Planned mode of birth after previous caesarean section and special educational needs in childhood: a population-based record linkage cohort study.

OBJECTIVE: To investigate the association between planned mode of birth after previous caesarean section and a child's risk of having a record of special educational needs (SENs). DESIGN: Population-based cohort study. SETTING: Scotland. POPULATION: A cohort of 44 892 singleton children born at term in Scotland between 2002 and 2011 to women with one or more previous caesarean sections. METHODS: Linkage of Scottish national health and education data sets. MAIN OUTCOME MEASURES: Any SENs and specific types of SEN recorded when a child was aged 4-11 years and attending a Scottish primary or special school. RESULTS: Children born following planned vaginal birth after previous caesarean (VBAC) compared with elective repeat caesarean section (ERCS) had a similar risk of having a record of any SENs (19.24 versus 17.63%, adjusted risk ratio aRR 1.04, 95% CI 0.99-1.09) or specific types of SEN. There was also little evidence that planned VBAC with or without labour induction compared with ERCS was associated with a child's risk of having a record of any SENs (21.42 versus 17.63%, aRR 1.09, 95% CI 1.01-1.17 and 18.78 versus 17.63%, aRR 1.03, 95% CI 0.98-1.08, respectively) or most types of SEN. However, an increased risk of sensory impairment was seen for planned VBAC with labour induction compared with ERCS (1.18 versus 0.78%, risk difference 0.4%, adjusted odds ratio aOR 1.60, 95% CI 1.09-2.34). CONCLUSIONS: This study provides little evidence of an association between planned mode of birth after previous caesarean and SENs in childhood beyond a small absolute increased risk of sensory impairment seen for planned VBAC with labour induction. This finding may be the result of performing multiple comparisons or residual confounding. The findings provide valuable information to manage and counsel women with previous caesarean section concerning their future birth choices. TWEETABLE ABSTRACT: There is little evidence planned mode of birth after previous caesarean section is associated with special educational needs in childhood.

Long-term cognitive and school outcomes of late-preterm and early-term births: a systematic review.

BACKGROUND: Children born before full term (39-41 weeks' gestation) are at increased risk of adverse cognitive outcomes. Risk quantification is important as late-preterm (LPT; 34-36 weeks) and early-term (ET; 37-38 weeks) births are common. METHOD: This review analyses the effect of LPT and ET births on long-term cognitive and educational outcomes. The primary outcome was general cognitive ability. Secondary outcomes included verbal/non-verbal intelligence quotient, subject-specific school performance and special educational needs. The search strategy included Medline and Embase from January 1975 to June 2013. Eligible studies investigated specified outcomes and included suitable gestational age participants assessed at 2 years and older. Outcome measures and socio-demographic descriptors were extracted, and data meta-analysed where possible. RESULTS: Eight studies compared ET birth with full-term birth. Fourteen studies compared LPT birth with either term birth (>37 weeks, n = 12 studies) or full-term birth (39-41 weeks, n = 2 studies). Substantial between-study heterogeneity existed. LPT and ET children underperformed in most outcomes compared with their term/full-term counterparts, respectively. For example, LPT children had an increased risk of lower general cognitive ability (adjusted risk ratio 1.38 [95% confidence interval 1.06-1.79]), and full-term children performed 5% of a standard deviation higher (z-score 0.05 [0.02, 0.08]) than ET children. Poorer outcomes persist into adulthood; term cohorts performed 5% of a standard deviation higher than LPT cohorts (z-score 0.05 [0.04, 0.07]), and full-term cohorts performed 3% of a standard deviation higher than ET cohorts (z-score 0.03 [0.02, 0.04]). CONCLUSION: This review critically examines the knowledge around long-term cognitive outcomes of LPT and ET births, demonstrating multiple, small, adverse differences between LPT/ET and term/full-term births.

The impact of the Covid-19 pandemic on postnatal anxiety and posttraumatic stress: Analysis of two population-based national maternity surveys in England.

