Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease (CLARITY): statistical analysis plan for a randomised controlled Bayesian adaptive sample size trial.

The CLARITY trial (Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease) is a two-arm, multi-centre, randomised controlled trial being run in India and Australia that investigates the effectiveness of angiotensin receptor blockers in addition to standard care compared to placebo (in Indian sites) with standard care in reducing the duration and severity of lung failure in patients with COVID-19. The trial was designed as a Bayesian adaptive sample size trial with regular planned analyses where pre-specified decision rules will be assessed to determine whether the trial should be stopped due to sufficient evidence of treatment effectiveness or futility. Here, we describe the statistical analysis plan for the trial and define the pre-specified decision rules, including those that could lead to the trial being halted. The primary outcome is clinical status on a 7-point ordinal scale adapted from the WHO Clinical Progression scale assessed at day 14. The primary analysis will follow the intention-to-treat principle. A Bayesian adaptive trial design was selected because there is considerable uncertainty about the extent of potential benefit of this treatment.Trial registrationClinicalTrials.gov NCT04394117 . Registered on 19 May 2020Clinical Trial Registry of India CTRI/2020/07/026831Version and revisionsVersion 1.0. No revisions.

Pre-conception 25-hydroxyvitamin D (25(OH)D) and fecundability.

STUDY QUESTION: Is pre-conception 25(OH)D associated with the per cycle probability of conception, i.e fecundability, in a prospective cohort study? SUMMARY ANSWER: There are suggestive associations of high 25(OH)D (at least 50 ng/ml) with increased fecundability and low 25(OH)D (<20 ng/ml) with reduced fecundability, but the estimates were imprecise. WHAT IS KNOWN ALREADY: Vitamin D has been associated with reproductive function and fertility in animal studies, but few human studies exist. STUDY DESIGN, SIZE, DURATION: This community-based prospective cohort study included 522 women attempting to become pregnant between 2010 and 2016. The women completed online daily and monthly diaries until a positive home pregnancy test was observed or 12 months had elapsed. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included women from central North Carolina who were aged 30-44 with no history of infertility, with no more than 3 months of attempt time at recruitment. Women recorded vaginal bleeding so that the ongoing number of attempt cycles could be counted and used to quantify a woman's pregnancy attempt time. Blood collected at the study entry was analysed for 25(OH)D using liquid chromatography tandem mass spectrometry. Associations with fecundability were estimated with a log-binomial discrete time-to-event model. MAIN RESULTS AND THE ROLE OF CHANCE: Among 522 women, 257 conceived during the study. The mean age was 33 years and the mean 25(OH)D was 36 ng/ml. There was an estimated 10% higher fecundability with each 10 ng/ml increase in 25(OH)D (fecundability ratio (FR) 1.10, 95% CI: 0.96, 1.25). The suggestive dose-response association with the continuous measure of 25(OH)D was driven by women in the lowest and the highest categories of 25(OH)D. Compared to women with 25(OH)D of 30-40 ng/ml, women below 20 ng/ml had an estimated 45% reduction in fecundability (FR (CI): 0.55 (0.23, 1.32)), and women with at least 50 ng/ml had an estimated 35% increase in fecundability (FR (CI): 1.35 (0.95, 1.91)). Across these three categories (25(OH)D of <20 ng/ml, 30-40 ng/ml and > 50 ng/ml), the probability of taking longer than 6 months to conceive was, respectively, 51% (17%, 74%), 28% (17%, 39%) and 15% (10%, 37%). LIMITATIONS, REASONS FOR CAUTION: While the distribution of 25(OH)D was wide, the number of observed cycles with high 25(OH)D (N = 107) or low 25(OH)D (N = 56) was small. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are consistent with prior reports of reduced fertility in women with 25(OH)D concentrations below the clinically defined deficiency level (20 ng/ml). Further studies are needed to evaluate the possible reproductive benefits of considerably higher 25(OH)D concentration (>50 ng/ml). STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH) under award numbers R00HD079659 and R01HD067683 and supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, under projects ES103086, ES049003 and ES044003. ClearBlue ovulation predictor kits were generously donated to AMZJ and AJW by Swiss Precision Diagnostics. Drs Wilcox and Jukic report non-financial support from Swiss Precision Diagnostics during the conduct of the study; Dr Jukic reports non-financial support from Theralogix, LLC, outside the submitted work. Otherwise there are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Jurors' perceptions of forensic science expert witnesses: Experience, qualifications, testimony style and credibility.

