A Mixed-Methods Exploration of the Needs of People Living with HIV (PLWH) Enrolled in Access to Care, a National HIV Linkage, Retention and Re-Engagement in Medical Care Program.

Competing needs pose barriers to engagement in HIV medical care. Mixed methods were used to explore and describe the needs of participants enrolled in Access to Care, a national HIV linkage, retention and re-engagement in care (LRC) program that served people living with HIV who knew their status but were not engaged in care. When asked to prioritize their most urgent needs, participants reported housing or shelter (31%), HIV medical services (24%), and employment (8%). When we assessed the HIV continuum of care by needs status, we found no significant differences in linkage, retention, or viral suppression between participants with and without basic needs. Qualitative interviews with program staff contextualized the barriers to HIV medical care faced by participants and explored the strategies used by LRC programs to address participant needs. Study findings will be of use to future programs and have implications for HIV policy, in particular the implementation of the National HIV/AIDS Strategy (2015-2020).

Enablers and barriers to physical activity in overweight and obese pregnant women: an analysis informed by the theoretical domains framework and COM-B model.

BACKGROUND: Obesity during pregnancy is associated with increased risk of gestational diabetes mellitus (GDM) and other complications. Physical activity is a modifiable lifestyle factor that may help to prevent these complications but many women reduce their physical activity levels during pregnancy. Interventions targeting physical activity in pregnancy are on-going but few identify the underlying behaviour change mechanisms by which the intervention is expected to work. To enhance intervention effectiveness, recent tools in behavioural science such as the Theoretical Domains Framework (TDF) and COM-B model (capability, opportunity, motivation and behaviour) have been employed to understand behaviours for intervention development. Using these behaviour change methods, this study aimed to identify the enablers and barriers to physical activity in overweight and obese pregnant women. METHODS: Semi-structured interviews were conducted with a purposive sample of overweight and obese women at different stages of pregnancy attending a public antenatal clinic in a large academic maternity hospital in Cork, Ireland. Interviews were recorded and transcribed into NVivo V.10 software. Data analysis followed the framework approach, drawing on the TDF and the COM-B model. RESULTS: Twenty one themes were identified and these mapped directly on to the COM-B model of behaviour change and ten of the TDF domains. Having the social opportunity to engage in physical activity was identified as an enabler; pregnant women suggested being active was easier when supported by their partners. Knowledge was a commonly reported barrier with women lacking information on safe activities during pregnancy and describing the information received from their midwife as 'limited'. Having the physical capability and physical opportunity to carry out physical activity were also identified as barriers; experiencing pain, a lack of time, having other children, and working prevented women from being active. CONCLUSION: A wide range of barriers and enablers were identified which influenced women's capability, motivation and opportunity to engage in physical activity with "knowledge" as the most commonly reported barrier. This study is a theoretical starting point in making a 'behavioural diagnoses' and the results will be used to inform the development of an intervention to increase physical activity levels among overweight and obese pregnant women.

Investigating the Perceived Benefits, Barriers and Beliefs towards Physical Activity in Pregnancy among Women with Gestational Diabetes Mellitus.

Gestational Diabetes Mellitus (GDM) is a growing concern and poses serious health risks to both mother and child1. The current study explores the psychological determinants of exercise behaviour in a sample of pregnant women with GDM. A cross-sectional survey design was employed to examine exercise behaviour, illness perceptions, perceived barriers and benefits, exercise beliefs, and exercise self-efficacy using validated questionnaires. A sample of 46 pregnant women was recruited from University College Hospital Galway, Letterkenny General Hospital, Cork University Hospital and Mayo General Hospital in Castlebar. Participant's varied; age (22-44 years), body mass index (19-41). High mean scores for Personal Control (24.5) and Treatment Control (30.2) subscales indicated strongly held positive beliefs in relation to controllability of the illness. Total MET-min/week score was not related to any psychological variables. Analysis of the IPQ-R data revealed 'diet' (n=37, 80.4%) as the most referred to cause of diabetes. Exercise belief data identified "managing weight gain" (n= 21, 45.7%), and "losing baby weight" (n= 31, 67.4%) as the most frequent beliefs for engaging in physical activity during pregnancy and post pregnancy. Further research on the psychological determinants of physical activity behaviour among this population group is needed in order to create successful intervention strategies.

