Biological and pathological mechanisms leading to the birth of a small vulnerable newborn.

The pathway to a thriving newborn begins before conception and continues in utero with a healthy placenta and the right balance of nutrients and growth factors that are timed and sequenced alongside hormonal suppression of labour until a mature infant is ready for birth. Optimal nutrition that includes adequate quantities of quality protein, energy, essential fats, and an extensive range of vitamins and minerals not only supports fetal growth but could also prevent preterm birth by supporting the immune system and alleviating oxidative stress. Infection, illness, undernourishment, and harmful environmental exposures can alter this trajectory leading to an infant who is too small due to either poor growth during pregnancy or preterm birth. Systemic inflammation suppresses fetal growth by interfering with growth hormone and its regulation of insulin-like growth factors. Evidence supports the prevention and treatment of several maternal infections during pregnancy to improve newborn health. However, microbes, such as Ureaplasma species, which are able to ascend the cervix and cause membrane rupture and chorioamnionitis, require new strategies for detection and treatment. The surge in fetal cortisol late in pregnancy is essential to parturition at the right time, but acute or chronically high maternal cortisol levels caused by psychological or physical stress could also trigger labour onset prematurely. In every pathway to the small vulnerable newborn, there is a possibility to modify the course of pregnancy by supporting improved nutrition, protection against infection, holistic maternal wellness, and healthy environments.

Modular literature review: a novel systematic search and review method to support priority setting in health policy and practice.

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.

Inflammatory Phenotypes Predict Changes in Arterial Stiffness Following Antiretroviral Therapy Initiation.

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 <100 cells/µL 2 weeks after starting ART in the REALITY trial (NCT01825031). Carotid femoral pulse-wave velocity (cfPWV) measured arterial stiffness 2, 12, 24, and 42 weeks post-ART initiation. Plasma inflammation markers were measured by electrochemiluminescence at weeks 2 and 42. Hierarchical clustering on principal components identified inflammatory clusters. RESULTS: 211 participants with HIV grouped into 3 inflammatory clusters representing 51 (24%; cluster-1), 153 (73%; cluster-2), and 7 (3%; cluster-3) individuals. Cluster-1 showed markedly higher CD4 and CD8 T-cell expression of HLADR and PD-1 versus cluster-2 and cluster-3 (all P < .0001). Although small, cluster-3 had significantly higher levels of cytokines reflecting inflammation (IL-6, IFN-γ, IP-10, IL-1RA, IL-10), chemotaxis (IL-8), systemic and vascular inflammation (CRP, ICAM-1, VCAM-1), and SAA (all P < .001). In mixed-effects models, cfPWV changes over time were similar for cluster-2 versus cluster-1 (relative fold-change, 0.99; 95% CI, .86-1.14; P = .91), but greater in cluster-3 versus cluster-1 (relative fold-change, 1.45; 95% CI, 1.01-2.09; P = .045). CONCLUSIONS: Two inflammatory clusters were identified: one defined by high T-cell PD-1 expression and another by a hyperinflamed profile and increases in cfPWV on ART. Further clinical characterization of inflammatory phenotypes could help target vascular dysfunction interventions to those at highest risk. CLINICAL TRIALS NETWORK: NCT01825031.

Baseline Inflammatory Biomarkers Identify Subgroups of HIV-Infected African Children With Differing Responses to Antiretroviral Therapy.

