanced gynaecological cancer: a qualitative study.

PURPOSE: With global moves to increase research among those living with advanced cancer and legitimise consumers as part of cancer research, this article aims to build an understanding of women's motivations and reasons for participating in gynaecological cancer research. As a secondary aim, we considered the role of qualitative methods in enabling active involvement of consumers in research. METHODS: We applied thematic discursive analysis to 18 in-depth interviews with women diagnosed with advanced (stage III-IV) gynaecological cancer living in Australia. RESULTS: We found that women viewed research as a vehicle for change in two directions: improving the lives of future generations and improving education and awareness. Underpinning these two framings of research, women spoke about their own role and reasons for participating in this interview study. Women's stories were painted against a backdrop of social and medical silences around gynaecological cancer. It was from such silence that women chose to speak up and position themselves as participating in service for knowledge production. CONCLUSION: We learned that trust, reciprocity and relationships are central to women's decisions to participate in cancer research. Legitimising consumers in cancer research requires methods, methodologies and practices that pay careful attention to power, control and representation.

In silico interrogation of the miRNAome of infected hematopoietic cells to predict processes important for human cytomegalovirus latent infection.

Human cytomegalovirus (HCMV) latency in CD34+ progenitor cells is the outcome of a complex and continued interaction of virus and host that is initiated during very early stages of infection and reflects pro- and anti-viral activity. We hypothesized that a key event during early infection could involve changes to host miRNAs, allowing for rapid modulation of the host proteome. Here, we identify 72 significantly upregulated miRNAs and three that were downregulated by 6hpi of infection of CD34+ cells which were then subject to multiple in silico analyses to identify potential genes and pathways important for viral infection. The analyses focused on the upregulated miRNAs and were used to predict potential gene hubs or common mRNA targets of multiple miRNAs. Constitutive deletion of one target, the transcriptional regulator JDP2, resulted in a defect in latent infection of myeloid cells; interestingly, transient knockdown in differentiated dendritic cells resulted in increased viral lytic IE gene expression, arguing for subtle differences in the role of JDP2 during latency establishment and reactivation of HCMV. Finally, in silico predictions identified clusters of genes with related functions (such as calcium signaling, ubiquitination, and chromatin modification), suggesting potential importance in latency and reactivation. Consistent with this hypothesis, we demonstrate that viral IE gene expression is sensitive to calcium channel inhibition in reactivating dendritic cells. In conclusion, we demonstrate HCMV alters the miRNAome rapidly upon infection and that in silico interrogation of these changes reveals new insight into mechanisms controlling viral gene expression during HCMV latency and, intriguingly, reactivation.

The cytomegalovirus gB/MF59 vaccine candidate induces antibodies against an antigenic domain controlling cell-to-cell spread.

Vaccination against human cytomegalovirus (CMV) infection remains high priority. A recombinant form of a protein essential for CMV entry, glycoprotein B (gB), demonstrated partial protection in a clinical trial (NCT00299260) when delivered with the MF59 adjuvant. Although the antibody titre against gB correlated with protection poor neutralising responses against the 5 known antigenic domains (AD) of gB were evident. Here, we show that vaccination of CMV seronegative patients induces an antibody response against a region of gB we term AD-6. Responses to the polypeptide AD-6 are detected in >70% of vaccine recipients yet in <5% of naturally infected people. An AD-6 antibody binds to gB and to infected cells but not the virion directly. Consistent with this, the AD-6 antibody is non-neutralising but, instead, prevents cell-cell spread of CMV in vitro. The discovery of AD-6 responses has the potential to explain part of the protection mediated by gB vaccines against CMV following transplantation.

Costoclavicular Brachial Plexus Block Facilitates Painless Upper Extremity Reduction: A Case Report.

