Myeloid conditioning with c-kit-targeted CAR-T cells enables donor stem cell engraftment

We report a novel approach to bone marrow (BM) conditioning using c-kit-targeted chimeric antigen receptor T (c-kit CAR-T) cells in mice. Previous reports using anti-c-kit or anti-CD45 antibody linked to a toxin such as saporin have been promising. We developed a distinctly different approach using c-kit CAR-T cells. Initial studies demonstrated in vitro killing of hematopoietic stem cells by c-kit CAR-T cells but poor expansion in vivo and poor migration of CAR-T cells into BM. Pre-treatment of recipient mice with low-dose cyclophosphamide (125 mg/kg) together with CXCR4 transduction in the CAR-T cells enhanced trafficking to and expansion in BM (\u3c1%-13.1%). This resulted in significant depletion of the BM c-ki

Gametogenic Cycle in the Non-Native Atlantic Surf Clam, Spisula solidissima (Dillwyn, 1817), Cultured in the Coastal Waters of Georgia

This study describes the gametogenic cycle of the Atlantic surf clam, Spisula solidissima (Dillwyn, 1817), cultured from fall to spring in the coastal waters of Georgia, where it is non-native. Early active stages of gametogenic development began in November, with the majority (83%) of the animals in the early active stage by December. Gonadal indices increased to late active stages by March, with ripe individuals present in April. Spawning commenced in May and continued into June. Sex ratio (0.48 female to 1.00 male) was significantly unequal. Results of this study indicate that clams achieved sexual maturity and spawned when cultured in the coastal waters of Georgia. An aquacultural enterprise in Georgia could obtain broodstock for the production of the following fall\u27s seed crop from the prior year\u27s growout field planted clams before their spring harvest

Gametogenic Cycle in the Non-Native Atlantic Surf Clam, Spisula solidissima (Dillwyn, 1817), Cultured in the Coastal Waters of Georgia

This study describes the gametogenic cycle of the Atlantic surf clam, Spisula solidissima (Dillwyn, 1817), cultured from fall to spring in the coastal waters of Georgia, where it is non-native. Early active stages of gametogenic development began in November, with the majority (83%) of the animals in the early active stage by December. Gonadal indices increased to late active stages by March, with ripe individuals present in April. Spawning commenced in May and continued into June. Sex ratio (0.48 female to 1.00 male) was significantly unequal. Results of this study indicate that clams achieved sexual maturity and spawned when cultured in the coastal waters of Georgia. An aquacultural enterprise in Georgia could obtain broodstock for the production of the following fall\u27s seed crop from the prior year\u27s growout field planted clams before their spring harvest

Developing cardiac and skeletal muscle share fast-skeletal myosin heavy chain and cardiac troponin-I expression

Skeletal muscle derived stem cells (MDSCs) transplanted into injured myocardium can differentiate into fast skeletal muscle specific myosin heavy chain (sk-fMHC) and cardiac specific troponin-I (cTn-I) positive cells sustaining recipient myocardial function. We have recently found that MDSCs differentiate into a cardiomyocyte phenotype within a three-dimensional gel bioreactor. It is generally accepted that terminally differentiated myocardium or skeletal muscle only express cTn-I or sk-fMHC, respectively. Studies have shown the presence of non-cardiac muscle proteins in the developing myocardium or cardiac proteins in pathological skeletal muscle. In the current study, we tested the hypothesis that normal developing myocardium and skeletal muscle transiently share both sk-fMHC and cTn-I proteins. Immunohistochemistry, western blot, and RT-PCR analyses were carried out in embryonic day 13 (ED13) and 20 (ED20), neonatal day 0 (ND0) and 4 (ND4), postnatal day 10 (PND10), and 8 week-old adult female Lewis rat ventricular myocardium and gastrocnemius muscle. Confocal laser microscopy revealed that sk-fMHC was expressed as a typical striated muscle pattern within ED13 ventricular myocardium, and the striated sk-fMHC expression was lost by ND4 and became negative in adult myocardium. cTn-I was not expressed as a typical striated muscle pattern throughout the myocardium until PND10. Western blot and RT-PCR analyses revealed that gene and protein expression patterns of cardiac and skeletal muscle transcription factors and sk-fMHC within ventricular myocardium and skeletal muscle were similar at ED20, and the expression patterns became cardiac or skeletal muscle specific during postnatal development. These findings provide new insight into cardiac muscle development and highlight previously unknown common developmental features of cardiac and skeletal muscle. © 2012 Clause et al

