Angiogenic factors and the lectin pathway of complement in women with secondary recurrent pregnancy loss.

The poor remodeling of placental spiral arteries seen in preeclampsia is also discussed to contribute to recurrent pregnancy loss (RPL) preceded by abnormal angiogenesis and excessive complement activation. Low levels of Mannose-binding-lectin (MBL), a pattern recognition molecule (PRM) of the lectin pathway, have been found in women with RPL. We propose that pregnancy loss is connected to defective angiogenesis with reperfusion damage in the placenta and decreased levels of PRM in the lectin pathway in women with RPL. In this cohort study, we investigate the angiogenic factors and the lectin complement pathway in early pregnancy and their time-dependent relationship with pregnancy outcomes in 76 women with secondary RPL (sRPL) who have at least four prior pregnancy losses and a live birth. We evaluated levels of Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Vascular Endothelial Growth Factor (VEGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PRMs, MBL, ficolin-1, -2, -3 and an additional soluble PRM, Pentraxin-3, during the 5th, 6th, and 7th gestational weeks. Our results showed that, compared to live births, pregnancies that ended in loss were associated with elevated VEGF levels and decreased levels of the Ang-2/Ang-1 ratio. Also, increasing levels of ficolin-2 were significantly associated with pregnancy loss, with MBL showing no association. Our research suggests that women with sRPL may have inadequate placentation with impaired angiogenesis in pregnancies ending in a loss.

Occupational risk of COVID-19 in foreign-born employees in Denmark.

BACKGROUND: Foreign-born workers in high-income countries experience higher rates of COVID-19 but the causes are only partially known. AIMS: To examine if the occupational risk of COVID-19 in foreign-born workers deviates from the risk in native-born employees in Denmark. METHODS: Within a registry-based cohort of all residents employed in Denmark (n = 2 451 542), we identified four-digit DISCO-08 occupations associated with an increased incidence of COVID-19-related hospital admission during 2020-21 (at-risk occupations). The sex-specific prevalence of at-risk employment in foreign born was compared with the prevalence in native born. Moreover, we examined if the country of birth modified the risk of a positive SARS-CoV-2 polymerase chain reaction (PCR) test and COVID-19-related hospital admission in at-risk occupations. RESULTS: Workers born in low-income countries and male workers from Eastern Europe more often worked in at-risk occupations (relative risks between 1.16 [95% confidence interval {CI} 1.14-1.17] and 1.87 [95% CI 1.82-1.90]). Being foreign-born modified the adjusted risk of PCR test positivity (test for interaction P < 0.0001), primarily because of higher risk in at-risk occupations among men born in Eastern European countries (incidence rate ratio [IRR] 2.39 [95% CI 2.09-2.72] versus IRR 1.19 [95% CI 1.14-1.23] in native-born men). For COVID-19-related hospital admission, no overall interaction was seen, and in women, country of birth did not consistently modify the occupational risk. CONCLUSIONS: Workplace viral transmission may contribute to an excess risk of COVID-19 in male workers born in Eastern Europe, but most foreign-born employees in at-risk occupations seem not to be at higher occupational risk than native born.

Oocyte diameter predicts the maturation rate of human immature oocytes collected ex vivo.

PURPOSE: To study the impact of oocyte diameter and cumulus cell mass on the potential for final maturation of immature human oocytes in vitro. METHODS: Immature oocytes (n = 1563) from 75 women undergoing fertility preservation by ovarian tissue cryopreservation (14-41 years) were collected. After preparation of the ovarian cortex for freezing, immature oocytes were collected from the surplus medulla. After collection, IVM was performed according to standard published methods. The mass of cumulus cell surrounding the immature oocyte was grouped according to size. After IVM, each oocyte was photographed, measured, and the diameter was calculated as a mean of two perpendicular measurements. RESULTS: The diameter of the oocytes ranged from 60 to 171 µm with a mean of 115 µm (SD:12.1) and an interquartile range from 107 to 124 µm. The oocyte diameter was positively associated with a higher incidence of MII (p < 0.001). MII oocytes had a significantly larger mean diameter than MI, GV, and degenerated oocytes. The size of the cumulus cell mass was significantly associated with the MII stage (p < 0.001) and larger oocyte diameter (p < 0.001). The results further confirm that the diameter of the fully grown oocyte is reached relatively early in human follicular development and that the factors governing oocyte maturation in vitro are connected to the surrounding cell mass and the oocyte. CONCLUSION: The diameter of the oocyte is a highly determining factor in the nuclear maturation of the human oocyte during in vitro maturation, and the size of the cumulus cell mass is closely positively associated with a larger diameter.

