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Abstract Background Reduced red blood cell deformability (RBCD) is associated with diabetic vascular complications, but early pathophysiological RBC changes and predictive demographic and clinical factors in populations with diabetes are unclear. An understanding of early diabetes-specific RBC changes associated with impaired RBCD is essential in investigating mechanisms that predispose to diabetic vascular complications. Methods We conducted an outpatient cross-sectional study of participants in a well-controlled diabetes cohort (N81) and nondiabetic controls (N78) at the National Institutes of Health. First, between-group differences in RBCD measures were assessed with shear stress-gradient ektacytometry. Differences in structural RBC parameters were assessed using osmotic gradient ektacytometry and NaCl osmotic fragility. Functional RBC changes were assessed using hemoglobin-oxygen dissociation: p50. Results All shear-stress gradient RBCD measures were significantly altered in the diabetes cohort vs. nondiabetic controls, even after adjustment for confounding covariates (p

Abstract Environmental activism presents an ideological dilemma for environmentally concerned scientists, who must balance traditional scientific values of objectivity and impartiality with the urgency of the climate and ecological crisis. This paper presents a critical discursive analysis of interviews with 27 scientists from 11 countries. It details the linguistic repertoires scientists draw on and the subject positions adopted to manage this dilemma. We observed that scientists employ two strategies to reconcile their professional identities with their activism: redefining the scientist identity, and reframing the work that scientists do. The subject positions adopted broadly serve to legitimize action, such as arguing that activism as a scientist is objective and rational, or that being a scientist conveys a moral duty to advocate for scientific information. By analyzing how scientists negotiate conflicting identities and values, this research offers valuable insights into fostering informed decision-making and action in addressing urgent environmental challenges.

Abstract Artificial intelligence has emerged as a technology to enhance productivity and improve life quality. However, its role in building energy efficiency and carbon emission reduction has not been systematically studied. This study evaluated artificial intelligence’s potential in the building sector, focusing on medium office buildings in the United States. A methodology was developed to assess and quantify potential emissions reductions. Key areas identified were equipment, occupancy influence, control and operation, and design and construction. Six scenarios were used to estimate energy and emissions savings across representative climate zones. Here we show that artificial intelligence could reduce cost premiums, enhancing high energy efficiency and net zero building penetration. Adopting artificial intelligence could reduce energy consumption and carbon emissions by approximately 8% to 19% in 2050. Combining with energy policy and low-carbon power generation could approximately reduce energy consumption by 40% and carbon emissions by 90% compared to business-as-usual scenarios in 2050.

Abstract Scientists are increasingly joining environmental movements. As knowledge producers and influential figures in society, scientists are uniquely positioned to drive change. Here we explore how scientist identity shapes engagement in environmental activism using qualitative and quantitative data from a multinational survey of 329 scientists from 41 countries. Scientist identity content, specifically perception of the science-activism relationship, was a stronger explanatory variable than strength of identification as a scientist. Perceiving a harmonious relationship between science and activism, endorsing environmental stewardship as a scientist’s duty, and believing objectivity and impartiality remained uncompromised by activism, each had significant correlations with engagement. These components formed a composite variable, which remained a robust explanatory variable of engagement even when accounting for the influence of activist identity. Scientists embracing scientist-activist compatibilism were also less inclined to view new technologies as a panacea for the climate crisis. This research underscores the important role of scientist identity content in shaping climate actions and perspectives.

Autonomous systems, such as drones, are critical for emergency mitigation, management, and recovery. They provide situational awareness and deliver communication services which effectively guide emergency responders’ decision making. This combination of technology and people comprises a socio-technical system. Yet, focusing on the use of drone technology as a solely operational tool, underplays its potential to enhance coordination between the different agents involved in mass emergencies, both human and non-human. This paper proposes a new methodological approach that capitalizes on social identity principles to enable this coordination in an evacuation operation. In the proposed approach, an adaptive drone uses sensor data to infer the group membership of the survivors it encounters during the operation. A corpus of 200 interactions of survivors’ talk during real-life emergencies was computationally classified as being indicative of a shared identity or personal/no identity. This classification model, then, informed a game-theoretic model of human-robot interactions. Bayesian Nash Equilibrium analysis determined the predicted behavior for the human agent and the strategy that the drone needs to adopt to help with survivor evacuation. Using linguistic and synthetic data, we show that the identity-adaptive architecture outperformed two non-adaptive architectures in the number of successful evacuations. The identity-adaptive drone can infer which victims are likely to be helped by survivors and where help from emergency teams is needed. This facilitates effective coordination and adaptive performance. This study shows decision-making can be an emergent capacity that arises from the interactions of both human and non-human agents in a socio-technical system.

