Oleguer Plana-Ripoll

Efficacy of anti-inflammatory or antibiotic treatment in patients with non-complicated acute bronchitis and discoloured sputum: randomised placebo controlled trial

Objective To evaluate the efficacy of oral anti-inflammatory or antibiotic treatment compared with placebo in the resolution of cough in patients with uncomplicated acute bronchitis and discoloured sputum. Design Multicentre, parallel, single blinded placebo controlled, randomised clinical trial. Setting Nine primary care centres in Spain. Participants Adults aged 18 to 70 presenting symptoms associated with respiratory tract infection of less than one week’s duration, with cough as the predominant symptom, the presence of discoloured sputum, and at least one other symptom of lower respiratory tract infection (dyspnoea, wheezing, chest discomfort, or chest pain). Interventions Patients were randomised to receive either ibuprofen 600 mg three times daily, amoxicillin-clavulanic acid 500 mg/125 mg three times daily, or placebo three times daily for 10 days. The duration of symptoms was measured with a diary card. Main outcome measure Number of days with frequent cough after the randomisation visit. Results 416 participants were randomised (136 to ibuprofen, 137 to antibiotic, and 143 to placebo) and 390 returned their symptom diaries fully completed. The median number of days with frequent cough was slightly lower among patients assigned to ibuprofen (9 days, 95% confidence interval 8 to 10 days) compared with those receiving amoxicillin-clavulanic acid (11 days, 10 to 12 days) or placebo (11 days, 8 to 14 days), albeit without statistically significant differences. Neither amoxicillin-clavulanic acid nor ibuprofen increased the probability of cough resolution (hazard ratio 1.03, 95% confidence interval 0.78 to 1.35 and 1.23, 0.93 to 1.61, respectively) compared with placebo. Adverse events were observed in 27 patients, and were more common in the antibiotic arm (12%) than ibuprofen or placebo arms (5% and 3%, respectively; P<0.01). Conclusion No significant differences were observed in the number of days with cough between patients with uncomplicated acute bronchitis and discoloured sputum treated with ibuprofen, amoxicillin-clavulanic acid, or placebo. Trial registration Current Controlled Trials ISRCTN07852892.

Prenatal exposure to maternal stress following bereavement and cardiovascular disease: A nationwide population-based and sibling-matched cohort study

Aims Cardiovascular disease (CVD) is among the leading determinants of mortality and morbidity, and causation may begin in the early intrauterine environment. Prenatal exposures to glucocorticoids or stress are potential risk factors of CVD later in life, but empirical evidence from large population studies is lacking. We explored the association between prenatal stress due to maternal bereavement following the death of a relative and CVD in the exposed offspring. Methods and results This population-based study included 2,607,851 children born in Denmark (1970–2008). Of these participants, 73,708 (2.8%) had a CVD event during follow-up (up to 40 years). A total of 50,940 (2.0%) subjects born to mothers who lost a relative during pregnancy or the year before were categorized as exposed. Cox Proportional Hazards models were used to analyse the data. The overall hazard ratio (HR) (95% confidence interval) of having a CVD was 1.13 (1.06–1.20); the estimate was 1.24 (1.11–1.38) for heart disease and 1.27 (1.01–1.60) for hypertension. Additional sibling-matched analyses showed an overall attenuated association (1.08 (0.94–1.24)). Conclusion Our results suggested a modest association between prenatal stress and CVD, both in childhood and early adulthood, which could be of importance, especially at an older age when the individuals are followed over a long period.

Severe stress following bereavement during pregnancy and risk of pregnancy loss: results from a population-based cohort study.

Background Previous findings on the association between stress during pregnancy and pregnancy loss are inconsistent. We aimed to estimate this association using a large prospective cohort. Methods This population-based study included all 1 303 660 clinically recognised pregnancies in Denmark between 1995 and 2008. We categorised women as exposed to severe stress if they lost a child, sibling or parent during pregnancy. Cox Proportional Hazards models were used to study the association between exposure and rate of fetal death, starting with the follow-up on the day of completion of week 4 of pregnancy. In an attempt to control for unknown potential confounders, we also designed a pregnancy-matched analysis in which each woman had her own baseline risk of pregnancy loss and controls therefore for genetic and time-stable environmental factors. Results A total of 146 031 pregnancies ended in clinically recognised fetal loss (11.2%) and a total of 10 808 (0.8%) women were categorised as exposed. The overall risk of pregnancy loss was similar in the exposed and unexposed (aHR=1.05, 95% CI 0.95 to 1.15). Results from the pregnancy-matched analysis (performed in 423 women) showed stronger and significant associations (aHR=1.83, 95% CI 1.49 to 2.25). All the analyses indicated a stronger effect of bereavement when the mother lost a child or when the death was unexpected. Conclusions Our main results suggested no strong association between severe stress during pregnancy and risk of pregnancy loss. Results from the pregnancy-matched analyses considered information from a selected and small group of women for whom there may exist a stronger association between stress during pregnancy and pregnancy loss. The fact that an unexpected death or the loss of a child had a stronger effect in both analyses may indicate that severe stressful situations increase the risk of pregnancy loss.