The judicial system calls upon expert witnesses to testify in court when complex or specialized knowledge, beyond that of the lay person, is needed to interpret the evidence. Previous research has indicated that particular traits of the expert witness can affect their credibility in the eyes of the jury, however most of this research has been undertaken using mock jurors. In contrast, this study investigated the perceptions of real jurors. In particular, the research focused on the juror's perception of the forensic scientists' expertise and credibility during testimony in homicide cases. Data was gathered from jurors after nine homicide trials using both questionnaire (n=29) and direct one to one interviews (n=22). The jurors defined what they thought an expert witness was and what attributes were important in a forensic scientist. Jurors suggested that the expert witness's education and years of experience were more important than certification or laboratory accreditation. The jurors' perceptions of the credibility of the expert was based upon the academic qualifications of the expert, the confidence they portrayed in answering the questions ask of them, their demeanor and their status of being government employee. The use of narrative language and demonstrative aids by the forensic science expert witness to explain the evidence was explored. Jurors described a deeper understanding as a result of narrative testimony and this was reported to be a key factor in the juror's acceptance that the witness was credible.

Offspring birthweight by gestational age and parental cardiovascular mortality: a population-based cohort study.

OBJECTIVE: To estimate risk of parental cardiovascular disease mortality by offspring birthweight. DESIGN: Population-based cohort study. SETTING AND POPULATION: Norwegian mothers and fathers with singleton births during 1967-2002 were followed until 2009 by linkage to the Norwegian cause of death registry. METHODS: Hazard ratios by offspring absolute birthweight in grams and birthweight adjusted for gestational age (z-score) were calculated using Cox regression and adjusted for parental age at delivery and year of first birth. Stratified analyses on preterm and term births were performed. MAIN OUTCOME MEASURES: Maternal and paternal cardiovascular mortality. RESULTS: We followed 711 726 mothers and 700 212 fathers and found a strong link between maternal cardiovascular mortality and offspring birthweight but only slight evidence of associations in fathers. Adjusting birthweight for gestational age (by z-score) uncovered an unexpected strong association of large birthweight (z-score > 2.5) with mothers' cardiovascular mortality (hazard ratio 3.0, 95% CI 2.0-4.6). This risk was apparently restricted to preterm births. In stratified analyses (preterm and term births) hazard ratios for maternal cardiovascular mortality were 1.5 (1.03-2.2) for large preterm babies and 0.9 (0.7-1.2) for large term babies (P-value for interaction = 0.02), using normal weight preterm and term, respectively, as references. CONCLUSION: Women having large preterm babies are at increased risk of both diabetes and cardiovascular mortality. The birth of a large preterm baby should increase clinical vigilance for onset of diabetes and other cardiovascular disease risk factors. TWEETABLE ABSTRACT: Birth of a large preterm baby should increase vigilance for cardiovascular-disease risk factors.

A missense mutation in Katnal1 underlies behavioural, neurological and ciliary anomalies.

Microtubule severing enzymes implement a diverse range of tissue-specific molecular functions throughout development and into adulthood. Although microtubule severing is fundamental to many dynamic neural processes, little is known regarding the role of the family member Katanin p60 subunit A-like 1, KATNAL1, in central nervous system (CNS) function. Recent studies reporting that microdeletions incorporating the KATNAL1 locus in humans result in intellectual disability and microcephaly suggest that KATNAL1 may play a prominent role in the CNS; however, such associations lack the functional data required to highlight potential mechanisms which link the gene to disease symptoms. Here we identify and characterise a mouse line carrying a loss of function allele in Katnal1. We show that mutants express behavioural deficits including in circadian rhythms, sleep, anxiety and learning/memory. Furthermore, in the brains of Katnal1 mutant mice we reveal numerous morphological abnormalities and defects in neuronal migration and morphology. Furthermore we demonstrate defects in the motile cilia of the ventricular ependymal cells of mutants, suggesting a role for Katnal1 in the development of ciliary function. We believe the data we present here are the first to associate KATNAL1 with such phenotypes, demonstrating that the protein plays keys roles in a number of processes integral to the development of neuronal function and behaviour.

