Estimated number of symptomatic Lyme borreliosis cases in Germany in 2021 after adjusting for under-ascertainment.

BACKGROUND: Although nine of 16 federal states in Germany conduct public health surveillance for Lyme borreliosis (LB), the extent of under-ascertainment is unknown. OBJECTIVE: As a model for European countries that conduct LB surveillance, we sought to estimate the population-based incidence of symptomatic LB after adjusting for under-ascertainment. METHODS: Estimating seroprevalence-derived under-ascertainment relies on data from seroprevalence studies, public health surveillance, and published literature. The number of symptomatic LB cases in states that conduct LB surveillance was estimated from studies reporting the seroprevalence of antibodies against Borrelia burgdorferi sensu lato, the proportion of LB cases that are asymptomatic, and the duration of antibody detection. The number of estimated incident symptomatic LB cases was compared with the number of surveillance-reported LB cases to derive under-ascertainment multipliers. The multipliers were applied to the number of 2021 surveillance-reported LB cases to estimate the population-based incidence of symptomatic LB in Germany. RESULTS: Adjusting for seroprevalence-based under-ascertainment multipliers, the estimated number of symptomatic LB cases in states that conducted surveillance was 129,870 (408 per 100,000 population) in 2021. As there were 11,051 surveillance-reported cases in 2021 in these states, these data indicate there were 12 symptomatic LB cases for every surveillance-reported LB case. CONCLUSIONS: We demonstrate that symptomatic LB is underdetected in Germany and that this seroprevalence-based approach can be applied elsewhere in Europe where requisite data are available. Nationwide expansion of LB surveillance would further elucidate the true LB disease burden in Germany and could support targeted disease prevention efforts to address the high LB disease burden.

Cost of illness of HER2-positive and metastatic and recurrent HER2-positive breast cancer - a Danish register-based study from 2005 to 2016.

BACKGROUND: Information and knowledge about cost of illness and labour productivity in patients with HER2-positive early-stage and metastatic breast cancer treated with trastuzumab is limited. The aim of this study was to estimate the direct and indirect costs associated with treatment of HER2-positive breast cancer among patients with early-stage and metastatic breast cancer, treated with trastuzumab, in a 10-year period after diagnosis. MATERIALS AND METHODS: This study included all Danish HER2-positive breast cancer patients (≥ 18 years) treated with trastuzumab between 2005 and 2016 identified in The Danish Patient Register and the Danish Cancer Register. Furthermore, we identified patients experiencing metastatic or recurrent breast cancer. For the study populations, we estimated total direct costs and indirect costs for one year prior to the breast cancer diagnosis and up to 10 years after diagnosis compared with a group of matched controls free of breast cancer. In addition to The Danish Patient Register and Cancer Register, we applied patient level data from The Civil Registration System, The National Pathology Register, National Health Service Register for Primary Care, Register of Medicinal Product Statistics, Register of Municipal Services, The DREAM database, and Population's Education Register. RESULTS: We identified 4,153 HER2-positive breast cancer patients, whereof 27% were identified with metastatic or recurrent breast cancer. During the follow-up period of 10 years, we estimated excess direct costs of EUR 115,000 among the total study population compared to controls; EUR 211,000 among patients with metastases or recurrence; and EUR 89,000 among patients without metastases or recurrence. Direct costs were found to be highest in the first year after diagnosis and also peaked in the year after recurrence. Labour productivity was significantly lower among patients with recurrence 10 years after breast cancer diagnosis compared with controls. CONCLUSIONS: In this study, we estimated the direct and indirect cost associated with HER2-positive breast cancer. The costs were significantly higher during the 10 years after diagnosis compared to the control group, specifically among patients experiencing metastases or recurrence of breast cancer.

Birth weight for gestational age and the risk of infertility: a Danish cohort study.