BACKGROUND: Identifying determinants of morbidity and mortality may help target future interventions for human immunodeficiency virus (HIV)-infected children. METHODS: CD4(+) T-cell count, HIV viral load, and levels of biomarkers (C-reactive protein, tumor necrosis factor α [TNF-α], interleukin 6 [IL-6], and soluble CD14) and interleukin 7 were measured at antiretroviral therapy (ART) initiation in the ARROW trial (case-cohort design). Cases were individuals who died, had new or recurrent World Health Organization clinical stage 4 events, or had poor immunological response to ART. RESULTS: There were 115 cases (54 died, 45 had World Health Organization clinical stage 4 events, and 49 had poor immunological response) and 485 controls. Before ART initiation, the median ages of cases and controls were 8.2 years (interquartile range [IQR], 4.4-11.4 years) and 5.8 years (IQR, 2.3-9.3 years), respectively, and the median percentages of lymphocytes expressing CD4 were 4% (IQR, 1%-9%) and 13% (IQR, 8%-18%), respectively. In multivariable logistic regression, cases had lower age-associated CD4(+) T-cell count ratio (calculated as the ratio of the subject's CD4(+) T-cell count to the count expected in healthy individuals of the same age; P < .0001) and higher IL-6 level (P = .002) than controls. Clustering biomarkers and age-associated CD4(+) and CD8(+) T-cell count ratios identified 4 groups of children. Group 1 had the highest frequency of cases (41% cases; 16% died) and profound immunosuppression; group 2 had similar mortality (23% cases; 15% died), but children were younger, with less profound immunosuppression and high levels of inflammatory biomarkers and malnutrition; group 3 comprised young children with moderate immunosuppression, high TNF-α levels, and high age-associated CD8(+) T-cell count ratios but lower frequencies of events (12% cases; 7% died); and group 4 comprised older children with low inflammatory biomarker levels, lower HIV viral loads, and good clinical outcomes (11% cases; 5% died). CONCLUSIONS: While immunosuppression is the major determinant of poor outcomes during ART, baseline inflammation is an additional important factor, identifying a subgroup of young children with similar mortality. Antiinflammatory interventions may help improve outcomes.

"Working on a Shoestring": Critical Resource Challenges and Place-Based Considerations for Telehealth in Northern Saskatchewan, Canada.

Rural, remote, and northern Indigenous communities in Canada frequently face limited access to healthcare services with ongoing physician and staff shortages, inadequate infrastructure, and resource challenges. These healthcare gaps have produced significantly poorer health outcomes for people living in remote communities than those living in southern and urban regions who have timely access to care. Telehealth has played a critical role in bridging long-standing gaps in accessing healthcare services by connecting patients and providers across distance. While the adoption of telehealth in Northern Saskatchewan is growing, its initial implementation faced several barriers related to limited and stretched human and financial resources, infrastructure challenges such as unreliable broadband, and a lack of community involvement and engaged decision-making. Emerging ethical issues during the initial implementation of telehealth in community contexts have been wide ranging including concerns around privacy that have also shaped patients' experiences and particularly the need to consider place and space within rural contexts. Drawing from a qualitative study with four Northern Saskatchewan communities, this paper offers critical perspectives on the resource challenges and place-based considerations that are shaping telehealth in the Saskatchewan context and provides recommendations and lessons learned that could inform other Canadian regions and countries. This work responds to the ethics of tele-healthcare in rural communities in Canada and contributes perspectives of community-based service providers, advisors, and researchers.

Antenatal interventions to reduce risk of low birth weight related to maternal infections during pregnancy.

BACKGROUND: Maternal infections during pregnancy have been linked to increased risk of adverse birth outcomes, including low birth weight (LBW), preterm birth (PTB), small for gestational age (SGA), and stillbirth (SB). OBJECTIVES: The purpose of this article was to summarize evidence from published literature on the effect of key interventions targeting maternal infections on adverse birth outcomes. METHODS: We searched MEDLINE, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and CINAHL Complete between March 2020 and May 2020 with an update to cover until August 2022. We included randomized controlled trials (RCTs) and reviews of RCTs of 15 antenatal interventions for pregnant women reporting LBW, PTB, SGA, or SB as outcomes. RESULTS: Of the 15 reviewed interventions, the administration of 3 or more doses of intermittent preventive treatment in pregnancy with sulphadoxine-pyrimethamine [IPTp-SP; RR: 0.80 (95% CI: 0.69, 0.94)] can reduce risk of LBW compared with 2 doses. The provision of insecticide-treated bed nets, periodontal treatment, and screening and treatment of asymptomatic bacteriuria may reduce risk of LBW. Maternal viral influenza vaccination, treatment of bacterial vaginosis, intermittent preventive treatment with dihydroartemisinin-piperaquine compared with IPTp-SP, and intermittent screening and treatment of malaria during pregnancy compared with IPTp were deemed unlikely to reduce the prevalence of adverse birth outcomes. CONCLUSIONS: At present, there is limited evidence from RCTs available for some potentially relevant interventions targeting maternal infections, which could be prioritized for future research.

A modular systematic review of antenatal interventions to address undernutrition during pregnancy in the prevention of low birth weight.