A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts.

Prior genome-wide association studies for oral clefts have focused on clinic-based samples with unclear generalizability. Prior samples were also small for investigating effects by cleft type and exclusively studied isolated clefts (those occurring without other birth defects). We estimated the effects of 17 top loci on cleft types in both isolated and nonisolated cases in the largest consortium to date of European-descent population-based studies. Our analytic approach focused on a mother-child dyad case-control design, but it also allowed analyzing mother-only or child-only genotypes to maximize power. Our total sample included 1,875 cases with isolated clefts, 459 cases with nonisolated clefts, and 3,749 controls. After correcting for multiple testing, we observed significant associations between fetal single-nucleotide polymorphisms (SNPs) at IRF6, PAX7, 8q21.3, 8q24, KIAA1598-VAX1, and MAFB and isolated cleft lip only (CLO) and cleft lip and palate (CLP). Significant associations were observed between isolated CLO and fetal SNPs near TPM1 and NOG1 and between CLP and fetal SNPs at ABCA4-ARHGAP29, THADA, FOXE1, and SPRY2. Overall, effects were similar for isolated CLO and CLP, except for ABCA4-ARHGAP29. A protective effect was observed for the fetal NOG1 SNP on cleft palate only, opposite in direction to the effect on CLO. For most fetal SNPs, a dose-response allelic effect was observed. No evidence of parent-of-origin or maternal genome effects was observed. Overall, effect direction and magnitude were similar between isolated and nonisolated clefts, suggesting that several loci are modifiers of cleft risk in both isolated and nonisolated forms. Our results provide reliable estimates of the effects of top loci on risks of oral clefts in a population of European descent.

Effects of Macromolecular Crowding on Alcohol Dehydrogenase Activity Are Substrate-Dependent.

Enzymes operate in a densely packed cellular environment that rarely matches the dilute conditions under which they are studied. To better understand the ramifications of this crowding, the Michaelis-Menten kinetics of yeast alcohol dehydrogenase (YADH) were monitored spectrophotometrically in the presence of high concentrations of dextran. Crowding decreased the maximal rate of the reaction by 40% for assays with ethanol, the primary substrate of YADH. This observation was attributed to slowed release of the reduced ß-nicotinamide adenine dinucleotide product, which is rate-limiting. In contrast, when larger alcohols were used as the YADH substrate, the rate-limiting step becomes hydride transfer and crowding instead increased the maximal rate of the reaction by 20-40%. This work reveals the importance of considering enzyme mechanism when evaluating the ways in which crowding can alter kinetics.

Characterization of a Cardiorenal-like Syndrome in Aged Chimpanzees (Pan troglodytes).

Cardiorenal syndrome involves disease and dysfunction of the heart that leads to progressive renal dysfunction. This study investigated the relationship between cardiac and renal disease in 91 aged chimpanzees at the Alamogordo Primate Facility by evaluation of the medical histories, metabolic parameters, functional measurements of the cardiovascular system, clinical pathology, and histopathology focused on the heart and kidney. Cardiac fibrosis was the most frequent microscopic finding in 82 of 91 animals (90%), followed by glomerulosclerosis with tubulointerstitial fibrosis in 63 of 91 (69%). Cardiac fibrosis with attendant glomerulosclerosis and tubulointerstitial fibrosis was observed in 58 of 91 animals (63%); there was a statistically significant association between the 2 conditions. As the severity of cardiac fibrosis increased, there was corresponding increase in severity of glomerulosclerosis with tubulointerstitial fibrosis. Altered metabolic, cardiovascular, and clinical pathology parameters indicative of heart and kidney failure were commonly associated with the moderate to severe microscopic changes, and concurrent heart and kidney failure were considered the cause of death. The constellation of findings in the chimpanzees were similar to cardiorenal syndrome in humans.

