Digital technology to facilitate Proactive Assessment of Obesity Risk during Infancy (ProAsk): a feasibility study

OBJECTIVE: To assess the feasibility and acceptability of using digital technology for Proactive Assessment of Obesity Risk during Infancy (ProAsk) with the UK health visitors (HVs) and parents. DESIGN: Multicentre, pre- and post-intervention feasibility study with process evaluation. SETTING: Rural and urban deprived settings, UK community care. PARTICIPANTS: 66 parents of infants and 22 HVs. INTERVENTION: ProAsk was delivered on a tablet device. It comprises a validated risk prediction tool to quantify overweight risk status and a therapeutic wheel detailing motivational strategies for preventive parental behaviour. Parents were encouraged to agree goals for behaviour change with HVs who received motivational interviewing training. OUTCOME MEASURES: We assessed recruitment, response and attrition rates. Demographic details were collected, and overweight risk status. The proposed primary outcome measure was weight-for-age z-score. The proposed secondary outcomes were parenting self-efficacy, maternal feeding style, infant diet and exposure to physical activity/sedentary behaviour. Qualitative interviews ascertained the acceptability of study processes and intervention fidelity. RESULTS: HVs screened 324/589 infants for inclusion in the study and 66/226 (29%) eligible infants were recruited. Assessment of overweight risk was completed on 53 infants and 40% of these were identified as above population risk. Weight-for-age z-score (SD) between the infants at population risk and those above population risk differed significantly at baseline (-0.67 SD vs 0.32 SD). HVs were able to collect data and calculate overweight risk for the infants. Protocol adherence and intervention fidelity was a challenge. HVs and parents found the information provided in the therapeutic wheel appropriate and acceptable. CONCLUSION: Study recruitment and protocol adherence were problematic. ProAsk was acceptable to most parents and HVs, but intervention fidelity was low. There was limited evidence to support the feasibility of implementing ProAsk without significant additional resources. A future study could evaluate ProAsk as a HV-supported, parent-led intervention. TRIAL REGISTRATION NUMBER: NCT02314494 (Feasibility Study Results).This work was supported by the Medical Research Council – Public Health Intervention Development Scheme, grant number PHIND 01/14-15

Paediatric radiology seen from Africa. Part I: providing diagnostic imaging to a young population

Article approval pendingPaediatric radiology requires dedicated equipment, specific precautions related to ionising radiation, and specialist knowledge. Developing countries face difficulties in providing adequate imaging services for children. In many African countries, children represent an increasing proportion of the population, and additional challenges follow from extreme living conditions, poverty, lack of parental care, and exposure to tuberculosis, HIV, pneumonia, diarrhoea and violent trauma. Imaging plays a critical role in the treatment of these children, but is expensive and difficult to provide. The World Health Organisation initiatives, of which the World Health Imaging System for Radiography (WHIS-RAD) unit is one result, needs to expand into other areas such as the provision of maintenance servicing. New initiatives by groups such as Rotary and the World Health Imaging Alliance to install WHIS-RAD units in developing countries and provide digital solutions, need support. Paediatric radiologists are needed to offer their services for reporting, consultation and quality assurance for free by way of teleradiology. Societies for paediatric radiology are needed to focus on providing a volunteer teleradiology reporting group, information on child safety for basic imaging, guidelines for investigations specific to the disease spectrum, and solutions for optimising imaging in children

ANGPTL4 variants E40K and T266M are associated with lower fasting triglyceride levels in Non-Hispanic White Americans from the Look AHEAD Clinical Trial

Background: Elevated triglyceride levels are a risk factor for cardiovascular disease. Angiopoietin-like protein 4 (Angptl4) is a metabolic factor that raises plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). In nondiabetic individuals, the ANGPTL4 coding variant E40K has been associated with lower plasma triglyceride levels while the T266M variant has been associated with more modest effects on triglyceride metabolism. The objective of this study was to determine whether ANGPTL4 E40K and T266M are associated with triglyceride levels in the setting of obesity and T2D, and whether modification of triglyceride levels by these genetic variants is altered by a lifestyle intervention designed to treat T2D. Methods: The association of ANGPTL4 E40K and T266M with fasting triglyceride levels was investigated in 2,601 participants from the Look AHEAD Clinical Trial, all of whom had T2D and were at least overweight. Further, we tested for an interaction between genotype and treatment effects on triglyceride levels. Results: Among non-Hispanic White Look AHEAD participants, ANGPTL4 K40 carriers had mean triglyceride levels of 1.61 +/- 0.62 mmol/L, 0.33 mmol/L lower than E40 homozygotes (p = 0.001). Individuals homozygous for the minor M266 allele (MAF 30%) had triglyceride levels of 1.75 +/- 0.58 mmol/L, 0.24 mmol/L lower than T266 homozygotes (p = 0.002). The association of the M266 with triglycerides remained significant even after removing K40 carriers from the analysis (p = 0.002). There was no interaction between the weight loss intervention and genotype on triglyceride levels. Conclusions: This is the first study to demonstrate that the ANGPTL4 E40K and T266M variants are associated with lower triglyceride levels in the setting of T2D. In addition, our findings demonstrate that ANGPTL4 genotype status does not alter triglyceride response to a lifestyle intervention in the Look AHEAD study