BACKGROUND: Few studies have evaluated postnatal anxiety and posttraumatic stress (PTS) before and during the Covid-19 pandemic using comparable data across time. We used data from two national maternity surveys in England to explore the impact of the pandemic on prevalence and risk factors for postnatal anxiety and PTS. METHODS: Analysis was conducted using population-based surveys carried out in 2018 (n = 4509) and 2020 (n = 4611). Weighted prevalence estimates for postnatal anxiety and PTS were compared across surveys. Adjusted risk ratios (aRR) were estimated for the association between risk factors and postnatal anxiety and PTS. FINDINGS: Prevalence of postnatal anxiety increased from 13.7 % in 2018 to 15.1 % in 2020 (+1.4 %(95%CI:-0.4-3.1)). Prevalence of postnatal PTS increased from 9.7 % in 2018 to 11.5 % in 2020 (+1.8 %(95%CI:0.3-3.4)), due to an increase in PTS related to birth trauma from 2.5 % to 4.3 % (+1.8 %(95%CI:0.9-2.6); there was no increase in PTS related to non-birth trauma. Younger age (aRR = 1.31-1.51), being born in the UK (aRR = 1.29-1.59), long-term physical or mental health problem(s) (aRR = 1.27-1.94), and antenatal anxiety (aRR = 1.97-2.22) were associated with increased risk of postnatal anxiety and PTS before and during the pandemic, whereas higher satisfaction with birth (aRR = 0.92-0.94) and social support (aRR = 0.81-0.82) were associated with decreased risk. INTERPRETATION: Prevalence of postnatal PTS was significantly higher during the pandemic, compared to before the pandemic, due to an increase in PTS related to birth trauma. Prevalence of postnatal anxiety was not significantly higher during the pandemic. Risk factors for postnatal anxiety and PTS were similar before and during the pandemic.

Persistent effects of women's parity and breastfeeding patterns on their body mass index: results from the Million Women Study.

OBJECTIVE: To explore the long-term effects of women's childbearing patterns on their body mass index. DESIGN: Cross-sectional analysis. SETTING: Population-based study of UK women. PARTICIPANTS: 740 628 postmenopausal participants in the Million Women Study who reported their height, weight, reproductive histories and other relevant factors. MAIN OUTCOME MEASURES: Standardized mean BMI (kg m(-2)) in groups defined by their parity and breastfeeding history. RESULTS: Women were aged 57.5 (s.d. 4) years on average, and had a mean BMI of 26.2 kg m(-2) (s.d. 5); 88% were parous, with 2.1 (s.d. 1.2) children on average. The standardised mean BMI increased progressively with the number of births from 25.6 kg m(-2) (95% confidence interval (CI): 25.5-25.6) in nulliparous women up to 27.2 kg m(-2) (CI: 27.2-27.3) for women with four or more births, a difference of 1.7 kg m(-2) (CI: 1.6-1.7). Among the parous women 70% had ever breastfed and their average total duration of breastfeeding was 7.7 (s.d. 8.8) months. At every parity level the standardised mean BMI was significantly lower among women who had breastfed than those who had not, decreasing by 0.22 kg m(-2) (CI: 0.21-0.22) for every 6 months of breastfeeding, that is, women's mean BMI was 1% lower for every 6 months that they had breastfed. These associations were highly statistically significant (P<0.0001) and independent of the effects of socioeconomic group, region of residence, smoking and physical activity. CONCLUSIONS: Childbearing patterns have a persistent effect on adiposity in this population. The reduction in BMI associated with just 6 months breastfeeding in UK women could importantly reduce their risk of obesity-related disease as they age.

Asthma in children born after infertility treatment: findings from the UK Millennium Cohort Study.

STUDY QUESTION: Is asthma more common in children born after subfertility and assisted reproduction technologies (ART)? SUMMARY ANSWER: Yes. Asthma, wheezing in the last year and anti-asthmatic medication were all more common in children born after a prolonged time to conception (TTC). This was driven specifically by an increase in children born after ART. WHAT IS KNOWN ALREADY: Few studies have investigated any association between ART and asthma in subsequent children, and findings to date have been mixed. A large registry-based study found an increase in asthma medication in ART children but suggests underlying infertility is the putative risk factor. Little is known about asthma in children after unplanned or mistimed conceptions. STUDY DESIGN, SIZE, DURATION: The Millennium Cohort Study is a UK-wide, prospective study of 18 818 children recruited at 9 months of age. Follow-up is ongoing. This study analyses data from follow-up surveys at 5 and 7 years of age (response rates of 79 and 70%, respectively). PARTICIPANTS/MATERIALS, SETTING, METHODS: Singleton children whose natural mothers provided follow-up data were included. Mothers reported whether their pregnancy was planned; planners provided TTC and details of any ART. The population was divided into 'unplanned' (unplanned and unhappy), 'mistimed' (unplanned but happy), 'planned' (planned, TTC < 12 months), 'untreated subfertile' (planned, TTC >12 months), 'ovulation induced' (received clomiphene citrate) and 'ART' (IVF or ICSI). The primary analysis used the planned children as the comparison group; secondary analysis compared the treatment groups to the children born to untreated subfertile parents. Outcomes were parent report of asthma and wheezing at 5 and 7 years, derived from validated questions in the International Study of Asthma and Allergies in Childhood, plus use of anti-asthmatic medications. A total of 13 041 (72%) children with full data on asthma and confounders were included at 5 years of age, and 11 585 (64%) at 7 years. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with planned children, those born to subfertile parents were significantly more likely to experience asthma, wheezing and to be taking anti-asthmatics at 5 years of age [adjusted odds ratio (OR): 1.39 (95% confidence interval (CI): 1.07, 1.80), OR: 1.27 (1.00, 1.63) and OR: 1.90 (1.32,2.74), respectively]. This association was mainly related to an increase among children born after ART (adjusted OR: 2.65 (1.48, 4.76), OR: 1.97, (1.10, 3.53) and OR: 4.67 (2.20, 9.94) for asthma, wheezing and taking anti-asthmatics, respectively). The association was also present, though reduced, at the age of 7 years. LIMITATIONS, REASONS FOR CAUTION: The number of singletons born after ART was relatively small (n = 104), and as such the findings should be interpreted with caution. However, data on a wide range of possible confounding and mediating factors were available and analysed. The data were weighted for non-response to minimize selection bias. WIDER IMPLICATIONS OF THE FINDINGS: The findings add to the growing body of evidence suggesting an association between subfertility, ART and asthma in children. Further work is needed to establish causality and elucidate the underlying mechanism. These findings are generalizable to singletons only, and further work on multiples is needed.

