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Background There is an unmet need for review methods to support priority-setting, policy-making and strategic planning when a wide variety of interventions from differing disciplines may have the potential to impact a health outcome of interest. This article describes a Modular Literature Review, a novel systematic search and review method that employs systematic search strategies together with a hierarchy-based appraisal and synthesis of the resulting evidence. Methods We designed the Modular Review to examine the effects of 43 interventions on a health problem of global significance. Using the PICOS (Population, Intervention, Comparison, Outcome, Study design) framework, we developed a single four-module search template in which population, comparison and outcome modules were the same for each search and the intervention module was different for each of the 43 interventions. A series of literature searches were performed in five databases, followed by screening, extraction and analysis of data. “ES documents”, source documents for effect size (ES) estimates, were systematically identified based on a hierarchy of evidence. The evidence was categorised according to the likely effect on the outcome and presented in a standardised format with quantitative effect estimates, meta-analyses and narrative reporting. We compared the Modular Review to other review methods in health research for its strengths and limitations. Results The Modular Review method was used to review the impact of 46 antenatal interventions on four specified birth outcomes within 12 months. A total of 61,279 records were found; 35,244 were screened by title-abstract. Six thousand two hundred seventy-two full articles were reviewed against the inclusion criteria resulting in 365 eligible articles. Conclusions The Modular Review preserves principles that have traditionally been important to systematic reviews but can address multiple research questions simultaneously. The result is an accessible, reliable answer to the question of “what works?”. Thus, it is a well-suited literature review method to support prioritisation, decisions and planning to implement an agenda for health improvement.

Objective To determine the impact of virological control on inflammation and cluster of differentiation 4 depletion among HIV-infected children initiating antiretroviral therapy (ART) in sub-Saharan Africa. Design Longitudinal cohort study. Methods In a sub-study of the ARROW trial (ISRCTN24791884), we measured longitudinal HIV viral loads, inflammatory biomarkers (C-reactive protein, tumour necrosis factor alpha, interleukin 6 (IL-6), soluble CD14) and (Uganda only) whole blood immunophenotype by flow cytometry in 311 Zimbabwean and Ugandan children followed for median 3.5 years on first-line ART. We classified each viral load measurement as consistent suppression, blip/post-blip, persistent low-level viral load or rebound. We used multi-level models to estimate rates of increase or decrease in laboratory markers, and Poisson regression to estimate the incidence of clinical events. Results Overall, 42% children experienced viral blips, but these had no significant impact on immune reconstitution or inflammation. Persistent detectable viraemia occurred in one-third of children and prevented further immune reconstitution, but had little impact on inflammatory biomarkers. Virological rebound to ≥5000 copies/ml was associated with arrested immune reconstitution, rising IL-6 and increased risk of clinical disease progression. Conclusions As viral load testing becomes more available in sub-Saharan Africa, repeat testing algorithms will be required to identify those with virological rebound, who need switching to prevent disease progression, whilst preventing unnecessary second-line regimen initiation in the majority of children with detectable viraemia who remain at low risk of disease progression.

Background Inflammation drives vascular dysfunction in HIV, but in low-income settings causes of inflammation are multiple, and include infectious and environmental factors. We hypothesized that patients with advanced immunosuppression could be stratified into inflammatory phenotypes that predicted changes in vascular dysfunction on ART. Methods We recruited Malawian adults with CD4, Adults starting Antiretroviral Therapy (ART) with advanced immunosuppression can be phenotyped into 3 inflammatory clusters. One cluster was defined by high T-cell PD-1 expression and another by a hyperinflamed biological profile. Changes in arterial stiffness on ART varied according to inflammatory phenotype.