Ultrasound prediction of perinatal outcome: the unrecognised value of sibling data.

OBJECTIVE: To identify high-risk fetuses at the first routinely performed ultrasound examination by making use of information from the mother's previous pregnancy. DESIGN: A population-based cohort study. SETTING: Norway, 1999-2009. POPULATION: All singleton first live births and their second-born siblings registered in the Medical Birth Registry of Norway (166,786 eligible sibling pairs). METHODS: Odds ratios were calculated by logistic regression. MAIN OUTCOME MEASURES: Very small for gestational age (vSGA; birthweight ≤-1.96 standard deviations) and perinatal death (stillbirth at ≥22 weeks of gestation or death within 28 days of life). RESULTS: Small fetal size at ultrasound (i.e. a fetus smaller than expected by last menstrual period, LMP) is only weakly predictive of vSGA or perinatal death; however, if the firstborn sibling was vSGA at birth, ultrasound measures in the next pregnancy become strongly informative of risk. The smaller the fetal size on ultrasound, the higher its risk of vSGA (3-18%; Ptrend < 0.0001) and perinatal death (4-19 per thousand, Ptrend = 0.012). In contrast, if the first baby was not vSGA, small fetal size on ultrasound is uninformative. CONCLUSIONS: When the firstborn baby is vSGA, discrepancies between fetal size on ultrasound and LMP become highly predictive of risk of vSGA and perinatal mortality in the second-born infant. The value of combining these routinely collected clinical data has not previously been recognised.

Frequency and diameter dependent viscoelastic properties of mitral valve chordae tendineae.

This study aimed to characterise viscoelastic properties of different categories of chordae tendineae over a range of frequencies. Dynamic Mechanical Analysis (DMA) was performed using a materials testing machine. Chordae (n=51) were dissected from seven porcine hearts and categorised as basal, marginal, strut or commissural. Chordae were loaded under a sinusoidally varying tensile load at a range of frequencies between 0.5 and 5Hz, both at a standardised load (i.e. same mean load of 4N for all chordae) and under chordal specific loading (i.e. based on in vivo loads for different chordae). Storage modulus and stiffness were frequency-dependent. Loss modulus and stiffness were frequency-independent. Storage and loss moduli, but not stiffness, decreased with chordal diameter. Therefore, strut chordae have the lowest moduli and marginal chordae the highest moduli. The hierarchy of dynamic storage and loss moduli is: marginal, commissural, basal and strut. In conclusion, viscoelastic properties of chordae are dependent on both frequency and chordal type. Future/novel replacement chordal materials should account for frequency and diameter dependent viscoelastic properties of chordae tendineae.

Length of human pregnancy and contributors to its natural variation.

