The combination of sucrose dilaurate and sucrose laurate suppresses HMGB1: an enhancer of melanocyte dendricity and melanosome transfer to keratinocytes.

BACKGROUND: Hyperpigmented spots are common issues in all ethnicities, involving multiple intrinsic and extrinsic factors such as UVB exposure, hormone balance, inflammatory status and ageing. OBJECTIVES: To determine (i) melanocyte dendricity in multiple facial spot types, (ii) impact of High Mobility Group Box 1 (HMGB1), and the combination of sucrose dilaurate and sucrose laurate (SDL) on melanogenesis and melanocyte dendricity, and (iii) SDL effect on facial spots in a human use test. METHODS: Facial spot and adjacent non-spot skin biopsies were collected from Chinese women (age 20-70). Histological assessment of melanocyte dendricity was performed for 3 spot types (solar lentigo, melasma and postinflammatory hyperpigmentation) by immunofluorescent staining for c-kit/MITF. Keratinocyte, melanocyte and melanocyte-keratinocyte co-culture models were used to assess HMGB1 release by UVB radiation, the effects of HMGB1 and SDL on melanin production, melanocyte dendricity and melanosome transfer. The effect of an SDL-containing moisturizer on appearance of facial hyperpigmented spots was assessed against a vehicle control in an 8-week human use test. RESULTS: Melanocytes in spot areas are more dendritic than melanocytes in adjacent non-spot skin across three investigated spot types. In cell culture models, a moderate UVB-radiation exposure caused release of HMGB1 from keratinocytes. HMGB1 did not alter melanin production in melanocytes, but enhanced melanocyte dendricity and melanosome transfer. SDL reduced HMGB1 release from keratinocytes, inhibited melanin production, reversibly suppressed melanocyte dendricity and reduced melanosome transfer. In the human use test, SDL-containing moisturizer reduced appearance of spots versus vehicle. CONCLUSION: Increased melanocyte dendricity was observed in multiple types of facial spots. Addition of HMGB1 protein increased melanocyte dendricity and melanosome transfer in cell cultures, implicating potential involvement in spot formation. SDL suppressed melanin production, melanocyte dendricity and melanosome transfer in vitro and reduced appearance of spots in the use test, suggesting SDL is an effective solution to address hyperpigmented spot concerns.

Seasonality and within-subject clustering of rotavirus infections in an eight-site birth cohort study.

Improving understanding of the pathogen-specific seasonality of enteric infections is critical to informing policy on the timing of preventive measures and to forecast trends in the burden of diarrhoeal disease. Data obtained from active surveillance of cohorts can capture the underlying infection status as transmission occurs in the community. The purpose of this study was to characterise rotavirus seasonality in eight different locations while adjusting for age, calendar time and within-subject clustering of episodes by applying an adapted Serfling model approach to data from a multi-site cohort study. In the Bangladesh and Peru sites, within-subject clustering was high, with more than half of infants who experienced one rotavirus infection going on to experience a second and more than 20% experiencing a third. In the five sites that are in countries that had not introduced the rotavirus vaccine, the model predicted a primary peak in prevalence during the dry season and, in three of these, a secondary peak during the rainy season. The patterns predicted by this approach are broadly congruent with several emerging hypotheses about rotavirus transmission and are consistent for both symptomatic and asymptomatic rotavirus episodes. These findings have practical implications for programme design, but caution should be exercised in deriving inferences about the underlying pathways driving these trends, particularly when extending the approach to other pathogens.

Distal radio-ulnar implant arthroplasty: a systematic review.

The use of implant arthroplasty in the hand and wrist is increasing, often with little evidence of outcomes in the literature. We therefore undertook a systematic review of the outcomes of distal radio-ulnar joint arthroplasties following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Papers were assessed for outcomes, implant survival and methodological quality. Fourteen papers assessed ulna head replacements. The implant survival rate was 93% at a mean follow-up of 45 months. One paper assessed a partial ulna head replacement. Fourteen papers assessed total distal radio-ulnar joint replacements; all but two used the Aptis prosthesis. These implants had a survival rate of 97% at a mean of 56 months. Complications rates were 28% in both groups, and many were major. Although these data are impressive, worldwide there are many more implants placed and not followed up. All studies were level IV and V studies with low Coleman scores. This systematic review demonstrates that implant arthroplasty for the distal radio-ulnar joint has produced acceptable results in small numbers of patients. Whilst these short term outcomes are encouraging, the indications should be carefully considered and there should be proper consideration of the potential for later failure. LEVEL OF EVIDENCE: III.