BackgroundNon-communicable diseases (NCDs) are increased amongst people living with HIV (PLWH) and are driven by persistent immune activation. The role of socioeconomic status (SES) in immune activation amongst PLWH is unknown, especially in low income sub Saharan Africa (SSA), where such impacts may be particularly severe.MethodsWe recruited Malawian adults with CD4NCT01825031), as well as volunteers without HIV infection. Clinical assessment, socioeconomic evaluation, blood draw for immune activation markers and carotid femoral pulse wave velocity (cfPWV) were carried out at 2 and 42 weeks post-ART initiation. Socioeconomic risk factors for immune activation and arterial stiffness were assessed using linear regression models.ResultsOf 279 PLWH, the median (IQR) age was 36 (31-43) years and 122 (44%) female. Activated CD8 T-cells increased from 70% amongst those with no education to 88% amongst those with a tertiary education (p=0.002); and from 71% amongst those earning less than 10 USD/month to 87% amongst those earning between 100-150 USD/month (p=0.0001). Arterial stiffness was also associated with higher SES (car ownership p=0.003, television ownership p=0.012 and electricity access p=0.029). Conversely, intermediate monocytes were higher amongst those with no education compared to a tertiary education (12.6% versus 7.3%; p=0.01) and amongst those earning less than 10 USD/month compared to 100-150 USD/month (10.5% versus 8.0%; p=0.08). Water kiosk use was protective against T cell activation (p=0.007), as well as endothelial damage (MIP1β, sICAM1 and sVCAM1 p=0.047, 0.026 and 0.031 respectively).ConclusionsSocioeconomic risk factors for persistent inflammation amongst PLWH in SSA differ depending on the type of inflammatory pathway. Understanding these pathways and their socioeconomic drivers will help identify those at risk and target interventions for NCDs. Future studies assessing drivers of inflammation amongst PLWH should include an SES assessment.Key pointsWhat is already known?Persistent immune activation drives an increased risk of non-communicable diseases amongst people living with HIV. The aetiology of persistent immune activation amongst PLWH is complex and includes microbial translocation, subclinical co-infection and continued low level HIV viral replication. However, the contribution of socioeconomic factors has not previously been investigated, and may be especially relevant amongst those living in low income settings.What are the new findings?The contribution of socioeconomic factors to persistent inflammation differs according to the type of inflammatory pathway. PLWH with higher socioeconomic status are at increased risk of T cell activation and arterial stiffness, perhaps as a result of more sedentary lifestyles. Conversely, evidence of innate immune activation is seen amongst those with lower socioeconomic status. Water kiosk use is associated with a favourable inflammatory profile.What do the findings imply?The phenotype of chronic immune activation amongst PLWH in a low-income sub-Saharan Africa setting differs according to socioeconomic status. We recommend incorporation of socioeconomic factors into future studies assessing the relationship between chronic inflammation and non-communicable diseases amongst HIV populations.

In this study, we aimed to quantify KREC (kappa-deleting recombination excision circle) levels and naive B cell output in healthy HIV-uninfected children, compared with HIV-infected South African children, before and after starting ART (antiretroviral therapy). Samples were acquired from a Child Wellness Clinic (n = 288 HIV-uninfected South African children, 2 weeks–12 years) and the Children with HIV Early Antiretroviral Therapy (CHER) trial (n = 153 HIV-infected South African children, 7 weeks–8 years). Naive B cell output was estimated using a mathematical model combining KREC levels to reflect B cell emigration into the circulation, flow cytometry measures of naive unswitched B cells to quantify total body naive B cells, and their rates of proliferation using the intracellular marker Ki67. Naive B cell output increases from birth to 1 year, followed by a decline and plateau into late childhood. HIV-infected children on or off ART had higher naive B cell outputs than their uninfected counterparts (p = .01 and p = .04). This is the first study to present reference ranges for measurements of KRECs and naive B cell output in healthy and HIV-infected children. Comparison between HIV-uninfected healthy children and HIV-infected children suggests that HIV may increase naive B cell output. Further work is required to fully understand the mechanisms involved and clinical value of measuring naive B cell output in children.

There have been changes in the political economy since the 1980s, and the Organization for Economic Cooperation and Development (OECD) has changed as well. Scholars have noted shifts in OECD discourse in some policy fields since that time: shifts away from what might be called classic neoliberal perspectives. This paper reflects on the changes in the political economy and in OECD and explores how they might be related to changes in OECD discourse in higher education. Specifically, it examines country reviews of higher education systems conducted by OECD in the mid-1990s and the late-2000s for evidence of shifts in its higher education discourse. Instead of a softening of neoliberal perspectives, it finds a further entrenchment of assumptions associated with neoliberalization. It also describes what appears to be a deepening contradiction in the discourse concerning the private and public benefits of higher education. Finally, it reflects on how the contexts of the political economy as framed by OECDs discourse, affects its proposed goals and strategies for higher education.