Introduction: The costoclavicular brachial plexus block (CCBPB) has emerged as a more effective approach to regional anesthesia of the upper extremity. The costoclavicular space is the anterior portion of the superior thoracic aperture, located between the clavicle and first rib. The brachial plexus cords traverse this space clustered together in a superficial location lateral to the axillary artery and share a consistent topographical relationship to one another. By targeting the brachial plexus at this specific anatomical location, the CCBPB offers a powerful, single-shot, sensorimotor block of the upper extremity below the shoulder. We present a novel application of the CCBPB to facilitate emergency department (ED) analgesia and closed reduction of an upper extremity fracture. Case Report: A 25-year-old male presented to the ED with a traumatic Colles fracture sustained during a high-speed motor vehicle collision. Despite multimodal analgesia, the patient reported intractable severe pain with intolerance of radial manipulation. An ultrasound-guided CCBPB was performed to augment pain control and avoid procedural sedation, resulting in dense, surgical anesthesia of the upper extremity, and painless fracture reduction. Conclusion: Regional anesthesia is an effective component of multimodal pain management and another tool in the emergency physician's analgesic armamentarium. In acute orthopedic traumas necessitating emergent reduction, regional blocks serve as rescue pain control and can obviate the need for procedural sedation. In terms of targeted upper extremity analgesia, the CCBPB offers effective, single-shot, sensorimotor blockade below the shoulder, mitigating use of opioids and their deleterious side effects, while simultaneously avoiding incomplete blockade or phrenic nerve palsy associated with other approaches to brachial plexus blockade.

Evasion of a Human Cytomegalovirus Entry Inhibitor with Potent Cysteine Reactivity Is Concomitant with the Utilization of a Heparan Sulfate Proteoglycan-Independent Route of Entry.

The dependence of viruses on the host cell to complete their replicative cycle renders cellular functions potential targets for novel antivirals. We screened a panel of broadly acting cellular ion channel inhibitors for activity against human cytomegalovirus (HCMV) and identified the voltage-gated chloride ion channel inhibitor 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS) as a potent inhibitor of HCMV replication. Time-of-addition studies demonstrated that DIDS inhibited entry via direct interaction with the virion that impeded binding to the plasma membrane. Synthesis and analysis of pharmacological variants of DIDS suggested that intrinsic cysteine, and not lysine, reactivity was important for activity against HCMV. Although sequencing of DIDS-resistant HCMV revealed enrichment of a mutation within UL100 (encoding glycoprotein M) and a specific truncation of glycoprotein RL13, these did not explain the DIDS resistance phenotype. Specifically, only the introduction of the RL13 mutant partially phenocopied the DIDS resistance phenotype. Serendipitously, the entry of DIDS-resistant HCMV also became independent of heparan sulfate proteoglycans (HSPGs), suggesting that evasion of DIDS lowered dependence on an initial interaction with HSPGs. Intriguingly, the DIDS-resistant virus demonstrated increased sensitivity to antibody neutralization, which mapped, in part, to the presence of the gM mutation. Taken together the data characterize the antiviral activity of a novel HCMV inhibitor that drives HCMV infection to occur independently of HSPGs and the generation of increased sensitivity to humoral immunity. The data also demonstrate that compounds with cysteine reactivity have the potential to act as antiviral compounds against HCMV via direct engagement of virions.IMPORTANCE Human cytomegalovirus (HCMV) is major pathogen of nonimmunocompetent individuals that remains in need of new therapeutic options. Here, we identify a potent antiviral compound (4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid [DIDS]), its mechanism of action, and the chemical properties required for its activity. In doing so, the data argue that cysteine-reactive compounds could have the capacity to be developed for anti-HCMV activity. Importantly, the data show that entry of DIDS-resistant virus became independent of heparan sulfate proteoglycans (HSPGs) but, concomitantly, became more sensitive to neutralizing antibody responses. This serendipitous observation suggests that retention of an interaction with HSPGs during the entry process in vivo may be evolutionarily advantageous through better evasion of humoral responses directed against HCMV virions.

Footbathing, formalin and foot trimming: The 3Fs associated with granulomas and shelly hoof in sheep.