STUDY QUESTION: Is birth weight for gestational age associated with infertility in adulthood among men and women? SUMMARY ANSWER: Being born small for gestational age (SGA) was associated with infertility in adulthood among men. WHAT IS KNOWN ALREADY: Fetal growth restriction may affect fertility, but results from previous studies have been inconsistent. STUDY DESIGN, SIZE, DURATION: In this population-based cohort study, we used data from a Danish birth cohort, including 5594 men and 5342 women born between 1984 and 1987. Information on infertility was obtained from Danish health registers during the period from the participants' 18th birthday and up until 31 December 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were men and women born in two Danish municipalities, Aalborg and Odense. Information on birth weight and gestational age was obtained from birth records, and information on infertility diagnoses and fertility treatment was retrieved from the Danish National Patient Registry (NPR) and the Danish In Vitro Fertilisation (IVF) registry. Information on potential maternal confounders was obtained from questionnaires during pregnancy and was included in adjusted analyses. Logistic regression analysis was used to estimate crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for infertility according to birth weight for gestational age. MAIN RESULTS AND THE ROLE OF CHANCE: Men born SGA had a 55% higher risk of being diagnosed with or treated for infertility compared to men born appropriate for gestational age (AGA) (adjusted OR = 1.55, 95% CI: 1.09-2.21). The association attenuated after exclusion of men born with hypospadias or cryptorchidism (OR = 1.37, 95% CI: 0.93-2.01). No association was found between women's birth weight for gestational age and risk of infertility (adjusted OR = 1.00, 95% CI: 0.73-1.37). LIMITATIONS, REASONS FOR CAUTION: Estimation of gestational age is associated with some uncertainty and might have caused non-differential misclassification. The study design implicitly assumed similar distribution of reproductive and health-seeking behaviour across the groups that were compared. WIDER IMPLICATIONS OF THE FINDINGS: Men born SGA had a higher risk of infertility. Genital malformations may account for part of the observed association, but this must be explored further. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by Health, Aarhus University. No competing interests are declared. TRIAL REGISTRATION NUMBER: N/A.

Network meta-analysis of urinary retention and mortality after Lichtenstein repair of inguinal hernia under local, regional or general anaesthesia.

BACKGROUND: Urinary retention and mortality after open repair of inguinal hernia may depend on the type of anaesthesia. The aim of this study was to investigate possible differences in urinary retention and mortality in adults after Lichtenstein repair under different types of anaesthesia. METHODS: Systematic searches were conducted in the Cochrane, PubMed and Embase databases, with the last search on 1 August 2018. Eligible studies included adult patients having elective unilateral inguinal hernia repair by the Lichtenstein technique under local, regional or general anaesthesia. Outcomes were urinary retention and mortality, which were compared between the three types of anaesthesia using meta-analyses and a network meta-analysis. RESULTS: In total, 53 studies covering 11 683 patients were included. Crude rates of urinary retention were 0·1 (95 per cent c.i. 0 to 0·2) per cent for local anaesthesia, 8·6 (6·6 to 10·5) per cent for regional anaesthesia and 1·4 (0·6 to 2·2) per cent for general anaesthesia. No death related to the type of anaesthesia was reported. The network meta-analysis showed a higher risk of urinary retention after both regional (odds ratio (OR) 15·73, 95 per cent c.i. 5·85 to 42·32; P < 0·001) and general (OR 4·07, 1·07 to 15·48; P = 0·040) anaesthesia compared with local anaesthesia, and a higher risk after regional compared with general anaesthesia (OR 3·87, 1·10 to 13·60; P = 0·035). Meta-analyses showed a higher risk of urinary retention after regional compared with local anaesthesia (P < 0·001), but no difference between general and local anaesthesia (P = 0·08). CONCLUSION: Local or general anaesthesia had significantly lower risks of urinary retention than regional anaesthesia. Differences in mortality could not be assessed as there were no deaths after elective Lichtenstein repair. Registration number: CRD42018087115 ( https://www.crd.york.ac.uk/prospero).

ANTECEDENTES: La retención de orina y la mortalidad tras la reparación abierta de las hernias inguinales puede depender del tipo de anestesia. El objetivo de este estudio fue investigar posibles diferencias en la retención de orina y mortalidad en adultos tras reparación de Lichtenstein bajo diferentes métodos anestésicos. MÉTODOS: Se efectuaron búsquedas sistemáticas en las bases de datos Cochrane, PubMed y Embase con la última revisión el 1 de agosto de 2018. Los estudios elegibles incluyeron pacientes adultos sometidos a reparación electiva de hernia inguinal unilateral mediante la técnica de Lichtenstein bajo anestesia local, regional o general. Las variables de resultados fueron la retención de orina y la mortalidad, comparándose los tres tipos de anestesia con metaanálisis y un metaanálisis en red. RESULTADOS: En total se incluyeron 53 estudios con un total de 11.683 pacientes. Las tasas crudas de retención de orina fueron del 0,1% (i.c. del 95% 0,0-0,2%) para la anestesia local, del 8,6% (i.c. del 95% 6,6-10,5%) para la anestesia regional y del 1,4% (i.c. del 95% 0,6-2,2%) para la anestesia general. No se observó mortalidad relacionada con el tipo de anestesia. El metaanálisis en red mostró un riesgo más elevado de retención de orina tras la anestesia regional (razón de oportunidades, odds ratio, OR 15,73 (i.c. del 95% 5,85-42,32), P < 0,001) y anestesia general (OR 4,07 (i.c. del 95% 1,07-15,48), P = 0,040) en comparación con la anestesia local y un riesgo más alto tras la regional en comparación con la anestesia general (OR 3,87 (i.c. del 95% 1,10-13,60), P = 0,035). Los metaanálisis mostraron un riesgo más alto de retención de orina tras la anestesia regional en comparación con la anestesia local (P < 0,001), pero sin diferencias entre anestesia general y local (P = 0,08). CONCLUSIÓN: La anestesia local o general presentaba un riesgo significativo menor de retención urinaria en comparación con la anestesia regional. Las diferencias en mortalidad no pudieron ser evaluadas ya ningún paciente falleció tras la reparación electiva de Lichtenstein.

