SARS-CoV-2 in first trimester pregnancy: a cohort study.

STUDY QUESTION: Does maternal infection with severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) in first trimester pregnancy have an impact on the fetal development as measured by nuchal translucency thickness and pregnancy loss? SUMMARY ANSWER: Nuchal translucency thickness at the first trimester scan was not significantly different in pregnant women with versus without SARS-CoV-2 infection in early pregnancy and there was no significantly increased risk of pregnancy loss in women with SARS-CoV-2 infection in the first trimester. WHAT IS KNOWN ALREADY: Pregnant women are more vulnerable to viral infections. Previous coronavirus epidemics have been associated with increased maternal morbidity, mortality and adverse obstetric outcomes. Currently, no evidence exists regarding possible effects of SARS-CoV-2 in first trimester pregnancies. STUDY DESIGN, SIZE, DURATION: Cohort study of 1019 women with a double test taken between 17 February and 23 April 2020, as a part of the combined first trimester risk assessment, and 36 women with a first trimester pregnancy loss between 14 April and 21 May 2020, prior to the double test. The study period was during the first SARS-CoV-2 epidemic wave in Denmark. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cohort 1 included pregnant women with a double test taken within the study period. The excess serum from each double test was analyzed for SARS-CoV-2 antibodies. Results were correlated to the nuchal translucency thickness and the number of pregnancy losses before or at the time of the first trimester scan. Cohort 2 included women with a pregnancy loss before the gestational age for double test sample. Serum from a blood test taken the day the pregnancy loss was identified was analyzed for SARS-CoV-2 antibodies. The study was conducted at a public university hospital serving ∼12% of pregnant women and births in Denmark. All participants in the study provided written informed consent. MAIN RESULTS AND THE ROLE OF CHANCE: Eighteen (1.8%) women had SARS-CoV-2 antibodies in the serum from the double test suggestive of SARS-CoV-2 infection in early pregnancy. There was no significant difference in nuchal translucency thickness for women testing positive for previous SARS-CoV-2 infection (n = 16) versus negative (n = 966) (P = 0.62). There was no significantly increased risk of pregnancy loss for women with antibodies (n = 1) (OR 3.4, 0.08-24.3 95% CI, P = 0.27). None of the women had been hospitalized due to SARS-CoV-2 infection. None of the women with pregnancy loss prior to the double test (Cohort 2) had SARS-CoV-2 antibodies. LIMITATIONS, REASONS FOR CAUTION: These results may only apply to similar populations and to patients who do not require hospitalization due to SARS-CoV-2 infection. A limitation of the study is that only 1.8% of the study population had SARS-CoV-2 antibodies suggestive of previous infection. WIDER IMPLICATION OF THE FINDINGS: Maternal SARS-CoV-2 infection had no effect on the nuchal translucency thickness and there was no significantly increased risk of pregnancy loss for women with SARS-CoV-2 infection in first trimester pregnancy. Evidence concerning COVID-19 in pregnancy is still limited. These data indicate that infection with SARS-CoV-2 in not hospitalized women does not pose a significant threat in first trimester pregnancies. Follow-up studies are needed to establish any risk to a fetus exposed to maternal SARS-CoV-2 infection. STUDY FUNDING/COMPETING INTEREST(S): Prof. H.S.N. and colleagues received a grant from the Danish Ministry of Research and Education for research of COVID-19 among pregnant women. The Danish government was not involved in the study design, data collection, analysis, interpretation of data, writing of the report or decision to submit the paper for publication. A.I., J.O.-L., J.B.-R., D.M.S., J.E.-F. and E.R.H. received funding from a Novo Nordisk Foundation (NNF) Young Investigator Grant (NNF15OC0016662) and a Danish National Science Foundation Center Grant (6110-00344B). A.I. received a Novo Scholarship. J.O.-L. is funded by an NNF Pregraduate Fellowship (NNF19OC0058982). D.W. is funded by the NNF (NNF18SA0034956, NNF14CC0001, NNF17OC0027594). A.M.K. is funded by a grant from the Rigshospitalet's research fund. H.S.N. has received speaker's fees from Ferring Pharmaceuticals, Merck Denmark A/S and Ibsa Nordic (outside the submitted work). N.l.C.F. has received a grant from Gedeon Richter (outside the submitted work). A.M.K. has received speaker's fee from Merck (outside the submitted work). The other authors did not report any potential conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

A distinctive epigenetic ageing profile in human granulosa cells.