Childhood atopic dermatitis is associated with a decreased chance of completing education later in life: a register-based cohort study.

BACKGROUND: Atopic dermatitis (AD) has far-reaching consequences in childhood and later in working life, but information on how it affects completion of education is sparse. OBJECTIVES: To compare the educational achievement of individuals with AD in childhood/adolescence and individuals without a history of AD. METHODS: The study population included patients diagnosed with AD prior to the age of 16 registered in the Danish National Patient Register (DNPR) born in the period 1977-1993 and a 23-fold matched control group from the background population. Cross-linkage of five different Danish registers from 1977 to 2015 allowed comparison of AD patients with controls regarding completion of education. RESULTS: In total, 10 173 individuals were registered with AD in the DNPR, while 234 683 individuals served as control group. Mild/moderate AD was associated with a decreased chance of completing basic compulsory education [hazard ratios (HR): 0.92, 95% CI: 0.90-0.95] and further academic education (HR: 0.96, 95% CI: 0.93-0.98). Severe AD was associated with a decreased chance of completing further academic education (HR: 0.86, 95% CI: 0.80-0.92), further vocational education (HR: 0.90, 95% CI: 0.84-0.97) and higher education: master's level (HR: 0.66, 95% CI: 0.53-0.81). CONCLUSION: Atopic dermatitis in childhood/adolescence is associated with a decreased chance of completing an education.

Social consequences of multiple sclerosis. Part 2. Divorce and separation: a historical prospective cohort study.

BACKGROUND: There is a need for follow-up studies of the familial situation of multiple sclerosis (MS) patients. OBJECTIVES: To evaluate the probability of MS patients to remain in marriage or relationship with the same partner after onset of MS in comparison with the population. PATIENTS AND METHODS: All 2538 Danes with onset of MS 1980-1989, retrieved from the Danish MS-Registry, and 50,760 matched and randomly drawn control persons were included. Information on family status was retrieved from Statistics Denmark. Cox analyses were used with onset as starting point. RESULTS: Five years after onset, the cumulative probability of remaining in the same relationship was 86% in patients vs. 89% in controls. The probabilities continued to deviate, and at 24 years, the probability was 33% in patients vs. 53% in the control persons (p < 0.001). Among patients with young onset (< 36 years of age), those with no children had a higher risk of divorce than those having children less than 7 years (Hazard Ratio 1.51; p < 0.0001), and men had a higher risk of divorce than women (Hazard Ratio 1.33; p < 0.01). CONCLUSION: MS significantly affects the probability of remaining in the same relationship compared with the background population.

Social consequences of multiple sclerosis: clinical and demographic predictors - a historical prospective cohort study.

BACKGROUND: Time to disability pension is one of the endpoints to be used to determine the prognosis of multiple sclerosis (MS) in prospective studies. OBJECTIVE: To assess the time to cessation of work and receiving disability pension in MS, and how it may depend on gender, type of work and age and symptom at onset. METHOD: A total of 2240 Danes with onset of definite/probable MS 1980-1989, identified from the Danish MS-Registry, were included. Information on social endpoints was retrieved from Statistics Denmark. Cox regression analyses were used with onset as starting point. RESULTS: Afferent onset symptoms [hazard ratio (HR 0.57)] and non-physical type of work (HR 0.70) were favourable prognostic factors compared with high age at onset, physical work and efferent symptoms at onset. The mean time to disability pension was 13 years for patients with afferent/brainstem onset symptom but 8.7 years for those with efferent onset symptoms (P < 0.0001). The effect of onset symptom was reduced and the effect of sex became significant when all covariates and age at onset were included in multivariate Cox regression. CONCLUSIONS: Onset age, type of onset symptom and work are robust predictors of disability pension in MS. Disability pension proves to be a reliable milestone in estimation of the prognosis of MS.