BACKGROUND: Poor nutrition during pregnancy can lead to adverse birth outcomes including low birth weight (LBW). OBJECTIVE: This modular systematic review aimed to provide evidence for the effects of seven antenatal nutritional interventions on the risks of LBW, preterm birth (PTB), small-for-gestational-age (SGA) and stillbirth (SB). METHODS: We searched MEDLINE, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and CINAHL Complete between April and June 2020, with a further update in September 2022 (Embase only). We included randomized controlled trials (RCTs) and reviews of RCTs to estimate the effect sizes of the selected interventions on the four birth outcomes. RESULTS: Evidence suggests that balanced protein and energy (BPE) supplementation for pregnant women with undernutrition can reduce the risk of LBW, SGA and SB. Evidence from low and lower middle-income countries (MIC) suggests that multiple micronutrient (MMN) supplementation can reduce the risk of LBW and SGA in comparison with iron or iron and folic acid supplementation and lipid-based nutrient supplements (LNS) with any quantity of energy can reduce the risk of LBW in comparison with MMN supplementation. Evidence from high and upper MIC suggests that supplementation with omega-3 fatty acids (O3FA) can reduce the risk and supplementation with high-dose calcium might possibly reduce the risk of LBW and PTB. Antenatal dietary education programs might possibly reduce the risk of LBW in comparison with standard-of-care. No RCTs were identified for monitoring weight gain followed by interventions to support weight gain in women who are underweight. CONCLUSIONS: Provision of BPE, MMN and LNS to pregnant women in populations with undernutrition can reduce the risk of LBW and related outcomes. The benefits of O3FA and calcium supplementation to this population require further investigation. Targeting interventions to pregnant women who are not gaining weight has not been tested with RCTs.

Antenatal interventions to address harmful behaviors and psychosocial risk factors in the prevention of low birth weight.

BACKGROUND: Risk factors related to the harmful behaviors, psychosocial wellbeing, and socio-economic circumstances in the lives of pregnant women can lead to adverse birth outcomes, including low birth weight (LBW). OBJECTIVE: This systematic search and review aims to provide a comparative evidence synthesis on the effect of eleven antenatal interventions targeted to address psychosocial risk factors on adverse birth outcomes. METHODS: We searched MEDLINE, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and CINAHL Complete between March 2020 and May 2020. We included randomized controlled trials (RCTs) and reviews of RCTs of eleven antenatal interventions for pregnant females reporting LBW, preterm birth (PTB), small-for-gestational-age or stillbirth as outcomes. For interventions where randomization was either not feasible or unethical, we accepted non-randomized controlled studies. RESULTS: Seven records contributed data to the quantitative estimates of the effect sizes and 23 contributed to narrative analysis. Psychosocial interventions for reducing smoking in pregnancy likely reduced the risk of LBW, and professionally provided psychosocial support for at-risk women possibly reduced the risk of PTB. Financial incentives or nicotine replacement therapy as smoking cessation aids, or virtually delivered psychosocial support did not appear to reduce the risk of adverse birth outcomes. The available evidence on these interventions was primarily from high-income countries. For other reviewed interventions (psychosocial interventions to reduce alcohol use, group based psychosocial support programs, intimate partner violence prevention interventions, antidepressant medication, and cash transfers) there was little evidence in any direction regarding the efficacy or the data was conflicting. CONCLUSIONS: Professionally provided psychosocial support during pregnancy in general and specifically as a means to reduce smoking can potentially contribute to improved newborn health. The gaps in the investments for research and implementation of psychosocial interventions should be addressed to better meet the global targets in LBW reduction.

A modular systematic review of antenatal interventions targeting modifiable environmental exposures in improving low birth weight.

BACKGROUND: Low birth weight (LBW) increases the risk of short- and long-term morbidity and mortality from early life to adulthood. Despite research effort to improve birth outcomes the progress has been slow. OBJECTIVE: This systematic search and review of English language scientific literature on clinical trials aimed to compare the efficacy antenatal interventions to reduce environmental exposures including a reduction of toxins exposure, and improving sanitation, hygiene, and health-seeking behaviors, which target pregnant women to improve birth outcomes. METHODS: We performed eight systematic searches in MEDLINE (OvidSP), Embase (OvidSP), Cochrane Database of Systematic Reviews (Wiley Cochrane Library), Cochrane Central Register of Controlled Trials (Wiley Cochrane Library), CINAHL Complete (EbscoHOST) between 17 March 2020 and 26 May 2020. RESULTS: Four documents identified describe interventions to reduce indoor air pollution: two randomised controlled trials (RCTs), one systematic review and meta-analysis (SRMA) on preventative antihelminth treatment and one RCT on antenatal counselling against unnecessary caesarean section. Based on the published literature, interventions to reduce indoor air pollution (LBW: RR: 0.90 [0.56, 1.44], PTB: OR: 2.37 [1.11, 5.07]) or preventative antihelminth treatment (LBW: RR: 1.00 [0.79, 1.27], PTB: RR: 0.88 [0.43, 1.78]) are not likely to reduce the risk of LBW or Preterm birth (PTB). Data is insufficient on antenatal counselling against caesarian-sections. For other interventions, there is lack of published research data from RCTs. CONCLUSIONS: We conclude that there is a paucity of evidence from RCT on interventions that modify environmental risk factors during pregnancy to potentially improve birth outcomes. Magic bullets approach might not work and that it would be important to study the effect of the broader interventions, particularly in LMIC settings. Global interdisciplinary action to reduce harmful environmental exposures, is likely to help to reach global targets for LBW reduction and sustainably improve long-term population health.