Light drinking versus abstinence in pregnancy - behavioural and cognitive outcomes in 7-year-old children: a longitudinal cohort study.

OBJECTIVE: To assess whether light drinking in pregnancy is linked to unfavourable developmental outcomes in children. DESIGN: Prospective population-based cohort. SETTING: UK. POPULATION: Ten thousand five hundred and thirty-four 7-year-olds. METHODS: Quasi-experimental using propensity score matching (PSM) to compare children born to light (up to 2 units per week) and non-drinkers. MAIN OUTCOME MEASURES: Behavioural difficulties rated by parents and teachers; cognitive test scores for reading, maths and spatial skills. RESULTS: Ordinary least squares (OLS) regression and PSM analyses are presented. For behavioural difficulties, unadjusted estimates for percentage standard deviation (SD) score differences ranged from 2 to 14%. On adjustment for potential confounders, differences were attenuated, with a loss of statistical significance, except for teacher-rated boys' difficulties. For boys, parent-rated behavioural difficulties: unadjusted, -11.5; OLS, -4.3; PSM, -6.8; teacher-rated behavioural difficulties: unadjusted, -13.9; OLS, -9.6; PSM, -10.8. For girls, parent-rated behavioural difficulties: unadjusted, -9.6; OLS, -2.9; PSM, -4.5; teacher-rated behavioural difficulties: unadjusted, -2.4; OLS, 4.9; PSM, 3.9. For cognitive test scores, unadjusted estimates for differences ranged between 12 and 21% of an SD score for reading, maths and spatial skills. After adjustment for potential confounders, estimates were reduced, but remained statistically significantly different for reading and for spatial skills in boys. For boys, reading: unadjusted, 20.9; OLS, 8.3; PSM, 7.3; maths: unadjusted, 14.7; OLS, 5.0; PSM, 6.5; spatial skills: unadjusted, 16.2; OLS, 7.6; PSM, 8.1. For girls, reading: unadjusted, 11.6; OLS, -0.3; PSM, -0.5; maths: unadjusted, 12.9; OLS, 4.3; PSM, 3.9; spatial skills: unadjusted, 16.2; OLS, 7.7; PSM, 6.4. CONCLUSION: The findings suggest that light drinking during pregnancy is not linked to developmental problems in mid-childhood. These findings support current UK Department of Health guidelines on drinking during pregnancy.

Prevalence and factors associated with postpartum posttraumatic stress in a population-based maternity survey in England.

