Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

The chemotherapeutic agent doxorubicin (DOX) has significantly increased survival rates of pediatric and adult cancer patients. However, 10% of pediatric cancer survivors will 10–20 years later develop severe dilated cardiomyopathy (DCM), whereby the exact molecular mechanisms of disease progression after this long latency time remain puzzling. We here revisit the hypothesis that elevated apoptosis signaling or its increased likelihood after DOX exposure can lead to an impairment of cardiac function and cause a cardiac dilation. Based on recent literature evidence, we first argue why a dilated phenotype can occur when little apoptosis is detected. We then review findings suggesting that mature cardiomyocytes are protected against DOX-induced apoptosis downstream, but not upstream of mitochondrial outer membrane permeabilisation (MOMP). This lack of MOMP induction is proposed to alter the metabolic phenotype, induce hypertrophic remodeling, and lead to functional cardiac impairment even in the absence of cardiomyocyte apoptosis. We discuss findings that DOX exposure can lead to increased sensitivity to further cardiomyocyte apoptosis, which may cause a gradual loss in cardiomyocytes over time and a compensatory hypertrophic remodeling after treatment, potentially explaining the long lag time in disease onset. We finally note similarities between DOX-exposed cardiomyocytes and apoptosis-primed cancer cells and propose computational system biology as a tool to predict patient individual DOX doses. In conclusion, combining recent findings in rodent hearts and cardiomyocytes exposed to DOX with insights from apoptosis signal transduction allowed us to obtain a molecularly deeper insight in this delayed and still enigmatic pathology of DC

Effect of spinal manipulation on sensorimotor functions in back pain patients: study protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Low back pain (LBP) is a recognized public health problem, impacting up to 80% of US adults at some point in their lives. Patients with LBP are utilizing integrative health care such as spinal manipulation (SM). SM is the therapeutic application of a load to specific body tissues or structures and can be divided into two broad categories: SM with a high-velocity low-amplitude load, or an impulse "thrust", (HVLA-SM) and SM with a low-velocity variable-amplitude load (LVVA-SM). There is evidence that sensorimotor function in people with LBP is altered. This study evaluates the sensorimotor function in the lumbopelvic region, as measured by postural sway, response to sudden load and repositioning accuracy, following SM to the lumbar and pelvic region when compared to a sham treatment.</p> <p>Methods/Design</p> <p>A total of 219 participants with acute, subacute or chronic low back pain are being recruited from the Quad Cities area located in Iowa and Illinois. They are allocated through a minimization algorithm in a 1:1:1 ratio to receive either 13 HVLA-SM treatments over 6 weeks, 13 LVVA-SM treatments over 6 weeks or 2 weeks of a sham treatment followed by 4 weeks of full spine "doctor's choice" SM. Sensorimotor function tests are performed before and immediately after treatment at baseline, week 2 and week 6. Self-report outcome assessments are also collected. The primary aims of this study are to 1) determine immediate pre to post changes in sensorimotor function as measured by postural sway following delivery of a single HVLA-SM or LVVA-SM treatment when compared to a sham treatment and 2) to determine changes from baseline to 2 weeks (4 treatments) of HVLA-SM or LVVA-SM compared to a sham treatment. Secondary aims include changes in response to sudden loads and lumbar repositioning accuracy at these endpoints, estimating sensorimotor function in the SM groups after 6 weeks of treatment, and exploring if changes in sensorimotor function are associated with changes in self-report outcome assessments.</p> <p>Discussion</p> <p>This study may provide clues to the sensorimotor mechanisms that explain observed functional deficits associated with LBP, as well as the mechanism of action of SM.</p> <p>Trial registration</p> <p>This trial is registered in ClinicalTrials.gov, with the ID number of <a href="http://www.clinicaltrials.gov/ct2/show/NCT00830596">NCT00830596</a>, registered on January 27, 2009. The first participant was allocated on 30 January 2009 and the final participant was allocated on 17 March 2011.</p

COVID-19 reopening strategies at the county level in the face of uncertainty: Multiple Models for Outbreak Decision Support

Policymakers make decisions about COVID-19 management in the face of considerable uncertainty. We convened multiple modeling teams to evaluate reopening strategies for a mid- sized county in the United States, in a novel process designed to fully express scientific uncertainty while reducing linguistic uncertainty and cognitive biases. For the scenarios considered, the consensus from 17 distinct models was that a second outbreak will occur within 6 months of reopening, unless schools and non-essential workplaces remain closed. Up to half the population could be infected with full workplace reopening; non-essential business closures reduced median cumulative infections by 82%. Intermediate reopening interventions identified no win-win situations; there was a trade-off between public health outcomes and duration of workplace closures. Aggregate results captured twice the uncertainty of individual models, providing a more complete expression of risk for decision-making purposes.Integrative Biolog

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

The next phase in patient safety education: Towards a standardized, tools-based pathology patient safety curriculum: A call to action from the Association of Pathology Chairs' Residency Program Directors Section Training Residents in Patient Safety Workgroup.