The Impact of Combined Radiation and Chemotherapy on Outcome in Uterine Clear Cell Carcinoma Compared with Chemotherapy Alone.

AIMS: To investigate the impact of pelvic radiation on survival in patients with uterine clear cell carcinoma (UCC) who received adjuvant chemotherapy. MATERIALS AND METHODS: Patients with stage I-IV UCC who had undergone surgery and chemotherapy were identified from the Surveillance, Epidemiology, and End Results (SEER) programm 2000-2009. Patients were divided into those who received only chemotherapy and those who received both chemotherapy and radiation therapy. Kaplan-Meier curves and Cox regression models were used for analysis. RESULTS: Of the 317 patients included, 195 (62%) were in the chemotherapy only group and 122 (38%) were in the chemotherapy and radiation therapy group. Pelvic radiation was associated with significant improvement in overall survival (median 88 versus 25 months, 5 year survival: 58% versus 33%, P<0.001) in the chemotherapy and radiation therapy group compared with the chemotherapy only group for the entire cohort. On subset analysis, chemotherapy and radiation therapy was associated with improved overall survival in late stage disease (III-IV) (5 year 54% versus 22%, P<0.001) compared with the chemotherapy only group, whereas in stage I-II UCC, there was no difference in overall survival between the chemotherapy and radiotherapy group and the chemotherapy only group (5 year 65% versus 67%, P=0.69). In multivariable analysis, pelvic radiation was associated with improved survival in patients with late stage disease (hazard ratio 0.57, 95% confidence interval 0.35-0.94, P=0.03) but not for early stage disease (hazard ratio 0.81, 95% confidence interval 0.33-2.0, P=0.65). Other significant predictors were advanced stage, positive cytology and extensive lymphadenectomy. CONCLUSIONS: Radiation was associated with significant improvement in survival in advanced stage UCC, but not in early stage UCC. These data support the beneficial role of radiation therapy in UCC, especially in patients with advanced stage disease.

Outcome after conservatively managed intracapsular fractures of the femoral neck.

INTRODUCTION: In 2012, 2.6% of hip-fracture patients in the UK were treated conservatively. There is little data on outcome for these patients. However, one study demonstrated that though 30-day mortality is higher, mortality over the rest of the year is comparable with that in surgical groups. Therefore, we assessed conservatively managed patients in our unit. METHODS: Patients with intracapsular fractures of the femoral neck treated by conservative means between 2010 and 2012 inclusive were identified. Data were collected: American Society of Anaesthesiologists (ASA) grade, Nottingham Hip Fracture Score (NHFS), mobility, mortality (30 days and one year) and pain levels. RESULTS: Thirty-two patients formed the study cohort. Mean age was 85.6 years. Median ASA grade was 4. Mortality at 30 days and one year was 31.3% and 56.3%, respectively. There was one case of pneumonia and one of infection. Pressure sores or venous thromboembolism were not documented. Three patients underwent surgery once their health improved. In general, mobility was decreased, but 30.8% of patients could mobilise with two aids or a frame. Only two cases had ongoing problems with pain. CONCLUSIONS: Our data are similar to those published previously. Our patients were likely to have higher mortality data due to selection bias. Thirty-day mortality was significantly higher than the national average, but patients surviving 30 days had a prevalence of mortality similar to those managed by surgical means. Despite mobility decreasing from the pre-admission status, a considerable number of patients were free of pain and could mobilise. These data suggest that conservative management of intracapsular fractures of the femoral neck can produce acceptable results.

Cost-effectiveness of tuberculosis screening and isoniazid treatment in the TB/HIV in Rio (THRio) Study.