An investigation of the pathology and pathogens associated with porcine respiratory disease complex in Denmark.

Respiratory infections are among the most important diseases of growing pigs. In order to elucidate the multifactorial aetiology of porcine respiratory disease complex (PRDC) in Denmark, lungs from 148 finishing pigs with cranioventral bronchopneumonia (case group) and 60 pigs without lung lesions (control group) were collected from abattoirs. The pathogens involved in PRDC and their interactions were identified and linked to the histopathological diagnosis. The lung samples were cultured for bacteria and tested by multiplex polymerase chain reaction for presence of swine influenza virus (type A), porcine reproductive and respiratory syndrome virus (both European and US type), porcine circovirus type 2 (PCV2), porcine respiratory coronavirus, porcine cytomegalovirus, Mycoplasma hyopneumoniae and Mycoplasma hyorhinis. All cases had cranioventral lobular bronchopneumonia consistent with PRDC. There was a broad range of microscopical lesions and the cases were characterized as acute (n=10), subacute (n=24) or chronic (n=114) bronchopneumonia. Five bacterial species, five viruses and two Mycoplasma spp. were detected in different combinations. PCV2, M. hyopneumoniae, M. hyorhinis and Pasteurella multocida were detected most frequently among the PRDC affected swine and the diversity and number of pathogens were higher in these animals compared with controls. No clear-cut associations were detected between pathogens and histological lesions or histopathological diagnoses. PRDC occurs more frequently than enzootic pneumonia among Danish finishing pigs and has complex and varied histopathology.

The clinical effect of neutralizing antibodies against interferon-beta is independent of the type of interferon-beta used for patients with relapsing-remitting multiple sclerosis.

OBJECTIVE: To establish whether the clinical effect of neutralizing antibodies (NAbs) against interferon-beta (IFN beta) depends on the type of IFNbeta (1a or 1b) used for treatment of patients with relapsing-remitting multiple sclerosis (MS). INTRODUCTION: NAbs against IFN beta-1b appear faster and may be more evenly distributed on IgG subclasses, whereas NAbs against IFN beta-1a develop more slowly and may be devoid of IgG3. This might cause different clinical responses to NAbs. DESIGN/PATIENTS: All Danish MS-patients who had started first-time treatment with IFNbeta-1a 22 microg s.c tiw (Rebif22) or IFN beta-1b 250 microg s.c. qod (Betaferon) before January 1st 2003 were included. Relapses were recorded at bi-annual visit. METHODS: We measured NAbs every 12 months using a clinically validated cytopathic effect assay. A blood sample with a neutralizing capacity of 20% or more was considered as NAb-positive. We used a mixed logistic regression analysis in which NAb-status (three levels), IFN beta-preparation, and time since treatment started were included as explanatory variables, and relapse rate as response variable. RESULTS: In 1,309 patients, who were observed for 21,958 months, 32.3% were classified as NAb-positive. The odds-ratio (OR) for relapses in NAb-positive months compared with NAb-negative months was 1.25; P = 0.02. The risk of relapses was higher with Betaferon than with Rebif22 (OR 1.26; P < 0.01). The effect of NAb-level on relapses was independent of whether the patients were treated with Betaferon or Rebif22 (P = 0.89) and of time (P = 0.80). CONCLUSION: NAbs caused by IFNbeta-1a s.c. do not differ from NAbs caused by IFNbeta-1b in their detrimental clinical effect.