STUDY QUESTION: How variable is the length of human pregnancy, and are early hormonal events related to gestational length? SUMMARY ANSWER: Among natural conceptions where the date of conception (ovulation) is known, the variation in pregnancy length spanned 37 days, even after excluding women with complications or preterm births. WHAT IS KNOWN ALREADY: Previous studies of length of gestation have either estimated gestational age by last menstrual period (LMP) or ultrasound (both imperfect measures) or included pregnancies conceived through assisted reproductive technology. STUDY DESIGN, SIZE, DURATION: The Early Pregnancy Study was a prospective cohort study (1982-85) that followed 130 singleton pregnancies from unassisted conception to birth, with detailed hormonal measurements through the conception cycle; 125 of these pregnancies were included in this analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: We calculated the length of gestation beginning at conception (ovulation) in 125 naturally conceived, singleton live births. Ovulation, implantation and corpus luteum (CL) rescue pattern were identified with urinary hormone measurements. We accounted for events that artificially shorten the natural length of gestation (Cesarean delivery or labor induction, i.e. 'censoring') using Kaplan-Meier curves and proportional hazards models. We examined hormonal and other factors in relation to length of gestation. We did not have ultrasound information to compare with our gold standard measure. MAIN RESULTS AND THE ROLE OF CHANCE: The median time from ovulation to birth was 268 days (38 weeks, 2 days). Even after excluding six preterm births, the gestational length range was 37 days. The coefficient of variation was higher when measured by LMP (4.9%) than by ovulation (3.7%), reflecting the variability of time of ovulation. Conceptions that took longer to implant also took longer from implantation to delivery (P = 0.02). CL rescue pattern (reflecting ovarian response to implantation) was predictive (P = 0.006): pregnancies with a rapid progesterone rise were longer than those with delayed rise (a 12-day difference in the median gestational length). Mothers with longer gestations were older (P = 0.02), had longer pregnancies in other births (P < 0.0001) and were heavier at birth (P = 0.01). We did not see an association between the length of gestation and several factors that have been associated with gestational length in previous studies: body mass index, alcohol intake, parity or offspring sex. LIMITATIONS, REASONS FOR CAUTION: The sample size was small and some exposures were rare, reducing power to detect weak associations. WIDER IMPLICATIONS OF THE FINDINGS: Human gestational length varies considerably even when measured exactly (from ovulation). An individual woman's deliveries tend to occur at similar gestational ages. Events in the first 2 weeks after conception are predictive of subsequent pregnancy length, and may suggest pathways underlying the timing of delivery. STUDY FUNDING/COMPETING INTEREST: This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. None of the authors has any conflict of interest to declare.

Provider use of and attitudes towards an active clinical alert: a case study in decision support.

BACKGROUND: In a previous study, we reported on a successful clinical decision support (CDS) intervention designed to improve electronic problem list accuracy, but did not study variability of provider response to the intervention or provider attitudes towards it. The alert system accurately predicted missing problem list items based on health data captured in a patient's electronic medical record. OBJECTIVE: To assess provider attitudes towards a rule-based CDS alert system as well as heterogeneity of acceptance rates across providers. METHODS: We conducted a by-provider analysis of alert logs from the previous study. In addition, we assessed provider opinions of the intervention via an email survey of providers who received the alerts (n = 140). RESULTS: Although the alert acceptance rate was 38.1%, individual provider acceptance rates varied widely, with an interquartile range (IQR) of 14.8%-54.4%, and many outliers accepting none or nearly all of the alerts they received. No demographic variables, including degree, gender, age, assigned clinic, medical school or graduation year predicted acceptance rates. Providers' self-reported acceptance rate and perceived alert frequency were only moderately correlated with actual acceptance rates and alert frequency. CONCLUSIONS: Acceptance of this CDS intervention among providers was highly variable but this heterogeneity is not explained by measured demographic factors, suggesting that alert acceptance is a complex and individual phenomenon. Furthermore, providers' self-reports of their use of the CDS alerting system correlated only modestly with logged usage.

Improving access to longitudinal patient health information within an emergency department.

We designed and implemented an electronic patient tracking system with improved user authentication and patient selection. We then measured access to clinical information from previous clinical encounters before and after implementation of the system. Clinicians accessed longitudinal information for 16% of patient encounters before, and 40% of patient encounters after the intervention, indicating such a system can improve clinician access to information. We also attempted to evaluate the impact of providing this access on inpatient admissions from the emergency department, by comparing the odds of inpatient admission from an emergency department before and after the improved access was made available. Patients were 24% less likely to be admitted after the implementation of improved access. However, there were many potential confounders, based on the inherent pre-post design of the evaluation. Our experience has strong implications for current health information exchange initiatives.

Association between inhibited binding of folic acid to folate receptor alpha in maternal serum and folate-related birth defects in Norway.

