Diastolic function assessed with speckle tracking over a decade and its prognostic value: The Copenhagen City Heart Study.

BACKGROUND: The ratio of transmitral early filling velocity to early diastolic strain rate (E/e'sr) may be a more accurate measure of LV filling pressure then ratio of early filling pressure to early tissue velocity. The aim of the study was to investigate the impact of age, sex, obesity, smoking, hypertension, hypercholesterolemia, diabetes, physical activity level, socioeconomic, and psychosocial status on E/e'sr over a decade. Additionally, the predictive value of ΔE/e'sr on future major adverse cardiovascular events (MACE) has never been explored. METHOD: The study included 623 participants from the general population, who participated in the 4th and 5th Copenhagen City Heart Study (CCHS4 and CCHS5). Examinations were median 10 years apart. MACE was the composite endpoint of heart failure, myocardial infarction, and all-cause death. RESULTS: Follow-up time was median 5.7 years, and 43 (7%) experienced MACE. Mean age was 51 ± 14 years, and 43% were male. Mean ΔE/e'sr was 2.1 ± 23.0 cm. After multivariable adjustment for demographic, clinical, and biochemistry variables, high age (stand. ß-coef. = .24, P < .001) and mean arterial blood pressure (MAP) (stand. ß-coef. = .17, P < .001) were significantly associated with an accelerated increase in E/e'sr In multivariable Cox regression, E/e'sr at CCHS5 and ΔE/e'sr were independent predictors of MACE (HR = 1.20, 95% CI [1.01; 1.42] per 10 cm increase for both). ΔE/e'sr did only provide incremental prognostic value to change in left atrial volume index of the conventional diastolic measurements. CONCLUSION: In the general population, age and MAP were predictors of an accelerated increase in E/e'sr over a decade. E/e'sr at CCHS5 and ΔE/e'sr were independent predictors of future MACE.

Ratio of transmitral early filling velocity to early diastolic strain rate predicts long-term risk of cardiovascular morbidity and mortality in the general population.

Aims: It has previously been demonstrated that the ratio of early mitral inflow velocity to global diastolic strain rate (E/e'sr) is a significant predictor of cardiac events in specific patient populations. The utility of this measurement to predict cardiovascular events in a general population has not been evaluated. Methods and results: A total of 1238 participants in a general population study underwent a health examination including echocardiography where global longitudinal strain (GLS) and E/e'sr were determined. The primary endpoint was the composite of incident heart failure (HF), acute myocardial infarction (AMI) or cardiovascular death (CVD). During follow-up (median 11 years), 140 (11.3%) participants reached the composite endpoint. E/e'sr was associated with adverse outcome [HR 1.17 95% CI (1.13-1.21); P < 0.001, per 10 cm increase]. After multivariable adjustment for echocardiographic and clinical parameters, E/e'sr remained an independent predictor of the composite endpoint [HR 1.08, 95% CI (1.02-1.13); P = 0.003] as opposed to E/e' [HR 1.03, 95% CI (0.99-1.06); P = 0.11 per 1 unit increase]. Global longitudinal strain modified the relationship between E/e'sr and outcome (P for interaction = 0.015). E/e'sr was a stronger predictor in participants with good systolic function as determined by GLS (GLS > 18%) after multivariable adjustment, when compared to participants with reduced systolic function (GLS < 18%) [HR 1.28 95% CI (1.06-1.54); P = 0.011, and HR 1.08 95% CI (1.02-1.14); P = 0.012, respectively). E/e'sr provided incremental information [Harrell's C-index: 0.839 (0.81-0.87) vs. 0.844 (0.82-0.87); P = 0.045] beyond the SCORE risk chart. Conclusion: In the general population, E/e'sr provides independent and incremental prognostic information regarding cardiovascular morbidity and mortality. Additionally, E/e'sr is a stronger predictor of cardiac events than E/e'.

Rapid Protective Effects of Early BCG on Neonatal Mortality Among Low Birth Weight Boys: Observations From Randomized Trials.