Prevalence, incidence, and autoimmune comorbidities of celiac disease: a nation-wide, population-based study in Denmark from 1977 to 2016

Aim The aim of this study was to describe and identify potential trends with respect to prevalence, incidence, age, sex, and autoimmune comorbidity of celiac disease (CD). Patients and methods A Danish nationwide cohort study of CD using data from The National Patient Register. Patients with a primary or secondary diagnosis code of CD during the period 1977 to 2016 were identified. Information on sex, date of birth, death, or immigration was obtained from the Danish Civil Registration System, and autoimmune comorbidities were identified in the Danish National Patient Register. The CD cohort was compared with the general Danish population using a control cohort and aggregated data obtained from Statistics Denmark. Results The CD cohort consisted of 11 802 (65% women) patients. The median age at diagnosis of CD varied between 30 years in 1980–1984 and 45 years in 1995–1999 and 27 years in 2015–2016. The prevalence of CD in 1986 and 2016 was 14 and 180 per 100 000 persons, respectively, with a female/male ratio changing from 1.3 to 2.0. Incidence rates (per 100 000 person-years) changed from 1.6 in 1980–1984 to 15.2 in 2015–2016, with the largest increase among females aged 0–9 years. In 2016, prevalence of autoimmune comorbidities was 16.4% among the CD patients compared with 5.3% in the general population. Conclusion The prevalence of diagnosed CD has doubled every decade in Denmark from 1986 to 2016, and in the same period the female/male ratio has increased and the median age at diagnosis has decreased. The prevalence of autoimmune comorbidity in 2016 was three times higher among CD patients compared with the general Danish population.

Correction: Prenatal Exposure to Maternal Bereavement and Childbirths in the Offspring: A Population-Based Cohort Study.

Introduction The decline in birth rates is a concern in public health. Fertility is partly determined before birth by the intrauterine environment and prenatal exposure to maternal stress could, through hormonal disturbance, play a role. There has been such evidence from animal studies but not from humans. We aimed to examine the association between prenatal stress due to maternal bereavement following the death of a relative and childbirths in the offspring. Materials and Methods This population-based cohort study included all subjects born in Denmark after 1968 and in Sweden after 1973 and follow-up started at the age of 12 years. Subjects were categorized as exposed if their mothers lost a close relative during pregnancy or the year before and unexposed otherwise. The main outcomes were age at first child and age-specific mean numbers of childbirths. Data was analyzed using Cox Proportional Hazards models stratified by gender and adjusted for several covariates. Subanalyses were performed considering the type of relative deceased and timing of bereavement. Results A total of 4,121,596 subjects were followed-up until up to 41 years of age. Of these subjects, 93,635 (2.3%) were exposed and 981,989 (23.8%) had at least one child during follow-up time. Compared to unexposed, the hazard ratio (HR) [95% confidence interval] of having at least one child for exposed males and females were 0.98 [0.96–1.01] and 1.01 [0.98–1.03], respectively. We found a slightly reduced probability of having children in females born to mothers who lost a parent with HR = 0.97 [0.94–0.99] and increased probability in females born to mothers who lost another child (HR = 1.09 [1.04–1.14]), the spouse (HR = 1.29 [1.12–1.48]) or a sibling (HR = 1.13 [1.01–1.27]). Conclusions Our results suggested no overall association between prenatal exposure to maternal stress and having a child in early adulthood but a longer time of follow-up is necessary in order to reach a firmer conclusion.

Psychiatric conditions and general practitioner attendance prior to HPV vaccination and the risk of referral to a specialized hospital setting because of suspected adverse events following HPV vaccination: a register-based, matched case–control study