This article describes results of a randomized controlled trial comparing a time-limited early-stage memory loss (ESML) support group program conducted by a local Alzheimer's Association chapter to a wait-list (WL) control condition.One hundred and forty-two dyads were randomized in blocks to ESML (n = 96) or WL (n = 46). Mean age of participants was 74.9 years, and mean Mini-Mental State Examination was 23.4. The primary outcome was participant's quality of life; secondary outcomes included mood, family communication, and perceived stress.On the intent-to-treat (ITT) pre-post analysis, significant differences were seen in participant quality of life (p.001), depression (p.01), and family communication (p.05). Within the care partner groups, there was no significant difference between ESML and WL in the ITT analysis. A post hoc exploratory examination of changes that were associated with improved quality of life in ESML participants revealed significant reductions of depressive symptoms and behavior problems (p.05), improved family communication (p.05), self-efficacy (p.01), Medical Outcomes Study short form (SF-36) role-emotional (p.05), SF-36 social functioning (p.05), and SF-36 mental health components (p.01) in improvers.These results support the efficacy of ESML support groups for individuals with dementia.

Objective To identify biomarkers in the first synovial fluid (SF) aspirate obtained from children with oligoarticular juvenile idiopathic arthritis (JIA), which could be used to identify children whose disease is likely to extend to a more severe phenotype. Methods Patients with recent-onset oligoarticular JIA were identified and grouped according to those whose mild disease persisted (persistent disease) or those whose disease would extend from a mild to more severe phenotype (extended-to-be disease) at 1 year after diagnosis. Flow cytometry was used to delineate differences in the mononuclear cell populations between the first blood sample and first SF aspirate from the same patient and between outcome (persistent versus extended-to-be) groups. Proportions of lymphocytes in the joint were modeled on chemotaxis of lymphocytes to CCL5, using Transwell migration assays. Levels of CCL5 in the SF were quantified by enzyme-linked immunosorbent assay. RNA profiles of SF mononuclear cells were compared between groups using the Affymetrix GeneChip hybridization protocol and hierarchical clustering analyses. Results Compared with peripheral blood mononuclear cells, SF mononuclear cells displayed an expansion of CD8+ T cells, reduced proportion of B cells, and expansion of CD16− natural killer cells. The lower CD4:CD8 ratio in the SF was recapitulated in vitro by the observed migration of blood T cells in response to CCL5. Synovial CCL5 levels were higher in children whose disease extended to a more severe phenotype. The CD4:CD8 ratio in the SF was significantly lower in patients with extended-to-be oligoarticular JIA (0.57 compared with 0.90 in the persistent disease group, difference 0.33, 95% confidence interval 0.04–0.62; P = 0.009). Gene expression profiling revealed that 344 genes were >1.5-fold differentially expressed between outcome groups (P < 0.05), and these included genes associated with inflammation and macrophage differentiation, which showed increased levels in patients with extended disease at 1 year, and genes associated with immune regulation, which showed increased levels in patients with persistent disease at 1 year. Conclusion Analyses of the proportions of synovial lymphocytes, levels of CCL5, and differential gene expression yielded potential biomarkers with which to predict the likelihood of extension of oligoarticular JIA to a more severe disease phenotype.

Objective To identify interleukin-17 (IL-17)–producing T cells from patients with juvenile idiopathic arthritis (JIA), and investigate their cytokine production, migratory capacity, and relationship to Treg cells at sites of inflammation, as well as to test the hypothesis that IL-17+ T cell numbers correlate with clinical phenotype in childhood arthritis. Methods Flow cytometry was used to analyze the phenotype, cytokine production, and chemokine receptor expression of IL-17–producing T cells in peripheral blood and synovial fluid mononuclear cells from 36 children with JIA, in parallel with analysis of forkhead box P3 (FoxP3)–positive Treg cells. Migration of IL-17+ T cells toward CCL20 was assessed by a Transwell assay. Synovial tissue was analyzed by immunohistochemistry for IL-17 and IL-22. Results IL-17+ T cells were enriched in the joints of children with JIA as compared with the blood of JIA patients (P = 0.0001) and controls (P = 0.018) and were demonstrated in synovial tissue. IL-17+ T cell numbers were higher in patients with extended oligoarthritis, the more severe subtype of JIA, as compared with patients with persistent oligoarthritis, the milder subtype (P = 0.046). Within the joint, there was an inverse relationship between IL-17+ T cells and FoxP3+ Treg cells (r = 0.61, P = 0.016). IL-17+,CD4+ T cells were uniformly CCR6+ and migrated toward CCL20, but synovial IL-17+ T cells had variable CCR4 expression. A proportion of IL-17+ synovial T cells produced IL-22 and interferon-γ. Conclusion This study is the first to define the frequency and characteristics of “Th17” cells in JIA. We suggest that these highly proinflammatory cells contribute to joint pathology, as indicated by relationships with clinical phenotypes, and that the balance between IL-17+ T cells and Treg cells may be critical to outcome.