OBJECTIVE: To estimate the incremental cost-effectiveness of tuberculosis (TB) screening and isoniazid preventive therapy (IPT) among human immunodeficiency virus (HIV) infected adults in Rio de Janeiro, Brazil. DESIGN: We used decision analysis, populated by data from a cluster-randomized trial, to project the costs (in 2010 USD) and effectiveness (in disability-adjusted life years [DALYs] averted) of training health care workers to implement the tuberculin skin test (TST), followed by IPT for TST-positive patients with no evidence of active TB. This intervention was compared to a baseline of usual care. We used time horizons of 1 year for the intervention and 20 years for disease outcomes, with all future DALYs and medical costs discounted at 3% per year. RESULTS: Providing this intervention to 100 people would avert 1.14 discounted DALYs (1.57 undiscounted DALYs). The median estimated incremental cost-effectiveness ratio was $2273 (IQR $1779-$3135) per DALY averted, less than Brazil's 2010 per capita gross domestic product (GDP) of $11,700. Results were most sensitive to the cost of providing the training. CONCLUSION: Training health care workers to screen HIV-infected adults with TST and provide IPT to those with latent tuberculous infection can be considered cost-effective relative to the Brazilian GDP per capita.

Management of extreme patella baja using in-situ hamstring tendon autograft.

Successful total knee arthroplasty requires a functioning extensor mechanism. Patella baja following total knee arthroplasty can cause extensor mechanism dysfunction and produce poor outcomes. We present a case of severe patella tendon shortening following revision total knee arthroplasty with almost complete ankylosis of the distal pole of the patella to the proximal tibia. This resulted in effective extensor mechanism dysfunction with pain and severely limited knee flexion. We report a novel method of reconstruction of the patella tendon at the time of revision arthroplasty together with the one-year clinical outcome and review of the literature.

Serial analysis of the gut and respiratory microbiome in cystic fibrosis in infancy: interaction between intestinal and respiratory tracts and impact of nutritional exposures.

UNLABELLED: Pulmonary damage caused by chronic colonization of the cystic fibrosis (CF) lung by microbial communities is the proximal cause of respiratory failure. While there has been an effort to document the microbiome of the CF lung in pediatric and adult patients, little is known regarding the developing microflora in infants. We examined the respiratory and intestinal microbiota development in infants with CF from birth to 21 months. Distinct genera dominated in the gut compared to those in the respiratory tract, yet some bacteria overlapped, demonstrating a core microbiota dominated by Veillonella and Streptococcus. Bacterial diversity increased significantly over time, with evidence of more rapidly acquired diversity in the respiratory tract. There was a high degree of concordance between the bacteria that were increasing or decreasing over time in both compartments; in particular, a significant proportion (14/16 genera) increasing in the gut were also increasing in the respiratory tract. For 7 genera, gut colonization presages their appearance in the respiratory tract. Clustering analysis of respiratory samples indicated profiles of bacteria associated with breast-feeding, and for gut samples, introduction of solid foods even after adjustment for the time at which the sample was collected. Furthermore, changes in diet also result in altered respiratory microflora, suggesting a link between nutrition and development of microbial communities in the respiratory tract. Our findings suggest that nutritional factors and gut colonization patterns are determinants of the microbial development of respiratory tract microbiota in infants with CF and present opportunities for early intervention in CF with altered dietary or probiotic strategies. IMPORTANCE: While efforts have been focused on assessing the microbiome of pediatric and adult cystic fibrosis (CF) patients to understand how chronic colonization by these microbes contributes to pulmonary damage, little is known regarding the earliest development of respiratory and gut microflora in infants with CF. Our findings suggest that colonization of the respiratory tract by microbes is presaged by colonization of the gut and demonstrated a role of nutrition in development of the respiratory microflora. Thus, targeted dietary or probiotic strategies may be an effective means to change the course of the colonization of the CF lung and thereby improve patient outcomes.

Long-term increases in young-of-the-year growth of Arctic cisco Coregonus autumnalis and environmental influences.

