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IMPORTANCE: Tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations and minimized patient-reported health status deterioration at 30 months in patients with transthyretin (ATTR) amyloidosis. However, the clinical significance of health status changes remains unclear, particularly in patients with New York Heart Association (NYHA) class III symptoms who experienced more cardiovascular-related hospitalizations than those with NYHA class I-II symptoms. OBJECTIVE: To evaluate the health status of patients taking tafamidis with baseline NYHA class III symptoms. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial post hoc analysis evaluated data for patients with transthyretin (ATTR) cardiac amyloidosis and NYHA class I-III symptoms at baseline who were enrolled in ATTR-ACT, a placebo-controlled study of tafamidis held at 48 sites in 13 countries. INTERVENTIONS: Tafamidis meglumine, 80 mg or 20 mg (pooled cohort), vs placebo. MAIN OUTCOMES AND MEASURES: Established thresholds for clinical benefit on the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) were used to define response groups (very large decline to very large improvement); the proportion of patients in each group was calculated within each baseline NYHA class. RESULTS: Among 441 patients (264 tafamidis, 177 placebo), the mean (SD) age was 74.3 (7.0) years; 398 (90%) were male and 43 (10%) were female. Mean (SD) baseline KCCQ-OS scores were 67.3 (21.4) in the tafamidis group and 65.9 (21.7) in the placebo group (range: 0-100, with 100 indicating the best health). There was a significant shift toward better KCCQ-OS scores in patients receiving tafamidis (odds ratio for 10-point improvement 2.4; 95% CI, 1.6-3.4; P < .001). More patients taking tafamidis were alive and not worse at all time points (37% vs 15% at month 30). These findings were similar in patients with NYHA class III symptoms. In patients with NYHA class III symptoms alive at 30 months, improvements in health status were more common (35% vs 10%) and declines were less common (38% vs 57%) with tafamidis vs placebo. CONCLUSIONS AND RELEVANCE: In ATTR-ACT, although patients with baseline NYHA class III symptoms had worse overall outcomes, treatment with tafamidis yielded better health status compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01994889

Aim:Delayed diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) represents a missed opportunity for intervention. This study estimates the health benefits of timely diagnosis and treatment with tafamidis. Methods:A disease simulation model was developed to predict health outcomes under scenarios of timely and delayed diagnosis and treatment. Efficacy and quality of life (QoL) profiles were derived from the pivotal tafamidis trial and diagnostic delay durations from the literature. Results:Timely diagnosis and treatment were predicted to extend mean life expectancy by 5.46 and 7.76 years, relative to delayed diagnosis, for wild-type and hereditary ATTR-CM, respectively. Corresponding QALY gains were 4.50 and 6.22. Conclusion:Timely diagnosis and treatment with tafamidis are predicted to significantly improve survival and QoL for ATTR-CM patients.

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, fatal and under-recognized disease. This targeted literature review assessed the extent and consequences of diagnostic delay and misdiagnosis in ATTR-CM. Methods: The Embase database was searched together with proceedings of eight cardiology conferences to identify publications or abstracts on ATTR-CM. Outcomes of interest were time from symptom onset to diagnosis, rates of delayed diagnosis and misdiagnosis, and costs, healthcare resource use or clinical outcomes whilst undiagnosed/misdiagnosed. Results: Twenty-three articles were included. Weighted means of reported mean and median diagnostic delays were 6.1 and 3.4 years for wild-type (ATTRwt-CM) and 5.7 and 2.6 years for hereditary (ATTRv-CM). Misdiagnosis occurred in 34–57% of patients when reported. Evaluation and misdiagnosis by multiple healthcare providers before receiving an ATTR-CM diagnosis was common, and there was evidence that patients undergo unnecessary or inappropriate evaluations or treatments while misdiagnosed. Diagnostic “red flags” were reported to be underused. Data on the consequences of delay for patients and health systems were sparse, but given the progressive nature of ATTR-CM, delay is likely to have adverse consequences. Conclusion: ATTR-CM patients commonly experience diagnostic delay and misdiagnosis. Efforts are required to provide timely diagnosis so that patients can benefit from earlier access to new disease-modifying therapies.