Effect of ampicillin, cephalexin, ceftiofur and tetracycline treatment on selection of resistant coliforms in a swine faecal microcosmos.

AIMS: To analyse and compare the effect of selection power for antimicrobial resistance (AMR) in coliforms of two kinds of ß-lactams-aminopenicillins; ampicillin (Amp) and cephalosporins; cephalexin (Cpn) and ceftiofur (Cef)-and tetracycline (Tet) using an approach based on a swine faecal microcosmos. METHODS AND RESULTS: Sixteen faecal samples from 32 pigs (mixed two by two) were treated with Amp, Cpn, Cef and Tet for 6 h (T6h) at concentrations expected to reach the animals gut when using in vivo standard doses. Controls (no drug added) were also tested. Next, samples were 1 : 100 diluted and left under the same conditions (no antimicrobial added) for further 20 h (T20h). The proportion of resistant coliform bacteria (R coliforms) to each antimicrobial was analysed just before starting the treatment (T0), at T6h and at T20h. Coselection was also studied by replica plating. Treatment for 6 h yielded significant increase in proportion of R coliforms, regardless of the drug and lack of selection pressure showed different effects at T20h depending on the antimicrobial used. Selective pressure was associated with the type of the ß-lactam with Amp selecting for significantly higher numbers of R coliforms than cephalosporins. CONCLUSIONS: AMR development was observed following short treatment, and for Amp and Tet treatment, resistance persisted 20 h beyond the interruption of treatment. An association between kind of ß-lactam and power of selection was found. SIGNIFICANCE AND IMPACT OF THE STUDY: AMR represents a threat to human health globally and antimicrobial treatment of livestock has a direct impact on this problem. Through our approach based on a swine faecal microcosmos, we demonstrated the effect on AMR development of several drugs commonly used in livestock. Cephalosporins, representing last-line antimicrobials in human medicine, exerted lower selective pressure than Amp under the conditions used and yielded higher proportion of multidrug-R strains.

Towards high-quality peri-operative care: a global perspective.

Article 25 of the United Nations' Universal Declaration of Human Rights enshrines the right to health and well-being for every individual. However, universal access to high-quality healthcare remains the purview of a handful of wealthy nations. This is no more apparent than in peri-operative care, where an estimated five billion individuals lack access to safe, affordable and timely surgical care. Delivery of surgery and anaesthesia in low-resource environments presents unique challenges that, when unaddressed, result in limited access to low-quality care. Current peri-operative research and clinical guidance often fail to acknowledge these system-level deficits and therefore have limited applicability in low-resource settings. In this manuscript, the authors priority-set the need for equitable access to high-quality peri-operative care and analyse the system-level contributors to excess peri-operative mortality rates, a key marker of quality of care. To provide examples of how research and investment may close the equity gap, a modified Delphi method was adopted to curate and appraise interventions which may, with subsequent research and evaluation, begin to address the barriers to high-quality peri-operative care in low- and middle-income countries.

Parental time to pregnancy, medically assisted reproduction and pubertal development in boys and girls.