Access to diagnostics in primary care and the impact on a primary care led health service.

We undertook a postal survey of GPs to establish their current access to radiological and endoscopic tests. More than one fifth of GPs do not have direct access to abdominal (n = 42, 21.4%) or pelvic (n = 49, 24.6%) ultrasound in the public system. Where access is available public patients have an average 14 week waiting period. In stark contrast in the private system virtually all GPs have direct access (n = 159, 99.2% and n = 156, 98.8% respectively for abdominal and pelvic ultrasound) with an average wait of just over four days. Direct access to CT scan in the public system is available to the minority of GPs, e.g. n = 31, 18.4% for chest scan, in the public system; even where available, there is an average 12 week wait for this. In comparison 151 (88.6%) GPs have access to CT chest scanning in the private sector with an average waiting time of 5.4 working days. Such limited access to diagnostics impacts on the delivery of a quality service.

The maximal cytoprotective function of the heat shock protein 27 is dependent on heat shock protein 70.

Endogenous heat shock proteins (HSPs) 70 and 25/27 are induced in renal cells by injury from energy depletion. Transfected over-expression of HSPs 70 or 27 (human analogue of HSP25), provide protection against renal cell injury from ATP deprivation. This study examines whether over-expressed HSP27 depends on induction of endogenous HSPs, in particular HSP70, to afford protection against cell injury. LLC-PK1 cells transfected with HSP27 (27OE cells) were injured by ATP depletion for 2h and recovered for 4h in the presence of HSF decoy, HSP70 specific siRNA (siRNA-70) and their respective controls. Injury in the presence of HSF decoy, a synthetic oligonucleotide identical to the heat shock element, the nuclear binding site of HSF, decreased HSP70 induction by 80% without affecting the over-expression of transfected HSP27. The HSP70 stress response was completely ablated in the presence of siRNA-70. Protection against injury, provided by over-expression of HSP27, was reduced by treatment with HSF decoy and abolished by treatment with siRNA-70. Immunoprecipitation studies demonstrated association of HSP27 with actin that was not affected by either treatment with HSF decoy or siRNA. Therefore, HSP27 is dependent on HSP70 to provide its maximal cytoprotective effect, but not for its interaction with actin. This study suggests that, while it has specific action on the cytoskeleton, HSP 25/27 must have coordinated activity with other HSP classes, especially HSP70, to provide the full extent of resistance to injury from energy depletion.

Challenges of Developing Robust AI for Intrapartum Fetal Heart Rate Monitoring.

Background: CTG remains the only non-invasive tool available to the maternity team for continuous monitoring of fetal well-being during labour. Despite widespread use and investment in staff training, difficulty with CTG interpretation continues to be identified as a problem in cases of fetal hypoxia, which often results in permanent brain injury. Given the recent advances in AI, it is hoped that its application to CTG will offer a better, less subjective and more reliable method of CTG interpretation. Objectives: This mini-review examines the literature and discusses the impediments to the success of AI application to CTG thus far. Prior randomised control trials (RCTs) of CTG decision support systems are reviewed from technical and clinical perspectives. A selection of novel engineering approaches, not yet validated in RCTs, are also reviewed. The review presents the key challenges that need to be addressed in order to develop a robust AI tool to identify fetal distress in a timely manner so that appropriate intervention can be made. Results: The decision support systems used in three RCTs were reviewed, summarising the algorithms, the outcomes of the trials and the limitations. Preliminary work suggests that the inclusion of clinical data can improve the performance of AI-assisted CTG. Combined with newer approaches to the classification of traces, this offers promise for rewarding future development.

The NRPB era.

Some 40 years ago, in May 1970, the Radiological Protection Bill was passed by the parliament of the United Kingdom. This legislation created the National Radiological Protection Board (NRPB). It lasted 35 years until absorbed by the Health Protection Agency in 2005. During that period, the NRPB discharged its basic duty of protecting the people from radiation hazards.