Arctic cisco Coregonus autumnalis young-of-year (YOY) growth was used as a proxy to examine the long-term response of a high-latitude fish population to changing climate from 1978 to 2004. YOY growth increased over time (r² = 0·29) and was correlated with monthly averages of the Arctic oscillation index, air temperature, east wind speed, sea-ice concentration and river discharge with and without time lags. Overall, the most prevalent correlates to YOY growth were sea-ice concentration lagged 1 year (significant correlations in 7 months; r² = 0·14-0·31) and Mackenzie River discharge lagged 2 years (significant correlations in 8 months; r² = 0·13-0·50). The results suggest that decreased sea-ice concentrations and increased river discharge fuel primary production and that life cycles of prey species linking increased primary production to fish growth are responsible for the time lag. Oceanographic studies also suggest that sea ice concentration and fluvial inputs from the Mackenzie River are key factors influencing productivity in the Beaufort Sea. Future research should assess the possible mechanism relating sea ice concentration and river discharge to productivity at upper trophic levels.

Controlled trial of active tuberculosis case finding in a Brazilian favela.

SETTING: A large, impoverished squatters' settlement (favela), Rio de Janeiro, Brazil. OBJECTIVE: To assess the community impact of active case finding for tuberculosis (TB) compared to an enhanced case-finding strategy. DESIGN: A pair-matched, cluster-randomized trial comparing household symptom screening and spot sputum collection (Arm 1) vs. distribution of an educational pamphlet (Arm 2) was performed in a large Brazilian favela. We compared TB case-notification rates, time from symptom onset to treatment start and treatment completion proportions between arms. Fourteen neighborhoods (estimated population 58,587) were pair-matched by prior TB case rates and randomly allocated to one of two interventions. TB was diagnosed using acid-fast bacilli smears. New TB cases were interviewed and clinic records were reviewed. RESULTS: A total of 193 TB cases were identified in the 14 study neighborhoods (incidence proportion 329 per 100,000 population). The case identification rate in Arm 1 was 934/100,000 person-years (py) vs. 604/100,000 py in Arm 2 (RR 1.55, 95%CI 1.10-1.99). No significant differences were found in time from cough onset to treatment start or proportion completing treatment. CONCLUSIONS: A door-to-door case-finding campaign was more effective (while ongoing) at detecting prevalent cases and influencing people to come for care than leafleting, but no differences were seen in time to treatment start or treatment completion.

Epidemiological studies of the non-specific effects of vaccines: II--methodological issues in the design and analysis of cohort studies.

We review sources of bias which can affect non-randomized cohort studies of non-specific effects of vaccines on child mortality. Using examples from the literature on non-specific effects, we describe different sources of selection and information bias, and, where possible, outline analysis strategies to mitigate or eliminate such biases.

Tuberculosis as primary cause of death among AIDS cases in Rio de Janeiro, Brazil.

SETTING: Data from the mortality database, Rio de Janeiro City (RJC) Health Department, Rio de Janeiro, Brazil. OBJECTIVES: To determine the role played by tuberculosis (TB) in Brazil's human immunodeficiency virus (HIV) positive population, we investigated the frequency of TB as the primary cause of death among HIV-positive subjects in RJC. DESIGN: Information about acquired immune-deficiency syndrome (AIDS) deaths from 1996 to 2005 in individuals aged >12 years was obtained from the Mortality Information System (SIM), and the cause of death was classified according to the International Classification of Diseases (ICD-10), through primary causes coded in Chapter I--B20 to B24 (HIV disease). RESULTS: There were 8601 AIDS-related deaths in RJC between 1996 and 2005. TB was the primary cause of death in 9.0% of all AIDS-related deaths, while Pneumocystis carinii pneumonia (PCP) accounted for 4.7%. TB cases erroneously classified under other infectious diseases may have contributed to an underestimation of the number of TB deaths among HIV-positive patients. CONCLUSION: Our study showed that TB is the leading cause of AIDS-related deaths and is responsible for twice as many deaths as PCP, in a scenario of free access to antiretrovirals. The potential benefits of TB preventive treatment and of the availability of highly active antiretroviral treatment could not be established by this analysis.

Climatic, temporal, and geographic characteristics of respiratory syncytial virus disease in a tropical island population.