STUDY QUESTION: Does women's age affect the DNA methylation (DNAm) profile differently in mural granulosa cells (MGCs) from other somatic cells? SUMMARY ANSWER: Accumulation of epimutations by age and a higher number of age-related differentially methylated regions (DMR) in MGCs were found compared to leukocytes from the same woman, suggesting that the MGCs have a distinctive epigenetic profile. WHAT IS KNOWN ALREADY: The mechanisms underlying the decline in women's fertility from the mid-30s remain to be fully elucidated. The DNAm age of many healthy tissues changes predictably with and follows chronological age, but DNAm age in some reproductive tissues has been shown to depart from chronological age (older: endometrium; younger: cumulus cells, spermatozoa). STUDY DESIGN, SIZE, DURATION: This study is a multicenter cohort study based on retrospective analysis of prospectively collected data and material derived from healthy women undergoing IVF or ICSI treatment following ovarian stimulation with antagonist protocol. One hundred and nineteen women were included from September 2016 to June 2018 from four clinics in Denmark and Sweden. PARTICIPANTS/MATERIALS, SETTING, METHODS: Blood samples were obtained from 118 healthy women with varying ovarian reserve status. MGCs were collected from 63 of the 119 women by isolation from pooled follicles immediately after oocyte retrieval. DNA from leukocytes and MGCs was extracted and analysed with a genome-wide methylation array. Data from the methylation array were processed using the ENmix package. Subsequently, DNAm age was calculated using established and tailored age predictors and DMRs were analysed with the DMRcate package. MAIN RESULTS AND ROLE OF CHANCE: Using established age predictors, DNAm age in MGCs was found to be considerable younger and constant (average: 2.7 years) compared to chronological age (average: 33.9 years). A Granulosa Cell clock able to predict the age of both MGCs (average: 32.4 years) and leukocytes (average: 38.8 years) was successfully developed. MGCs differed from leukocytes in having a higher number of epimutations (P = 0.003) but predicted telomere lengths unaffected by age (Pearson's correlation coefficient = -0.1, P = 0.47). DMRs associated with age (age-DMRs) were identified in MGCs (n = 335) and in leukocytes (n = 1) with a significant enrichment in MGCs for genes involved in RNA processing (45 genes, P = 3.96 × 10-08) and gene expression (152 genes, P = 2.3 × 10-06). The top age-DMRs included the metastable epiallele VTRNA2-1, the DNAm regulator ZFP57 and the anti-Müllerian hormone (AMH) gene. The apparent discordance between different epigenetic measures of age in MGCs suggests that they reflect difference stages in the MGC life cycle. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: No gene expression data were available to associate with the epigenetic findings. The MGCs are collected during ovarian stimulation, which may influence DNAm; however, no correlation between FSH dose and number of epimutations was found. WIDER IMPLICATIONS OF THE FINDINGS: Our findings underline that the somatic compartment of the follicle follows a different methylation trajectory with age than other somatic cells. The higher number of epimutations and age-DMRs in MGCs suggest that their function is affected by age. STUDY FUNDING/COMPETING INTEREST(S): This project is part of ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS, the Danish National Research Foundation and the European Research Council. The authors declare no conflict of interest.

Disseminated histoplasmosis and AIDS: a prospective and multicentre study to evaluate the performance of different diagnostic tests.

The burden of histoplasmosis has been poorly documented in most of the endemic areas for the disease, including Brazil. Also, modern non-culture-based diagnostic tests are often non-available in these regions. This was a prospective cohort study in HIV-infected patients with suspected disseminated disease evaluated with different diagnostic tests. Patients were enrolled in three referral medical centres in Porto Alegre, Brazil. Among 78 evaluated patients, disseminated histoplasmosis was confirmed in eight individuals (10.3%) by the means of classical (culture/histopathology) tests. Antigen detection in the urine was found to be more sensitive: IMMY® ALPHA ELISA detected 13 positive cases (16.7%) and the in-house ELISA test developed by the Centers for Disease Prevention and Control (CDC) detected 14 (17.9%). IMMY® and CDC tests provided concordant results in 96.2% of cases. This is the first study to compare the performance of the in-house CDC ELISA test with the IMMY® commercial test for the diagnosis of histoplasmosis, and a high degree of concordance was observed. The study revealed that H. capsulatum is an important agent of disseminated disease in AIDS patients in Brazil, reinforcing the importance of making available modern diagnostic tests as well as safer antifungal agents for the treatment of histoplasmosis.

A role for the MutL homologue MLH2 in controlling heteroduplex formation and in regulating between two different crossover pathways in budding yeast.