BACKGROUND: Studies on prevalence and factors associated with postpartum posttraumatic stress (PTS) typically do not distinguish between PTS related to childbirth (PTS-C) and PTS related to other stressors (PTS-O). This study aimed to describe the prevalence, clinical characteristics, and factors associated with PTS-C and PTS-O in postpartum women. METHODS: The study was a cross-sectional population-based survey of 16,000 postpartum women, selected at random from birth registrations in England to receive a postal questionnaire, including the Primary Care Posttraumatic Stress Disorder Screen. RESULTS: Questionnaires were returned by 4,509 women. The median age was 32 years (IQR=29-36), 64% were married, 77% were UK-born, and 76% were White-British. Prevalence of PTS-C was 2.5% (95%CI:2.0-3.0) and prevalence of PTS-O was 6.8% (95%CI:6.0-7.8). Women with PTS-C were significantly more likely to report re-experiencing symptoms (Chi-Square=7.69,p<0.01). Factors associated with PTS-C were: higher level of deprivation, not having a health professional to talk to about sensitive issues during pregnancy, and the baby being admitted for neonatal intensive care. Factors associated with PTS-O were: age ≤24 years, depression during pregnancy, and having a pregnancy affected by long-term health problems. Factors associated with both were: living without a partner, anxiety during pregnancy, pregnancy-specific health problems, and lower birth satisfaction. CONCLUSIONS: PTS during the postpartum period is relatively common and, for many women, unrelated to childbirth. Increased awareness among health professionals of prevalence, clinical characteristics and factors associated with postpartum PTS-C and PTS-O will aid the development of appropriate management protocols to identify and support women during the perinatal period. Posttraumatic stress, posttraumatic stress disorder, postpartum PTSD/PTS, birth-related PTSD/PTS, birth trauma, perinatal mental health.

Cognitive development following ART: effect of choice of comparison group, confounding and mediating factors.

BACKGROUND: Epidemiological studies have examined the health of children born after assisted reproductive technology (ART), with contradictory results. In this article, we address the question 'Do singletons born after ART have a poorer cognitive developmental outcome at 3 years of age?' We assess the implications of using different comparison groups, and discuss appropriate analytical approaches for the control of confounding and mediating variables. METHODS: Data were drawn from the Millennium Cohort Study. Interviews captured sociodemographic, behavioural and pregnancy information. Developmental assessments conducted at age three included the British Ability Scales II Naming Vocabulary (BAS-NV) instrument. We compared ART infants (born after IVF or ICSI) to four comparison groups: a 'matched' group; a 'subfertile' group (time to conception >12 months); a 'fertile' group (time to conception <12 months); and an 'any spontaneous conceptions' group. Linear regression provided estimates of the difference in mean BAS-NV scores in the ART and comparison groups; both unadjusted estimates and those adjusted for confounding and mediating factors are presented. RESULTS: In the unadjusted analyses, ART children gained significantly better BAS-NV test results than did the comparison group children. When converted to an estimate of developmental age gap, ART children were 2.5, 2.7, 3.6 and 4.5 months ahead of the 'matched', 'subfertile', 'fertile' and 'spontaneous conception' children, respectively. After adjusting for confounding and mediating factors, the differences were reduced, and were not statistically significant. CONCLUSIONS: ART is not associated with poorer cognitive development at 3 years. We have highlighted methodological considerations for researchers planning to study the effect of infertility and ART on childhood outcomes.

Formula milk versus donor breast milk for feeding preterm or low birth weight infants.

BACKGROUND: When sufficient maternal breast milk is not available, the alternative sources of enteral nutrition for preterm or low birth weight infants are donor breast milk or artificial formula milk. Feeding preterm or low birth weight infants with formula milk might increase nutrient input and growth rates. However, since feeding with formula milk may be associated with a higher incidence of feeding intolerance and necrotising enterocolitis, this may adversely affect growth and development. OBJECTIVES: To determine the effect of formula milk compared with donor human breast milk on growth and development in preterm or low birth weight infants. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966 - May 2007), EMBASE (1980 - May 2007), CINAHL (1982 - May 2007), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised controlled trials comparing feeding with formula milk versus donor breast milk in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: Data were extracted using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two reviewer authors, and synthesis of data using relative risk, risk difference and weighted mean difference. MAIN RESULTS: Eight trials fulfilled the inclusion criteria. Only one trial used nutrient-fortified donor breast milk. Enteral feeding with formula milk compared with donor breast milk resulted in higher rates of growth in the short term. There was no evidence of an effect on long-term growth rates or neurodevelopmental outcomes. Meta-analysis of data from five trials demonstrated a statistically significantly higher incidence of necrotising enterocolitis in the formula fed group: typical relative risk 2.5 (95% confidence interval 1.2, 5.1); typical risk difference: 0.03 (95% confidence interval 0.01, 0.06; number needed to harm: 33 (95% confidence interval 17, 100). AUTHORS' CONCLUSIONS: In preterm and low birth weight infants, feeding with formula milk compared with donor breast milk results in a higher rate of short-term growth but also a higher risk of developing necrotising enterocolitis. There are only limited data on the comparison of feeding with formula milk versus nutrient-fortified donor breast milk. This limits the applicability of the findings as nutrient fortification of breast milk is now a common practice in neonatal care. Future trials may compare growth, development and adverse outcomes in infants who receive formula milk versus nutrient-fortified donor breast milk given as a supplement to maternal expressed breast milk or as a sole diet.