Introduction: In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT; ClinicalTrials.gov number NCT01994889), tafamidis reduced the risk of all-cause mortality in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) by 30% versus placebo. Median overall survival was not achieved in either treatment arm (57.1 and 70.5% of patients in the placebo and tafamidis groups, respectively, survived at 30 months), limiting assessment of the potential survival benefits of treatment. Methods: A survival extrapolation analysis was conducted following technical support guidelines from the National Institute for Health and Care Excellence. Multiple models (i.e., exponential, Weibull, gamma, log-logistic, log-normal, Gompertz, generalized gamma, and generalized F) were applied to systematically fit different candidate curves to existing patient-level data from the 30-month treatment period in ATTR-ACT. The relative goodness-of-fit for each candidate curve was then tested by Akaike’s and Bayesian information criteria to select a single model that was fitted to the placebo and pooled tafamidis treatment arms. Results: A gamma distribution was selected as best fitting model and fitted to both treatment arms. The resulting estimated median overall survival was 35.16 months for placebo and 52.64 months for tafamidis (difference 17.48 months). Conclusions: This extrapolation of survival data from ATTR-ACT further supports the efficacy of tafamidis in patients with ATTR-CM. Owing to the limitations of this analysis, these survival estimates should be interpreted with caution; however, they are consistent with recently presented findings from a combined analysis of data from ATTR-ACT and interim data from an ongoing long-term extension study (median follow-up 36 months; ClinicalTrials.gov number NCT02791230). Trial Registration: ClinicalTrials.gov: NCT01994889.

ABSTRACTThe “Big Man” phenomenon is often associated with the African dictator. However, with the rise of modern “strongman” leaders such as Trump, Putin, and Xi, it is not surprising that the notion of the Big Man has come to represent a global condition, one that not only characterises African dictatorship but that also has a precedent in Western tradition. A potent visual and conceptual fictional archetype for the Big Man can be found in Alfred Jarry's Père Ubu, the central character for his play Ubu Roi(1896). While the tyrannical Père Ubu is an evocation of the European psyche of the late 19th century, he is equally compelling today as an archetype and symbol of the contemporary tyrant. This article seeks to investigate this claim by engaging with works by Robert Hodgins and William Kentridge inspired by Père Ubu. The Jarry-inspired Ubu theme is well known throughout Hodgins's and Kentridge's work. However, this article asserts the relevance of their work featuring this theme, given the evocation of an archetypal tyrant figure that has global significance and is pertinent to notions of tyranny in Africa (including South Africa).

Shiga toxin (Stx)-producing Escherichia colihemolytic uremic syndrome (STEC-HUS) is the leading cause of acute kidney injury in children, with an associated mortality of up to 5%. The mechanisms underlying STEC-HUS and why the glomerular microvasculature is so susceptible to injury following systemic Stx infection are unclear.

Precision-cut lung slices (PCLS) are used for a variety of applications. However, methods to manipulate genes in PCLS are currently limited. We developed a new method, TAT-Cre recombinase-mediated floxed allele modification in tissue slices (TReATS), to induce highly effective and temporally controlled gene deletion or activation in ex vivo PCLS. Treatment of PCLS from Rosa26-flox-stop-flox-EYFP mice with cell-permeant TAT-Cre recombinase induced ubiquitous EYFP protein expression, indicating successful Cre-mediated excision of the upstream loxP-flanked stop sequence. Quantitative real-time PCR confirmed induction of EYFP. We successfully replicated the TReATS method in PCLS from Vangl2flox/flox mice, leading to the deletion of loxP-flanked exon 4 of the Vangl2 gene. Cre-treated Vangl2flox/flox PCLS exhibited cytoskeletal abnormalities, a known phenotype caused by VANGL2 dysfunction. We report a new method that bypasses conventional Cre-Lox breeding, allowing rapid and highly effective gene manipulation in ex vivo tissue models.