Head injury is not a risk factor for multiple sclerosis: a prospective cohort study.

BACKGROUND: The idea of physical trauma being involved in the causation of multiple sclerosis (MS) had been discussed since the earliest description of the illness. Despite the ongoing debate, the proposed association between physical and especially head trauma and MS failed to be proved or to be refuted conclusively. OBJECTIVE: To determine whether head trauma is associated with an increased risk of developing MS. METHOD: A cohort of 150,868 subjects, 95,111 men, and 55,757 women registered in the National Danish Patient Registry with hospital admission for cerebral concussion, contusion, or skull fracture between 1977 and 1992, aged under 55, was selected. This trauma cohort was linked with the Danish MS Registry and followed up to the end of 1999 to retrieve subjects who had onset of MS after the year of the head trauma. We calculated the expected number of subjects, who, under a null-hypothesis, would subsequently develop MS, by using population age-, year-, and sex-specific MS-incidence densities from the Danish MS Registry. RESULTS: For men and women combined, the observed to expected number of MS cases (possible cases included) with onset after the head injury was 182/193.6 (standardized incidence ratio [SIR], 0.94; 95% CI, 0.81-1.09) and for possible MS excluded, 171/164.7 (SIR, 1.04; 95% CI, 0.89-1.21). In an analysis of a sub-cohort of 16,425 subjects with severe trauma (contusion, traumatic cerebral hemorrhage, and base or skull fracture), the observed to expected numbers, including possible MS, were 15/15.3 (SIR, 0.98; 95% CI, 0.55-1.62) and with possible MS excluded, 13/12.9 (SIR, 1.01; 95% CI, 0.53-1.73). As for the total group and for any of the subgroups and for men and women separately, none of the SIRs differed statistically significantly from unity. Neither were there any trends, which could be missed by type II errors. CONCLUSION: Head injury of any severity does not affect the risk of acquiring MS later in life.

Is the treatment effect of IFN-beta restored after the disappearance of neutralizing antibodies?

OBJECTIVE: To establish whether multiple sclerosis (MS) patients, who have lost the therapeutic effect of interferon-beta (IFN-beta) owing to neutralizing antibodies (NAbs) and subsequently revert from a NAb-positive to a NAb-negative state under continued IFN-beta-1b therapy, regain clinical effect after reversion. BACKGROUND: Several studies have shown that a significant proportion of patients treated with IFN-beta develop NAbs that hamper or abolish the therapeutic effect of IFN-beta. However, some patients, who become NAb-positive under treatment with IFN-beta-1b, may revert to a NAb-negative state under continuous treatment. METHODS: We identified 40 patients from the Danish IFN protocol, who fulfilled the criteria: NAb-positive status for at least 12 months followed by reversion to NAb-negative state for at least 12 months. For comparison, we included 64 matching cases that had remained NAb-negative during an observation time of at least 36 months. The two groups were clinically and demographically alike. We measured NAb-neutralizing capacity using a clinically validated cytopathic effect assay. A blood sample with a neutralizing capacity of 20% or more was considered as NAb-positive. A patient was defined as NAb-positive after two consecutive blood tests separated by at least 6 months. Reversion to a NAb-negative state required at least two consecutive negative tests. To allow for the confounding effect of time we employed a mixed Poisson model. RESULTS: Patients who had been NAb-positive and reverted to a NAb-negative state regained treatment effect with the relapse rate as before the NAb-positive period adjusting for the effect of time, and the relapse rate was the same as in the permanently NAb-negative patients in corresponding time periods. The relapse rate ratio comparing the NAb-positive with the NAb-negative periods was 1.98 (95% confidence interval: 1.32-2.97). CONCLUSION: Under NAb-positive periods, the clinical effect of IFN-beta was abolished. When NAbs disappeared spontaneously under continued treatment, patients regained the full effect of INF-beta-1b therapy with no negative carry-over effect from the previous NAb-positive period.