Exclusive breastfeeding duration and infant infection.

BACKGROUND/OBJECTIVES: We estimated the risk of infection associated with the duration of exclusive breastfeeding (EBF). SUBJECT/METHODS: We analysed the data on 15 809 term, singleton infants from the UK Millennium Cohort Study. Infants were grouped according to months of EBF: never, <2, 2-4, 4-6 and 6 (the latter being World Health Organisation (WHO) policy since 2001: 'post-2001 WHO policy'). Among those EBF for 4-6 months, we separated those who started solids, but not formula, before 6 months, and were still breastfeeding at 6 months (that is, WHO policy before 2001: 'pre-2001 WHO policy'), from other patterns. Outcomes were infection in infancy (chest, diarrhoeal and ear). RESULTS: EBF was not associated with the ear infection, but was associated with chest infection and diarrhoea. EBF for <4 months was associated with a significantly increased risk of chest infection (adjusted risk ratios (RR) 1.24-1.28) and diarrhoea (adjusted RRs 1.42-1.66) compared with the pre-2001 WHO policy. There was an excess risk of the chest infection (adjusted RR 1.19, 95% confidence interval (CI): 0.97-1.46) and diarrhoea (adjusted RR 1.66, 95% CI: 1.11, 2.47) among infants EBF for 4-6 months, but who stopped breastfeeding by 6 months, compared with the pre-2001 WHO policy. There was no significant difference in the risk of chest infection or diarrhoea in those fed according to the pre-2001 versus post-2001 WHO policy. CONCLUSIONS: There is an increased risk of infection in infants EBF for <4 months or EBF for 4-6 months who stop breastfeeding by 6 months. These results support current guidelines of EBF for either 4-6 or 6 months, with continued breastfeeding thereafter.

Management of ankle sprains: a randomised controlled trial of the treatment of inversion injuries using an elastic support bandage or an Aircast ankle brace.

BACKGROUND: Lateral ligament ankle sprains are the single most common sports injury. OBJECTIVE: To determine the functional outcome of the ankle joint after a moderate or severe inversion injury, comparing standard treatment with an elastic support bandage against an Aircast ankle brace. DESIGN: Prospective, randomised controlled trial. SETTING: Two accident and emergency departments. METHOD: Fifty patients presenting consecutively were randomised into two equal groups: one group was treated with an elastic support bandage and the other with an Aircast ankle brace. All patients were given a standardised advice sheet referring to rest, ice, compression, and elevation. Patients were reviewed after 48-72 hours, 10 days, and one month. PRIMARY OUTCOME MEASURE: Ankle joint function assessed at 10 days and one month using the modified Karlsson scoring method (maximum score 90). SECONDARY OUTCOME MEASURE: The difference in ankle girth (swelling) and pain score at 10 days. RESULTS: Seventeen patients in the elastic support bandage group (six defaulted, two excluded) and 18 patients in the Aircast ankle brace group (six defaulted, one excluded) completed the study. There were no significant differences between the two groups at presentation in terms of age (mean 35.3 and 32.6 years respectively), sex, dominant leg, left or right ankle injured, previous injury, time to presentation (median three and four hours respectively), difference in ankle girth (mean 14.5 and 14.3 mm respectively), and pain scores (mean 6.2 and 5.8 respectively). The Karlsson score was significantly higher in the Aircast ankle cast group than in the elastic bandage group at 10 days (mean 50 v 35, p = 0.028, 95% confidence interval (CI) 1.7 to 27.7) and one month (mean 68 v 55, p = 0.029, 95% CI 1.4 to 24.8) (Student's t test). There was no difference between the groups in the secondary outcome measures (swelling, p = 0.09; pain, p = 0.07). When hierarchical multiple regression analysis was used to correct for possible baseline confounding factors, the Aircast ankle brace group was significantly associated with higher Karlsson scores at 10 days (p = 0.009) and one month (p = 0.024). CONCLUSION: The use of an Aircast ankle brace for the treatment of lateral ligament ankle sprains produces a significant improvement in ankle joint function at both 10 days and one month compared with standard management with an elastic support bandage.

Potential economic impacts from improving breastfeeding rates in the UK.