STUDY QUESTION: Does parental fertility, measured by time to pregnancy (TTP), or use of medically assisted reproduction (MAR) affect pubertal development in the offspring? SUMMARY ANSWER: Neither TTP nor type of MAR treatment had clinically relevant implications for mean age at achieving individual pubertal milestones or overall timing of puberty in boys and girls. WHAT IS KNOWN ALREADY: Parental TTP and MAR have been associated with impaired semen quality in adult sons. Timing of puberty reflects earlier signals of reproductive health, but it remains unclear whether parental fertility or MAR affects pubertal development, especially in the growing generation of children conceived by IVF or ICSI. STUDY DESIGN, SIZE, DURATION: In this study, 15 819 children born by mothers in the Danish National Birth Cohort from 2000 to 2003 participated in a nationwide puberty cohort (participation rate = 70%). Parental TTP and use of MAR were reported by mothers in early pregnancy and children's pubertal development data was self-recorded in web-based questionnaires from 11 years of age and 6 monthly throughout puberty (2012-2018). PARTICIPANTS/MATERIALS, SETTING, METHODS: Pubertal development in children (of planned pregnancies, n = 13 285) born by untreated subfecund (TTP: 6-12 months) (n =2038), untreated severely subfeund (TTP: >12 months) (n = 1242), treated subfecund (n = 230) and treated severely subfecund (n = 1234) parents were compared to children born to more fertile parents (TTP: ≤5 months). We estimated mean monthly differences in mean age at achieving individual pubertal milestones (i.e. age at menarche, voice break, first ejaculation and Tanner stages 2, 3, 4 and 5 for breast or genital development and pubic hair growth) and a combined indicator of timing of puberty. Further, we compared mean age at achieving the individual pubertal milestones in children born by use of IVF or ICSI (n = 480) with children born by controlled ovarian stimulation or ovulation induction with or without intrauterine insemination (n = 902). MAIN RESULTS AND THE ROLE OF CHANCE: We found tendencies towards slightly later mean age at male pubertal timing and slightly earlier mean age at female pubertal timing among children born by untreated subfecund, treated subfecund, untreated severely subfecund and treated severely subfecund parents. There were no specific patterns with increasing TTP, use of MAR nor type of MAR treatment, and the magnitude of the mean differences for individual milestones and overall timing of puberty were small, i.e. 0.9 months (95% CI: -1.0; 2.8) for first ejaculation and -0.5 months (95% CI: -2.0; 1.0) months for age at menarche in boys and girls, respectively, born by treated severely subfecund parents when compared with children born by more fertile parents. LIMITATIONS, REASONS FOR CAUTION: Non-differential misclassification of the self-reported information on parental TTP and pubertal development in the offspring may serve as an alternative explanation of the findings, possibly biasing the estimates towards the null. The information on pubertal development was collected from around 11 years of age and onwards. WIDER IMPLICATIONS OF THE FINDINGS: This study adds to the growing body of literature suggesting only limited harmful effects of parental subfecundity and MAR on offspring's long-term growth and development. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Danish Council for Independent Research [DFF 4183-00152]; and the Faculty of Health at Aarhus University. The authors have no financial relationships or competing interests to disclose.

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 child's 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 child's 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.

Maternal hypothyroidism in the perinatal period and childhood asthma in the offspring.

BACKGROUND: There is increasing interest in the possible link between maternal hypothyroidism in the perinatal period and childhood asthma risk. We explored this in this study while accounting for the timing of hypothyroidism diagnosis. Further, we evaluated whether the risk was moderated by thyroid hormone treatment during pregnancy. METHODS: We conducted a population-based cohort study using Danish national registers. All live-born singletons in Denmark from 1998 to 2007 were identified. Maternal hypothyroidism and asthma in the children were defined by data from the Patient Register and Prescription Registry. We estimated incidence rate ratios (IRRs) of asthma among children born to hypothyroid mothers versus children born to mothers with no recorded thyroid dysfunction using Poisson regression models. RESULTS: Of 595 669 children, 3524 children were born to mothers with hypothyroidism diagnosed before delivery and 4664 diagnosed after delivery. Overall, 48 990 children received treatment for asthma. The IRRs of asthma was 1.16 (95% confidence interval (CI): 1.03-1.30) and 1.12 (95% CI: 1.02-1.24) for children born to mothers with hypothyroidism diagnosed before and after delivery, compared to children born to mothers with no thyroid dysfunction. The highest risk was observed among children born to mothers with hypothyroidism diagnosed before delivery who did not receive thyroid hormone treatment during pregnancy (IRR=1.37, 95% CI: 1.04-1.80). CONCLUSION: Our findings suggest that maternal hypothyroidism, especially when it is untreated, increases childhood asthma risk. Early detection and appropriate treatment of hypothyroidism in pregnant women may be an area for possible prevention of childhood asthma.