Evaluation of community-level interventions to increase early initiation of antenatal care in pregnancy: protocol for the Community REACH study, a cluster randomised controlled trial with integrated process and economic evaluations

BACKGROUND: The provision of high-quality maternity services is a priority for reducing inequalities in health outcomes for mothers and infants. Best practice includes women having their initial antenatal appointment within the first trimester of pregnancy in order to provide screening and support for healthy lifestyles, well-being and self-care in pregnancy. Previous research has identified inequalities in access to antenatal care, yet there is little evidence on interventions to improve early initiation of antenatal care. The Community REACH trial will assess the effectiveness and cost-effectiveness of engaging communities in the co-production and delivery of an intervention that addresses this issue. METHODS/DESIGN: The study design is a matched cluster randomised controlled trial with integrated process and economic evaluations. The unit of randomisation is electoral ward. The intervention will be delivered in 10 wards; 10 comparator wards will have normal practice. The primary outcome is the proportion of pregnant women attending their antenatal booking appointment by the 12th completed week of pregnancy. This and a number of secondary outcomes will be assessed for cohorts of women (n = approximately 1450 per arm) who give birth 2-7 and 8-13 months after intervention delivery completion in the included wards, using routinely collected maternity data. Eight hospitals commissioned to provide maternity services in six NHS trusts in north and east London and Essex have been recruited to the study. These trusts will provide anonymised routine data for randomisation and outcomes analysis. The process evaluation will examine intervention implementation, acceptability, reach and possible causal pathways. The economic evaluation will use a cost-consequences analysis and decision model to evaluate the intervention. Targeted community engagement in the research process was a priority. DISCUSSION: Community REACH aims to increase early initiation of antenatal care using an intervention that is co-produced and delivered by local communities. This pragmatic cluster randomised controlled trial, with integrated process and economic evaluation, aims to rigorously assess the effectiveness of this public health intervention, which is particularly complex due to the required combination of standardisation with local flexibility. It will also answer questions about scalability and generalisability. TRIAL REGISTRATION: ISRCTN registry: registration number 63066975 . Registered on 18 August 2015

The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study

Objective To determine whether there is a link between hypoglycaemia and mortality among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial

An exploration of knowledge, attitudes and advice given by health professionals to parents in Ireland about the introduction of solid foods. A pilot study

<p>Abstract</p> <p>Background</p> <p>For the purposes of this paper "weaning is defined as the introduction of the first solid foods to infants". Global recommendations by the World Health Organisation (WHO) recommend that all infants be exclusively breast-fed for the first six months of life. No global recommendations have been made for formula fed infants. In Europe it is recommended that weaning foods should be introduced between 18 weeks and 26 weeks regardless of whether infants are breast or formula fed. In the United Kingdom it is recommended that solids be introduced at around six-months for both breast and formula fed infants. In Ireland official guidelines recommend that breast fed infants should be introduced solids at 6 months of age while for formula fed infants the recommendation is for 4 months. The disparity between these global, European, UK and local recommendations may be a source of confusion for parents and health care professional based in Ireland. Emerging evidence suggests that babies in Ireland are given solid foods before the recommended age but there has been little investigation of the weaning advice provided by health professionals. Since community health professionals have routine parent interactions in the pre-weaning and early-weaning period and hence are in a unique position to positively influence parental weaning decisions, this study aimed to explore their knowledge, attitudes and advice practices about weaning.</p> <p>Methods</p> <p>A mixed-methods approach was used for the research, commencing with a multi-disciplinary focus group to guide and develop a questionnaire. Questionnaires were then distributed in a postal survey to General Practitioners (GPs) (<it>n </it>179), Practice Nurses (PNs) (<it>n </it>121), Public Health Nurses (PHNs) (<it>n </it>107) and Community Dieticians (CDs) (<it>n </it>8).</p> <p>Results</p> <p>The results indicate varying levels of knowledge of official weaning recommendations and a variety of advice practices. CDs and PHNs acknowledged a clear role in providing weaning advice while demonstrating high confidence levels in providing this advice. However, 19% of PNs and 7% of GP respondents did not acknowledge that they have a role in providing weaning advice to parents; even though Health Service Executive (HSE) written literature given to parents states that they should seek information from PNs and GPs.</p> <p>Conclusion</p> <p>Small pockets of misinformation about the introduction of solid foods persist amongst health professionals which may lead to inconsistent advice for parents. Further research is needed.</p