RATIONALE: Studies suggest that increased breastfeeding rates can provide substantial financial savings, but the scale of such savings in the UK is not known. OBJECTIVE: To calculate potential cost savings attributable to increases in breastfeeding rates from the National Health Service perspective. DESIGN AND SETTINGS: Cost savings focussed on where evidence of health benefit is strongest: reductions in gastrointestinal and lower respiratory tract infections, acute otitis media in infants, necrotising enterocolitis in preterm babies and breast cancer (BC) in women. Savings were estimated using a seven-step framework in which an incidence-based disease model determined the number of cases that could have been avoided if breastfeeding rates were increased. Point estimates of cost savings were subject to a deterministic sensitivity analysis. RESULTS: Treating the four acute diseases in children costs the UK at least £89 million annually. The 2009-2010 value of lifetime costs of treating maternal BC is estimated at £959 million. Supporting mothers who are exclusively breast feeding at 1 week to continue breast feeding until 4 months can be expected to reduce the incidence of three childhood infectious diseases and save at least £11 million annually. Doubling the proportion of mothers currently breast feeding for 7-18 months in their lifetime is likely to reduce the incidence of maternal BC and save at least £31 million at 2009-2010 value. CONCLUSIONS: The economic impact of low breastfeeding rates is substantial. Investing in services that support women who want to breast feed for longer is potentially cost saving.

Male circumcision and risk of HIV infection in sub-Saharan Africa: a systematic review and meta-analysis.

OBJECTIVE: To systematically review studies of male circumcision and the risk of HIV-1 infection in men in sub-Saharan Africa, and to summarize the findings in a meta-analysis. DESIGN: A meta-analysis of observational studies. METHODS: A systematic literature review was carried out of studies published up to April 1999 that included circumcision as a risk factor for HIV-1 infection among men in sub-Saharan Africa. A random effects meta-analysis was used to calculate a pooled relative risk (RR) and 95% confidence interval (CI) for all studies combined, and stratified by type of study population. Further analyses were conducted among those studies that adjusted for potential confounding factors. RESULTS: Twenty-seven studies were included. Of these, 21 showed a reduced risk of HIV among circumcised men, being approximately half that in uncircumcised men (crude RR = 0.52, CI 0.40-0.68). In 15 studies that adjusted for potential confounding factors, the association was even stronger (adjusted RR = 0.42, CI 0.34-0.54). The association was stronger among men at high risk of HIV (crude RR = 0.27; adjusted RR = 0.29, CI 0.20-0.41) than among men in general populations (crude RR = 0.93; adjusted RR = 0.56, CI 0.44-0.70). CONCLUSION: Male circumcision is associated with a significantly reduced risk of HIV infection among men in sub-Saharan Africa, particularly those at high risk of HIV. These results suggest that consideration should be given to the acceptability and feasibility of providing safe services for male circumcision as an additional HIV prevention strategy in areas of Africa where men are not traditionally circumcised.

Long-term effect of preventive therapy for tuberculosis in a cohort of HIV-infected Zambian adults.

OBJECTIVE: To determine the long-term effect of preventive therapy (PT) for tuberculosis on the rates of tuberculosis, mortality and HIV progression. METHODS: In a randomized controlled trial, 1053 HIV-positive Zambian adults received isoniazid (H) for 6 months, rifampicin plus pyrazinamide (RZ) for 3 months, or a placebo. CD4 percentage, neopterin, absolute lymphocyte count and haemoglobin were measured from enrolment (absolute CD4 cell counts from 12 months after enrolment). Because PT reduced the incidence of tuberculosis, eligible placebo subjects were offered H. Here, tuberculosis and mortality rates are compared in the three original arms (intention to treat) using data beyond the end of the trial (average follow-up 3 years; maximum 7 years). RESULTS: There were 102 cases of tuberculosis and 281 deaths (rates 3.6 and 9.0/100 person-years, respectively). There was no significant difference between the tuberculosis rates in the H and RZ groups at any time. The effect of H/RZ on tuberculosis diminished over time (P = 0.011) but the cumulative risk of tuberculosis in the first 2.5 years was significantly lower in the H/RZ group than the placebo group (rate ratio 0.55; 95% confidence interval 0.32-0.93; P = 0.028). There was no significant effect of PT on mortality or progression markers. Tuberculosis was associated with an increased mortality (adjusted rate ratio 1.96; 95% confidence interval 1.21-3.18; P = 0.006). CONCLUSIONS: Both PT regimens protect against tuberculosis for at least 2.5 years but appear to have no effect on HIV progression or mortality. These results may be used in cost-effectiveness models of PT.

HIV-1-related pleural tuberculosis: elevated production of IFN-gamma, but failure of immunity to Mycobacterium tuberculosis.