Analysis of postural stability following posterior spinal fusion in adolescents with idiopathic scoliosis.

This study uses experimental data acquired from adolescents with idiopathic scoliosis to assess their postural control during quiet standing before and after posterior spinal fusion. Statistically significant differences were seen when comparing the pre- and post-surgical measures of balance calculated from data for three different test conditions.

The discovery of quarks.

Quarks are widely recognized today as being among the elementary particles of which matter is composed. The key evidence for their existence came from a series of inelastic electron-nucleon scattering experiments conducted between 1967 and 1973 at the Stanford Linear Accelerator Center. Other theoretical and experimental advances of the 1970s confirmed this discovery, leading to the present standard model of elementary particle physics.

Effect of reducing the dose of stavudine on body composition, bone density, and markers of mitochondrial toxicity in HIV-infected subjects: a randomized, controlled study.

BACKGROUND: Stavudine is widely used in developing countries. Lipoatrophy and mitochondrial toxicity have been linked to stavudine use, but it is unclear whether switching to a lower dose can reduce these toxicities while maintaining human immunodeficiency virus (HIV) suppression. METHODS: HIV-infected subjects receiving standard-dose stavudine with undetectable HIV type 1 RNA for > or =6 months were randomized (ratio, 3:2) to receive one-half of the stavudine dose (switch arm) or to maintain the dose (continuation arm) while continuing to receive all other prescribed antiretrovirals. The following measurements were obtained at baseline and week 48: fasting lactate, pyruvate, and lipid levels; results of whole-body dual-energy x-ray absorptiometry; and mitochondrial DNA (mtDNA) measurements in fat and peripheral blood mononuclear cells. Change from baseline to week 48 was compared within and between groups. RESULTS: Twenty-four patients (79% of whom were men and 79% of whom were African American; median age, 45 years) were enrolled in the study, 15 were enrolled in the switch arm, and 9 were enrolled in the continuation arm. The median duration of stavudine treatment was 55 months (range, 21-126 months). The median CD4 cell count was 558 cells/mm(3) (range, 207-1698 cells/mm(3)). At baseline, the study arms had similar demographic characteristics and laboratory indices, except for body mass index, total lean body mass, and triglyceride levels (all of which were higher in the switch arm). Three patients (2 in the switch arm) discontinued the study because of study-unrelated reasons. CD4 cell counts remained unchanged. At 48 weeks, 6 patients (4 [27%] in the switch arm and 2 [22%] in the continuation arm) had detectable HIV RNA levels (median, 972 copies/mL; range, 60-49,400 copies/mL). All patients with detectable HIV RNA levels reported significant lapses in treatment adherence; none exhibited mutations in HIV genotype. After the treatment switch, significant changes from study entry to week 48 were noted only for lactate level (median change, -0.27 mmol/L; range, -1.2 to 0.25 mmol/L; P = .02) and fat mtDNA (median change, 40 copies/cell; range, -49 to 261 copies/cell; P = .02). In the continuation arm, a significant loss of bone mineral density was seen at week 48 (median change, -1.7%; range, -6.3% to 0.8%; P = .02). The only significant between-group difference was the change in bone mineral density from baseline (P = .003). CONCLUSIONS: Reducing stavudine dose by one-half increased fat mtDNA and decreased lactate levels, suggesting improvement in mitochondrial indices while preserving HIV suppression in subjects who maintained adherence. A significant loss of bone mineral density was seen in patients receiving standard-dose stavudine but not in those receiving low-dose stavudine. These results suggest that switching to low-dose stavudine may improve mitochondrial indices while maintaining virological suppression.

Uridine supplementation in HIV lipoatrophy: pilot trial on safety and effect on mitochondrial indices.