Background: Three randomized trials (RCTs) in low-weight (<2.5 kg) infants have shown that Bacille Calmette-Guérin (BCG) vaccine nonspecifically reduces all-cause mortality in the neonatal period. Methods: Using data from 3 RCTs of early BCG (n = 6583) we examined potential sex differences in the timing of the mortality reduction in the neonatal period, presenting metaestimates of the main outcome mortality rate ratios (MRR) for BCG-vaccinated and controls. Results: Among controls, boys had a particularly high mortality during the first week after randomization: male-female MRR 2.71 (95% CI, 1.70-4.50). During the first week, BCG had a marked beneficial effect for boys, reducing mortality 3-fold (MRR [BCG/no BCG] = 0.36 [0.20-0.67]). In weeks 2-4 the effect waned for boys (MRR = 0.91 [0.51-1.69]). In girls, the pattern was opposite with a limited effect in the first week (MRR = 0.85 [0.46-1.54]), but a significant reduction in weeks 2-4 (MRR = 0.56 [0.31-1.00]). This was consistent in all 3 trials. Verbal autopsies linked early benefit to fewer sepsis-related deaths among BCG-vaccinated boys. Discussion: The marked reduction in mortality in the days after BCG vaccination in boys emphasizes the importance of providing BCG soon after birth. Trial registration numbers: ClinicalTrials.gov (NCT00146302) and ClinicalTrials.gov (NCT00625482).

Effect of an Early Dose of Measles Vaccine on Morbidity Between 18 Weeks and 9 Months of Age: A Randomized, Controlled Trial in Guinea-Bissau.

Background: Children in Guinea-Bissau receive measles vaccine (MV) at 9 months of age, but studies have shown that an additional dose before 9 months of age might have beneficial nonspecific effects. Within a randomized trial designed to examine nonspecific effects of early MV receipt on mortality, we conducted a substudy to investigate the effect of early MV receipt on morbidity. Methods: Children were randomly assigned at a ratio of 2:1 to receive 2 doses of MV at 18 weeks and age 9 months (intervention group) or 1 dose of MV at age 9 months, in accordance with current practice (control group). Children were visited weekly from enrollment to age 9 months; the mother reported morbidity, and the field assistants examined the children. Using Cox and binomial regression models, we compared the 2 randomization groups. Results: Among the 1592 children, early measles vaccination was not associated with a higher risk of the well-known adverse events of fever, rash, and convulsions within the first 14 days. From 15 days after randomization to age 9 months, early measles vaccination was associated with reductions in maternally reported diarrhea (hazard ratio [HR], 0.89; 95% confidence interval [CI], .82-.97), vomiting (HR, 0.86; 95% CI, .75-.98), and fever (HR, 0.93; 95% CI, .87-1.00). Conclusion: Early MV receipt was associated with reduced general morbidity in the following months, supporting that early MV receipt may improve the general health of children.

Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial.

Background: BCG vaccine may reduce overall mortality by increasing resistance to nontuberculosis infections. In 2 randomized trials in Guinea-Bissau of early BCG-Denmark (Statens Serum Institut) given to low-weight (LW) neonates (<2500 g at inclusion) to reduce infant mortality rates, we observed a very beneficial effect in the neonatal period. We therefore conducted the present trial to test whether early BCG-Denmark reduces neonatal mortality by 45%. We also conducted a meta-analysis of the 3 BCG-Denmark trials. Methods: In 2008-2013, we randomized LW neonates to "early BCG-Denmark" (intervention group; n = 2083) or "control" (local policy for LW and no BCG-Denmark; n = 2089) at discharge from the maternity ward or at first contact with the health center. The infants were randomized (1:1) without blinding in blocks of 24. Data was analyzed in Cox hazards models providing mortality rate ratios (MRRs). We had prespecified an analysis censoring follow-up at oral poliovirus vaccine campaigns. Results: Early administration of BCG-Denmark was associated with a nonsignificant reduction in neonatal mortality rate (MRR, 0.70; 95% confidence interval [CI], .47-1.04) and a 34% reduction (0.66; .44-1.00) when censoring for oral poliovirus vaccine campaigns. There was no reduction in mortality rate for noninfectious diseases, but a 43% reduction in infectious disease mortality rate (MRR, 0.57; 95% CI, .35-.93). A meta-analysis of 3 BCG trials showed that early BCG-Denmark reduced mortality by 38% (MRR, 0.62; 95% CI, .46-.83) within the neonatal period and 16% (0.84; .71-1.00) by age 12 months. Conclusion: Early administration of BCG-Denmark in LW infants is associated with major reductions in mortality rate. It is important that all LW infants receive early BCG in areas with high neonatal mortality rates. Clinical Trials Registration: NCT00625482.