Bereavement, multimorbidity and mortality: a population-based study using bereavement as an indicator of mental stress.

BACKGROUND: Mental stress is associated with higher mortality, but it remains controversial whether the association is causal or a consequence of a higher physical disease burden in those with a high mental stress load. Understanding causality is important when developing targeted interventions. We aimed to estimate the effect of mental stress on mortality by performing a 'natural' experiment using spousal bereavement as a disease-independent mental stressor. METHODS: We followed a population-based matched cohort, including all individuals in Denmark bereaved in 1997-2014, for 17 years. Prospectively recorded register data were obtained for civil and vital status, 39 mental and physical diagnoses, and socioeconomic factors. RESULTS: In total, 389 316 bereaved individuals were identified and 137 247 died during follow-up. Bereaved individuals had higher all-cause mortality than non-bereaved references in the entire study period. The relative mortality in the bereaved individuals was highest shortly after the loss (adjusted hazard ratio (aHR), first month: 2.50, 95% confidence interval (CI) 2.37-2.63; aHR, 6-12 months: 1.38, 95% CI 1.34-1.42). The excess mortality rate associated with bereavement rose with increasing number of physical diseases (1.33 v. 7.00 excess death per 1000 person-months for individuals with 0 v. ⩾3 physical conditions during the first month) and was exacerbated by the presence of mental illness. The excess mortality among bereaved individuals was primarily due to death from natural causes. CONCLUSIONS: Bereavement was associated with increased short-term and long-term mortality, even after adjustment for morbidities, which suggests that mental stress may play a causal role in excess mortality.

Isolation of vancomycin-resistant Enterococcus from apparently healthy human animal attendants, cattle and cattle wastes in Tanzania.

AIM: The study aimed to isolate and characterize Enterococcus species from apparently healthy waste attendants, cattle and cattle waste in Tanzania. Emphasis was given to antimicrobial resistance and in particular occurrence of vancomycin (VA)-resistant enterococci. METHODS AND RESULTS: Faecal samples were collected from healthy cattle, cattle waste attendants and cattle house wastes, and isolation of Enterococcus species was performed using Slanetz Bartley agar. Isolates were characterized with regard to species, antimicrobial susceptibility and presence of VA resistance genes. Enterococcus faecalis was the most prevalent species from all sources of isolation (43·5%), followed by Enterococcus faecium (38·4%). Isolates of E. faecium showed a higher number of phenotypic antimicrobial resistance than isolates of E. faecalis. Fifty-eight isolates, which showed resistance or intermediate resistance to VA by disc diffusion test, were analysed for VA-resistant Enterococcus (VRE) by PCR. The vanA gene was detected in 14 isolates of E. faecium and 12 isolates of E. faecalis, while vanB was detected in three isolates. No isolates were found to carry vanC1-gene. CONCLUSION: VRE was detected in both human and cattle samples, despite no known use of antimicrobial agents that can select for VRE in livestock in Tanzania. Enterococcus faecalis was the most commonly isolated species from cattle and humans. SIGNIFICANCE AND IMPACT OF THE STUDY: The study provides information on the prevalence of VRE in human and nonhuman samples in Tanzania calling for further studies on the origin of VRE in such isolates, since no selection mechanism in Tanzania are known.

In vivo measurements of blood vessels' distribution in non-melanoma skin cancer by dynamic optical coherence tomography - a new quantitative measure?

BACKGROUND: Skin biopsies only provide point-in-time data making longitudinal studies difficult. Using Dynamic optical coherence tomography (D-OCT) in vivo, non-invasive imaging of the microvasculature becomes possible. The current OCT literature is almost exclusively based on qualitative information but quantitative data may offer additional advantages, for example, by reducing observer variation. The objective of this study was to evaluate the in vivo superficial distribution of blood vessels, defined as the surface-to-first-vessel distance, in actinic keratosis, basal cell carcinoma, squamous cell carcinoma and normal skin. METHODS: D-OCT images of 52 histologically verified lesions and corresponding normal skin were included. The dataset consisted of 13 AK, 22 BCC and 17 SCC. No tumour sub-classification was done. RESULTS: The quantitative measurement of the surface-to-first-vessel distance showed a significant difference between NMSC and corresponding normal skin. Significant differences were also seen for BCC, and it is hypothesized that the measure may also be able to distinguish between AK and SCC (borderline significant differences). CONCLUSION: Our results could prove useful in discriminating between non-melanoma skin cancer lesions and healthy skin and in making a specific diagnosis. It is suggested that collecting different quantitative measurements increases the utility of D-OCT and makes the method less observer-dependent.