BACKGROUND AND AIMS: Mismatch repair proteins play important roles during meiotic recombination in the budding yeast Saccharomyces cerevisiae and most eukaryotic organisms studied to date. To study the functions of the mismatch repair protein Mlh2p in meiosis, we constructed mlh2Delta strains and measured rates of crossing over, gene conversion, post-meiotic segregation and spore viability. We also analysed mlh1Delta, mlh3Delta, msh4Delta, msh5Delta, exo1Delta and mus81Delta mutant strains singularly and in various combinations. RESULTS: Loss of MLH2 resulted in a small but significant decrease in spore viability and a significant increase in gene conversion frequencies but had no apparent effect on crossing over. Deletion of MLH2 in mlh3Delta, msh4Delta or msh5Delta strains resulted in significant proportion of the "lost" crossovers found in single deletion strains being regained in some genetic intervals. We and others propose that there are at least two pathways to generate crossovers in yeast (Ross-Macdonald and Roeder, 1994; Zalevsky et al., 1999; Khazanehdari and Borts, 2000; Novak et al., 2001; de los Santos et al., 2003). Most recombination intermediates are processed by the "major", Msh4-dependent pathway, which requires the activity of Mlh1p/Mlh3p/Msh4p/Msh5p as well as a number of other proteins. The minor pathway(s) utilizes Mms4p/Mus81p. We suggest that the absence of Mlh2p allows some crossovers from the MSH4 pathway to traverse the MUS81-dependent pathway.

Meiotic recombination intermediates and mismatch repair proteins.

Mismatch repair proteins are a highly diverse group of proteins that interact with numerous DNA structures during DNA repair and replication. Here we review data for the role of Msh4, Msh5, Mlh1, Mlh3 and Exo1 in crossing over. Based on the paradigm of interactions developed from studies of mismatch repair, we propose models for the mechanism of crossover implementation by Msh4/Msh5 and Mlh1/Mlh3.

Activation of heat shock transcription factor in yeast is not influenced by the levels of expression of heat shock proteins.

Heat shock transcription factor (HSF) transiently induces the expression of a universally conserved set of proteins, the heat shock proteins (Hsps), when cells are exposed to elevated temperatures as well as to a wide range of other environmental stresses. The tight control of heat shock gene expression has prompted a model, according to which HSF activity and 'free' heat shock protein levels are tied up in a regulatory loop. Other data have indicated that HSF senses stress directly. Here, we report that yeast cells in which the basal expression levels of Hsps have been significantly increased exhibit improved thermotolerance but display no detectable difference in the temperature required for transient activation of HSF. In a separate experiment, overexpression of SSA2, a member of the Hsp70 family and a prominent candidate for the feedback regulation of HSF, did not inhibit the heat shock response. Our findings challenge the dogma that relief of the suppression of HSF activity by Hsps can account for the acute heat shock response.

Physician's unions: handle with care.

In an attempt to battle the growing number and expanding power of MCOs, physicians are attempting to form or become a part of unions. By banding together, doctors believe that they can fight the MCO's ever-tightening grip on their practices and gain bargaining power that has been lost.

Computer mouse operation: is the left-handed user disadvantaged?

A survey of University of Melbourne student-use computers showed that 100% had the mouse installed on the right-hand side. An experiment was performed to determine if the left-handed user was disadvantaged by this arrangement. Times to move the cursor to targets of different sizes and distances showed that left-handed users were not significantly disadvantaged and that, in accord with other tests, they were as good using their non-preferred hand as they were with their preferred hand. As expected, left-handers were superior to right-handed users when using their non-preferred hand.

The 1996 Justice Department/FTC statements on physician joint ventures and multiprovider organizations.

The 1996 Justice Department/FTC statements suggest that under some market conditions, competitors who are members of a provider organization may fix prices if the agreement on price is reasonably necessary and subordinate to potential efficiencies created by the group. The author discusses to what extent agencies' statements protect an agreement on price among competitors from being challenged under the antitrust laws.

Scaling of relative velocity between vehicles.