Aim No association between human papilloma virus (HPV) vaccination and numerous diseases has been found. Still, a large number of Danish women are reporting suspected adverse events. Other factors may play a role, and the aim of this study is to examine the association between psychiatric conditions, general practitioner (GP) attendance and indicators of psychological symptoms prior to HPV vaccination and the risk of referral to an HPV center following vaccination. Study design and setting Register-based, matched case–control study. Cases were identified from five Danish, regional HPV centers, and health data for cases and controls were obtained from national registries. Participants Cases were defined as women referred to an HPV center between January 1, 2015 and December 31, 2015 (n=1,496). Each case was matched with five controls on age, region and time of first vaccine registration. The total study population consisted of 8,976 women. Results Overall, women above 18 years who had been referred to an HPV center were more likely to have used psychiatric medication (odds ratio [OR]: 1.88 [95% CI 1.48–2.40]) or to have been hospitalized because of a psychiatric disorder within 5 years prior to the first vaccine registration (OR: 2.13 [95% CI 1.59–2.86]). Specifically, referred women were more likely to have used antipsychotics, antidepressants, attention deficit hyperactivity disorder (ADHD) medication or anxiolytics, and to have been hospitalized for affective disorders or anxiety, but not to have been hospitalized for schizoid, ADHD or eating disorders. In addition, they were more likely to have had talk therapy or psychometric test performed prior to vaccination (OR: 1.72 [95% CI 0.1.35–2.18] and OR: 1.67 [95% CI 1.30–2.13], respectively). Referred women of all ages had higher use of GP before vaccination. Population attributable fraction analyses indicated that psychiatric medication, hospitalization due to a psychiatric disorder and use of talk therapy, or psychometric test “explained” 13%, 10%, 12% and 11% of the referrals, respectively. Results did not change substantially when adjusted for potential confounders. Conclusion Women referred to HPV centers because of suspected adverse events after vaccination more often had preexisting psychiatric conditions, psychological symptoms or frequent GP attendance prior to HPV vaccination.

Selecting the primary endpoint in a randomized clinical trial: The ARE method

ABSTRACT The decision on the primary endpoint in a randomized clinical trial is of paramount importance and the combination of several endpoints might be a reasonable choice. Gómez and Lagakos (2013) have developed a method that quantifies how much more efficient it could be to use a composite instead of an individual relevant endpoint. From the information provided by the frequencies of observing the component endpoints in the control group and by the relative treatment effects on each individual endpoint, the asymptotic relative efficiency (ARE) can be computed. This article presents the applicability of the ARE method as a practical and objective tool to evaluate which components, among the plausible ones, are more efficient in the construction of the primary endpoint. The method is illustrated with two real cardiovascular clinical trials and is extended to allow for different dependence structures between the times to the individual endpoints. The influence of this choice on the recommendation on whether or not to use the composite endpoint as the primary endpoint for the investigation is studied. We conclude that the recommendation between using the composite or the relevant endpoint only depends on the frequencies of the endpoints and the relative effects of the treatment.

Is C-reactive protein testing useful to predict outcome in patients with acute bronchitis?

BACKGROUND A recent clinical trial could not find differences between anti-inflammatory drugs, antibiotics and placebo in shortening the duration of symptoms in acute bronchitis. OBJECTIVES To investigate if C-reactive protein (CRP) concentrations at presentation are predictive of symptom resolution in these patients. METHODS We performed a secondary analysis of the data from a placebo-controlled, randomized clinical trial carried out in primary care. Patients from 18 to 70 years of age presenting a respiratory tract infection of <1 week of evolution, with cough as the predominant symptom and the presence of discoloured expectoration, were enrolled in the study. On the baseline visit, CRP was determined in capillary blood and a five-item symptom diary was given. Patients were followed up to 30 days. The main outcome measure was the number of days with persistent cough. RESULTS A total of 312 subjects fulfilled all the criteria for the efficacy analysis and had undergone the CRP test; of these, 56.4% presented a CRP value <8 mg/l and 76% presented <20 mg/l. There were no significant differences in the median duration of cough: 10 days among patients with CRP concentrations <8 mg/l [95% confidence interval (CI): 8-11 days], 11 days among those with concentrations ranging from 8 to 19 mg/l (95% CI: 8-16) and 11 days in those with CRP >20 mg/l (95% CI: 9-12) (P = 0.337). CONCLUSION Among patients with uncomplicated acute bronchitis and discoloured sputum, the CRP concentrations at presentation are not helpful for predicting symptom resolution.