Heterologous immunological effects of early BCG vaccination in low-birth-weight infants in Guinea-Bissau: a randomized-controlled trial.

BACKGROUND: Bacillus Calmette-Guérin (BCG) seems to have beneficial nonspecific effects; early BCG vaccination of low-birth-weight (LBW) newborns reduces neonatal mortality by >40% due to prevention of primarily septicemia and pneumonia. METHODS: Within a randomized trial in LBW infants in Guinea-Bissau of early BCG vs the usual postponed BCG, a subgroup was bled 4 weeks after randomization. Levels of interleukin (IL)-1ß, IL-5, IL-6, IL-10, IL-17, interferon (IFN)-γ and tumor necrosis factor (TNF)-α were measured from whole-blood assays stimulated with innate agonists to Toll-like receptor (TLR)-2, -4 or -7/8, or purified protein derivative (PPD). RESULTS: Among 467 infants, BCG significantly increased the in vitro cytokine responses to purified protein derivative of Mycobacterium tuberculosis (PPD), as expected. BCG was also associated with increased responses to heterologous innate stimulation, particularly of the cytokines IL-1ß, IL-6, TNF-α, and IFN-γ. CONCLUSION: Four weeks after immunization, BCG-vaccinated infants have a significantly increased production of cytokines upon heterologous challenge, particularly T helper cell type 1 polarizing and typically monocyte-derived pro-inflammatory cytokines. BCG may accelerate the development of the neonatal immune system, mediating comprehensive protection against infections and mortality.

The Effect of Oral Polio Vaccine at Birth on Infant Mortality: A Randomized Trial.

BACKGROUND: Routine vaccines may have nonspecific effects on mortality. An observational study found that OPV given at birth (OPV0) was associated with increased male infant mortality. We investigated the effect of OPV0 on infant mortality in a randomized trial in Guinea-Bissau. METHODS: A total of 7012 healthy normal-birth-weight neonates were randomized to BCG only (intervention group) or OPV0 with BCG (usual practice). All children were to receive OPV with pentavalent vaccine (diphtheria, tetanus, pertussis, Haemophilus influenzae type b, and hepatitis B) at 6, 10, and 14 weeks of age. Seven national OPV campaigns were also conducted during the trial period. Children were followed to age 12 months. We used Cox regression to calculate hazard ratios (HRs) for mortality. RESULTS: The trial contradicted the original hypothesis about OPV0 increasing male infant mortality. Within 12 months, 73 children in the BCG + OPV group and 87 children in the BCG-only group died, all from infectious diseases. Comparing BCG + OPV0 vs BCG only, the HR was 0.83 (95% confidence interval [CI], .61-1.13): 0.72 (95% CI, .47-1.10) in boys and 0.97 (95% CI, .61-1.54) in girls. For children enrolled within the first 2 days of life, the HR for BCG + OPV0 vs BCG only was 0.58 (95% CI, .38-.90). From enrollment until the time of OPV campaigns, the HR was 0.68 (95% CI, .45-1.00), the beneficial effect being separately significant for males (0.55 [95% CI, .32-.95]). CONCLUSIONS: This is the only randomized trial of the effect of OPV0 on mortality. OPV0 may be associated with nonspecific protection against infectious disease mortality, particularly when given early in life. There are reasons to monitor mortality when OPV is being phased out. CLINICAL TRIALS REGISTRATION: NCT00710983.

Tuberculin reaction and BCG scar: association with infant mortality.

OBJECTIVE: To test the hypothesis that having a scar and a positive tuberculin skin test (TST) response after vaccination with Bacille Calmette-Guérin (BCG) is associated with reduced infant mortality. METHODS: We studied cohorts of 2709 normal-birthweight (NBW) and 1102 low-birthweight (LBW) infants in Guinea-Bissau. Children were enrolled in randomised trials between year 2002 and 2008 and received BCG vaccination at birth. BCG scars and TST responses were assessed at 2 and 6 months of age. The infants were followed for mortality to 12 months of age, and survival was analysed using Cox regression. RESULTS: At age 2 months, 88% of NBW children and 91% of LBW children had a BCG scar, and 36% and 17% had a TST response, respectively. The LBW infants had nearly twofold higher mortality (4.5%) than the NBW infants (2.8%) between 2 and 12 months of age. In the LBW cohort, the adjusted mortality rate ratio (MRR) comparing children with a BCG scar with those without was 0.42 (95% CI = 0.19; 0.93). There was a similar tendency for TST positivity: MRR = 0.47 (95% CI = 0.14; 1.54). For LBW children who had both a positive TST reaction and a scar, the MRR was 0.22 (95% CI = 0.05; 0.87). For NBW children, a scar and a positive TST were associated with 20% reductions in mortality, which did not reach statistical significance. CONCLUSION: We confirmed previous observations that having a scar and a TST response after BCG vaccination is associated with lower mortality risk. The possibility of revaccinating scar-negative children should be considered.