The allocation of critical care resources and triaging patients garnered a great deal of attention during the COVID-19 pandemic, but there is a paucity of guidance regarding the ethical aspects of resource allocation and patient prioritization in ‘normal’ circumstances for Canadian healthcare systems. One context where allocation and prioritization decisions are required are surgical waitlists, which have been globally exacerbated due to the COVID-19 pandemic. In this paper, we detail the process used to develop an ethics framework to support prioritization for elective surgery at The Hospital for Sick Children, Toronto, a tertiary pediatric hospital. Our goal was to provide guidance for the more value-laden aspects of prioritization, particularly when clinical urgency alone is insufficient to dictate priority. With this goal in mind, we worked to capture familial, relational, and equity considerations. As part of our institution’s concerted efforts to ethically and effectively address our surgical backlog, an ethics working group was formed comprising clinicians from surgery, anesthesiology, intensive care, a hospital bioethicist, a parent advisor, and an academic bioethics researcher. A reflective equilibrium process was used to develop an ethics framework. To this end, the same methodology was used to create a support for patient prioritization that identifies clinically and morally relevant factors for prioritization among medically similar surgical cases, with a substantive goal being to identify and redress health inequities in surgical prioritization, inasmuch as this is possible. While further steps are needed to validate several aspects of the framework, our research suggests that an ethics framework grounded in the practical realities of hospital operations provides consistency, transparency, and needed support for decisions that are often left to individual clinicians, as well as an opportunity to reflect upon the presence of health inequities in all domains of healthcare delivery.

This paper discusses Responsible (Research and) Innovation (RRI) within a UKRI project funded through the Trustworthy Autonomous Systems Hub, Imagining Robotic Care: Identifying conflict and confluence in stakeholder imaginaries of autonomous care systems. We used LEGO® Serious Play® as an RRI methodology for focus group workshops exploring sociotechnical imaginaries about how robots should (or should not) be incorporated into the existing UK health-social care system held by care system stakeholders, users and general publics. We outline the workshops’ protocol and some emerging insights from early data collection, including the ways that LSP aids in the surfacing of tacit knowledge, allowing participants to develop their own scenarios and definitions of ‘robot’ and ‘care’. We further discuss the implications of LSP as a method for upstream stakeholder engagement in general and how this may contribute to embedding RRI in robotics research on a larger scale.

Hematopoiesis, a process that results in the differentiation of all blood lineages, is essential throughout life. The production of 1x1012 blood cells per day, including 200x109 erythrocytes, is highly dependent on nutrient consumption. Notably though, the relative requirements for micronutrients during the perinatal period, a critical developmental window for immune cell and erythrocyte differentiation, have not been extensively studied. More specifically, the impact of the vitamin C/ascorbate micronutrient on perinatal as compared to adult hematopoiesis has been difficult to assess in animal models. Even though humans cannot synthesize ascorbate, due to a pseudogenization of the L-gulono-γ-lactone oxidase (GULO) gene, its generation from glucose is an ancestral mammalian trait. Taking advantage of a Gulo-/- mouse model, we show that ascorbic acid deficiency profoundly impacts perinatal hematopoiesis, resulting in a hypocellular bone marrow (BM) with a significant reduction in hematopoietic stem cells, multipotent progenitors, and hematopoietic progenitors. Furthermore, myeloid progenitors exhibited differential sensitivity to vitamin C levels; common myeloid progenitors and megakaryocyte-erythrocyte progenitors were markedly reduced in Gulo-/- pups following vitamin C depletion in the dams, whereas granulocyte-myeloid progenitors were spared, and their frequency was even augmented. Notably, hematopoietic cell subsets were rescued by vitamin C repletion. Consistent with these data, peripheral myeloid cells were maintained in ascorbate-deficient Gulo-/- pups while other lineage-committed hematopoietic cells were decreased. A reduction in B cell numbers was associated with a significantly reduced humoral immune response in ascorbate-depleted Gulo-/- pups but not adult mice. Erythropoiesis was particularly sensitive to vitamin C deprivation during both the perinatal and adult periods, with ascorbate-deficient Gulo-/- pups as well as adult mice exhibiting compensatory splenic differentiation. Furthermore, in the pathological context of hemolytic anemia, vitamin C-deficient adult Gulo-/- mice were not able to sufficiently increase their erythropoietic activity, resulting in a sustained anemia. Thus, vitamin C plays a pivotal role in the maintenance and differentiation of hematopoietic progenitors during the neonatal period and is required throughout life to sustain erythroid differentiation under stress conditions.