Impact of sub-optimal HIV viral control on activated T cells.

OBJECTIVE: HIV viral load (VL) monitoring is generally conducted 6-12 monthly in low- and middle-income countries, risking relatively prolonged periods of poor viral control. We explored the effects of different levels of loss of viral control on immune reconstitution and activation. DESIGN: Two hundred and eight participants starting protease inhibitor (PI)-based second-line therapy in the EARNEST trial (ISRCTN37737787) in Uganda and Zimbabwe were enrolled and CD38 + /HLA-DR + immunophenotyping performed (CD8-FITC/CD38-PE/CD3-PerCP/HLA-DR-APC; centrally gated) in real-time at 0, 12, 48, 96 and 144 weeks from randomization. METHODS: VL was assayed retrospectively on samples collected every 12-16 weeks and classified as continuous suppression (<40 copies/ml throughout); suppression with transient blips; low-level rebound (two or more consecutive VL >40, <5000 copies/ml); high-level rebound/nonresponse (two or more consecutive VL >5000 copies/ml). RESULTS: Immunophenotype reconstitution varied between that defined by numbers of cells and that defined by cell percentages. Furthermore, VL dynamics were associated with substantial differences in expression of CD4 + and CD8 + cell activation markers, with only individuals with high-level rebound/nonresponse (>5000 copies/ml) experiencing significantly greater activation and impaired reconstitution. There was little difference between participants who suppressed consistently and who exhibited transient blips or even low-level rebound by 144 weeks ( P  > 0.2 vs. suppressed consistently). CONCLUSION: Detectable viral load below the threshold at which WHO guidelines recommend that treatment can be maintained without switching (1000 copies/ml) appear to have at most, small effects on reconstitution and activation, for patients taking a PI-based second-line regimen.

Biologic predictors of extension of oligoarticular juvenile idiopathic arthritis as determined from synovial fluid cellular composition and gene expression.

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.

The impact of viraemia on inflammatory biomarkers and CD4+ cell subpopulations in HIV-infected children in sub-Saharan Africa.

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.

Inflammatory pathways amongst people living with HIV in Malawi differ according to socioeconomic status.

BACKGROUND: Non-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. METHODS: We recruited Malawian adults with CD4<100 cells/ul two weeks after starting ART in the REALITY trial (NCT01825031), 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. RESULTS: Of 279 PLWH, the median (IQR) age was 36 (31-43) years and 122 (44%) were 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 trended towards being higher 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 showed a protective association against T cell activation (p = 0.007), as well as endothelial damage (MIP1ß, sICAM1 and sVCAM1 p = 0.047, 0.026 and 0.031 respectively). CONCLUSIONS: Socioeconomic 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 in HIV should include an SES assessment.

Naive B Cell Output in HIV-Infected and HIV-Uninfected Children.

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.

Building a Professional Identity and an Academic Career Track in Translational Medicine.

Biomedical scientists aim to contribute to further understanding of disease pathogenesis and to develop new diagnostic and therapeutic tools that relieve disease burden. Yet the majority of biomedical scientists do not develop their academic career or professional identity as "translational scientists," and are not actively involved in the continuum from scientific concept to development of new strategies that change medical practice. The collaborative nature of translational medicine and the lengthy process of bringing innovative findings from bench to bedside conflict with established pathways of building a career in academia. This collaborative approach also poses a problem for evaluating individual contributions and progress. The traditional evaluation of scientific success measured by the impact and number of publications and grants scientists achieve is inadequate when the product is a team effort that may take decades to complete. Further, where scientists are trained to be independent thinkers and to establish unique scientific niches, translational medicine depends on combining individual insights and strengths for the greater good. Training programs that are specifically geared to prepare scientists for a career in translational medicine are not widespread. In addition, the legal, regulatory, scientific and clinical infrastructure and support required for translational research is often underdeveloped in academic institutions and funding organizations, further discouraging the development and success of translational scientists in the academic setting. In this perspective we discuss challenges and potential solutions that could allow for physicians, physician scientists and basic scientists to develop a professional identity and a fruitful career in translational medicine.