Patient safety education is a mandated Common Program Requirement of the Accreditation Council for Graduate Medical Education and for the Royal College of Physicians and Surgeons of Canada in all medical residency and fellowship programs. Although many hospitals and healthcare environments have general patient safety education tools for trainees, few to none focus on the unique training milieu of pathologists, including a mix of highly automated and manual error-prone processes, frequent multiplicity of events, and lack of direct patient relationships for error disclosure. We established a national Association of Pathology Chairs-Program Directors Section&nbsp;Workgroup focused on patient safety education for pathology trainees entitled Training Residents in Patient Safety (TRIPS). TRIPS included diverse&nbsp;representatives from across the United States, as well as representatives from pathology organizations including the American Board of Pathology, the American Society for Clinical Pathology, the United States and Canadian Academy of Pathology, the College of American Pathologists, and the Society to Improve Diagnosis in Medicine. Objectives of the workgroup included developing a standardized patient safety curriculum, designing teaching and assessment tools, and refining them with pilot sites. Here we report the establishment of TRIPS as well as data from national needs assessment of Program Directors across the country, who confirmed the need for a standardized patient safety curriculum

Villes et politiques urbaines au Canada et aux États-Unis

L'analyse de l'évolution de la ville nord-américaine, surtout depuis les années 1960, permet d'identifier les maux actuels, d'étudier les solutions envisageables et d'évaluer les enjeux sociaux, économiques, urbanistiques et politiques. La perspective comparative a été volontairement privilégiée car elle permet de mieux dégager la spécificité de la ville canadienne. La comparaison est essentiellement centrée sur le Canada et les États-Unis mais n'exclut pas quelques allusions au modèle britannique. Trois avenues disciplinaires ont été privilégiées, celle qui relève du politique, celle qui relève du sociologique et celle qui a trait aux disciplines liées à l'étude et à l'aménagement de l'espace (pour cette dernière, trois axes ou trois niveaux d'analyse ont été retenus et traitent de l'organisation de l'espace, du fonctionnement de l'économie et de la gestion politique tant au niveau national/fédéral que régional ou local). On constate les signes d'une évidente évolution, qu'il s'agisse du passage du semi-social au pénal, c'est-à-dire d'un système de protection à un système de pénalisation ou bien encore du passage de la sphère publique à celle du privé et, enfin, d'une dévolution de pouvoirs qui transfère les responsabilités du niveau central à l'échelon local. On est ainsi passé de la phase de la réglementation par le sommet à une phase de désengagement qui permet les initiatives de la base et du socio-communautaire. Le bilan d'ensemble est à la fois clair et plutôt sombre. Face à l'affaiblissement de la notion de responsabilité collective, l'Impression dominante est de se trouver de plus en plus face à des problèmes sans issue, sans solution mais il est vital de ne pas abandonner. Notre volonté également partagée doit être celle de bâtir la cité idéale, même si cela peut relever de l'utopie. L'ère des illusions et des attentes déçues a conduit à celle du soupçon et de l'impatience. Nous aimerions pouvoir entretenir encore l'Illusion ultime que le progrès est possible. Ce n'est qu'à ce prix que la ville cessera d'être le monde de la barbarie pour devenir celui de la civilisation

Lumbar nerve root injections: a prospective cohort outcomes study comparing age- and gender-matched patients who returned an outcomes-based postal questionnaire with patients who did not return the postal questionnaire

OBJECTIVE: The purpose of this study is to investigate if relying on postal questionnaires returned by patients provides an accurate representation of reported outcomes from patients receiving imaging-guided lumbar nerve root injections (NRIs). MATERIALS AND METHODS: Patients who received imaging-guided transforaminal lumbar NRIs were given short questionnaires inquiring about pain level [numerical rating scale (NRS)] and overall improvement [Patient's Global Impression of Change (PGIC)]. Those who did not return the questionnaires (non-responders) were telephoned and asked about pain level and overall change in condition. Age and gender matching of responders and non-responders resulted in 97 patients in each group. The proportion of patients reporting clinically relevant "improvement" or "worsening" in each group was calculated and the Chi-square test was used to detect differences. NRS and PGIC scores for responders and non-responders were compared using Student's t test and the Mann-Whitney U test, respectively. RESULTS: A higher proportion of non-responders reported clinically relevant improvement (53.6 %) compared to responders (42.6 %) and responders reported significantly higher levels of worsening of condition (p = 0.01). Both responders and non-responders had significant (p ≤ 0.05) improvement on the 20-30-min and 1-month NRS scores compared to their pre-injection baseline scores. Non-responders had significantly higher baseline NRS scores but no significant difference at the 20-30-min and 1-month NRS scores compared to responders. CONCLUSIONS: Patients returning postal questionnaires reported less favorable outcomes compared to those who did not return their questionnaires