The COVID-19 pandemic is worsening loneliness for many older people through the challenges it poses in engaging with their social worlds. Digital technology has been offered as a potential aid, however, many popular digital tools have not been designed to address the needs of older adults during times of limited contact. We propose that the Social Identity Model of Identity Change (SIMIC) could be a foundation for digital loneliness interventions. While SIMIC is a well-established approach for maintaining wellbeing during life transitions, it has not been rigorously applied to digital interventions. There are known challenges to integrating psychological theory in the design of digital technology to enable efficacy, technology acceptance, and continued use. The interdisciplinary field of Human Computer Interaction has a history of drawing on models originating from psychology to improve the design of digital technology and to design technologies in an appropriate manner. Drawing on key lessons from this literature, we consolidate research and design guidelines for multidisciplinary research applying psychological theory such as SIMIC to digital social interventions for loneliness.

Abstract Background Classic symptoms of acute appendicitis are well known but are uncommon and often misinterpreted in pediatric patients, potentially delaying diagnosis and resulting in rare sequelae. Methods We conducted a comprehensive systematic literature search of case reports detailing pericardial disease as a rare complication of pediatric appendicitis through MEDLINE, Embase, and Cochrane Databases. Inclusion criteria was that the patient must be

Objectives: We initiated an outpatient pulse oximetry program to facilitate more rapid detection of clinical deterioration of persons with COVID-19. Methods: Vermont residents in non-congregate settings with laboratory-confirmed SARS-CoV-2 infection were eligible for inclusion. Results: Acceptance of pulse oximetry occurred more frequently among those who were older or symptomatic, spoke English, or who had underlying medical conditions. Conclusions: We provide the first description of an outpatient pulse oximetry program for COVID-19 by a state health department in the U.S.

Traditional work on bystander intervention in violent emergencies has found that the larger the group, the less the chance that any individual will intervene. Here, we tested the impact on helping behavior of the affiliation of the bystanders with respect to the participants. We recruited 40 male supporters of the U.K. Arsenal football club for a two-factor between groups study with 10 participants per group. Each participant spoke with a virtual human Arsenal supporter (V), the scenario displayed in a virtual reality system. During this conversation, another virtual character (P), not an Arsenal fan, verbally abused V for being an Arsenal fan leading eventually to physical pushing. There was a group of three virtual bystanders who were all either Arsenal supporters indicated by their shirts, or football fans wearing unbranded shirts. These bystanders either encouraged the participant to intervene or dissuaded him. We recorded the number of times that participants intervened to help V during the aggression. We found that participants were more likely to intervene when the bystanders were out-group with respect to the participant. By comparing levels of intervention with a “baseline” study (identical except for the presence of bystanders), we conclude that the presence of in-group bystanders decreases helping. We argue therefore that, other things being equal, diffusion of responsibility is more likely to be overcome when participant and victim share group membership, but bystanders do not. Our findings help to develop understanding of how diffusion of responsibility works by combining elements of both the bystander effect and the social identity approach to bystander behavior.

Abstract Background Observational research suggests that combined therapy with Vitamin C, thiamine and hydrocortisone may reduce mortality in patients with septic shock. Methods and design The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a multicenter, double-blind, adaptive sample size, randomized, placebo-controlled trial designed to test the efficacy of combination therapy with vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) given every 6 h for up to 16 doses in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. The primary outcome is ventilator- and vasopressor-free days with mortality as the key secondary outcome. Recruitment began in August 2018 and is ongoing; 501 participants have been enrolled to date, with a planned maximum sample size of 2000. The Data and Safety Monitoring Board reviewed interim results at N = 200, 300, 400 and 500, and has recommended continuing recruitment. The next interim analysis will occur when N = 1000. This update presents the statistical analysis plan. Specifically, we provide definitions for key treatment and outcome variables, and for intent-to-treat, per-protocol, and safety analysis datasets. We describe the planned descriptive analyses, the main analysis of the primary end point, our approach to secondary and exploratory analyses, and handling of missing data. Our goal is to provide enough detail that our approach could be replicated by an independent study group, thereby enhancing the transparency of the study. Trial registration ClinicalTrials.gov, NCT03509350 . Registered on 26 April 2018.