Dynamic optical coherence tomography of histamine induced wheals.

BACKGROUND: Dynamic optical coherence tomography (D-OCT) is a noninvasive imaging technique providing images of the skin and detecting movement in the tissue ie, measuring blood flow. The "attenuation coefficient" describes light absorption and scattering abilities of the tissue, while the dynamic signal provides a quantitative measure of the blood flow. AIM: The study objective is to describe the dynamic changes of the skin and skin vessels during histamine release using D-OCT. METHODS: Healthy volunteers had local histamine injections in the skin and D-OCT-scans performed at 2-minute intervals to detect changes in blood flow, attenuation and clinical symptoms. RESULTS: 9/10 participants showed clinical wheals. An increase in blood flow was shown at all depths (P < .001 at 2 minutes). The highest relative increase was seen at 300 µm. The signal at 500 µm decreased to insignificant values and remained low after 4 minutes. A decrease in visualization depth of up to 32.7% as well as a significant increase in the attenuation coefficient was shown (P < .001 at 12 minutes for both tests). CONCLUSION: Dynamic optical coherence tomography is able to reliably identify changes in blood flow of histamine induced wheals. Dermal oedema reduces visualization depth and increases the attenuation coefficient.

Contemporary factors influencing genetic diversity in the Alaska humpback whitefish Coregonus clupeaformis complex.

Thirteen microsatellite loci were used to address three hypotheses regarding genetic diversity in the humpback whitefish Coregonus clupeaformis complex in Alaska. The test results provided further insight into the factors influencing C. clupeaformis complex population structure and level of genetic variation. First, the microsatellite data did not provide evidence of two spatially distinct Beringian and Eurasian refugial groups as revealed in previous phylogeographic analyses of mitochondrial DNA variation. Rather, the population structure inferred from the microsatellite variation appears to reveal the influence of factors on a more recent time scale, including gene flow among the refugial groups and isolation of some anadromous and freshwater resident populations. Second, anadromous C. clupeaformis complex collections exhibited higher intra-population genetic diversity than freshwater resident collections. This outcome is consistent with previous meta analyses suggesting that freshwater resident populations probably have smaller historical effective population sizes and less conspecific gene flow because the habitat tends to be smaller and supports fewer and smaller populations. Finally, the analysis of contemporary immigration rates was consistent with, but did not provide statistical support for, the hypothesis that gene flow among anadromous C. clupeaformis complex populations along coastal Alaska is influenced by the Alaska Coastal Current. Further studies are needed to evaluate gene flow among coastal Alaska C. clupeaformis complex populations.

Impact of lifestyle intervention for obese women during pregnancy on maternal metabolic and inflammatory markers.

BACKGROUND: Offspring of obese mothers have increased risk of developing obesity and related short- and long-term disease. The cause is multifactorial and may partly be explained by the unfavorable intrauterine environment. Intervention during pregnancy leading to a healthier lifestyle among obese may alter this. OBJECTIVE: To assess the effect of lifestyle intervention on markers of maternal metabolism and inflammation in 'the TOP (Treatment of Obese Pregnant Women) study', a randomized controlled trial. METHODS: In the TOP-study 425 participants with body mass index ⩾30 kg/m2 were randomized to intervention with dietary advices and physical activity assessed by pedometer (PA+D), physical activity assessed by pedometer (PA) or control (C). Of 389 participants completing the study 376 had available blood samples. Serum was analyzed for insulin, c-peptide, lipid profile, leptin, high-sensitivity CRP (hsCRP) and Soluble urokinase Plasminogen Activator Receptor (suPAR), in week 18-20 and 28-30, and simultaneously a 2-h oral glucose-tolerance-test was performed. Diet was assessed in gestational week 11-14 and 36-37 using a validated 360-item Food Frequency Questionnaire. RESULTS: Median levels of hsCRP in gestational week 28-30 were lower in each of the intervention groups (8.3 mg/l in PA+D group, P=0.03; and 8.8 mg/l in PA group, P=0.02) versus the control group (11.5 mg/l). Obtaining 11 000 steps per day as aimed for resulted in a 21% lower hsCRP compared to non-compliant women. Women reporting high carbohydrate intake had around 30% higher hsCRP concentrations in late gestation than women reporting the lowest intake. There were no differences in lipid profile or any of the metabolic markers in gestational week 28-30 when comparing the intervention and control groups. CONCLUSIONS: Lifestyle intervention in obese women can reduce hsCRP representing a marker of inflammation during pregnancy. The effect may partly be mediated by more physical activity and partly by changes in intake of carbohydrates and the glycaemic load.