Early BCG vaccine to low-birth-weight infants and the effects on growth in the first year of life: a randomised controlled trial.

BACKGROUND: Randomised trials have shown that early Bacille Calmette-Guérin (BCG) vaccine reduces overall neonatal and infant mortality. However, no study has examined how BCG affects growth. We investigated the effect on infant growth of early BCG vaccine given to low-birth-weight (LBW) infants. METHODS: Two-thousand three hundred forty-three LBW infants were randomly allocated 1:1 to "early BCG" (intervention group) or "late BCG" (current practice). Furthermore, a subgroup (N = 1717) were included in a two-by-two randomised trial in which they were additionally randomised 1:1 to vitamin A supplementation (VAS) or placebo. Anthropometric measurements were obtained 2, 6, and 12 months after enrolment. RESULTS: Overall there was no effect of early BCG on growth in the first year of life. The effect of early BCG on weight and mid-upper-arm circumference at 2 months tended to be beneficial among girls but not among boys (interaction between "early BCG" and sex: weight p = 0.03 and MUAC p = 0.04). This beneficial effect among girls was particularly seen among the largest infants weighing 2.0 kg or more at inclusion. CONCLUSION: Though BCG vaccination is not recommended to be given to LBW infants at birth in Guinea-Bissau, early BCG had no negative effect on infant growth and may have had a beneficial effect for girls. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT00146302).

Factors associated with thymic size at birth among low and normal birth-weight infants.

OBJECTIVE: To study the effect of gestational and perinatal exposures on thymic size in 366 normal birth weight and 426 low birth weight (LBW) neonates in Guinea-Bissau in West Africa. STUDY DESIGN: In a cross-sectional study, thymic size was measured at birth by the use of ultrasound. Information on possible determinants was collected from pregnancy cards, hospital records, and interviews with the mother. We used the log-transformed thymic index and thymus/weight index as outcome measures. Data were analyzed with adjusted linear regression models providing geometric mean ratios (GMRs) with 95% CI. RESULTS: Determinants of thymic size among normal birth weight infants were pathologic amniotic fluid (adjusted GMR for thymic index: 0.84 [0.74-0.96]) and male sex (GMR: 1.13 [1.06-1.22]). Among LBW infants, birth season (1.11 [1.01-1.22]), maternal body temperature (0.89 [0.79-0.98]), antibiotic treatment at the time of labor (0.84 [0.70-1.00]), number of pregnancy consultations (1.03 [1.00-1.05]), maternal age (0.91 [0.84-0.98]), Apgar score (1.06 [1.03-1.10]), and infant convulsions (0.44 [0.29-0.65]) were all independent determinants of thymic index but not all were determinants of thymus/weight index. Pathologic amniotic fluid and cesarean delivery were associated with thymus/weight index among LBW infants (0.85 [0.75-0.95] and 0.80 [0.67-0.96]) but were only borderline significant for thymic index. CONCLUSION: Exposures mainly related to stress and infections were associated with a smaller thymus, mainly in LBW infants.

Neonatal vitamin A supplementation associated with a cluster of deaths and poor early growth in a randomised trial among low-birth-weight boys of vitamin A versus oral polio vaccine at birth.