Abstract Background Sepsis accounts for 30% to 50% of all in-hospital deaths in the United States. Other than antibiotics and source control, management strategies are largely supportive with fluid resuscitation and respiratory, renal, and circulatory support. Intravenous vitamin C in conjunction with thiamine and hydrocortisone has recently been suggested to improve outcomes in patients with sepsis in a single-center before-and-after study. However, before this therapeutic strategy is adopted, a rigorous assessment of its efficacy is needed. Methods The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial. It will enroll patients with sepsis causing respiratory or circulatory compromise or both. Patients will be randomly assigned (1:1) to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 h or matching placebos until a total of 16 administrations have been completed or intensive care unit discharge occurs (whichever is first). Patients randomly assigned to the comparator group are permitted to receive open-label stress-dose steroids at the discretion of the treating clinical team. The primary outcome is consecutive days free of ventilator and vasopressor support (VVFDs) in the 30 days following randomization. The key secondary outcome is mortality at 30 days. Sample size will be determined adaptively by using interim analyses with pre-stated stopping rules to allow the early recognition of a large mortality benefit if one exists and to refocus on the more sensitive outcome of VVFDs if an early large mortality benefit is not observed. Discussion VICTAS is a large, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial that will test the efficacy of vitamin C, thiamine, and hydrocortisone as a combined therapy in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. Because the components of this therapy are inexpensive and readily available and have very favorable risk profiles, demonstrated efficacy would have immediate implications for the management of sepsis worldwide. Trial registration ClinicalTrials.gov Identifier: NCT03509350. First registered on April 26, 2018, and last verified on December 20, 2018. Protocol version: 1.4, January 9, 2019

The authors wish to make a change to the author names (deleting one author—Constantine Daskalakis) for this paper [...]

Eyewitnesses to crimes sometimes search for a culprit on social media before viewing a police lineup, but it is not known whether this affects subsequent lineup identification accuracy. The present online study was conducted to address this. Two hundred and eighty-five participants viewed a mock crime video, and after a 15–20 min delay either (i) viewed a mock social media site including the culprit, (ii) viewed a mock social media site including a lookalike, or (iii) completed a filler task. A week later, participants made an identification from a photo lineup. It was predicted that searching for a culprit on social media containing the lookalike (rather than the culprit) would reduce lineup identification accuracy. There was a significant association between social media exposure and lineup accuracy for the Target Present lineup (30% more of the participants who saw the lookalike on social media failed to positively identify the culprit than participants in the other conditions), but for the Target Absent lineup (which also included the lookalike) there was no significant association with lineup identification accuracy. The results suggest that if an eyewitness sees a lookalike (where they are expecting to see the culprit) when conducting a self-directed search on social media, they are less likely to subsequently identify the culprit in the formal ID procedure.

Background: Oxidative stress and protein aggregation are key mechanisms in amyotrophic lateral sclerosis (ALS) disease. Reduced glutathione (GSH) is the most important intracellular antioxidant that protects neurons from reactive oxygen species. We hypothesized that levels of GSH measured by MR spectroscopic imaging (MRSI) in the motor cortex and corticospinal tract are linked to clinical trajectory of ALS patients.Objectives: Investigate the value of GSH imaging to probe clinical decline of ALS patients in combination with other neurochemical and structural parameters.Methods: Twenty-four ALS patients were imaged at 3 T with an advanced MR protocol. Mapping GSH levels in the brain is challenging, and for this purpose, we used an optimized spectral-edited 3D MRSI sequence with real-time motion and field correction to image glutathione and other brain metabolites. In addition, our imaging protocol included (i) an adiabatic T1ρ sequence to image macromolecular fraction of brain parenchyma, (ii) diffusion tensor imaging (DTI) for white matter tractography, and (iii) high-resolution anatomical imaging.Results: We found GSH in motor cortex (r = −0.431, p = 0.04) and corticospinal tract (r = −0.497, p = 0.016) inversely correlated with time between diagnosis and imaging. N-Acetyl-aspartate (NAA) in motor cortex inversely correlated (r = −0.416, p = 0.049), while mean water diffusivity (r = 0.437, p = 0.033) and T1ρ (r = 0.482, p = 0.019) positively correlated with disease progression measured by imputed change in revised ALS Functional Rating Scale. There is more decrease in the motor cortex than in the white matter for GSH compared to NAA, glutamate, and glutamine.Conclusions: Our study suggests that a panel of biochemical and structural imaging biomarkers defines a brain endophenotype, which can be used to time biological events and clinical progression in ALS patients. Such a quantitative brain endophenotype may stratify ALS patients into more homogeneous groups for therapeutic interventions compared to clinical criteria.