Predictors of retention in an alcohol, tobacco, and other drug prevention study.

This article explored retention patterns, as well as factors that predicted these patterns, in the evaluation of a relationship-based substance abuse prevention intervention study that targeted inner-city African American youth. A total of 851 contacts were made to retain 82% (n = 104) of the baseline sample (N = 127) in the evaluation. Results from multinomial regression analyses indicated that participants who were retained in the evaluation were more likely to perceive alcohol, tobacco, and other drug use as less risky and were more likely to report higher levels of family supervision than were evaluation attrits. Those who were easy to retain reported lower family conflict and fewer family relocations during the past year than those who were difficult to retain. Implications of these findings for developing retention strategies, as well as future research, are discussed.

Cervical leukocytes and spontaneous preterm birth.

The objective was to characterise cervical leukocyte populations and inflammatory mediators associated with term and recurrent spontaneous preterm birth (SPTB) in pregnant women with a history of SPTB. A prospective observational study was undertaken on 120 women with a history of SPTB. A cytobrush was used to sample cells from the cervix at 12-25 weeks' gestation. Cells were enumerated and characterised by flow cytometry. Cytokines and chemokines were also measured. Participants were then grouped according to delivery at term (>36+6 weeks), late SPTB (34-36+6 weeks) or early SPTB (<34 weeks). Differences in leukocyte sub-populations, cytokine and chemokine levels were compared with outcome. Cervical leukocytes comprised up to 60% of the host-derived cells. Most of these (90-100%) were polymorphonuclear cells (PMN). Most of the remaining cells were mucosal macrophages expressing CD68 and CD103 in addition to markers shared with blood-borne monocytes. Failure to detect cervical macrophages in at least 250,000 cervical epithelial cells was a feature of women who experienced early SPTB (6 out of 6 cases, 95% CI 61-100%) compared with 34% (30 out of 88 cases, 95% CI 25-43%, P<0.001) of women delivering after 34 weeks. CCL2 (MCP-1) was also low in SPTB before 34 weeks and levels above 75 ng/g and/or the presence of macrophages increased the specificity for birth after 34 weeks from 66% to 82% (55 out of 67 cases, 95% CI 73-91%). Absence of cervical macrophages and low CCL2 may be features of pregnancies at risk of early SPTB.

BCL-6 is expressed in breast cancer and prevents mammary epithelial differentiation.

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.

Alcohol elimination at low blood concentrations among women taking combined oral contraceptives.

OBJECTIVE: Evidence implicating a role of natural and synthetic estrogens and/or progestin on ethanol pharmacokinetics can be traced back to the mid-1970s when reports of large metabolic differences were found suggesting that sex hormones interfered with the efficient clearance of alcohol at the liver microsomal level. Research teams in this area manipulate sex hormone levels by either examining natural-cycling women at different phases of their menstrual cycle or others taking oral contraceptives that synthetically regulate the hormonal fluctuations. These collective studies (over a dozen to date involving over 200 participants) have all been similar in focus and outcome. With one important exception, the published laboratory research since 1976 has failed to replicate the earliest research suggesting sex hormone effects. One well-controlled study in 1987 did generate renewed interest in the area with the paradoxical finding that progesterone actually enhanced alcohol elimination at low blood concentrations (<.025%). The present study represented the most direct attempt to replicate this particular finding using 5-minute breath alcohol readings that extended below blood alcohol concentrations of .025%. METHOD: A total of 17 women taking combined oral contraceptives were tested during both menstruation and the luteal phase (Days 16-22) of their cycle in counterbalanced sequence. RESULTS: Pharmacokinetics differences were not found. CONCLUSION: These results contribute further to a literature base demonstrating the limited effects of both natural and synthetic sex hormones on alcohol metabolism in women.

Early-stage memory loss support groups: outcomes from a randomized controlled clinical trial.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. DISCUSSION: These results support the efficacy of ESML support groups for individuals with dementia.