Respiratory syncytial virus (RSV) is an important cause of morbidity in children worldwide, although data from equatorial regions are limited. We analysed climatic, spatial, and temporal data for children presenting to hospitals in Lombok island, Indonesia with clinical pneumonia. During the study period, 2878 children presented and 741 RSV cases were identified. In multivariate analysis with an 8-day lag, occurrence of rain was associated with 64% higher incidence of RSV disease [incidence rate ratio (IRR) 1.64, 95% confidence interval (CI) 1.13-2.38]. A 1% rise in mean relative humidity and 1 degree C increase in mean air temperature was associated with a 6% (IRR 1.06, 95% CI 1.03-1.10) and 44% (IRR 1.44, 95% CI 1.24-1.66) increase in RSV cases, respectively. Four statistically significant local clusters of RSV pneumonia were identified within the annual island-wide epidemics. This study demonstrates statistical association of monsoon-associated weather in equatorial Indonesia with RSV. Moreover, within the island-wide epidemics, localized RSV outbreaks suggest local factors influence RSV disease.

Adoption of safer infant feeding and postpartum sexual practices and their relationship to maternal HIV status and risk of acquiring HIV in Zimbabwe.

OBJECTIVE: To examine the relationships between maternal knowledge and concern about HIV status, adoption of preventive practices and risk of acquiring HIV in Zimbabwe. METHODS: Knowledge and behavioural data were collected via interview from 2595 mothers enrolled in ZVITAMBO, a randomized trial of postpartum vitamin A supplementation that also offered education on safer infant feeding and sexual practices. Mothers were tested for HIV at delivery; those uninfected at baseline were retested during study follow-up. Logistic regression methods were used to identify variables associated with adoption of preventive behaviours and, for HIV-negative mothers, their relationship to risk of acquiring HIV post-delivery. RESULTS: A total of 518 mothers (20%) reported practicing safer sex and 289 mothers (11%) reported modifying their feeding behaviour because of HIV. Fear of transmitting HIV (50.4%) and protecting the baby's health (30.9%) were the most frequently cited reasons for behaviour change. Forty-nine HIV-negative mothers acquired HIV during the first postpartum year. After taking into account other significant covariates, mothers who were concerned about their own HIV status were 1.9 times more likely (95% CI: 1.05-3.52; P = 0.03), and those reporting safer sex practices were 58% less likely to become infected (adjusted odds ratio: 0.42; 95% CI: 0.17-1.04; P = 0.06). Married women who reported practicing abstinence to prevent HIV were 3.2 times more likely to become infected than non-abstaining mothers (P = 0.01), while there were no new HIV infections among abstaining single mothers. CONCLUSIONS: Greater emphasis should be given to safer sex practices among women who test negative in mother-to-child HIV prevention programmes.

HIV-1 and HIV-2 prevalence and associated risk factors among postnatal women in Harare, Zimbabwe.

Studies of antenatal women form the predominant source of data on HIV-1 prevalence in Africa. Identifying factors associated with prevalent HIV is important in targeting diagnostic services and care. Between November 1997 and January 2000, 14,110 postnatal women from Harare, Zimbabwe were tested by ELISAs reactive to both HIV-1 and HIV-2; a subset of positive samples was confirmed with assays specific for HIV-1 and HIV-2. Baseline characteristics were elicited and modelled to identify risk factors for prevalent HIV infection. HIV-1 and HIV-2 prevalences were 32.0% (95% CI 31.2-32.8) and 1.3% (95% CI 1.1-1.5), respectively; 4% of HIV-1-positive and 99% of HIV-2-positive women were co-infected. HIV-1 prevalence increased from 0% among 14-year-olds to >45% among women aged 29-31 years, then fell to <20% among those aged>40 years. In multivariate analyses, prevalence increased with parity, was lower in married women than in single women, divorcees and widows, and higher in women with the lowest incomes and those professing no religion. Adjusted HIV-1 prevalence increased during 1998 and decreased during 1999. Age modified the effects of parity, home ownership and parental education. Among older women, prevalence was greater for women who were not homeowners. Among younger women, prevalence increased with parity and low parental education. None of these factors distinguished women co-infected with HIV-2 from those infected with HIV-1 alone. Prevalent HIV-1 infection is associated with financial insecurity and weak psychosocial support. The ZVITAMBO study apparently spanned the peak of the HIV-1 epidemic among reproductive women in Harare.

Evaluation of the indirect effects of a pneumococcal vaccine in a community-randomized study.