Oxidative stress (OS) in non-alcoholic fatty liver disease (NAFLD) promotes liver injury and inflammation. Treatment with vitamin E (α-tocopherol, αT), a lipid-soluble antioxidant, improves liver injury but also decreases steatosis, thought to be upstream of OS, through an unknown mechanism. To elucidate the mechanism, we combined a mechanistic human trial interrogating pathways of intrahepatic triglyceride (IHTG) accumulation and in vitro experiments. 50% of NAFLD patients (n = 20) treated with αT (200–800 IU/d) for 24 weeks had a ≥ 25% relative decrease in IHTG by magnetic resonance spectroscopy. Paired liver biopsies at baseline and week 4 of treatment revealed a decrease in markers of hepatic de novo lipogenesis (DNL) that strongly predicted week 24 response. In vitro, using HepG2 cells and primary human hepatocytes, αT inhibited glucose-induced DNL by decreasing SREBP-1 processing and lipogenic gene expression. This mechanism is dependent on the antioxidant capacity of αT, as redox-silenced methoxy-αT is unable to inhibit DNL in vitro. OS by itself was sufficient to increase S2P expression in vitro, and S2P is upregulated in NAFLD livers. In summary, we utilized αT to demonstrate a vicious cycle in which NAFLD generates OS, which feeds back to augment DNL and increases steatosis.Clinicaltrials.gov: NCT01792115.

Despite the widespread availability of effective vaccines, new cases of infection with severe acute respiratory syndrome coronavirus-2, the cause of coronavirus disease 2019 (COVID-19), remain a concern in the settings of vaccine hesitancy and vaccine breakthrough. In this randomized, controlled, phase 2 trial, we hypothesized that high-dose ascorbic acid delivered intravenously to achieve pharmacologic concentrations may target the high viral phase of COVID-19 and thus improve early clinical outcomes. Sixty-six patients admitted with COVID-19 and requiring supplemental oxygen were randomized to receive either escalating doses of intravenous ascorbic acid plus standard of care or standard of care alone. The demographic and clinical characteristics were well-balanced between the two study arms. The primary outcome evaluated in this study was clinical improvement at 72 h after randomization. While the primary outcome was not achieved, point estimates for the composite outcome and its individual components of decreased use of supplemental oxygen, decreased use of bronchodilators, and the time to discharge were all favorable for the treatment arm. Possible favorable effects of ascorbic acid were most apparent during the first 72 h of hospitalization, although these effects disappeared over the course of the entire hospitalization. Future larger trials of intravenous ascorbic acid should be based on our current understanding of COVID-19 with a focus on the potential early benefits of ascorbic in hospitalized patients.

Despite its transport by glucose transporters (GLUTs) in vitro, it is unknown whether dehydroascorbic acid (oxidized vitamin C, DHA) has any in vivo function. To investigate, we created a chemical transport knockout model using the vitamin C analog 6-bromo-ascorbate. This analog is transported on sodium-dependent vitamin C transporters but its oxidized form, 6-bromo-dehydroascorbic acid, is not transported by GLUTs. Mice (gulo−/−) unable to synthesize ascorbate (vitamin C) were raised on 6-bromo-ascorbate. Despite normal survival, centrifugation of blood produced hemolysis secondary to near absence of red blood cell (RBC) ascorbate/6-bromo-ascorbate. Key findings with clinical implications were that RBCs in vitro transported dehydroascorbic acid but not bromo-dehydroascorbic acid; RBC ascorbate in vivo was obtained only via DHA transport; ascorbate via DHA transport in vivo was necessary for RBC structural integrity; and internal RBC ascorbate was essential to maintain ascorbate plasma concentrations in vitro/in vivo.

Trial registration ClinicalTrials.gov : NCT03509350 . Registered on 26 April 2018.