Prenatal antibiotics and atopic dermatitis among 18-month-old children in the Danish National Birth Cohort.

BACKGROUND: Despite extensive research, the aetiology of atopic dermatitis remains largely unknown, but reduced intestinal microbiota diversity in neonates has been linked to subsequent atopic dermatitis. Consequently, postnatal antibiotics have been proposed as a risk factor, but a potential association between prenatal antibiotics and atopic dermatitis is not well studied. Overall, the current evidence suggests a positive association between exposure to prenatal antibiotics and atopic dermatitis. OBJECTIVE: To investigate the association between prenatal antibiotics and atopic dermatitis among 18-month-old children. METHODS: This study conducted within the Danish National Birth Cohort included 62 560 mother-child pairs. Data on maternal prenatal antibiotics were collected in the 30th gestation week and 6 months post-partum, and offspring atopic dermatitis 18 months post-partum through telephone interviews. Antibiotic use was categorized by the timing of exposure as 1st-2nd trimester (gestation week 0-29), 3rd trimester (gestation week 30-birth), all three trimesters or none. Data were analysed by logistic regression analyses adjusting for potential confounders. RESULTS: Exposure to antibiotics prenatally was associated with increased odds of atopic dermatitis among children born by atopic mothers but only when used in both 1st-2nd and 3rd trimester (ORadj 1.45, 95% CI: 1.19-1.76). The findings were consistent using different definitions of atopic dermatitis. CONCLUSIONS AND CLINICAL RELEVANCE: Prenatal exposure to antibiotics throughout pregnancy was associated with an increased risk of atopic dermatitis but only within the first 18 months of life among children born by atopic mothers. The clinical usefulness of this finding must rest on corroboration in independent data sources.

Inflammation and post-operative recovery in patients undergoing total knee arthroplasty-secondary analysis of a randomized controlled trial.

OBJECTIVE: Reduced function persists for many patients after total knee arthroplasty (TKA). Inflammation is part of osteoarthritis' pathophysiology, and surgery induces a marked inflammatory response. We therefore wanted to explore the role of inflammation in long-term recovery after TKA, and thus conducted this secondary analysis of our randomized controlled trial (RCT) of physical rehabilitation ± progressive strength training (PST). We aimed to investigate whether (1) inflammation is associated with functional performance, knee-extension strength, and knee pain before TKA; (2) PST affects inflammation, and the inflammatory state over time; (3) baseline or surgery-induced inflammation modifies the effect of rehabilitation ± PST on change in 6-min walk test (Δ6MWT); and (4) baseline or surgery-induced inflammation is associated with Δ6MWT following TKA. DESIGN: In the primary trial report's per-protocol analysis, 72/82 patients were included. Sixty had ≥1 blood sample before and after TKA, and were included in this secondary analysis. Inflammation was measured by interferon γ-inducible protein (IP)-10, soluble urokinase plasminogen activator receptor (suPAR), interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α at baseline; day 1, week 4, 8, and 26 after TKA. RESULTS: At baseline, suPAR (P = 006) was negatively associated with 6MWT. Neither baseline nor surgery-induced inflammation modified the response to rehabilitation ± PST. Only surgery-induced IL-10 was associated with Δ6MWT26 weeks-baseline (P = 0.001), also adjusted for 6MWTbaseline, age, sex and body mass index (BMI). CONCLUSION: In this secondary analysis, only increased surgery-induced IL-10 response was associated with decreased long-term functional performance after TKA. The importance of controlling the surgery-induced immune response remains to be investigated further. TRIAL IDENTIFICATION: NCT01351831.

Prenatal maternal bereavement and mortality in the first decades of life: a nationwide cohort study from Denmark and Sweden.

