The Persistent Southern Disadvantage in Us Early Life Mortality, 1965‒2014

Background: Recent studies of US adult mortality demonstrate a growing disadvantage among southern states. Few studies have examined long-term trends and geographic patterns in US early life (ages 1 to 24) mortality, ages at which key risk factors and causes of death are quite different than among adults. Objective: This article examines trends and variations in early life mortality rates across US states and census divisions. We assess whether those variations have changed over a 50-year time period and which causes of death contribute to contemporary geographic disparities. Methods: We calculate all-cause and cause-specific death rates using death certificate data from the Multiple Cause of Death files, combining public-use files from 1965‒2004 and restricted data with state geographic identifiers from 2005‒2014. State population (denominator) data come from US decennial censuses or intercensal estimates. Results: Results demonstrate a persistent mortality disadvantage for young people (ages 1 to 24) living in southern states over the last 50 years, particularly those located in the East South Central and West South Central divisions. Motor vehicle accidents and homicide by firearm account for most of the contemporary southern disadvantage in US early life mortality. Contribution: Our results illustrate that US children and youth living in the southern United States have long suffered from higher levels of mortality than children and youth living in other parts of the country. Our findings also suggest the contemporary southern disadvantage in US early life mortality could potentially be reduced with state-level policies designed to prevent deaths involving motor vehicles and firearms

Adoptive transfer of mRNA-Transfected T cells redirected against diabetogenic CD8 T cells can prevent diabetes

Chimeric major histocompatibility complex (MHC) molecules supplemented with T cell receptor (TCR) signaling motifs function as activation receptors and can redirect gene-modified T cells against pathogenic CD8 T cells. We have shown that β2 microglobulin (β2m) operates as a universal signaling component of MHC-I molecules when fused with the CD3-ζ chain. Linking the H-2Kd-binding insulin B chain peptide insulin B chain, amino acids 15–23 (InsB15–23) to the N terminus of β2m/CD3-ζ, redirected polyclonal CD8 T cells against pathogenic CD8 T cells in a peptide-specific manner in the non-obese diabetic (NOD) mouse. Here, we describe mRNA electroporation for delivering peptide/β2m/CD3-ζ genes to a reporter T cell line and purified primary mouse CD8 T cells. The peptide/β2m/CD3-ζ products paired with endogenous MHC-I chains and transmitted strong activation signals upon MHC-I cross-linking. The reporter T cell line transfected with InsB15–23/β2m/CD3-ζ mRNA was activated by an InsB15–23-H-2Kd-specific CD8 T cell hybrid only when the transfected T cells expressed H-2Kd. Primary NOD CD8 T cells expressing either InsB15–23/β2m/CD3-ζ or islet-specific glucose-6-phosphatase catalytic subunit-related protein, amino acids 206–214 (IGRP206–214)/β2m/CD3-ζ killed their respective autoreactive CD8 T cell targets in vitro. Furthermore, transfer of primary CD8 T cells transfected with InsB15–23/β2m/CD3-ζ mRNA significantly reduced insulitis and protected NOD mice from diabetes. Our results demonstrate that mRNA encoding chimeric MHC-I receptors can redirect effector CD8 against diabetogenic CD8 T cells, offering a new approach for the treatment of type 1 diabetes

Development of a National Pain Management Competency Profile to Guide Entry-Level Physiotherapy Education in Canada

Background National strategies from North America call for substantive improvements in entry-level pain management education to help reduce the burden of chronic pain. Past work has generated a valuable set of interprofessional pain management competencies to guide the education of future health professionals. However, there has been very limited work that has explored the development of such competencies for individual professions in different regions. Developing profession-specific competencies tailored to the local context is a necessary first step to integrate them within local regulatory systems. Our group is working toward this goal within the context of entry-level physiotherapy (PT) programs across Canada. Aims This study aimed to create a consensus-based competency profile for pain management, specific to the Canadian PT context. Methods A modified Delphi design was used to achieve consensus across Canadian university-based and clinical pain educators. Results Representatives from 14 entry-level PT programs (93% of Canadian programs) and six clinical educators were recruited. After two rounds, a total of 15 competencies reached the predetermined endorsement threshold (75%). Most participants (85%) reported being “very satisfied” with the process. Conclusions This process achieved consensus on a novel pain management competency profile specific to the Canadian PT context. The resulting profile delineates the necessary abilities required by physiotherapists to manage pain upon entry to practice. Participants were very satisfied with the process. This study also contributes to the emerging literature on integrated research in pain management by profiling research methodology that can be used to inform related work in other health professions and regions

Heart Fields: Spatial Polarity and Temporal Dynamics

In chick and mouse, heart fields undergo dynamic morphological spatiotemporal changes during heart tube formation. Here, the dynamic change in spatial polarity of such fields is discussed and a new perspective on the heart fields is proposed. The heart progenitor cells delaminate through the primitive streak and migrate in a semicircular trajectory craniolaterally forming the bilateral heart fields as part of the splanchnic mesoderm. They switch their polarity from anteroposterior to mediolateral. The anterior intestinal portal posterior descent inverts the newly formed heart field mediolateral polarity into lateromedial by 125° bending. The heart fields revert back to their original anteroposterior polarity and fuse at the midline forming a semi heart tube by completing their half circle movement. Several names and roles were assigned to different portions of the heart fields: posterior versus anterior, first versus second, and primary versus secondary heart field. The posterior and anterior heart fields define basically physical fields that form the inflow–outflow axis of the heart tube. The first and second heart fields are, in contrast, temporal fields of differentiating cardiomyocytes expressing myosin light chain 2a and undifferentiated and proliferating precardiac mesoderm expressing Isl1 gene, respectively. The two markers present a complementary pattern and are expressed transiently in all myocardial lineages. Thus, Isl1 is not restricted to a portion of the heart field or one of the two heart lineages as has been often assumed. Anat Rec, 297:175–182, 2014. © 2013 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102627/1/ar22831.pd

Phase III trial of postoperative cisplatin, interferon alpha-2b, and 5-FU combined with external radiation treatment versus 5-FU alone for patients with resected pancreatic adenocarcinoma – CapRI: study protocol [ISRCTN62866759]

After surgical intervention with curative intention in specialised centres the five-year survival of patients with carcinoma of the exocrine pancreas is only 15%. The ESPAC-1 trial showed an increased five-year survival of 21% achieved with adjuvant chemotherapy. Investigators from the Virginia Mason Clinic have reported a 5-year survival rate of 55% in a phase II trial evaluating adjuvant chemotherapy, immunotherapy and external-beam radiation. DESIGN: The CapRI study is an open, controlled, prospective, randomised multi-centre phase III trial. Patients in study arm A will be treated as outpatients with 5-Fluorouracil; Cisplatin and 3 million units Interferon alpha-2b for 5 1/2 weeks combined with external beam radiation. After chemo-radiation the patients receive continuous 5-FU infusions for two more cycles. Patients in study arm B will be treated as outpatients with intravenous bolus injections of folinic acid, followed by intravenous bolus injections of 5-FU given on 5 consecutive days every 28 days for 6 cycles. A total of 110 patients with specimen-proven R0 or R1 resected pancreatic adenocarcinoma will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patients' enrolment. DISCUSSION: The aim of this study is to evaluate the overall survival period attained by chemo-radiotherapy including interferon alpha 2b administration with adjuvant chemotherapy. The influence of interferon alpha on the effectiveness of the patients' chemoradiation regimen, the toxicity, the disease-free interval and the quality of life are analysed. Different factors are tested in terms of their potential role as predictive markers