BACKGROUND: The effect of oral polio vaccine administered already at birth (OPV0) on child survival was not examined before being recommended in 1985. Observational data suggested that OPV0 was harmful for boys, and trials have shown that neonatal vitamin A supplementation (NVAS) at birth may be beneficial for boys. We set out to test this research question in a randomised trial. METHODS: The trial was carried out at the Bandim Health Project, Guinea-Bissau. We planned to enrol 900 low-birth weight (LBW) boys in a randomised trial to investigate whether NVAS instead of OPV0 could lower infant mortality for LBW boys. At birth, the children were randomised to OPV (usual treatment) or VAS (intervention treatment) and followed for 6 months for growth and 12 months for survival. Hazard Ratios (HR) for mortality were calculated using Cox regression. We compared the individual anthropometry measurements to the 2006 WHO growth reference. We compared differences in z-scores by linear regression. Relative risks (RR) of being stunted or underweight were calculated in Poisson regression models with robust standard errors. RESULTS: In the rainy season we detected a cluster of deaths in the VAS group and the trial was halted immediately with 232 boys enrolled. The VAS group had significantly higher mortality than the OPV0 group in the rainy season (HR: 9.91 (1.23 - 80)). All deaths had had contact with the neonatal nursery; of seven VAS boys enrolled during one week in September, six died within two months of age, whereas only one died among the six boys receiving OPV (p = 0.05). Growth (weight and arm-circumference) in the VAS group was significantly worse until age 3 months. CONCLUSION: VAS at birth instead of OPV was not beneficial for the LBW boys in this study. With the premature closure of the trial it was not possible to answer the research question. However, the results of this study call for extra caution when testing the effect of NVAS in the future. TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT00625482. Registered 18 February 2008.

The effect of neonatal vitamin A supplementation on growth in the first year of life among low-birth-weight infants in Guinea-Bissau: two by two factorial randomised controlled trial.

BACKGROUND: Vitamin A supplementation (VAS) may amplify the effect of vaccines. We therefore investigated if neonatal VAS given with and without Bacille Calmette-Guérin (BCG) vaccine to low-birth-weight (LBW) neonates had an effect on growth in the first year of life. We hypothesised that VAS would be particularly beneficial when provided with BCG. METHODS: We conducted a randomised two-by-two factorial trial in Guinea-Bissau; 1,717 LBW neonates were randomly allocated to VAS or placebo at birth as well as early or the usual postponed BCG vaccination. Anthropometric measurements were obtained at 2, 6, and 12 months after inclusion. RESULTS: Overall there was no effect of neonatal VAS on growth in the first year of life. By 2 months, VAS tended to have a beneficial effect on weight and head circumference when given with BCG but not when given without BCG (interaction: weight-for-age p = 0.07 and head circumference-for-age: p = 0.06). By 6 months, there was a beneficial effect of VAS on head circumference and weight among children who had not received DTP vaccine 2 months after inclusion (weight: 0.18 (0.00; 0.36) and head circumference 0.27 (0.06; 0.48)), but no beneficial effect among those who had received DTP. CONCLUSION: The results support other trials indicating that neonatal VAS does not have consistent effects on childhood growth and if anything the effects seem to be temporary. They also show that the effect may differ by vaccination status, being beneficial when given with BCG at birth and when DTP is delayed. TRIAL REGISTRATION: www.ClinicalTrials.gov (NCT00168610).

Time trends in socio-economic factors and risk of hospitalisation with infectious diseases in pre-school children 1985-2004: a Danish register-based study.

The purpose of this study was to examine socio-economic differences in the risk of hospitalisation among children aged 0-5 years in Denmark from 1985 to 2004. All children born between 1985 and 2004 (n=1,278,286) were followed for hospital admissions for infectious diseases from the 29th day of life until the children reached the age of 6 years or the end of 2004, whichever came first. Information on parental socio-economic position (education, labour market attachment and household income) was gathered through record linkage with administrative registries. Infections were grouped into upper respiratory, lower respiratory, gastrointestinal, ear and fever infections. The data were analysed using Cox regression. Children of parents on sick leave or early retirement had an increased risk of being hospitalised with an infection compared with children of employed parents. A clear inverse educational gradient in risk of offspring hospitalisation was also found. From 1985 to 2004 the inverse associations between parental education and risk of hospitalisation grew stronger, whereas the comparatively weaker association between household income and risk of offspring hospitalisation decreased in magnitude. The association between socio-economic status and hospitalisation was strongest for lower respiratory, gastrointestinal and ear infections. This study documented a socially patterned hospitalisation of pre-school children in Denmark. Future studies should investigate possible explanations for the increased risk among children from families with low socio-economic status.

Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period?