OBJECTIVES: Uridine abrogates mitochondrial toxicities of nucleoside reverse transcriptase inhibitor in adipocyte cell culture. We aim to study the effect of uridine supplementation on human adipocyte mitochondrial DNA (mtDNA) levels in subjects with human immunodeficiency (HIV) lipoatrophy. METHODS: Sixteen patients with lipoatrophy on stavudine-containing antiretroviral therapy were enrolled, and received NucleomaxX, a dietary supplement with a high bioavailability of uridine (36 g TID every other day for 16 weeks). Patients were then followed off-uridine for another 16 weeks. Highly active antiretroviral therapy remained unchanged during the trial. RESULTS: Fourteen patients completed the study. Two subjects dropped out before week 4 for study-unrelated reasons. No adverse events were noted throughout the study. HIV-1 RNA, CD4 counts, liver enzymes and hemoglobin remained unchanged. Body mass index, lactate, lipids, insulin and homeostasis model assessment of insulin resistance were unaltered. Fat and peripheral blood and mononuclear cell mtDNA levels did not correlate with each other and exhibited no changes throughout the study. Lipoatrophy scores by patients and physician improved significantly at weeks 16 and 32 compared to study entry. CONCLUSION: In this pilot study, NucleomaxX was safe, well tolerated without apparent deleterious effect on HIV indices. In contrast to in vitro data, NucleomaxX did not lead to changes in fat or blood mtDNA levels.

Patient outcomes and economics of once-daily tacrolimus in renal transplant patients: results of a modeling analysis.

PURPOSE: The objective of this study was to model patient outcomes and treatment costs over a 5-year horizon time for renal transplant patients comparing twice-daily tacrolimus to once-daily extended-release tacrolimus as a primary immunosuppressive agent. METHODS: We constructed a stochastic state-transition model to simulate the incidence of acute rejection, graft loss and subsequent return to dialysis, retransplantation, and mortality among transplanted patients, as well as their associated costs. The two immunosuppressive treatment arms analyzed were twice-daily tacrolimus plus mycophenolate mofetil (MMF) and once-daily extended-release tacrolimus plus MMF. Estimates for the current rate of adherence to twice-daily medication, as well as the improvement in adherence expected in a once-daily medication, were taken from literature reviews. Sensitivities around these estimates were analyzed. Cost data for medical procedures and hospitalization were obtained from Medicare and the United States Renal Data System (USRDS). Medicare ASP prices from July 2006 were used to price pharmaceutical products. Once-daily extended-release tacrolimus was assumed to have the same daily cost as twice-daily tacrolimus. RESULTS: Patient outcomes included a decrease in acute rejections, increase in graft survival, and a corresponding decrease in number of patients on dialysis. Using once-daily extended-release tacrolimus increased graft survival at 5 years from 63.0% to 69.1% an absolute increase of 6.1 percentage points. Overall cost savings averaged $9411 per patient over the 5-year treatment using a 5% discount rate. Total costs, including initial transplantation, were $238,144 for twice-daily tacrolimus and $228,734 for once-daily extended-release tacrolimus.

Prevalence of suboptimal vitamin D status during pregnancy.

Low maternal vitamin D status has been associated with reduced intrauterine long bone growth and shorter gestation, decreased birth weight, as well as reduced childhood bone-mineral accrual. Despite data from other countries indicating low maternal vitamin D status is common during pregnancy, there is a dearth of information about vitamin D status during pregnancy in the Irish female population. Therefore, we prospectively assessed vitamin D nutritive status and the prevalence of suboptimal vitamin D status in a cohort of Irish pregnant women. The mean (SD) daily intake of vitamin D by the group of pregnant women was 3.6 (1.9) microg/day. None of the women achieved the recommended daily vitamin D intake value for Irish pregnant women (10 microg/day). Taking all three trimesters collectively, 14.3-23.7% and 34.3-52.6% of Irish women had vitamin D deficiency (serum 25 (OH) D <25 nmol/l) and insufficiency (serum 25 (OH) D 25-50 nmol/l), respectively during pregnancy. Both the levels of serum 25 (OH) D and the prevalence of vitamin D deficiency/adequacy were dramatically influenced by season, with status being lowest during the extended winter period and best during the extended summer period. These findings show that inadequate vitamin D status is common in Irish pregnant women.