This article argues that Israel's occupation of Palestinian territory represents criminalized state behaviour at the most systematic, intricately planned and executed. Evoking the quantum physics of Israel's matrix of control, the article argues that to understand how it feels to live as a Palestinian today requires the mindset of a particle physicist, not a social scientist. Life in Israel/Palestine involves negotiating a host of forces over which the average Palestinian has as much control as the average electron or proton does over the nuclear and quantum forces determining its path. The power embodied in Israel's matrix of control lies in the state's ability to shift rules, tactics, amplitude and frequency of the forces, strategies and techniques and technologies of occupation. The article argues that the Occupation and the conditions it creates have become normalized, and that maintaining a situation of confusion and ambiguity is key to making the Occupation effectively permanent.

This articles explores the explosion of artistic production in the Arab world during the so-called Arab Spring. Focusing on music, poetry, theatre, and graffiti and related visual arts, I explore how these “do-it-yourself” scenes represent, at least potentially, a “return of the aura” to the production of culture at the edge of social and political transformation. At the same time, the struggle to retain a revolutionary grounding in the wake of successful counter-revolutionary moves highlights the essentially “religious” grounding of “committed” art at the intersection of intense creativity and conflict across the Arab world.

Strategies to prevent diabetic microvascular angiopathy focus on the vascular endothelium. Because red blood cells (RBCs) are less deformable in diabetes, we explored an original concept linking decreased RBC deformability to RBC ascorbate and hyperglycemia. We characterized ascorbate concentrations from human and mouse RBCs and plasma, and showed an inverse relationship between RBC ascorbate concentrations and deformability, measured by osmotic fragility. RBCs from ascorbate deficient mice were osmotically sensitive, appeared as spherocytes, and had decreased β-spectrin. These aberrancies reversed with ascorbate repletion in vivo. Under physiologic conditions, only ascorbate's oxidation product dehydroascorbic acid (DHA), a substrate for facilitated glucose transporters, was transported into mouse and human RBCs, with immediate intracellular reduction to ascorbate. In vitro, glucose inhibited entry of physiologic concentrations of dehydroascorbic acid into mouse and human RBCs. In vivo, plasma glucose concentrations in normal and diabetic mice and humans were inversely related to respective RBC ascorbate concentrations, as was osmotic fragility. Human RBC β-spectrin declined as diabetes worsened. Taken together, hyperglycemia in diabetes produced lower RBC ascorbate with increased RBC rigidity, a candidate to drive microvascular angiopathy. Because glucose transporter expression, DHA transport, and its inhibition by glucose differed for mouse versus human RBCs, human experimentation is indicated.

Post-aggression consolation is assumed to occur in humans as well as in chimpanzees. While consolation following peer aggression has been observed in children, systematic evidence of consolation in human adults is rare. We used surveillance camera footage of the immediate aftermath of nonfatal robberies to observe the behaviors and characteristics of victims and bystanders. Consistent with empathy explanations, we found that consolation was linked to social closeness rather than physical closeness. While females were more likely to console than males, males and females were equally likely to be consoled. Furthermore, we show that high levels of threat during the robbery increased the likelihood of receiving consolation afterwards. These patterns resemble post-aggression consolation in chimpanzees and suggest that emotions of empathic concern are involved in consolation across humans and chimpanzees.

Claudin-low breast cancer is a molecular type of breast cancer originally identified by gene expression profiling and reportedly associated with poor survival. Claudin-low tumors have been recognised to preferentially display a triple-negative phenotype, however only a minority of triple-negative breast cancers are claudin-low. We sought to identify an immunohistochemical profile for claudin-low tumors that could facilitate their identification in formalin fixed paraffin embedded tumor material. First, an in silico collection of ~1600 human breast cancer expression profiles was assembled and all claudin-low tumors identified. Second, genes differentially expressed between claudin-low tumors and all other molecular subtypes of breast cancer were identified. Third, a number of these top differentially expressed genes were tested using immunohistochemistry for expression in a diverse panel of breast cancer cell lines to determine their specificity for claudin-low tumors. Finally, the immunohistochemical panel found to be most characteristic of claudin-low tumors was examined in a cohort of 942 formalin fixed paraffin embedded human breast cancers with >10 years clinical follow-up to evaluate the clinico-pathologic and survival characteristics of this tumor subtype. Using this approach we determined that claudin-low breast cancer is typically negative for ER, PR, HER2, claudin 3, claudin 4, claudin 7 and E-cadherin. Claudin-low tumors identified with this immunohistochemical panel, were associated with young age of onset, higher tumor grade, larger tumor size, extensive lymphocytic infiltrate and a circumscribed tumor margin. Patients with claudin-low tumors had a worse overall survival when compared to patients with luminal A type breast cancer. Interestingly, claudin-low tumors were associated with a low local recurrence rate following breast conserving therapy. In conclusion, a limited panel of antibodies can facilitate the identification of claudin-low tumors. Furthermore, claudin-low tumors identified in this manner display similar clinical, pathologic and survival characteristics to claudin-low tumors identified from fresh frozen tumor material using gene expression profiling.