Advancing specificity in delirium: The delirium subtyping initiative

BACKGROUND: Delirium, a common syndrome with heterogeneous etiologies and clinical presentations, is associated with poor long-term outcomes. Recording and analyzing all delirium equally could be hindering the field's understanding of pathophysiology and identification of targeted treatments. Current delirium subtyping methods reflect clinically evident features but likely do not account for underlying biology. METHODS: The Delirium Subtyping Initiative (DSI) held three sessions with an international panel of 25 experts. RESULTS: Meeting participants suggest further characterization of delirium features to complement the existing Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision diagnostic criteria. These should span the range of delirium-spectrum syndromes and be measured consistently across studies. Clinical features should be recorded in conjunction with biospecimen collection, where feasible, in a standardized way, to determine temporal associations of biology coincident with clinical fluctuations. DISCUSSION: The DSI made recommendations spanning the breadth of delirium research including clinical features, study planning, data collection, and data analysis for characterization of candidate delirium subtypes. HIGHLIGHTS: Delirium features must be clearly defined, standardized, and operationalized. Large datasets incorporating both clinical and biomarker variables should be analyzed together. Delirium screening should incorporate communication and reasoning

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24&nbsp;months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500&nbsp;steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30&nbsp;minutes spent performing activities ≥500&nbsp;counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24&nbsp;months), both the number of steps per day (per 500&nbsp;steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500&nbsp;counts per minute (per 30&nbsp;minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score &gt;10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

Biomarkers of folate status in NHANES: a roundtable summary123456

A roundtable to discuss the measurement of folate status biomarkers in NHANES took place in July 2010. NHANES has measured serum folate since 1974 and red blood cell (RBC) folate since 1978 with the use of several different measurement procedures. Data on serum 5-methyltetrahydrofolate (5MTHF) and folic acid (FA) concentrations in persons aged ≥60 y are available in NHANES 1999–2002. The roundtable reviewed data that showed that folate concentrations from the Bio-Rad Quantaphase II procedure (Bio-Rad Laboratories, Hercules, CA; used in NHANES 1991–1994 and NHANES 1999–2006) were, on average, 29% lower for serum and 45% lower for RBC than were those from the microbiological assay (MA), which was used in NHANES 2007–2010. Roundtable experts agreed that these differences required a data adjustment for time-trend analyses. The roundtable reviewed the possible use of an isotope-dilution liquid chromatography–tandem mass spectrometry (LC-MS/MS) measurement procedure for future NHANES and agreed that the close agreement between the MA and LC-MS/MS results for serum folate supported conversion to the LC-MS/MS procedure. However, for RBC folate, the MA gave 25% higher concentrations than did the LC-MS/MS procedure. The roundtable agreed that the use of the LC-MS/MS procedure to measure RBC folate is premature at this time. The roundtable reviewed the reference materials available or under development at the National Institute of Standards and Technology and recognized the challenges related to, and the scientific need for, these materials. They noted the need for a commutability study for the available reference materials for serum 5MTHF and FA