BACKGROUND: The loss of a close relative is one of the most stressful life events. In pregnancy, this experience has been associated with a higher risk of fetal death and under-five mortality, but little is known about potential effects on long-term mortality in offspring. We examined the association between prenatal maternal bereavement and mortality in a cohort of 5.3 million children followed until up to 37 years of age. METHOD: The population-based cohort study included 5 253 508 live singleton births in Denmark (1973-2004) and Sweden (1973-2006). Children born to mothers who lost a child, spouse, sibling, or parent during or 1 year before pregnancy were categorized as exposed. RESULTS: Prenatal maternal bereavement was associated with a 10% increased all-cause mortality risk in offspring [mortality rate ratio (MRR) 1.10, 95% confidence interval (CI) 1.03-1.18]. The association was the most pronounced for children of mothers who lost a child/spouse (MRR 1.28, 95% CI 1.14-1.44) and was stronger during the first 10 years of life. Prenatal maternal bereavement may have stronger effects on natural causes of death in offspring, including infectious/parasitic disease (MRR 1.86, 95% CI 1.07-3.23), endocrine/nutritional/metabolic diseases (MRR 3.23, 95% CI 2.02-5.17), diseases of nervous system (MRR 3.36, 95% CI 2.47-4.58), and congenital malformations (MRR 1.39, 95% CI 1.08-1.80). No excess mortality risk in offspring was observed for unnatural causes of death. CONCLUSION: Prenatal maternal bereavement was associated with an increased long-term mortality risk in offspring, particularly for selected natural causes of diseases and medical conditions. Our results support the fetal programming hypothesis that prenatal stress may contribute to ill health from physical diseases later in life.

Prenatal exposure to maternal bereavement and offspring psoriasis: a Danish nationwide cohort study.

BACKGROUND: Prenatal stress may alter immune competence of the fetus. Limited data exist on the role of antenatal stress in psoriasis development. OBJECTIVES: To investigate whether prenatal exposure to maternal bereavement increases the risk of offspring psoriasis. METHODS: This register-based cohort study included 1 811 917 live singletons born from 1978 to 2008 in Denmark. The children were assigned to the bereaved group if their mothers lost a child, partner/spouse, parent or sibling during pregnancy or up to 12 months before pregnancy. Follow-up started at the date of birth and ended at the date of first hospital treatment for psoriasis or a prescription redeemed for topical vitamin D derivatives (often used to treat psoriasis), emigration, death or 31 December 2010, whichever came first. We evaluated the hazard ratio (HR) of psoriasis in bereaved children using Cox proportional hazards regressions, compared with the nonbereaved group. RESULTS: During 28 million person-years of follow-up, 7956 children were hospitalized or prescribed medications for psoriasis. By the age of 30 years, 1·54% [95% confidence interval (CI) 1·25-1·90%] of children from the bereaved group were diagnosed with psoriasis, compared with 1·34% (95% CI 1·30-1·38%) of nonbereaved children. Overall, prenatal exposure to maternal bereavement was not associated with risk of psoriasis in general (HR 1·05, 95% CI 0·91-1·20). However, children born to mothers who lost a partner/spouse or an older child had an increased risk of psoriasis (HR 1·33, 95% CI 1·02-1·73). CONCLUSIONS: Prenatal exposure to the most stressful life event may contribute to the development and/or exacerbation of psoriasis.

Soluble urokinase plasminogen activator receptor (suPAR) is a novel, independent predictive marker of myocardial infarction in HIV-1-infected patients: a nested case-control study.

OBJECTIVES: Patients infected with HIV are at increased risk of myocardial infarction (MI). Increased plasma levels of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) have been associated with increased risk of cardiovascular diseases (CVD), including MI in the general population. We tested suPAR as a predictive biomarker of MI in HIV-1-infected individuals. METHODS: suPAR levels were investigated in a nested case-control study of 55 HIV-1-infected cases with verified first-time MI and 182 HIV-1-infected controls with no known CVD. Controls were matched for age, gender, duration of antiretroviral therapy (ART), smoking and no known CVD. suPAR was measured in the four plasma samples available for each patient at different time-points; 1, Before initiation of ART; 2, 3 months after initiation of ART; 3, 1 year before the case's MI; and 4, The last sample available before the case's MI. RESULTS: In unadjusted conditional regression analysis, higher levels of suPAR were associated with a significant increase in risk of MI at all time-points. Patients in the third and fourth suPAR quartiles had a three- to 10-fold higher risk of MI compared to patients in the lowest suPAR quartile at all time-points. suPAR remained a strong significant predictor of MI, when adjusting for HIV-1 RNA, total cholesterol, triglycerides and high-density lipoprotein. CONCLUSION: Elevated suPAR levels were associated with increased risk of MI in HIV-infected patients, suggesting that suPAR could be a useful biomarker for prediction of first-time MI in this patient group, even years before the event.