The work of the room attendant is central to the reinstatement of guest rooms, a particularly profitable product in most hotels. However, room attendant work remains, in large part, both academically and empirically unseen. To raise the visibility of this work quantitative and qualitative data has been gathered from room attendants in hotels in Cardiff, Wales. A profile of accommodation workers is constructed along with an examination of the ways in which their work is organised, controlled and rewarded. The perception of this work as ‘unskilled’ is reviewed. A consideration of intrinsic job satisfaction factors in both traditional and ‘empowered’ settings suggests that there may be more scope for job satisfaction than anticipated.

Appropriately timed proliferation, differentiation and apoptosis are essential to the normal functions of the mammary epithelium. Here, we report that the transcription factor BCL-6 is expressed in mammary epithelium in nonpregnant animals as well as during early pregnancy. When overexpressed in the nontransformed EpH4 mammary epithelial cell line, BCL-6 prevents the STAT-driven expression of the milk protein beta-casein and duct formation, and prevents apoptosis. Consistent with an antiapoptotic function, we demonstrate that BCL-6 is expressed in 68% of histologically high-grade ductal breast carcinomas, which are clinically the most aggressive. BCL-6 has previously been characterized as a regulator of B lymphocyte growth and development, but our work identifies a novel role for it in mammary epithelial differentiation, which may also implicate it in carcinogenesis.

PURPOSE/OBJECTIVES To describe the experience of families when a member is diagnosed with cancer. DESIGN Descriptive, qualitative study. SETTING Patients' homes. SAMPLE Eight adults, two to five months postdiagnosis, who were receiving radiotherapy or chemotherapy for stage I or II solid tumors and family members, including seven children between the ages of 13-18. Thirty people interviewed total. METHODS Patients recruited from an oncology outpatient clinic and gynecologic inpatient unit of a teaching hospital interviewed on one occasion with at least two immediate family members in patients' homes. Semistructured interviews were tape-recorded and analyzed for themes and categories using the techniques of constant comparison. MAIN RESEARCH VARIABLES Transitions from health to illness. FINDINGS Families described a learning process in which information was gathered, interpreted, and shared. Families learned together by reviewing the past, gathering and sharing information, and sharing their experiences of living with someone undergoing treatment for cancer. By revealing their own personal perspectives, patients taught their families about their illness experiences and what constituted effective support. CONCLUSIONS Interactive family learning is a mode of learning and a form of support in which the whole family may participate early in the process of learning to live with cancer. IMPLICATIONS FOR NURSING Nurses can facilitate patient and family learning by considering the interactive manner in which families acquire information. By acknowledging how past experiences with cancer inform the present, nurses can help families identify beliefs influencing the illness experience. By including families in teaching sessions; facilitating communication between patients, families, physicians, and nurses; and providing take-home learning materials, nurses can facilitate shared information gathering. Nurses should acknowledge the value of learning about illness by experience, accept patients and families as experts, and encourage revelation of patients' and families' perspectives of the illness to enhance feedback on support and coping.

In this study, we demonstrate the developmental activation, in the zebrafish embryo, of a surveillance mechanism which triggers apoptosis to remove damaged cells. We determine the time course of activation of this mechanism by exposing embryos to camptothecin, an agent which specifically inhibits topoisomerase I within the DNA replication complex and which, as a consequence of this inhibition, also produces strand breaks in the genomic DNA. In response to an early (pre-gastrula) treatment with camptothecin, apoptosis is induced at a time corresponding approximately to mid-gastrula stage in controls. This apoptotic response to a block of DNA replication can also be induced by early (pre-MBT) treatment with the DNA synthesis inhibitors hydroxyurea and aphidicolin. After camptothecin treatment, a high proportion of cells in two of the embryo's three mitotic domains (the enveloping and deep cell layers), but not in the remaining domain (the yolk syncytial layer), undergoes apoptosis in a cell-autonomous fashion. The first step in this response is an arrest of the proliferation of all deep- and enveloping-layer cells. These cells continue to increase in nuclear volume and to synthesize DNA. Eventually they become apoptotic, by a stereotypic pathway which involves cell membrane blebbing, “margination” and fragmentation of nuclei, and cleavage of the genomic DNA to produce a nucleosomal ladder. Fragmentation of nuclei can be blocked by the caspase-1,4,5 inhibitor Ac-YVAD-CHO, but not by the caspase-2,3,7[,1] inhibitor Ac-DEVD-CHO. This suggests a functional requirement for caspase-4 or caspase-5 in the apoptotic response to camptothecin. Recently,Xenopushas been shown to display a developmental activation of the capability for stress- or damaged-induced apoptosis at early gastrula stage.En masse,our experiments suggest that the apoptotic responses in zebrafish andXenopusare fundamentally similar. Thus, as for mammals, embryos of the lower vertebrates exhibit the activation of surveillance mechanisms, early in development, to produce the selective apoptosis of damaged cells.