Reproduction after the loss of a child: a population-based matched cohort study

STUDY QUESTION Is the death of a child associated with higher subsequent fertility? SUMMARY ANSWER Women who had lost a child had higher fertility both shortly after the loss and throughout the entire follow-up, independent of the childs age at the time of death. WHAT IS KNOWN ALREADY Women who lose a child in the perinatal period often have another child shortly after. However, to our knowledge no previous study has investigated if the death of an older child affects reproductive behavior. STUDY DESIGN, SIZE, DURATION The source population for this matched cohort study consisted of all women who gave birth in Denmark from 1978 to 2004 and in Sweden from 1973 to 2002 (N = 1 979 958). Women were followed through to the end of 2008 in Denmark and the end of 2006 in Sweden. PARTICIPANTS/MATERIALS, SETTING, METHODS Women who had lost a child before the age of 45 years during the study period (exposed group; n = 36 511) were matched with up to five women who were from the same country and of similar age and family characteristics and had not lost a child at the time of matching (unexposed group; n = 182 522). MAIN RESULTS AND THE ROLE OF CHANCE During follow-up, 74% of exposed and 46% of unexposed women had another birth (live- or stillbirth) after a gestation of 28 weeks or more. Compared with unexposed women, exposed women had a shorter interpregnancy interval and, consequently, a higher rate of conception leading to a birth (HR = 5.5 [95% CI: 5.4-5.6]). Rates for exposed women were higher from the first month following the childs death, but the largest difference was between 2 and 3 months after the event. This pattern was independent of the age of the deceased child. Exposed women had more subsequent children than unexposed, leading to a comparable number of living children at the end of follow-up. LIMITATIONS, REASONS FOR CAUTION The use of population-based registers allows for the inclusion of virtually all eligible women and nearly complete follow-up; the potential for selection bias is thus negligible. However, only pregnancies that led to a live birth or a stillbirth could be identified, thus fetal losses occurring before week 28 of gestation were missing. WIDER IMPLICATIONS OF THE FINDINGS Our findings corroborate the previous evidence suggesting that women try to conceive again shortly after a perinatal death, and many succeed. In addition, this is the first study to investigate the reproductive trajectory after losing an older child. The current study indicates that most women who lose a child between the ages of 6 months and 5 years conceive shortly after the loss, and they have a comparable number of living children at the end of the follow-up compared to those who do not lose a child. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by Grant ERC-2010-StG-260242 from the European Research Council, 176673 and 186200 from the Nordic Cancer Union, DFF-6110-00019 from the Danish Council for Independent Research, 904414 and 15199 from TrygFonden, Karen Elise Jensens Fond (2016), and the Program for Clinical Research Infrastructure (PROCRIN) established by the Lundbeck Foundation and the Novo Nordisk Foundation. The authors do not declare any conflicts of interests. TRIAL REGISTRATION NUMBER N/A.

Reproductive life in women with celiac disease; a nationwide, population-based matched cohort study

STUDY QUESTION How does celiac disease (CD) influence womens reproductive life, both prior to and after the diagnosis? SUMMARY ANSWER Prior to the diagnosis of CD, an increased risk of adverse pregnancy outcomes was seen, whereas after the diagnosis, no influence on reproductive outcomes was found. WHAT IS KNOWN ALREADY CD has been associated with several conditions influencing female reproduction and pregnancy outcomes including spontaneous abortion and stillbirth. STUDY DESIGN, SIZE, DURATION A nationwide matched cohort study following 6319 women diagnosed with CD and 63166 comparison women and identifying reproductive events between the ages of 15 and 50 years. PARTICIPANTS/MATERIALS, SETTING, METHODS Through linkage of several Danish national health registers, we identified all women diagnosed with CD between 1977 and 2016. We identified an age- and sex-matched comparison cohort and obtained data on reproductive outcomes for both cohorts. Adjusted stratified Cox and logistic regression models were used to estimate differences in reproductive outcomes between women with and without CD. MAIN RESULTS AND THE ROLE OF CHANCE Comparing women with diagnosed CD with the non-CD women, the chance of pregnancy, live birth and risk of stillbirth, molar and ectopic pregnancy, spontaneous abortion and abortion due to foetal disease was the same. However, prior to being diagnosed, CD women had an excess risk of spontaneous abortion equal to 11 extra spontaneous abortions per 1000 pregnancies (adjusted odds ratio (OR) = 1.12, 95% CI: 1.03, 1.22) and 1.62 extra stillbirths per 1000 pregnancies (adjusted OR = 1.57, 95% CI: 1.05, 2.33) compared with the non-CD women. In the period 0-2 years prior to diagnosis fewer pregnancies occurred in the undiagnosed CD group, equal to 25 (95% CI: 20-31) fewer pregnancies per 1000 pregnancies compared to the non-CD group and in addition, fewer undiagnosed CD women initiated ART-treatment in this period, corresponding to 4.8 (95% CI: 0.9, 8.7) fewer per 1000 women compared to non-CD women. LIMITATIONS, REASONS FOR CAUTION Validity of the diagnoses in the registers was not confirmed, but reporting to the registers is mandatory for all hospitals in Denmark. Not all spontaneous abortions will come to attention and be registered, whereas live- and stillbirths, ectopic and molar pregnancies and abortion due to foetal disease are unlikely not to be registered. We adjusted for several confounding factors but residual confounding cannot be ruled out. WIDER IMPLICATIONS OF THE FINDINGS These findings suggest that undiagnosed CD can affect female reproduction and the focus should be on early detection of CD in risk groups. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the Health Research Fund of Central Denmark Region and The Hede Nielsens Foundation, Denmark. The authors report no conflicts of interest in this work.