BACKGROUND: Pleural tuberculosis can resolve spontaneously, suggesting that the inflammatory process may represent a protective immune response. However, pleural tuberculosis is strongly associated with HIV infection. It has been suggested that cell-mediated immune responses may be reduced, and direct bacterial invasion may have a role in pathogenesis, in HIV-positive cases. To test this hypothesis, we compared production of the pro-inflammatory cytokines, interferon (IFN)-gamma and tumour necrosis factor(TNF)-alpha, production of the immunosuppressive cytokine, interleukin (IL)-10, and mycobacterial culture positivity, in HIV-negative and HIV-positive patients with pleural tuberculosis. METHODS: Cytokine levels were measured in serum and pleural fluid, and in supernatants of blood and pleural fluid stimulated in vitro using mycobacterial antigens. Intracellular IFN-gamma and TNF-alpha production was measured after stimulation with phorbol myristate acetate and ionomycin in vitro. RESULTS: IFN-gamma was strikingly elevated in serum and pleural fluid in HIV-positive, compared to HIV-negative subjects (P < or = 0.02). TNF-alpha was elevated, but this was not statistically significant. IL-10 levels were higher in serum (P < 0.001), but similar in pleural fluid. IFN-gamma responses to soluble mycobacterial antigen in vitro were reduced in peripheral blood (P = 0.006), but not pleural fluid, of HIV-positive subjects. Intracellular cytokine staining suggested that CD8+ T cells were a major source of IFN-gamma in HIV-positive subjects. The proportion of subjects with a positive culture for Mycobacterium tuberculosis from pleural fluid was higher in the HIV-positive group. CONCLUSIONS: HIV-positive patients with pleural tuberculosis show elevated production of IFN-gamma, for which CD8+ T cells may be a major source. Mycobacterium tuberculosis can proliferate despite high levels of pro-inflammatory cytokines.

Diagnostic accuracy of physician review, expert algorithms and data-derived algorithms in adult verbal autopsies.

BACKGROUND: The verbal autopsy (VA) is used to collect information on cause-specific mortality from bereaved relatives. A cause of death may be assigned by physician review of the questionnaires, or by an algorithm. We compared the diagnostic accuracy of physician review, an expert algorithm, and data-derived algorithms. METHODS: Data were drawn from a multicentre validation study of 796 adult deaths that occurred in hospitals in Tanzania, Ethiopia, and Ghana. A 'gold standard' cause of death was assigned using hospital records and death certificates. The VA interviews were carried out by trained fieldworkers 1-21 months after the subject's death. A cause of death was assigned by physician review and an expert algorithm. Data-derived algorithms that most accurately estimated the cause-specific mortality fraction (CSMF) for each cause of death were identified using logistic regression. RESULTS: The most common causes of death were tuberculosis/AIDS (CSMF = 18.6%), malaria (CSMF = 10.7%), meningitis (CSMF = 8.3%), and cardiovascular disorders (CSMF = 8.2%). The CSMF obtained using physician review was within +/-20% of the gold standard value for 12 causes of death including the four common causes. The CSMF obtained using the expert algorithm was within +/-20% of the gold standard for eight causes of death, including tuberculosis/AIDS, malaria, and meningitis. The CSMF obtained using the data-derived algorithms was within +/-20% of the gold standard for seven causes of death, including tuberculosis/ AIDS, meningitis, and cardiovascular disorders. All three methods yielded a specificity of at least 80% for all causes of death, and a sensitivity of at least 80% for deaths due to injuries and rabies. CONCLUSIONS: For those settings where physician review is not feasible, expert and data-derived algorithms provide an alternative approach for assigning many causes of death. We recommend that the algorithms proposed herein are validated further.

Decreased parietal cell acid secretion after vagotomy is not associated with altered gastric prostaglandin levels.

In a previous investigation we demonstrated that after vagotomy there is a decreased ability of parietal cells to use intracellular cyclic adenosine monophosphate (cAMP). Prostaglandins are present in gastric mucosa and have been demonstrated to be inhibitors of in vivo and in vitro acid secretion through a cAMP-mediated mechanism. In the present study we have examined in vitro acid secretion and prostaglandin E2 levels in rabbits 8 weeks after vagotomy and pyloroplasty compared with control animals to investigate the possible role of prostaglandins in postvagotomy-impaired cAMP use. In vitro acid secretion was assessed in isolated gastric glands by 14C-labeled aminopyrine uptake and prostaglandin E2-generating capacity measured by high-pressure liquid chromatography. After vagotomy, there was a decrease in basal aminopyrine uptake (p less than 0.05), as well as that simulated by histamine and 8-bromo-cAMP (p less than 0.007). No differences were observed in prostaglandin E2 levels in either gastric glands or intact fundic mucosa (p greater than 0.5). These data suggest that impaired cAMP use observed in parietal cells after vagotomy is not the result of alterations in gastric prostaglandin levels.

Assessment of Leishmaniasis notification system in Santiago del Estero, Argentina, 1990-1993.