Granulomas and shelly hoof (SH), are lesions of sheep feet. Our objective was to use data from four questionnaires on lameness sent to English sheep farmers in 2004, 2013, 2014 and 2015 to further understanding of the risks and aetiologies of both lesions. Granulomas were more likely in flocks where routine foot trimming (odds ratio [OR]=3.17; 95% confidence intervals [CI] 1.11-11.47) and routine footbathing (OR=2.38; 95% CI 1.19-4.83) were practised than where these management protocols were not. SH was more likely in flocks that were footbathed in formalin compared with not footbathing (OR=1.65; 95% CI 1.19-2.30), and was less common in flocks that stocked ewes at more than eight vs. four per acre (OR=0.34; 95% CI 0.17-0.68). There were weak associations between SH and foot trimming. In 2004 only, SH was more likely in flocks where therapeutic foot trimming was practised than not practised (OR=2.24; 95% CI 1.12-4.68). In 2014 only, SH was marginally less likely in flocks where no feet bled during trimming, compared with flocks not routinely trimmed (OR=0.55; CI 0.30-1.00); SH was not related to foot trimming once severe footrot was included. We propose that flocks with granulomas and SH would decrease if farmers stopped footbathing in general, in particular with formalin, and avoided foot trimming whether as a therapeutic or routine practice. Further work is needed to understand the role of stocking density.

WITHDRAWN: Fighting for access: Research at the National Abortion Federation's 43rd Annual Meeting.

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α-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by α-TGFß antibody to promote durable rejection and immunity in squamous cell carcinomas.

BACKGROUND: Checkpoint blockade immunotherapy has improved metastatic cancer patient survival, but response rates remain low. There is an unmet need to identify mechanisms and tools to circumvent resistance. In human patients, responses to checkpoint blockade therapy correlate with tumor mutation load, and intrinsic resistance associates with pre-treatment signatures of epithelial mesenchymal transition (EMT), immunosuppression, macrophage chemotaxis and TGFß signaling. METHODS: To facilitate studies on mechanisms of squamous cell carcinoma (SCC) evasion of checkpoint blockade immunotherapy, we sought to develop a novel panel of murine syngeneic SCC lines reflecting the heterogeneity of human cancer and its responses to immunotherapy. We characterized six Kras-driven cutaneous SCC lines with a range of mutation loads. Following implantation into syngeneic FVB mice, we examined multiple tumor responses to α-PD-1, α-TGFß or combinatorial therapy, including tumor growth rate and regression, tumor immune cell composition, acquired tumor immunity, and the role of cytotoxic T cells and Tregs in immunotherapy responses. RESULTS: We show that α-PD-1 therapy is ineffective in establishing complete regression (CR) of tumors in all six SCC lines, but causes partial tumor growth inhibition of two lines with the highest mutations loads, CCK168 and CCK169. α-TGFß monotherapy results in 20% CR and 10% CR of established CCK168 and CCK169 tumors respectively, together with acquisition of long-term anti-tumor immunity. α-PD-1 synergizes with α-TGFß, increasing CR rates to 60% (CCK168) and 20% (CCK169). α-PD-1 therapy enhances CD4 + Treg/CD4 + Th ratios and increases tumor cell pSmad3 expression in CCK168 SCCs, whereas α-TGFß antibody administration attenuates these effects. We show that α-TGFß acts in part through suppressing immunosuppressive Tregs induced by α-PD-1, that limit the anti-tumor activity of α-PD-1 monotherapy. Additionally, in vitro and in vivo, α-TGFß acts directly on the tumor cell to attenuate EMT, to activate a program of gene expression that stimulates immuno-surveillance, including up regulation of genes encoding the tumor cell antigen presentation machinery. CONCLUSIONS: We show that α-PD-1 not only initiates a tumor rejection program, but can induce a competing TGFß-driven immuno-suppressive program. We identify new opportunities for α-PD-1/α-TGFß combinatorial treatment of SCCs especially those with a high mutation load, high CD4+ T cell content and pSmad3 signaling. Our data form the basis for clinical trial of α-TGFß/α-PD-1 combination therapy (NCT02947165).