BACKGROUND: Folic acid intake during pregnancy can reduce the risk of neural tube defects (NTDs) and perhaps also oral facial clefts. Maternal autoantibodies to folate receptors can impair folic acid binding. We explored the relationship of these birth defects to inhibition of folic acid binding to folate receptor α (FRα), as well as possible effects of parental demographics or prenatal exposures. METHODS: We conducted a nested case-control study within the Norwegian Mother and Child Cohort Study. The study included mothers of children with an NTD (n = 11), cleft lip with or without cleft palate (CL/P, n= 72), or cleft palate only (CPO, n= 27), and randomly selected mothers of controls (n = 221). The inhibition of folic acid binding to FRα was measured in maternal plasma collected around 17 weeks of gestation. On the basis of prior literature, the maternal age, gravidity, education, smoking, periconception folic acid supplement use and milk consumption were considered as potential confounding factors. RESULTS: There was an increased risk of NTDs with increased binding inhibition [adjusted odds ratio (aOR) = 1.4, 95% confidence interval (CI) 1.0-1.8]. There was no increased risk of oral facial clefts from inhibited folic acid binding to FRα (CL/P aOR = 0.7, 95% CI 0.6-1.0; CPO aOR = 1.1, 95% CI 0.8-1.4). No association was seen between smoking, folate supplementation or other cofactors and inhibition of folic acid binding to FRα. CONCLUSIONS: Inhibition of folic acid binding to FRα in maternal plasma collected during pregnancy was associated with increased risk of NTDs but not oral facial clefts.

The association of maternal factors with delayed implantation and the initial rise of urinary human chorionic gonadotrophin.

BACKGROUND Late implantation and the pattern of early rise in hCG have been associated with early pregnancy loss. We explored factors that might be predictive of these markers of poor embryonic health in spontaneously conceived pregnancies. METHODS Participants in the North Carolina Early Pregnancy Study collected daily first-morning urine specimens while attempting to conceive. Samples were assayed for estrogen and progesterone metabolites (to identify day of ovulation) and hCG (to detect conception). Data were available for 190 pregnancies, 48 of which ended in early loss (within 6 weeks of the last menstrual period). We used logistic regression to identify characteristics associated with late implantation (≥10 days post-ovulation). For pregnancies surviving at least 6 weeks (n= 142), we used linear mixed models to identify factors associated with variations in hCG rise in the first 7 days from detection. RESULTS Later implantation was associated with current maternal smoking [odds ratio (OR): 5.7; 95% confidence interval (CI): 1.1-30] and with oocytes that were likely to have been fertilized late in their post-ovulatory lifespan (OR: 5.1; CI: 1.9-16). Older women had a faster rise in hCG (P= 0.01), as did women who had relatively late menarche (P for trend = 0.02). Women exposed in utero to diethylstilbestrol showed an unusual pattern of slow initial hCG rise followed by a fast increase, a pattern significantly different from that of unexposed women (P= 0.002). CONCLUSIONS Although limited by small numbers and infrequent exposures, our analyses suggest that a woman's exposures both early in life and at the time of pregnancy may influence early development of the conceptus.

Influence of muscle training on resting blood flow and forearm vessel diameter in patients with chronic renal failure.

BACKGROUND: Blood flow and vessel diameter are predictors of the success of vascular access procedures. This study investigated whether a simple exercise programme could influence these variables. METHODS: Twenty-three patients with chronic kidney disease were prescribed a simple exercise programme for one arm only; the investigators were blinded to the patients' choice. All underwent arterial and venous duplex imaging, handgrip strength and blood pressure measurements before and 1 month after the exercise programme. RESULTS: Twelve patients exercised their dominant and 11 their non-dominant arm. In the trained arm, the exercise programme resulted in a significant increase in handgrip strength, by a median (interquartile range) of 4 (0-8) kg (P < 0.001), and in the diameter of the brachial artery (0.2 (0.1-0.3) mm; P < 0.001), radial artery (0.3 (0.2-0.4) mm; P < 0.001), and cephalic vein (0.6 (0.4-1.2) mm in the forearm and 1.1 (0.4-1.2) mm above the elbow; P < 0.001). There was an increase in brachial artery mean velocity (3 (1-7) cm/s; P = 0.009) and peak systolic velocity (8 (1-15) cm/s; P = 0.020), despite a marginally lower systolic blood pressure (-8 (-16 to 0) mmHg; P = 0.007). There was no change in any of these parameters in the non-exercised arm. CONCLUSION: In patients with chronic kidney disease, forearm exercise increased blood flow and vessel diameters. This may be beneficial before vascular access formation.