The article offers information on the status of two-tiered justice system in Saskatchewan, citing the cases of Colten Boushie and Haven Dubois. Topics discussed include discrimination against in Indigenous people, police investigations into the death of Boushie and Dubois, and experiences of the victims' mothers in fighting for justice.

Although next-generation sequencing has revolutionized the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by a lack of knowledge of the functions and pathobiological mechanisms of most genes. To address this challenge, the International Mouse Phenotyping Consortium is creating a genome- and phenome-wide catalog of gene function by characterizing new knockout-mouse strains across diverse biological systems through a broad set of standardized phenotyping tests. All mice will be readily available to the biomedical community. Analyzing the first 3,328 genes identified models for 360 diseases, including the first models, to our knowledge, for type C Bernard–Soulier, Bardet–Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations were novel, providing functional evidence for 1,092 genes and candidates in genetically uncharacterized diseases including arrhythmogenic right ventricular dysplasia 3. Finally, we describe our role in variant functional validation with The 100,000 Genomes Project and others.

The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor that plays a pivotal role in extracellular calcium homeostasis. The CaSR is also highly expressed in pancreatic islet α- and β-cells that secrete glucagon and insulin, respectively. To determine whether the CaSR may influence systemic glucose homeostasis, we characterized a mouse model with a germline gain-of-function CaSR mutation, Leu723Gln, referred to as Nuclear flecks (Nuf). Heterozygous- (CasrNuf/+) and homozygous-affected (CasrNuf/Nuf) mice were shown to have hypocalcemia in association with impaired glucose tolerance and insulin secretion. Oral administration of a CaSR antagonist compound, known as a calcilytic, rectified the glucose intolerance and hypoinsulinemia of CasrNuf/+ mice and ameliorated glucose intolerance in CasrNuf/Nuf mice. Ex vivo studies showed CasrNuf/+ and CasrNuf/Nuf mice to have reduced pancreatic islet mass and β-cell proliferation. Electrophysiological analysis of isolated CasrNuf/Nuf islets showed CaSR activation to increase the basal electrical activity of β-cells independently of effects on the activity of the adenosine triphosphate (ATP)-sensitive K+ (KATP) channel. CasrNuf/Nuf mice also had impaired glucose-mediated suppression of glucagon secretion, which was associated with increased numbers of α-cells and a higher α-cell proliferation rate. Moreover, CasrNuf/Nuf islet electrophysiology demonstrated an impairment of α-cell membrane depolarization in association with attenuated α-cell basal KATP channel activity. These studies indicate that the CaSR activation impairs glucose tolerance by a combination of α- and β-cell defects and also influences pancreatic islet mass. Moreover, our findings highlight a potential application of targeted CaSR compounds for modulating glucose metabolism.

At its Canadian premier, Dominic Gagnon's Of the North (2015) launched a passionate debate regarding the ethics of image appropriation and digital filmmaking about Indigenous communities. Of the North follows Gagnon's “natively” digital method, which involves the sampling and montage of public domain images and sounds posted by internauts with the stated intent of documenting how people represent themselves online. In a controversy that crystallized around questions of “digital sovereignty,” Inuit critics decried the recontextualization of personal video posts by a film, they argued, that did not promote an Inuit view of Inuit experience. This article addresses the ways in which Gagnon's digital method collapsed cultural contexts, bringing to light divergent cultural and generational expectations regarding digital presence and sovereignty. An analysis of the film's heated reception and new digital works by young Indigenous filmmakers suggests an intercultural ethics for visual ethnographies.