Acetylated lipoproteins impair erythroid growth factor release from endothelial cells.

Endothelial cells are a known source of hematopoietic growth-enhancing factors, including platelet-derived growth factor (PDGF). In addition, endothelium interacts directly with plasma lipoproteins which have been shown to modulate hematopoiesis. To determine the relationship of these properties, we measured the release of an erythroid growth-enhancing factor from bovine endothelial cells under lipid-loaded and control conditions. Human bone marrow cells cultured under serum-free conditions form more erythroid, granulocyte/macrophage, and mixed hematopoietic colonies when supplemented with endothelial cell-conditioned medium (ECCM) than do controls (P less than 0.05). The activity is expressed over a wide range of erythropoietin, lymphocyte-conditioned medium (LCM), recombinant human interleukin-3, and colony-stimulating factor (CSF) concentrations, and is related to ECCM dose. In contrast, enhancing activity in ECCM prepared with 0-400 micrograms/ml acetylated low density lipoproteins (AcLDL) or native LDL is diminished to 0% in a dose-dependent fashion (relative to ECCM from unexposed cells or from cells incubated with very low density lipoproteins, P less than 0.05). Upon dilution, medium prepared from cells incubated with LDL shows a rightward shift in the dose-response curve for erythroid colony formation, while that prepared from AcLDL loaded cells demonstrates a downward shift, indicating that the inhibitory activities are kinetically distinct. Delipidation of ECCM prior to addition to marrow culture removes the inhibitory action of native LDL (P less than 0.05) but not that of AcLDL (P greater than 0.10). Immunochemical analysis suggests that the erythropoietic activity in ECCM is unrelated to that of PDGF, recombinant human CSF, and erythroid burst-promoting activity (BPA) present in LCM. This conclusion is supported by Northern blot analysis of endothelial cells using a cDNA probe for the v-sis homologue of the PDGF beta chain and by immunoprecipitation of metabolically labeled PDGF. The relative amounts of c-sis transcripts and of secreted PDGF were similar in endothelial cells incubated with or without AcLDL. We conclude that AcLDL impair the synthesis or release of an erythropoietic growth-enhancing factor(s) which is biologically distinct from PDGF and BPA present in LCM.

Nuclear proteins that bind the human gamma-globin gene promoter: alterations in binding produced by point mutations associated with hereditary persistence of fetal hemoglobin.

The molecular mechanisms responsible for the human fetal-to-adult hemoglobin switch have not yet been elucidated. Point mutations identified in the promoter regions of gamma-globin genes from individuals with nondeletion hereditary persistence of fetal hemoglobin (HPFH) may mark cis-acting sequences important for this switch, and the trans-acting factors which interact with these sequences may be integral parts in the puzzle of gamma-globin gene regulation. We have used gel retardation and footprinting strategies to define nuclear proteins which bind to the normal gamma-globin promoter and to determine the effect of HPFH mutations on the binding of a subset of these proteins. We have identified five proteins in human erythroleukemia cells (K562 and HEL) which bind to the proximal promoter region of the normal gamma-globin gene. One factor, gamma CAAT, binds the duplicated CCAAT box sequences; the -117 HPFH mutation increases the affinity of interaction between gamma CAAT and its cognate site. Two proteins, gamma CAC1 and gamma CAC2, bind the CACCC sequence. These proteins require divalent cations for binding. The -175 HPFH mutation interferes with the binding of a fourth protein, gamma OBP, which binds an octamer sequence (ATGCAAAT) in the normal gamma-globin promoter. The HPFH phenotype of the -175 mutation indicates that the octamer-binding protein may play a negative regulatory role in this setting. A fifth protein, EF gamma a, binds to sequences which overlap the octamer-binding site. The erythroid-specific distribution of EF gamma a and its close approximation to an apparent repressor-binding site suggest that it may be important in gamma-globin regulation.

Enzyme-altered foci in colons of carcinogen-treated rats.