BACKGROUND: Observational studies have suggested that BCG may have nonspecific beneficial effects on survival. Low-birth-weight (LBW) children are not given BCG at birth in Guinea-Bissau; we conducted a randomized trial of BCG at birth (early BCG) vs delayed BCG. METHODS: In the period 2004-2008 we recruited 2320 LBW children in Bissau. The children were visited at home at 2, 6, and 12 months of age. With a pretrial infant mortality of 250 per 1000, we hypothesized a 25% reduction in infant mortality for LBW children. RESULTS: Infant mortality was only 101 per 1000 during the trial. In the primary analysis, infant mortality was reduced insignificantly by 17% (mortality rate ratio [MRR] = .83 [.63-1.08]). In secondary analyses, early BCG vaccine was safe with an MRR of .49 (.21-1.15) after 3 days and .55 (.34-.89) after 4 weeks. The reduction in neonatal mortality was mainly due to fewer cases of neonatal sepsis, respiratory infection, and fever. The impact of early BCG on infant mortality was marked for children weighing <1.5 kg (MRR = .43 [.21-.85]) who had lower coverage for diphtheria-tetanus-pertussis vaccinations. CONCLUSIONS: Though early BCG did not reduce infant mortality significantly, it may have a beneficial effect in the neonatal period. This could be important for public health because BCG is often delayed in low-income countries.

Regional longitudinal strain patterns according to left ventricular hypertrophy in the general population.

AIMS: A pattern of reduced basal longitudinal strain (BLS) is often observed with left ventricular (LV) hypertrophy (LVH). Whether this pattern is associated with poor outcome is unclear. We aimed to evaluate the prognostic value of regional longitudinal strain according to LV geometry. METHODS AND RESULTS: We investigated participants in the 4th Copenhagen City Heart Study who had an echocardiogram with speckle tracking performed. Participants were stratified according to the presence of LVH (LV mass index ≥116 g/m2 for men and ≥96 g/m2 for women). The outcome was major adverse cardiovascular events (MACE) defined as a composite of myocardial infarction, heart failure, and/or cardiovascular death. The study population consisted of 1090 participants. Mean LVEF was 60% and 160 (15%) had LVH. During a median follow-up of 14.7 years, there were 137 events. Both BLS and midventricular strain, but not apical strain, became incrementally impaired in the spectrum from normal to hypertensives subjects without LVH, and to participants with hypertension and LVH. After multivariable adjustment, BLS and midventricular strain were independently associated with MACE in participants with LVH (BLS: HR 1.08, 95% CI 1.00-1.17, P = 0.041; midventricular strain: HR 1.10, 95% CI 1.00-1.21, P = 0.041) but not in participants without LVH (BLS: HR 0.96, 95% CI 0.90-1.01, P = 0.13; midventricular strain: HR 0.97, 95% CI 0.91-1.03, P = 0.36). CONCLUSION: BLS and midventricular strain, but not apical strain, become incrementally impaired in the spectrum from normal geometry to LVH, and are independently associated with MACE in participants with LVH.

Usefulness of left atrial strain for predicting incident atrial fibrillation and ischaemic stroke in the general population.

AIMS: Left atrial enlargement predicts incident atrial fibrillation (AF). However, the prognostic value of peak atrial longitudinal strain (PALS) for predicting incident AF in participants from the general population is currently unknown. Our aim was to investigate if PALS can be used to predict AF and ischaemic stroke in the general population. METHODS AND RESULTS: A total of 400 participants from the general population underwent a health examination, including two-dimensional speckle tracking echocardiography of the left atrium. The primary endpoint was incident AF at follow-up. All participants with known AF and prior stroke at baseline were excluded (n = 54). The secondary endpoint consisted of the composite of AF and ischaemic stroke. During a median follow-up of 16 years, 36 participants (9%) were diagnosed with incident AF and 30 (7%) experienced an ischaemic stroke, resulting in 66 (16%) experiencing the composite outcome. PALS was a univariable predictor of AF [per 5% decrease: hazard ratio (HR) 1.42; 95% confidence interval (CI) (1.19-1.69), P < 0.001]. However, the prognostic value of PALS was modified by age (P = 0.002 for interaction). After multivariable adjustment PALS predicted AF in participants aged <65 years [per 5% decrease: HR 1.46; 95% CI (1.06-2.02), P = 0.021]. In contrast, PALS did not predict AF in participants aged ≥65 years after multivariable adjustment [per 5% decrease: HR 1.05; 95% CI (0.81-1.35), P = 0.72]. PALS also predicted the secondary endpoint in participants aged <65 years and the association remained significant after multivariable adjustment. CONCLUSION: In a low-risk general population, PALS provides novel prognostic information on the long-term risk of AF and ischaemic stroke in participants aged <65 years.