The purpose of this qualitative descriptive study was to describe the experience of uncertainty in young adults with cancer. A purposeful sample of 6 young adults between the ages of 19 and 30 years undergoing chemotherapy treatment was recruited. Participants were interviewed twice using semistructured interviews. The investigators used constant comparison to examine the content of the transcript for common words, phrases, statements, or units of text that related to uncertainty. Findings revealed 3 major emerging themes. The first one being "types of uncertainty," which includes uncertainty and efforts at the right place, uncertainty and aspects of treatment, uncertainty and personal abilities, and uncertainty and the feasibility of plans related to life goals. Uncertainty was also found to trigger the development of certainties, which led to the second theme, "certainties: helpful or not?" A third emerging theme, dealing with uncertainty, described a variety of strategies used by young adults that included living on a day-to-day basis, being selfish, believing, getting information, trusting the physician, concentrating on positive things, keeping energy by pacing oneself, choosing social support, and trying to live a normal life. A consequence of dealing with the uncertainty and the cancer journey is the "enlightened path." It emerged and revealed how the cancer journey changed their lives. A number of implications for nursing practice therefore warrant consideration, especially fostering a sense of normalcy by identifying common behaviors, feelings, or needs among these young adults with cancer. Sharing this information and facilitating interactions with other young adults with cancer has the potential to promote coping with uncertainty.

Background Human regulatory T cells (T reg) are classically defined as CD4+ CD25hi Foxp3+. There is increasing evidence that T cells may be subject to regulation via the conversion of proinflammatory ATP to anti-inflammatory adenosine. Methotrexate, the standard therapy for children with JIA, is proposed to work via this mechanism. CD39 belongs to a family of ectoenzymes that convert ATP into an adenosine precursor. ATPase activity may therefore represent an important regulatory mechanism in JIA.

Transcriptomics and proteomics are transforming our understanding of juvenile idiopathic arthritis by revealing molecular signatures associated with the various clinical classifications. The challenge now is to find biomarkers that will predict disease course and response to medication in order to improve outcomes for children with arthritis.

We have identified a novel gene in a gene trap screen that encodes a protein related to the DnaJ co-chaperone in E. coli. The gene, named Mrj (mammalian relative of DnaJ) was expressed throughout development in both the embryo and placenta. Within the placenta, expression was particularly high in trophoblast giant cells but moderate levels were also observed in trophoblast cells of the chorion at embryonic day 8.5, and later in the labyrinth which arises from the attachment of the chorion to the allantois (a process called chorioallantoic fusion). Insertion of the ROSAβgeo gene trap vector into the Mrj gene created a null allele. Homozygous Mrj mutants died at mid-gestation due to a failure of chorioallantoic fusion at embryonic day 8.5, which precluded formation of the mature placenta. At embryonic day 8.5, the chorion in mutants was morphologically normal and expressed the cell adhesion molecule α4 integrin that is known to be required for chorioallantoic fusion. However, expression of the chorionic trophoblast-specific transcription factor genes Err2 and Gcm1 was significantly reduced. The mutants showed no abnormal phenotypes in other trophoblast cell types or in the embryo proper. This study indicates a previously unsuspected role for chaperone proteins in placental development and represents the first genetic analysis of DnaJ-related protein function in higher eukaryotes. Based on a survey of EST databases representing different mouse tissues and embryonic stages, there are 40 or more DnaJ-related genes in mammals. In addition to Mrj, at least two of these genes are also expressed in the developing mouse placenta. The specificity of the developmental defect in Mrj mutants suggests that each of these genes may have unique tissue and cellular activities.