How much can we influence the rate of innovation?

Innovation is how organizations drive technological change, but the rate of innovation can vary considerably from one technological domain to another. To understand why some domains flourish more rapidly than others, we studied a model of innovation in which products are built out of components. We derived a conservation law for the average size of the product space as more components are acquired and tested our insights using historical data from language, gastronomy, mixed drinks, and technology. We find that the innovation rate is partly influenceable and partly predetermined, similar to how traits are partly set by nurture and partly set by nature. The predetermined aspect is fixed solely by the distribution of the complexity of products in each domain. Different distributions can produce markedly different innovation rates. This helps explain why some domains show faster innovation than others, despite similar efforts to accelerate them. Our insights also give a quantitative perspective on lean methodology, frugal innovation, and mechanisms to encourage tinkering.

Implication of Major Adverse Postoperative Events and Myocardial Injury on Disability and Survival: A Planned Subanalysis of the ENIGMA-II Trial.

BACKGROUND: Globally, >300 million patients have surgery annually, and ≤20% experience adverse postoperative events. We studied the impact of both cardiac and noncardiac adverse events on 1-year disability-free survival after noncardiac surgery. METHODS: We used the study cohort from the Evaluation of Nitrous oxide in Gas Mixture of Anesthesia (ENIGMA-II) trial, an international randomized trial of 6992 noncardiac surgical patients. All were ≥45 years of age and had moderate to high cardiac risk. The primary outcome was mortality within 1 postoperative year. We defined 4 separate types of postoperative adverse events. Major adverse cardiac events (MACEs) included myocardial infarction (MI), cardiac arrest, and myocardial revascularization with or without troponin elevation. MI was defined using the third Universal Definition and was blindly adjudicated. A second cohort consisted of patients with isolated troponin increases who did not meet the definition for MI. We also considered a cohort of patients who experienced major adverse postoperative events (MAPEs), including unplanned admission to intensive care, prolonged mechanical ventilation, wound infection, pulmonary embolism, and stroke. From this cohort, we identified a group without troponin elevation and another with troponin elevation that was not judged to be an MI. Multivariable Cox proportional hazard models for death at 1 year and assessments of proportionality of hazard functions were performed and expressed as an adjusted hazard ratio (aHR) and 95% confidence intervals (CIs). RESULTS: MACEs were observed in 469 patients, and another 754 patients had isolated troponin increases. MAPEs were observed in 631 patients. Compared with control patients, patients with a MACE were at increased risk of mortality (aHR, 3.36 [95% CI, 2.55-4.46]), similar to patients who suffered a MAPE without troponin elevation (n = 501) (aHR, 2.98 [95% CI, 2.26-3.92]). Patients who suffered a MAPE with troponin elevation but without MI had the highest risk of death (n = 116) (aHR, 4.29 [95% CI, 2.89-6.36]). These 4 types of adverse events similarly affected 1-year disability-free survival. CONCLUSIONS: MACEs and MAPEs occur at similar frequencies and affect survival to a similar degree. All 3 types of postoperative troponin elevation in this analysis were associated, to varying degrees, with increased risk of death and disability.

Effectiveness of extended contact interventions for weight management delivered via text messaging: a systematic review and meta-analysis.