Background: Approximately 20% of all newly diagnosed breast cancer cases in Canada occur in women less than 50 years of age. Young women diagnosed with breast cancer (YWBC) may experience unique physical and psycho-social issues. There is a lack of data outlining the specific needs and experiences across the trajectory of care in YWBC. This study aimed to gather and analyze the physical, psycho-social and informational needs of YWBC at a regional cancer centre. Methods: Participants attended either a focus group or interview that was moderated by following a semi-structured interview format. Transcripts were reviewed independently and then compiled by themes and recurring responses by two reviewers using constant comparative method. Discrepancies were resolved via consensus and definitions were revised. Results: Focus groups and interviews were conducted with a total of 16 women, 40 years of age or less, diagnosed with breast cancer within the last year. Several themes arose from the data which included the need for: age appropriate information; timely referral to fertility services and supportive care services. Most participants reported experiencing a timely work-up and diagnosis. All participants expressed distress. The most common triggers were telling their children of their diagnosis, waiting for biopsy results and fear of recurrence. Conclusion: Most YWBC reported they were provided with adequate medical information for decision-making. However gaps were found in supports for psycho-social, fertility, and sexuality needs. Further research is needed to understand how changes could be implemented to help better meet the needs of YWBC.

Introduction Parenteral anticoagulants may improve outcomes in patients with cancer by reducing risk of venous thromboembolic disease and through a direct antitumour effect. Study-level systematic reviews indicate a reduction in venous thromboembolism and provide moderate confidence that a small survival benefit exists. It remains unclear if any patient subgroups experience potential benefits.Methods and analysis First, we will perform a comprehensive systematic search of MEDLINE, EMBASE and The Cochrane Library, hand search scientific conference abstracts and check clinical trials registries for randomised control trials of participants with solid cancers who are administered parenteral anticoagulants. We anticipate identifying at least 15 trials, exceeding 9000 participants. Second, we will perform an individual participant data meta-analysis to explore the magnitude of survival benefit and address whether subgroups of patients are more likely to benefit from parenteral anticoagulants. All analyses will follow the intention-to-treat principle. For our primary outcome, mortality, we will use multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect. We will adjust analysis for important prognostic characteristics. To investigate whether intervention effects vary by predefined subgroups of patients, we will test interaction terms in the statistical model. Furthermore, we will develop a risk-prediction model for venous thromboembolism, with a focus on control patients of randomised trials.Ethics and dissemination Aside from maintaining participant anonymity, there are no major ethical concerns. This will be the first individual participant data meta-analysis addressing heparin use among patients with cancer and will directly influence recommendations in clinical practice guidelines. Major cancer guideline development organisations will use eventual results to inform their guideline recommendations. Several knowledge users will disseminate results through presentations at clinical rounds as well as national and international conferences. We will prepare an evidence brief and facilitate dialogue to engage policymakers and stakeholders in acting on findings.Trial registration number PROSPERO CRD42013003526.

Background: Ascorbate (vitamin C) has been evaluated as a potential treatment for cancer as an independent agent and in combination with standard chemotherapies. This review assesses the evidence for safety and clinical effectiveness of intravenous (IV) ascorbate in treating various types of cancer. Methods: Single arm and randomized Phase I/II trials were included in this review. The PubMed, MEDLINE, and Cochrane databases were searched. Results were screened by three of the authors (GN, RP, and CJP) to determine if they met inclusion criteria, and then summarized using a narrative approach. Results: A total of 23 trials involving 385 patients met the inclusion criteria. Only one trial, in ovarian cancer, randomized patients to receive vitamin C or standard of care (chemotherapy). That trial reported an 8.75 month increase in progression-free survival (PFS) and an improved trend in overall survival (OS) in the vitamin C treated arm. Conclusion: Overall, vitamin C has been shown to be safe in nearly all patient populations, alone and in combination with chemotherapies. The promising results support the need for randomized placebo-controlled trials such as the ongoing placebo-controlled trials of vitamin C and chemotherapy in prostate cancer.