Using a capture-recapture method, this study evaluates the completeness of the cutaneous leishmaniasis (CL) surveillance system in four districts of Santiago del Estero province, Argentina, for the period 1990-1993. Four reporting sources were evaluated: medical records kept by health facilities, interviews conducted during a case-control study, and the national and provincial levels of the leishmaniasis surveillance system (LSS). Using the capture-recapture method it was estimated that 210 cases (95% confidence interval [CI]: 202-218) of CL occurred in the four districts during the study period. Completeness of reporting to the leishmaniasis surveillance system at the national level was estimated to be 44.8% (95% CI: 43.2-46.4). The study results indicate that there is substantial underreporting within the LSS, although it did show the appropriate secular trends. The reasons for under-reporting and methods for addressing this problem are discussed.

The immune response to Mycobacterium tuberculosis in HIV-infected and uninfected adults in Uganda: application of a whole blood cytokine assay in an epidemiological study.

SETTING: Out-patient clinic, Entebbe, Uganda. BACKGROUND: It has been proposed that 'type 1' cytokines are essential in protective immunity to Mycobacterium tuberculosis and that suppression of 'type 1' or a switch to a 'type 2' profile is deleterious. We employed a simple assay to examine whether the dependence of the immunological responses to mycobacterial antigens on a range of explanatory factors could be determined in a population where tuberculosis is endemic. OBJECTIVE: To determine the relationship between the tuberculin skin test response and cytokine profile, and the effect of human immunodeficiency virus (HIV) infection. DESIGN: A cross-sectional study of 97 Ugandan adults (22 HIV-positive, 75 HIV-negative). Whole blood was stimulated in vitro using mycobacterial antigens (purified protein derivative [PPD] and culture filtrate proteins [CFP]). 'Type 1' cytokines (gamma interferon [IFN-gamma] and interleukin-2 [IL-2]), 'type 2' cytokines (IL-5 and IL-10) and tumour necrosis factor alpha (TNF-alpha) were measured in culture supernatants. RESULTS: Among HIV-negative subjects, a positive tuberculin skin test was associated with type 1 or mixed (type 1 + type 2) cytokine production, but a positive IFN-gamma response also occurred in a proportion of tuberculin skin test negative subjects (36% for PPD, 17% for CFP). In association with HIV infection, IFN-gamma responses to mycobacterial antigens were profoundly impaired (odds ratio [OR] 0.10 for PPD, 0.06 for CFP, P< or =0.001), but production of IL-2, IL-5 and TNF-alpha was relatively sustained, and IL-10 increased or sustained (OR 3.97 for PPD, P = 0.01, 1.14 for CFP, P = 0.99). CONCLUSION: The type 1/type 2 cytokine balance was not defined by the tuberculin skin test response, and may have a closer relation to protective immunity. IFN-gamma production was strikingly impaired in association with HIV infection, while production of type 2 cytokines was sustained or increased. Use of a simple assay allowed a large sample of subjects to be examined, producing epidemiologically meaningful results.

Frequencies contributing to functional connectivity in the cerebral cortex in "resting-state" data.

BACKGROUND AND PURPOSE: In subjects performing no specific cognitive task ("resting state"), time courses of voxels within functionally connected regions of the brain have high cross-correlation coefficients ("functional connectivity"). The purpose of this study was to measure the contributions of low frequencies and physiological noise to cross-correlation maps. METHODS: In four healthy volunteers, task-activation functional MR imaging and resting-state data were acquired. We obtained four contiguous slice locations in the "resting state" with a high sampling rate. Regions of interest consisting of four contiguous voxels were selected. The correlation coefficient for the averaged time course and every other voxel in the four slices was calculated and separated into its component frequency contributions. We calculated the relative amounts of the spectrum that were in the low-frequency (0 to 0.1 Hz), the respiratory-frequency (0.1 to 0.5 Hz), and cardiac-frequency range (0.6 to 1.2 Hz). RESULTS: For each volunteer, resting-state maps that resembled task-activation maps were obtained. For the auditory and visual cortices, the correlation coefficient depended almost exclusively on low frequencies (<0.1 Hz). For all cortical regions studied, low-frequency fluctuations contributed more than 90% of the correlation coefficient. Physiological (respiratory and cardiac) noise sources contributed less than 10% to any functional connectivity MR imaging map. In blood vessels and cerebrospinal fluid, physiological noise contributed more to the correlation coefficient. CONCLUSION: Functional connectivity in the auditory, visual, and sensorimotor cortices is characterized predominantly by frequencies slower than those in the cardiac and respiratory cycles. In functionally connected regions, these low frequencies are characterized by a high degree of temporal coherence.