BACKGROUND: Extended contact interventions provide support for continued weight management (weight loss/prevention of weight regain) following a weight loss intervention. Text messages offer a medium for delivery in a potentially cost-effective, broad-reach manner. OBJECTIVES: This study aims to examine (i) the effectiveness of extended contact, text message interventions for adults in supporting weight management, and (ii) which intervention characteristics are common to those that are effective. METHODS: A systematic database search (to 19 September 2016) was conducted. Meta-analyses were performed to quantify the average weight changes (kg) during the extended contact intervention, net of control (if a control group was present) and within-group. RESULTS: Seven studies were eligible for inclusion. The pooled effect of the extended contact intervention compared with control (n = 3 studies) was -0.82 kg (95% confidence interval -1.43, -0.21), while the pooled within-group weight loss (n = 6 studies) during the extended contact interventions was -2.16 kg (95% confidence interval -3.40, -0.91). Interventions considered 'effective' (n = 4) were more likely to be >12 weeks duration, compared with interventions considered 'ineffective' (n = 3). CONCLUSION: Evidence from the small number of studies reviewed suggests that extended contact, text message-delivered interventions are effective. Further research is required to elucidate effective intervention components and the longer-term impact on weight, diet and physical activity behaviour.

Serendipity and strategy in rapid innovation.

Innovation is to organizations what evolution is to organisms: it is how organizations adapt to environmental change and improve. Yet despite advances in our understanding of evolution, what drives innovation remains elusive. On the one hand, organizations invest heavily in systematic strategies to accelerate innovation. On the other, historical analysis and individual experience suggest that serendipity plays a significant role. To unify these perspectives, we analysed the mathematics of innovation as a search for designs across a universe of component building blocks. We tested our insights using data from language, gastronomy and technology. By measuring the number of makeable designs as we acquire components, we observed that the relative usefulness of different components can cross over time. When these crossovers are unanticipated, they appear to be the result of serendipity. But when we can predict crossovers in advance, they offer opportunities to strategically increase the growth of the product space.

Can weight gain be prevented in women receiving treatment for breast cancer? A systematic review of intervention studies.

BACKGROUND: Obesity and weight gain have been associated with poor disease-specific and health-related outcomes in women with breast cancer. OBJECTIVES: This review aimed to evaluate the effectiveness of weight gain prevention interventions among women with breast cancer. METHODS: Completed and ongoing trials evaluating a behaviourally based dietary intervention with or without physical activity and with a focus on weight gain prevention during treatment for breast cancer were reviewed. Weight change and body composition data were extracted. Within-group weight change of ±1 kg and between-group (intervention versus control) weight difference of ≥2 kg were defined as successful weight gain prevention. RESULTS: Five completed trials (seven intervention arms) and five ongoing trials were identified. Completed trials exclusively recruited premenopausal or premenopausal and postmenopausal women. Within-group weight gain was prevented in two intervention arms, two arms achieved weight loss and three arms reported weight gain. Of the five comparisons with control groups, two reported significant differences in weight change between groups. Ongoing trials will provide further evidence on longer-term outcomes, cost-effectiveness and blood markers. CONCLUSION: This small but growing number of studies provides preliminary and promising evidence that weight gain can be prevented in women with breast cancer undergoing chemotherapy.

LPS promotes a monocyte phenotype permissive for human cytomegalovirus immediate-early gene expression upon infection but not reactivation from latency.

Human cytomegalovirus (HCMV) infection of myeloid cells is closely linked with the differentiation status of the cell. Haematopoietic progenitors and CD14+ monocytes are usually non-permissive for lytic gene expression which can lead to the establishment of latent infections. In contrast, differentiation to macrophage or dendritic cell (DC) phenotypes promotes viral reactivation or renders them permissive for lytic infection. The observation that high doses of Lipopolysaccharide (LPS) drove rapid monocyte differentiation in mice led us to investigate the response of human monocytes to HCMV following LPS stimulation in vitro. Here we report that LPS triggers a monocyte phenotype permissiveness for lytic infection directly correlating with LPS concentration. In contrast, addition of LPS directly to latently infected monocytes was not sufficient to trigger viral reactivation which is likely linked with the failure of the monocytes to differentiate to a DC phenotype. Interestingly, we observe that this effect on lytic infection of monocytes is transient, appears to be dependent on COX-2 activation and does not result in a full productive infection. Thus LPS stimulated monocytes are partially permissive lytic gene expression but did not have long term impact on monocyte identity regarding their differentiation and susceptibility for the full lytic cycle of HCMV.