It is the current authors’ perspective that the successful implementation of Changing Directions, Changing Lives,which seeks to improve mental health and well-being in Canada, cannot be realized effectively without considering FASD. Given that 94% of individuals with FASD also have mental disorders, practitioners in the mental health system are encountering these individuals every day. Most mental health professionals have not been trained to identify or diagnose FASD, and therefore it goes largely “unseen,” and individual treatment plans lack efficacy. Implementation of FASD-informed recommendations, such as those of the Truth and Reconciliation Commission of Canada (2015), can provide a more effective approach to mental health services and improve mental health outcomes.

The impact on parental psychological functioning as a result of living with disruptive, challenging, and dangerous behaviours exhibited by some children with Autism Spectrum Disorder (ASD) is investigated. Core features of ASD along with aggression, elopement, self-injury, and suicidal ideation can cause significant parental distress. This parenting experience may be associated with depression, anxiety, somatisation, and anger-hostility. It is proposed that a traumatic stress framework may assist in conceptualising some parents’ experiences and psychological symptomatology. A systematic review revealed only one study that had explored posttraumatic stress symptoms amongst parents of children with ASD. Consequently, a narrative literature review has been conducted to explore this emerging area of enquiry. The Diagnostic and Statistical Manual of Mental Health Disorders (fifth edition) recognises direct experience as well as witnessing actual or threatened serious injury as a traumatic event that can lead to trauma-related psychopathology. Despite some parents of children with ASD experiencing traumatic events (e.g. their child engaging in self-injurious behaviours), prevalence rates of Posttraumatic Stress Disorder amongst this population are unknown. Further research is required to determine the validity of adopting a traumatic stress framework when considering parent symptomatology, and if such a framework were valid, there would be significant implications for optimising support and intervention for parents.

Better understanding of suicide risk and its management in older adults with cognitive impairment and/or dementia remain significant unmet public health needs. Urgency to address them derives from concern that CNS treatments for dementia may impact suicide risk. Regulatory guidances requiring assessment of emergent suicidal ideation and behavior (SI/SB) at every clinical trial visit emphasize the need for understanding their prevalence.

The AARR task force on suicidal ideation and behavior (SI/SB) in dementia conducted an online survey on the extent of SI/SB in individuals diagnosed with mild cognitive impairment (MCI) or dementia who were participating in clinical trials.

Individuals with multiple sclerosis (MS) experience diminished health outcomes. However, little is known about how these outcomes differ according to disease severity. The aim of this study is to compare health-related quality of life (HRQoL), work productivity, activity impairment, and resource use between MS patients and controls, as well as across MS patients with varying self-reported disease severity.

The increased worldwide awareness of seasonal and pandemic influenza, including pandemic H1N1 virus, has stimulated interest in the development of economic platforms for rapid, large-scale production of safe and effective subunit vaccines. In recent years, plants have demonstrated their utility as such a platform and have been used to produce vaccine antigens against various infectious diseases. Previously, we have produced in our transient plant expression system a recombinant monomeric hemagglutinin (HA) protein (HAC1) derived from A/California/04/09 (H1N1) strain of influenza virus and demonstrated its immunogenicity and safety in animal models and human volunteers. In the current study, to mimic the authentic HA structure presented on the virus surface and to improve stability and immunogenicity of the HA antigen, we generated trimeric HA by introducing a trimerization motif from a heterologous protein into the HA sequence. Here, we describe the engineering, production in Nicotiana benthamianaplants, and characterization of the highly purified recombinant trimeric HA protein (tHA-BC) from A/California/04/09 (H1N1) strain of influenza virus. The results demonstrate the induction of serum hemagglutination inhibition antibodies by tHA-BC and its protective efficacy in mice against a lethal viral challenge. In addition, the immunogenic and protective doses of tHA-BC were much lower compared with monomeric HAC1. Further investigation into the optimum vaccine dose and/or regimen as well as the stability of trimerized HA is necessary to determine whether trimeric HA is a more potent vaccine antigen than monomeric HA.

The article discusses the role of multidisciplinary teams (MDTs) concerning the combat and prevention of child abuse among the Native American communities, also known as Indian Country, across the U.S. It mentions that MDT investigates and prosecutes a case effective without victimizing and causing further trauma to the child. It highlights the benefits of MDTs to the law enforcement agencies which include child empowerment, enhanced treatment of victims and fostering efficient investigations. INSET: An MDT Success Story.