Data are presented on the ability of drivers to perceive and scale the relative velocity between their own and a lead vehicle. Experiments were carried out on four groups of subjects using Ekman's ratio-rating method. Only when the subtended angular velocity of the lead vehicle exceeded about 0.003 rad/s were the subjects able to scale the relative velocity. The threshold subtended angular velocity obtained in the experiments was very much affected by the ability of subjects to use the concept of a ratio-engineering students found this a simpler task than did subjects from the general population. The result of this was that the values used by engineering students were closer to the real values. The relative velocity was perceived non-linearly, with a Stevens' power law exponent of about 0.8. It was found that linear models gave as good a fit to the data. The implications of the results of the experiments are (i) traffic flow models that include human visual characteristics must consider the "dead zones" in response produced by thresholds of subtended angle change subtended angular velocity; (ii) it may be necessary to consider the non-linear relationship between perceived relative velocity and actual relative velocity; (iii) in overtaking, the driver will not be able to scale the speed of the oncoming vehicle as the subtended angular velocity will be below the threshold value at the time of making the decision to overtake.

The Use of Dimensional Analysis in Movement Studies.

Application of the technique of dimensional analysis to problems in the study of human movements is illustrated. The method is of use in design of experiments, for presentation of data, and for investigating possible relationships between dependent and independent variables.

Effect of target shape on movement time in a Fitts task.

Experiments on the effect of target shape in a Fitts movement task are reported. Two experiments investigated the movement time vs. index of difficulty relationship for targets that were square, circular, diamond and triangular in shape. The ratio of standard deviation of hits in the vertical and horizontal directions was constant for all target shapes and thus the movement time could be expressed in terms of the constraint in the direction of motion. Correlation of movement time in terms of an Index of Difficulty based on the standard deviation of hits in the direction of motion showed all data fitting on a single line. Thus the constraint effects of the various shapes occurred from the way in which the hits were distributed within each shape. Various models were tried to account for the effect of the target shape. It was found that the experimental data were best accounted for by a 'cookie-cutter' model in which the target shape was cut into a bivariate normal distribution of hits on the target to obtain a 'shape factor' that defined the difficulty of the task relative to the usual rectangular target used in Fitts task experiments.

Drivers' estimates of time to collision.

Drivers' estimates of time to collision were determined in a laboratory simulation using film segments made from a following vehicle approaching a lead vehicle, which was also in motion. Headway, approach speed, and viewing time were varied to make a total of 48 conditions. It was found that, provided the angular velocity subtended by the lead vehicle was above a threshold value of about .003 radians/sec, the driver was able to give reasonable estimates of time to collision. The standard deviation of the estimates varied linearly with the time to collision. Although drivers underestimated the time to collision when it was small, the large standard deviation shows the possibility of rear-end collisions due to poor estimation of time to collision, especially when the times for control action and vehicle deceleration are considered.

Estimation of time to vehicle arrival--effects of age on use of available visual information.

Subjects estimated time of vehicle arrival while viewing twenty-four film clips of an approaching vehicle, half with a constant viewing time of 4.2 s and half with a constant vehicle-movement distance of 40 m. The distances from the subject at which the film ended were 20, 60, and 100 m. Speeds of approach varied between 7.45 and 15.44 m s-1. Performance was strongly dependent on age of the subject. Subjects in the 5-6-year-old group made estimates based on the distance of the vehicle; at 7-8 years an interaction between the effects of distance and velocity appeared and for 9-10-year-olds there was a main effect of the vehicle velocity. Only for adults was the information from distance and velocity fully integrated. There was no significant difference between males and females for any of the age groups. Performance of adults was very similar to that reported by other authors in that subjects underestimated the time to arrival of the vehicle, with estimated times about 60% of the actual times. Standard deviations of the estimated times were such that a small percentage of subjects overestimated times and hence would have caused a collision if they had proceeded with a crossing. The mechanism of time estimation was strongly dependent on the angular velocity of the vehicle subtended at the eye of the observer. This must exceed a threshold value of about 0.002 rad s-1 (adults) if a linear relationship between estimated and actual times is to be obtained.

Finger width corrections in Fitts' law: implications for speed-accuracy research.

This note points out that using the finger as a test probe in a Fitts task may lead to misleading results, because of the increased target tolerance resulting from the width of the finger pad. An experiment demonstrates the need to use a corrected target width when calculating the index of difficulty; without this correction, information processing rates are overestimated. An example is given of a developmental study in which the finger pad size changes with age. The resulting changes in the calculated rates of information processing are shown to be markedly different for the different age groups.

A comparison of hand and foot movement times.

Three experiments are reported in which a comparison is made between the times for movement of the hand and the foot. Both ballistic and visually-controlled movements were studied. It was found that execution time for foot movements is generally about twice as long as that for the equivalent arm movement. The times for foot movements were described well by the Welford, Norris and Shock modification of Fitts' Law for visually-controlled movements and, for ballistic movements, by the square-root-of-amplitude equation found by Hoffmann for arm movements.