Under what conditions will a bystander intervene to try to stop a violent attack by one person on another? It is generally believed that the greater the size of the crowd of bystanders, the less the chance that any of them will intervene. A complementary model is that social identity is critical as an explanatory variable. For example, when the bystander shares common social identity with the victim the probability of intervention is enhanced, other things being equal. However, it is generally not possible to study such hypotheses experimentally for practical and ethical reasons. Here we show that an experiment that depicts a violent incident at life-size in immersive virtual reality lends support to the social identity explanation. 40 male supporters of Arsenal Football Club in England were recruited for a two-factor between-groups experiment: the victim was either an Arsenal supporter or not (in-group/out-group), and looked towards the participant for help or not during the confrontation. The response variables were the numbers of verbal and physical interventions by the participant during the violent argument. The number of physical interventions had a significantly greater mean in the in-group condition compared to the out-group. The more that participants perceived that the Victim was looking to them for help the greater the number of interventions in the in-group but not in the out-group. These results are supported by standard statistical analysis of variance, with more detailed findings obtained by a symbolic regression procedure based on genetic programming. Verbal interventions made during their experience, and analysis of post-experiment interview data suggest that in-group members were more prone to confrontational intervention compared to the out-group who were more prone to make statements to try to diffuse the situation.

BackgroundPreclinical data support further investigation of ascorbic acid in pancreatic cancer. There are currently insufficient safety data in human subjects, particularly when ascorbic acid is combined with chemotherapy.Methods and findings14 subjects with metastatic stage IV pancreatic cancer were recruited to receive an eight week cycle of intravenous ascorbic acid (three infusions per week), using a dose escalation design, along with standard treatment of gemcitabine and erlotinib. Of 14 recruited subjects enrolled, nine completed the study (three in each dosage tier). There were fifteen non-serious adverse events and eight serious adverse events, all likely related to progression of disease or treatment with gemcitabine or erlotinib. Applying RECIST 1.0 criteria, seven of the nine subjects had stable disease while the other two had progressive disease.ConclusionsThese initial safety data do not reveal increased toxicity with the addition of ascorbic acid to gemcitabine and erlotinib in pancreatic cancer patients. This, combined with the observed response to treatment, suggests the need for a phase II study of longer duration.Trial registrationClinicaltrials.gov NCT00954525.

Anecdotal information and case reports suggest that intravenously administered vitamin C is used by Complementary and Alternate Medicine (CAM) practitioners. The scale of such use in the U.S. and associated side effects are unknown.We surveyed attendees at annual CAM Conferences in 2006 and 2008, and determined sales of intravenous vitamin C by major U.S. manufacturers/distributors. We also queried practitioners for side effects, compiled published cases, and analyzed FDA's Adverse Events Database. Of 199 survey respondents (out of 550), 172 practitioners administered IV vitamin C to 11,233 patients in 2006 and 8876 patients in 2008. Average dose was 28 grams every 4 days, with 22 total treatments per patient. Estimated yearly doses used (as 25 g/50 ml vials) were 318,539 in 2006 and 354,647 in 2008. Manufacturers' yearly sales were 750,000 and 855,000 vials, respectively. Common reasons for treatment included infection, cancer, and fatigue. Of 9,328 patients for whom data is available, 101 had side effects, mostly minor, including lethargy/fatigue in 59 patients, change in mental status in 21 patients and vein irritation/phlebitis in 6 patients. Publications documented serious adverse events, including 2 deaths in patients known to be at risk for IV vitamin C. Due to confounding causes, the FDA Adverse Events Database was uninformative. Total numbers of patients treated in the US with high dose vitamin C cannot be accurately estimated from this study.High dose IV vitamin C is in unexpectedly wide use by CAM practitioners. Other than the known complications of IV vitamin C in those with renal impairment or glucose 6 phosphate dehydrogenase deficiency, high dose intravenous vitamin C appears to be remarkably safe. Physicians should inquire about IV vitamin C use in patients with cancer, chronic, untreatable, or intractable conditions and be observant of unexpected harm, drug interactions, or benefit.

In 2004, the United States Food and Drug Administration approved a radiofrequency identification (RFID) device that is implanted under the skin of the upper arm of patients and that stores the patient's medical identifier. When a scanner is passed over the device, the identifier is displayed on the screen of an RFID reader. An authorized health professional can then use the identifier to access the patient's clinical information, which is stored in a separate, secure database. Such RFID devices may have many medical benefits--such as expediting identification of patients and retrieval of their medical records. But critics of the technology have raised several concerns, including the risk of the patient's identifying information being used for nonmedical purposes.