The objectives of this study were to evaluate the effects of switching from quetiapine to ziprasidone on weight, safety, and effectiveness

H5N1 avian influenza continues to be a potential pandemic threat. Several vaccine candidates based on potentially pandemic influenza strains and antiviral drugs have been tested in preclinical and clinical studies. The data obtained so far have shown some promise, but have also revealed some shortcomings with both of these approaches. We have identified and characterized an H5N1 neuraminidase-specific monoclonal antibody which specifically inhibits N1 neuraminidase activity of highly pathogenic avian influenza (HPAI) strains from clades 1 and 2. We have also shown the protective efficacy of this antibody in animal challenge models using homologous virus. Specific and effective inhibition of N1 NA could make this mAb a useful therapeutic tool in the treatment of human infection, in particular with oseltamivir- and zanamivir-resistant strains of HPAI.

The health and economic burden of infectious diseases in general and bioterrorism in particular necessitate the development of medical countermeasures. One proven approach to reduce the disease burden and spread of pathogen is treatment with monoclonal antibodies (mAb). mAbs can prevent or reduce severity of the disease by variety of mechanisms, including neutralizing pathogen growth, limiting its spread from infected to adjacent cells, or by inhibiting biological activity of toxins, such as anthrax lethal toxin. Here, we report the production of glycosylated (pp-mAbPA) and non-glycosylated (pp-mAbPANG) versions of a plant-derived mAb directed against protective antigen (PA) of Bacillus anthracisin Nicotiana benthamianaplants using agroinfiltration. Both forms of the antibody were able to neutralize anthrax lethal toxin activity in vitro and protect mice against an intraperitoneal challenge with spores of B. anthracisSterne strain. A single 180 µg intraperitoneal dose of pp-mAbPAor pp-mAbPANGprovided 90% and 100% survival, respectively. When tested in non-human primates, pp-mAbPANGwas demonstrated to be superior to pp-mAbPAin that it had a significantly longer terminal half-life and conferred 100% protection against a lethal dose of aerosolized anthrax spore challenge after a single 5 mg/kg intravenous dose compared to a 40% survival rate conferred by pp-mAbPA. This study demonstrates the potential of a plant-produced non-glycosylated antibody as a useful tool for the treatment of inhalation anthrax.

The article addresses the problem of settler colonialism and systems of oppression and privilege in Canada. Topics discussed are the recommendations of the Truth and Reconciliation Commission (TRC), the proposed reform of Canada's justice system, obscurity of the systemic nature of racism, and oppression as an outcome of specific systems of justice, education, health and social services.

Rituximab, an anti-CD20 chimeric monoclonal antibody, is widely used in hematologic malignancies and has been introduced as a therapeutic option in autoimmune disorders. In recent studies, rituximab has shown promising activity in steroid-refractory chronic graft-versus-host disease (cGvHD) at a weekly dose of 375 mg/m2. We now report on 13 subjects after peripheral blood stem-cell transplantation receiving low-dose rituximab (50 mg/m2) for steroid-refractory cGvHD and autoimmune disorders (membranous glomerulonephritis and immune thrombocytopenic purpura). The overall response rate was 69%, including two patients with complete responses. In accordance, we observed clearance of periperal blood B cells even after the first dose of rituximab in four patients. We conclude that low-dose rituximab seems to be active and safe in intensively pretreated patients with steroid-refractory cGvHD.

This study explores spouses' experiences of their partners' absence due to frequent business travel. Semi-structured interviews were conducted with five male and five female participants, all of whom had at least one child living with and dependent on them. The findings indicate that respondents generally do not find their spouses' absence to be inherently stressful. However, negative outcomes were more common than positive ones. Various dynamics operate in the remaining spouses' appraisal of the situation. The main coping resources utilised included work flexibility and social support. Spouses used both problem and emotion-focused coping strategies to cope with their partners' absence. Women in the sample tended to make greater use of coping strategies as well as having more extensive and varied coping repertoires, particularly with respect to emotion-focused coping.