Effect of early two-dose measles vaccination on childhood mortality and modification by maternal measles antibody in Guinea-Bissau, West Africa: A single-centre open-label randomised controlled trial.

Background: Early 2-dose measles vaccine (MV) at 4 and 9 months of age vs. the WHO strategy of MV at 9 months of age reduced all-cause child mortality in a previous trial. We aimed to test two hypotheses: 1) a 2-dose strategy reduces child mortality between 4 and 60 months of age by 30%; 2) receiving early MV at 4 months in the presence versus absence of maternal measles antibodies (MatAb) reduces child mortality by 35%. Methods: Single-centre open-label community-based randomised controlled trial in Guinea-Bissau, with 2:1 block-randomisation by sex to a 2-dose (4 + 9 months) vs. 1-dose (9 months) MV strategy. Healthy children were eligible 4 weeks after the 3rd diphtheria-tetanus-pertussis-containing vaccine. Before randomisation a blood sample was collected to determine MatAb level. The primary outcome was all-cause mortality. Hazard ratios (HR) were derived from Cox regression in the per protocol population. We tested for interactions with national campaigns with oral polio vaccine (C-OPV). Trial registration: NCT01486355. Findings: Between August 2011-April 17th 2015, 6,636 children were enroled, 6,598[n2-dose=4,397; n1-dose=2,201] were included in the analysis of the primary outcome, The HR(2-dose/1-dose) between 4 and 60 months was 1.38 (95%CI: 0.92-2.06) [deaths: n2-dose=90; n1-dose=33]. Before the 9-month MV and the HR(1-dose/no dose) was 0.94 (0.45-1.96) [deaths: n2-dose=21; n1-dose=11]. The HR(2-dose/1-dose) was 0.81 (0.29-2.22) for children, who received no C-OPV [deaths/children: n2-dose=10/2,801; n1-dose=6/1,365], and 4.73 (1.44-15.6) for children, who received C-OPV before and after enrolment (p for interaction=0.027) [deaths/children: n2-dose=27/1,602; n1-dose=3/837]. In the 2-dose group receiving early MV at 4 months, mortality was 50% (20-68%) lower for those vaccinated in the presence of MatAb vs. the absence of MatAb [deaths/children: nMatAb=51/3,132; nnoMatAb=31/1,028]. Interpretation: The main result contrasts with previous findings but may, though based on a small number of events, be explained by frequent OPV campaigns that reduced the mortality rate, but apparently interacted negatively with early MV. The beneficial non-specific effects of MV in the presence of MatAb should be investigated further. Funding: ERC, Danish National Research Foundation, the Danish Council for Development Research, Ministry of Foreign Affairs, Novo Nordisk Foundation, European Union and the Lundbeck Foundation.

Penta is associated with an increased female-male mortality ratio: cohort study from Bangladesh.

Diphtheria-tetanus-pertussis (DTP) vaccine may be associated with excess female deaths. There are few studies of possible nonspecific effects of the DTP-containing vaccine Penta (DTP-hepatitis B-Haemophilus influenzae type b). We therefore investigated whether Penta vaccinations were associated with excess female deaths in rural Bangladesh. Between June 29, 2011 and April 20, 2016, we examined the mortality rates of 7644 children followed between 6 weeks and 9 months of age. We analyzed mortality using crude mortality rate ratio (MRR) and age-adjusted MRR (aMRR) from a Cox proportional hazards model. Mortality was analyzed according to sex, number of doses of Penta, and the order in which BCG and Penta were administered. During follow-up, 43 children died. For children who were only BCG vaccinated (BCG-only), the adjusted F/M MRR was 0.47 (0.09-2.48). However, among children who had Penta as their most recent vaccination, the adjusted F/M MRR was 9.91 (1.16-84.44). Hence, the adjusted F/M MRR differed significantly for BCG-only and for Penta as the most recent administered vaccination. Although the mortality rate was low in rural Bangladesh, there was a marked difference between adjusted F/M MRR's for children vaccinated with BCG-only compared with children where Penta was the most recent administered vaccination. Although usually ascribed to differential treatment and access to care, DTP-containing vaccines may be part of the explanation for the excessive female mortality reported in some regions.