Testing gene-environment interactions in gene-based association studies

Gene-based and single-nucleotide polymorphism (SNP) set association studies provide an important complement to SNP analysis. Kernel-based nonparametric regression has recently emerged as a powerful and flexible tool for this purpose. Our goal is to explore whether this approach can be extended to incorporate and test for interaction effects, especially for genes containing rare variant SNPs. Here, we construct nonparametric regression models that can be used to include a gene-environment interaction effect under the framework of the least-squares kernel machine and examine the performance of the proposed method on the Genetic Analysis Workshop 17 unrelated individuals data set. Two hundred simulated replicates were used to explore the power for detecting interaction. We demonstrate through a genome scan of the quantitative phenotype Q1 that the simulated gene-environment interaction effect in the data can be detected with reasonable power by using the least-squares kernel machine method

Stage-Specific Inhibition of MHC Class I Presentation by the Epstein-Barr Virus BNLF2a Protein during Virus Lytic Cycle

gamma-herpesvirus Epstein-Barr virus (EBV) persists for life in infected individuals despite the presence of a strong immune response. During the lytic cycle of EBV many viral proteins are expressed, potentially allowing virally infected cells to be recognized and eliminated by CD8+ T cells. We have recently identified an immune evasion protein encoded by EBV, BNLF2a, which is expressed in early phase lytic replication and inhibits peptide- and ATP-binding functions of the transporter associated with antigen processing. Ectopic expression of BNLF2a causes decreased surface MHC class I expression and inhibits the presentation of indicator antigens to CD8+ T cells. Here we sought to examine the influence of BNLF2a when expressed naturally during EBV lytic replication. We generated a BNLF2a-deleted recombinant EBV (ΔBNLF2a) and compared the ability of ΔBNLF2a and wild-type EBV-transformed B cell lines to be recognized by CD8+ T cell clones specific for EBV-encoded immediate early, early and late lytic antigens. Epitopes derived from immediate early and early expressed proteins were better recognized when presented by ΔBNLF2a transformed cells compared to wild-type virus transformants. However, recognition of late antigens by CD8+ T cells remained equally poor when presented by both wild-type and ΔBNLF2a cell targets. Analysis of BNLF2a and target protein expression kinetics showed that although BNLF2a is expressed during early phase replication, it is expressed at a time when there is an upregulation of immediate early proteins and initiation of early protein synthesis. Interestingly, BNLF2a protein expression was found to be lost by late lytic cycle yet ΔBNLF2a-transformed cells in late stage replication downregulated surface MHC class I to a similar extent as wild-type EBV-transformed cells. These data show that BNLF2a-mediated expression is stage-specific, affecting presentation of immediate early and early proteins, and that other evasion mechanisms operate later in the lytic cycle

Expression and Differential Responsiveness of Central Nervous System Glial Cell Populations to the Acute Phase Protein Serum Amyloid A

Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves hepatic production of acute-phase proteins, including serum amyloid A (SAA). Extrahepatically, SAA immunoreactivity is found in axonal myelin sheaths of cortex in Alzheimer's disease and multiple sclerosis (MS), although its cellular origin is unclear. We examined the responses of cultured rat cortical astrocytes, microglia and oligodendrocyte precursor cells (OPCs) to master pro-inflammatory cytokine tumour necrosis factor (TNF)-\u3b1 and lipopolysaccaride (LPS). TNF-\u3b1 time-dependently increased Saa1 (but not Saa3) mRNA expression in purified microglia, enriched astrocytes, and OPCs (as did LPS for microglia and astrocytes). Astrocytes depleted of microglia were markedly less responsive to TNF-\u3b1 and LPS, even after re-addition of microglia. Microglia and enriched astrocytes showed complementary Saa1 expression profiles following TNF-\u3b1 or LPS challenge, being higher in microglia with TNF-\u3b1 and higher in astrocytes with LPS. Recombinant human apo-SAA stimulated production of both inflammatory mediators and its own mRNA in microglia and enriched, but not microglia-depleted astrocytes. Co-ultramicronized palmitoylethanolamide/luteolin, an established anti-inflammatory/neuroprotective agent, reduced Saa1 expression in OPCs subjected to TNF-\u3b1 treatment. These last data, together with past findings suggest that co-ultramicronized palmitoylethanolamide/luteolin may be a novel approach in the treatment of inflammatory demyelinating disorders like MS