Hypoxic/ischemic encephalopathy associated with placental insufficiency in a cloned foal.

Hypoxic/ischemic encephalopathy in a cloned American Quarter horse foal was initially associated with placental insufficiency and exacerbated by protracted hypotension during anesthesia for a surgical procedure. The foal, born at the Texas A&M Veterinary Medical Center, was diagnosed at birth with neonatal maladjustment syndrome that was accompanied by dysmaturity, muscle contracture of the front limbs, and a blood clot within the lumen of the urinary bladder. Seizures that developed after anesthesia were attributed to hypoxia/ischemia during anesthesia and culminated in death. Macroscopically, the cerebrum had flattened cerebral gyri with shallow sulci, yellowish cortical discoloration, and apple-green autofluorescence (under 365-nm ultraviolet light) at the cortical/white matter junction. Microscopically, there was laminar cortical necrosis with prominent diffuse ischemic change of neuronal cell bodies. The white matter had prominent rarefaction with focal axonal and myelin degeneration and focal macrophage (gitter cell) accumulation. Additionally, there was astrocytic hypertrophy with gemistocyte formation. The chorioallantois was diffusely thickened in the area corresponding to the uterine horns. Histologically, microcotyledons were markedly attenuated with absence of chorionic villi.

Urinary hCG patterns during the week following implantation.

BACKGROUND: Human chorionic gonadotrophin (hCG) is used to monitor pregnancy status. Yet the pattern of hCG excretion in the first week following implantation has not been adequately described. Therefore the aim of this study was to describe the average profile of hCG and its variability during the 7 days following estimated implantation in a population of naturally conceived pregnancies. METHODS: We measured daily hCG concentrations in first-morning urine for 142 clinical pregnancies from women with no known fertility problems. Mixed-effects regression models were used to estimate the hCG trajectory and its variability in relation to pregnancy outcomes. RESULTS: hCG rose 3-fold between the day of detection and the next day (95% CI = 2.7-3.4). The relative rate of rise decreased thereafter, reaching 1.6-fold (95% CI = 1.5-1.8) between days 6 and 7. HCG levels followed a log-quadratic trajectory, and the patterns of rise were unrelated to number of fetuses, risk of spontaneous abortion or sex of the baby. Later implantations (after 10 luteal days) produced slower rates of increase. CONCLUSIONS: Although mean hCG follows a log-quadratic trajectory during the first week of detectability, there is high variability across pregnancies. Later implantation may reflect characteristics of the uterus or conceptus that slow hCG production.

Life expectancy and death from cardiomyopathy amongst carriers of Duchenne and Becker muscular dystrophy in Scotland.

OBJECTIVES: To assess life expectancy and cardiovascular mortality in carriers of Duchenne and Becker muscular dystrophy. DESIGN: Family pedigrees of individuals affected with these conditions, held by the four genetics centres in Scotland, were examined to identify a cohort of definite carriers. Electronic death registration data, held by the General Register Office for Scotland, were used to identify death certificates of carriers who had died, to obtain age at death and cause of death. Survival and mortality data were obtained for the general population for comparison. PATIENTS: 397 definite carriers in 202 pedigrees were identified from which 94 deaths were identified by record linkage to death certificates. MAIN OUTCOME MEASURES: Observed numbers surviving to certain ages and numbers dying of cardiac causes were compared with expected numbers calculated from general population data. RESULTS: There were no significant differences between observed and expected numbers surviving to ages 40-90. The standardised mortality ratio for the 371 carriers alive in 1974 was 0.53 (95% confidence interval 0.32 to 0.82). CONCLUSIONS: Whereas female carriers may have clinical features of cardiomyopathy, this study does not suggest that this is associated with reduced life expectancy or increased risk of cardiac death. Routine cardiac surveillance of obligate carriers is therefore probably unnecessary.