The distal colon and rectum from male F344 rats treated with 15 mg/kg 1,2-dimethylhydrazine.2HCl (DMH) for 20 weeks were analyzed for focal areas of enzyme alteration. Tissues were embedded in methacrylate at 4 degrees C and cut in 2- to 4-micron serial sections. In DMH-treated rats, 8.8 +/- 2.4 foci/cm2 of examined mucosa were observed at 20 weeks and 7.7 +/- 1.1 foci/cm2 at 31 to 52 weeks, compared with 1.2 +/- 0.6 foci/cm2 in control rats (P = 0.01). The number of foci at 31 to 52 weeks compared with 20 weeks did not change significantly, but the area of altered rectal mucosa increased from 0.22 +/- 0.2% at 20 weeks to 1.47 +/- 0.6% at 31 to 52 weeks (P = 0.051). Most foci had decreased N-acetyl-beta-D-glucosaminidase, alpha-naphthyl butyrate esterase, and mucin in epithelial cells and increased gamma-glutamyl transpeptidase in the stroma. Morphologically, the foci varied from normal to overtly dysplastic. Grossly, tumors were identified in 5 of 20 DMH-treated rats killed at 31 to 52 weeks but not in 12 DMH-treated rats killed at 20 weeks or 30 control rats killed at 20 to 52 weeks. These data suggest but do not establish that enzyme-altered foci are putative preneoplastic lesions in the colon.

Aberrant crypts: putative preneoplastic foci in human colonic mucosa.

Aberrant crypts were identified for the first time in whole-mount preparations of normal-appearing human colonic mucosa after staining with methylene blue. The foci of aberrant crypts varied from single altered glands to plaques of greater than 30 crypts. The mean proportion of colonic mucosa altered and the number of foci with aberrant crypts per cm2 of colonic mucosa were (a) higher in patients with colon cancer than in patients without colon cancer or predisposing conditions and (b) highest in our single case of Gardner's syndrome. Aberrant crypts are postulated to be the earliest identifiable potential precursors of colon cancer. Analysis of aberrant crypts may facilitate the study of the early pathological and molecular changes that precede colon cancer.

Overexpression of GATA-2 inhibits erythroid and promotes megakaryocyte differentiation.

GATA-1 and GATA-2 transcription factors are required for effective hematopoiesis. These regulatory proteins present overlapping yet distinct patterns of expression in hematopoietic cells. Absence of GATA-2 leads to defective hematopoiesis and an embryonic lethal phenotype. Disruption of GATA-1 results in a compensatory increase in GATA-2 in early erythroid cells and incomplete erythropoiesis with embryos dying at 11.5 days. We examine the specific role of GATA-2 later in hematopoiesis, during erythroid differentiation. Stable K562 cell lines expressing various levels of GATA-2 were generated using a GATA-2 expression plasmid. Overexpression of GATA-2 transcripts was determined by quantitative polymerase chain reaction (PCR). Cytospin smears, growth curve analysis, PCR, and flow cytometry were used to examine the effects of increased levels of GATA-2 in altering cell phenotype and activation of megakaryocytic markers. Human progenitor erythroid cells also were transfected with a GATA-2 expression vector. Growth curve analysis, benzidine staining, and high-performance liquid chromatographic analysis were used to study the effects of GATA-2 on erythroid maturation and proliferation.K562/GATA-2 cell lines expressing high levels of GATA-2 mRNA showed a marked decrease in proliferation and a shift in phenotype toward the megakaryocyte lineage. Ploidy analyses showed that these cell lines developed a multinuclear phenotype, including tetraploids and octaploids. PCR analysis showed activation of megakaryocyte-specific genes including thrombopoietin receptor (c-mpl). Surface expression of platelet glycoprotein receptors Ib/IX (CD42b/CD42a) and IIb/IIIa (CD41/CD61) also was demonstrated by flow cytometry. In primary human adult erythroid cultures transfected with a GATA-2 expression vector, production of total hemoglobin and cell proliferation decreased in a dose-dependent manner.GATA-2 plays an important role in deciding cell lineage throughout hematopoiesis, and increased expression of GATA-2 determines megakaryocytic differentiation. Downregulation of GATA-2 is required for erythroid differentiation.