Direction of the formation of anterior lumbar vertebral osteophytes

<p>Abstract</p> <p>Background</p> <p>X-ray images of lumbar degenerative diseases often show not only claw osteophytes, but also pairs of osteophytes that form in a direction away from the adjacent disc. We have investigated the direction of the formation of anterior lumbar vertebral osteophytes across the lumbar vertebrae using a sufficient number of lumbar radiographs, because osteophytes images can provide essential information that will contribute to the understanding of the pathology and progress of lumbar spine degeneration.</p> <p>Methods</p> <p>The direction of the formation of 14,250 pairs of anterior lumbar vertebral osteophytes across the adjacent intervertebral discs in 2,850 patients who were all over 60 years old was investigated. Anterior lumbar vertebral osteophytes were distributed into six groups based on the direction of extension of each pair of osteophytes across the intervertebral disc space.</p> <p>Results</p> <p>In L1–L2 and L2–L3, the number of patients classified into groups B (the pair of osteophytes extended in the direction of the adjacent disc) and C (almost complete bone bridge formation by a pair of osteophytes across the intervertebral disc space) was larger than that classified into group D (the pair of osteophytes extended in a direction away from the adjacent disc). In L3–L4, L4–L5 and L5-S1, the number of patients in group D was greater than that of patients belonging to groups B and C.</p> <p>Conclusion</p> <p>Our study showed that pairs of osteophytes frequently formed in the direction of the adjacent disc in the upper lumbar vertebrae (L1–L2 and L2–L3) and in the direction away from the adjacent disc in middle or lower lumbar vertebrae (L3–L4, L4–L5, and L5-S1).</p

Changes in Body Composition Over 8 Years in a Randomized Trial of a Lifestyle Intervention: The Look AHEAD Study

Objective To determine the effects of an intensive lifestyle intervention versus a comparison group on body composition in obese or overweight persons with type 2 diabetes at baseline and at 1, 4, and 8 years. Methods Body composition was measured by dual‐energy X‐ray absorptiometry in a subset of 1019 Look AHEAD study volunteers randomized to intervention or comparison groups. The intervention was designed to achieve and maintain ≥7% weight loss through increased physical activity and reduced caloric intake. The comparison group received social support and diabetes education. Results At 1 year, the intervention group lost fat (5.6 ± 0.2 kg) and lean mass (2.3 ± 0.1 kg) but regained fat (∼100%) and lost lean mass between years 1 and 8. Between baseline and year 8, weight loss was greater in intervention versus comparison groups (4.0 ± 0.4 vs. 2.3 ± 0.4 kg); comparison group weight loss was mostly lean mass (2.1 ± 0.17 kg). Fat mass in the intervention group was lower than that of the comparison group at all post‐baseline time points. Conclusions Reduced fat mass may place the intervention group at a lower risk of obesity‐linked sequelae, a hypothesis that can be tested by future studies of this cohort

Extraforaminal ligament attachments of the thoracic spinal nerves in humans

An anatomical study of the extraforaminal attachments of the thoracic spinal nerves was performed using human spinal columns. The objectives of the study are to identify and describe the existence of ligamentous structures at each thoracic level that attach spinal nerves to structures at the extraforaminal region. During the last 120 years, several mechanisms have been described to protect the spinal nerve against traction. All the described structures were located inside the spinal canal proximal to the intervertebral foramen. Ligaments with a comparable function just outside the intervertebral foramen are mentioned ephemerally. No studies are available about ligamentous attachments of thoracic spinal nerves to the spine. Five embalmed human thoracic spines (Th2–Th11) were dissected. Bilaterally, the extraforaminal region was dissected to describe and measure anatomical structures and their relationships with the thoracic spinal nerves. Histology was done at the sites of attachment of the ligaments to the nerves and along the ligaments. The thoracic spinal nerves are attached to the transverse process of the vertebrae cranial and caudal to the intervertebral foramen. The ligaments consist mainly of collagenous fibers. In conclusion, at the thoracic level, direct ligamentous connections exist between extraforaminal thoracic spinal nerves and nearby structures. They may serve as a protective mechanism against traction and compression of the nerves by positioning the nerve in the intervertebral foramen

Rapid Intradermal Delivery of Liquid Formulations Using a Hollow Microstructured Array

Purpose The purpose of this work is to demonstrate rapid intradermal delivery of up to 1.5 mL of formulation using a hollow microneedle delivery device designed for self-application. Methods 3M’s hollow Microstructured Transdermal System (hMTS) was applied to domestic swine to demonstrate delivery of a variety of formulations including small molecule salts and proteins. Blood samples were collected after delivery and analyzed via HPLC or ELISA to provide a PK profile for the delivered drug. Site evaluations were conducted post delivery to determine skin tolerability. Results Up to 1.5 mL of formulation was infused into swine at a max rate of approximately 0.25 mL/min. A red blotch, the size of the hMTS array, was observed immediately after patch removal, but had faded so as to be almost indistinguishable 10 min post-patch removal. One-mL deliveries of commercial formulations of naloxone hydrochloride and human growth hormone and a formulation of equine anti-tetanus toxin were completed in swine. With few notable differences, the resulting PK profiles were similar to those achieved following subcutaneous injection of these formulations. Conclusions 3M’s hMTS can provide rapid, intradermal delivery of 300–1,500 µL of liquid formulations of small molecules salts and proteins, compounds not typically compatible with passive transdermal delivery. KEY WORDS transdermal drug delivery. microneedles. intradermal. hollow microstructures. MT