When a sufficiently high proportion of a population is immunized with a vaccine, reduction in secondary transmission of disease can confer significant protection to unimmunized population members. We propose a straightforward method to estimate the degree of this indirect effect of vaccination in the context of a community-randomized vaccine trial. A conditional logistic regression model that accounts for within-randomization unit correlation over time is described, which models risk of disease as a function of community-level covariates. The approach is applied to an example data set from a pneumococcal conjugate vaccine study, with study arm and immunization levels forming the covariates of interest for the investigation of indirect effects.

Combined human and porcine mass chemotherapy for the control of T. solium.

A combined (human and porcine) mass chemotherapy program was tested in a controlled design in 12 village hamlets in the Peruvian highlands. A single dose of 5 mg of praziquantel was given to eliminate intestinal taeniasis in humans, and two rounds of oxfendazole (30 mg/kg) were administered to all pigs. The total population in the study villages was 5,658 resident individuals, and the porcine population at the beginning of the study was 716 pigs. Human treatment coverage was 75%, ranging from 69% to 80%. There were only a few refusals of owners for porcine treatment of their animals. The effect of the intervention was measured by comparing incidence rates (seroconversion in pigs who were seronegative 4 months before) in treatment versus control villages, before and up to 18 months after treatment. There was a clear effect in decreasing prevalence (odds ratio, 0.51; P < 0.001) and incidence (odds ratio, 0.39; P < 0.013) in the treatment area after the intervention, which did not leave to extinction of the parasite but stabilized in slightly decreased rates persisting along the follow-up period. Mass chemotherapy was effective in decreasing infection pressure in this hyperendemic area. However, the magnitude of the effect was small and did not attain the goal of eliminating transmission.

Community level risk factors for numbers of landmine victims in Chad and Thailand.

STUDY OBJECTIVE: To determine commonalities of landmine victim risk factors in two very different countries. DESIGN AND SETTING: Data on 249 communities in Chad and 530 in Thailand were collected during 2000-2001 as part of the Global Landmine Survey. Community level variables were analysed in a series of Poisson mixture models with number of landmine victims as the dependent variable. Models developed for each country were tested on the other to investigate similarities and robustness of identification of risk factors. MAIN RESULTS: Increased community level risk was associated with population size, closeness to another community with victims, emplacement in the previous two years, blocked water or pasture, and the proximity of unexploded ordnance or anti-tank mines. In Chad, risk factors tended to be more related to identifying communities that had crossed a threshold between near zero and moderate risk; Thailand, factors were more related to increases in victim rates. CONCLUSIONS: Current systems of collecting data on community characteristics and landmine victims can provide meaningful risk factor information. Remediation approaches that focus on blockage of important resources and areas of recent, high intensity conflicts may be the most beneficial in reducing the numbers of victims.

Factors constraining adherence to referral advice for severely ill children managed by the Integrated Management of Childhood Illness approach in Imbabura Province, Ecuador.

AIM: Low referral completion rates in developing countries undermine the Integrated Management of Childhood Illness (IMCI) strategy for lowering child mortality. This study sought to identify factors constraining adherence to referral advice in a health system using the IMCI approach. METHODS: Caregivers of 160 children urgently referred to hospital were prospectively interviewed. Caregivers who accessed and did not access hospital were compared for potential referral constraining factors, including demographics, family dynamics, the severity of their child's illness, their interaction with the health system, self-perceived problems, and physical and financial access. RESULTS: 67/160 (42%) referred children did not access hospital. Six factors were associated with non-access, including two health worker actions: not being given a referral slip [adjusted odds ratio (OR)= 15.3, 95% confidence interval (95% CI) 4.4-64.6] and not being told to go to the hospital immediately (adjusted OR = 5.3, 95% CI 1.9-16.3). Receiving both of these interventions reduced the risk of not accessing hospital to 19%, from 96% for those who received neither intervention. Several indicators of illness severity, including caregivers' ranking of their children's illness severity, the presence of severe illness signs and mortality, were investigated and found not to be important explanatory factors. CONCLUSION: Providing a referral slip and counseling the caregivers of severely ill children to go to the hospital immediately appear to be powerful tools for increasing successful referral outcomes.