Neonatal Bacille Calmette-Guérin vaccination and tuberculin skin test reactions at 2- and 6-months: Effects on mortality up to 1 year of age.

BACKGROUND: In randomized trials, Bacille Calmette-Guérin (BCG) vaccine has been associated with reduced all-cause mortality. BCG-induced Tuberculin Skin Test (TST) reactions have also been associated with reduced all-cause mortality. We aimed to assess the association between TST responses and subsequent mortality in three birth cohorts and conducted a meta-analysis of existing studies. METHODS: Observational study within three Guinea-Bissau BCG trial birth cohorts (conducted 2002-04, 2009-2013 and 2014-18) that encompassed children who were BCG-vaccinated within 28 days with TSTs performed at 2- (n = 1389) and 6-months (n = 2635) of age. We evaluated TST reaction determinants by binomial regression and assessed the association between TSTs > 1 mm (reactors) vs. ≤ 1 mm (non-reactors) and subsequent mortality risk up to age 12 months in Cox-models providing Mortality Rate Ratios (MRRs). We searched PubMed for studies to calculate meta-estimates of the association between TST reactivity by age 2- and 6-months and all-cause mortality. RESULTS: Large post-vaccination wheal size was associated with 6-month TST positivity and so was receiving BCG-Denmark or BCG-Japan, compared with BCG-Russia. By age 2 months, 22% (302/1389) of infants were TST reactors with a 2-12-month mortality risk of 1.7% (5/302) vs. 3.3% (36/1087) for non-reactors, the corresponding reactor/non-reactor MRR = 0.49 (0.19-1.26). By age 6 months, 44% (1149/2635) of infants were reactors and the 6-12-month mortality risk was 0.4% (4/1149) vs. 0.6% (9/1486) for non-reactors, the MRR = 0.87 (0.27-2.86). The literature search provided 3 studies. The meta-analysis revealed a uniform pattern of reduced mortality associated with TST reactivity, a TST response by 2 months being associated with an MRR of 0.59 (0.39-0.90); for 6-month TST responses the MRR was 0.65 (0.43-1.00). CONCLUSION: Among BCG-vaccinated infants, TST reactions were associated with markedly reduced mortality. Improved vaccination technique and using certain BCG strains could lead to a higher TST reaction prevalence, which would enhance BCG's beneficial non-specific effects.

Global longitudinal strain predicts atrial fibrillation in individuals without hypertension: A Community-based cohort study.

BACKGROUND: Global longitudinal strain (GLS) is a sensitive marker of myocardial dysfunction and atrial reservoir function. We sought to evaluate its value for predicting atrial fibrillation (AF) in the general population. METHODS: Participants from the Copenhagen City Heart Study examined with echocardiography, including speckle tracking analyses, were included. The endpoint was AF obtained through national registries. Proportional hazards Cox regression was applied, including multivariable adjustments made for CHADS2 and CHARGE-AF risk factors. Abnormal GLS was defined as >-18%. RESULTS: The data from 1,309 participants were analyzed. Of those, 153 (12%) developed AF during a median follow-up time of 15.9 years. The follow-up was 100%. The mean age was 57 years, 38% had hypertension, and GLS was  - 18%. In unadjusted analysis, GLS was a univariable predictor of outcome (1.08 (1.04-1.13), p < 0.001, per 1% absolute decrease), but did not remain an independent predictor after adjusting for neither CHADS2 nor CHARGE-AF risk factors. However, hypertension modified the relationship between GLS and AF (p for interaction = 0.010), such that GLS only predicted AF in subjects without hypertension. In participants without hypertension, GLS remained an independent predictor of AF after adjusting for CHADS2 and CHARGE-AF (HR = 1.11 (1.03-1.20) and HR = 1.09 (1.01-1.19), respectively). In these participants, an abnormal GLS was associated with a more than twofold increased risk of AF (HR = 2.16 (1.26-3.72). The incidence rate was 3.17 and 6.81 per 1000 person-years for normal vs. abnormal GLS, respectively. CONCLUSION: Global longitudinal strain predicts AF in individuals without hypertension from the general population, independently of common risk scores.