This paper is about contact. Kingston, the capital of Jamaica, is presented as a contact setting in an urban environment, and use is made of the components of the setting to analyse the influences on the formation of basilectal varieties there. In this paper, focus is, on the role which external ecologies played in the early development of the lectal varieties closest to the basilect in Kingston.The study tracks the peopling of Kingston from its formation to the Morant Bay Rebellion. It is divided sectionally by period and focuses on the role which external ecologies such as those mentioned above, played in the early development of the lectal varieties closest to the basilect in Kingston. Within each period, the linguistic implications of relevant aspects of the contact situation are discussed. The population growth and distribution in the 18th century, and an analysis in some detail is made of the social composition of the in-migrants who were in large part responsible for the growth experienced throughout the century. The period leading up to, and immediately following full Emancipation (1800–1865), ends the inquiry. This provides a logical end-point for the investigation since, as will become evident in the reading.

The stereospecific synthesis of nine trans-combretastatin analogs (5 - 13) is described. The trans geometry of these products was ascertained by the vinylenic proton NMR coupling constants of 15 - 16 Hz, and also by a single crystal x-ray structure of the tetramethoxy compound 6. Continuous 3-day exposure of murine B16 melanoma cells to the trans-combretastatin analogs 5 - 13 showed that two of the analogs (2 and 4) had good cytotoxicity. According to a MTT assay, the IC50 values for compounds 2 and 4 were 4.5 μM and 13.5 μM, respectively. Compounds that exhibited cytotoxic properties contain a 4,4'-dimethoxy-transstilbene skeleton.

Introduction:The C57BL/6J and C57BL/6N are two of the most commonly used mouse strains in biological research. We recently discovered C57BL/6N males develop a modest dilated cardiomyopathy (DCM) by 12 months, which is absent from the closely related C57BL/6J. We identified a variant (Chr8:85365179A>T, c.-5T>A) in myosin light chain kinase 3 (Mylk3) in the 5’ UTR of the primary isoform resident to C57BL/6N substrains, which abolishes translation of this isoform. Myosin light chain 2 (MYL2) is the primary target of MYLK3, and its phosphorylation is vital for survival.Hypothesis:Loss of MYLK3 expression alters phosphorylation of key cardiac proteins.Results:Surprisingly, we found no difference in MYL2 phosphorylation by western blot between C57BL/6N and C57BL/6J hearts, at any of the reported target residues. Phosphoproteomics corroborated this, but highlighted significantly different phosphorylation at a number of phosphosites in other proteins linked to cardiomyopathies and cardiac development, particularly a reduction of a number of residues in ACTN2. We also detected peptide sequences that mapped to the C-terminus and middle of MYLK3 in the C57BL/6N. Western blotting with a C-terminal specific antibody revealed expression of a shorter isoform, present at lower levels in both strains, that is unaffected by the variant due to a distinct N-terminus. Using this antibody in IHC showed similar spatial expression of MYLK3 in hearts from both strains, localizing to the Z-disc, although the expression was much lower in the C57BL/6N presumed to be due to lack of the more abundant full-length isoform. Using immunoprecipitation, we found both isoforms bound to MYL2 in vivoand in vitro, and both were capable of phosphorylating MYL2 in vitro.However, the shorter isoform was not as readily bound to alpha-actinin-2 (ACTN2), a key sarcomeric protein that is reported to bind full-length MYLK3 isoform by its N-terminus.Conclusions:This data indicates loss of full-length MYLK3 causes DCM via a MYL2-independent mechanism, possibly due to lack of phosphorylation of alternative target(s), such as ACTN2. The expression of the shorter MYLK3 isoform in C57BL/6N mice may explain the persistence of MYL2 phosphorylation in these mice and enable their survival.