Application of Digital Cognitive Biomarkers for Alzheimer's Disease: Identifying Cognitive Process Changes and Impending Cognitive Decline.

BACKGROUND: Recent Alzheimer's disease (AD) trials have faced significant challenges to enroll pre-symptomatic or early stage AD subjects with biomarker positivity, minimal or no cognitive impairment, and likelihood to decline cognitively during a short trial period. Our previous study showed that digital cognitive biomarkers (DCB), generated by a hierarchical Bayesian cognitive process (HBCP) model, were able to distinguish groups of cognitively normal individuals with impending cognitive decline from those without. We generated DCBs using only baseline Auditory Verbal Learning Test's wordlist memory (WLM) item response data from the Mayo Clinic Alzheimer's Disease Patient Registry. OBJECTIVES: To replicate our previous findings, using baseline ADAS-Cog WLM item response data from the Alzheimer's Disease Neuroimaging Initiative, and compare DCBs to traditional approaches for scoring word-list memory tests. DESIGN: Classified decliner subjects (n = 61) as those who developed amnestic MCI or AD dementia within 3 years of normal baseline assessment and non-decliner (n = 442) as those who did not. MEASURES: Evaluated the relative value of DCBs compared to traditional measures, using three analytic approaches to group differences: 1) logistic regression of summary scores per ADAS-Cog WLM task; 2) Bayesian modeling of summary scores; and 3) HBCP modeling to generate DCBs from item-level responses. RESULTS: The HBCP model produced posterior distributions of group differences, of which Bayes factor assessment identified three DCBs with notable group differences: Immediate Retrieval from Durable Storage, (BFds = 11.8, strong evidence); One-Shot Learning, (BFds = 4.5, moderate evidence); and Partial Learning (BFds = 2.9, weak evidence). In contrast, logistic regression of summary scores did not significantly discriminate between groups, and the Bayes factor assessment of modeled summary scores provided moderate evidence that the groups were equivalent (BFsd = 3.4, 3.1, 2.9, and 1.4, respectively). CONCLUSIONS: This study demonstrated DCBs' ability to distinguish , at baseline, between impending cognitive decline and non-decline groups where individuals in both groups were classified as cognitively normal. This validated findings from our previous study, demonstrating DCBs' advantages over traditional approaches. This study warrants further refinement of the HBCP DCBs to predict impending cognitive decline in individuals and other factors associated with AD, such as physical biomarker load.

Crocodylian diversity peak and extinction in the late Cenozoic of the northern Neotropics.

Northern South America and South East Asia are today's hotspots of crocodylian diversity with up to six (mainly alligatorid) and four (mainly crocodylid) living species respectively, of which usually no more than two or three occur sympatrically. In contrast, during the late Miocene, 14 species existed in South America. Here we show a diversity peak in sympatric occurrence of at least seven species, based on detailed stratigraphic sequence sampling and correlation, involving four geological formations from the middle Miocene to the Pliocene, and on the discovery of two new species and a new occurrence. This degree of crocodylian sympatry is unique in the world and shows that at least several members of Alligatoroidea and Gavialoidea coexisted. By the Pliocene, all these species became extinct, and their extinction was probably related to hydrographic changes linked to the Andean uplift. The extant fauna is first recorded with the oldest Crocodylus species from South America.

[Acute fatty liver of pregnancy: a rare pathology of the third trimester]. / Stéatose hépatique aiguë gravidique: une pathologie rare du troisième trimestre de grossesse.

Acute fatty liver of pregnancy is a rare clinical syndrome of pregnancy that occurs during the third trimester. Clinicians must have a high index of suspicion for this condition when a woman has nausea or vomiting during the last trimester. Early diagnosis and prompt delivery improve foetal and maternal prognosis. We report a case of a previously healthy 23-year-old woman who presented an acute fatty liver of pregnancy with intrauterine fetal death. Based on this experience as well as on medical literature, characteristics of this uncommon pathology are discussed.

[Obstetrical risk factors of 365 primiparous adolescent pregnancies in Reunion Island]. / Etude des facteurs de risques obstétricaux dans le suivi de 365 grossesses primipares adolescentes à l'île de la Réunion.

OBJECTIVES: Analysis of obstetrical risk factors in teenage primiparous pregnancies in Reunion Island (4% of total births). MATERIALS AND METHODS: Retrospective study, between 2001 and 2002, comparing primiparous adolescents (13-17 years, n = 365), with primiparous controls (18-29 years, n = 2050). The analysis included demographical factors, maternal medical histories, prenatal follow-up, obstetrical risk factors, delivery modes and neonatal characteristics. RESULTS: Adolescents attended on average 8 prenatal consultations, however 4% had poor prenatal care (less than 3 visits, OR 4.2, P < 0.001 vs controls). They presented less gestational diabetes, but there were no differences concerning pre-existing hypertension, hypertensive disorders of pregnancy, medical reasons of hospitalisation between the two groups. Mode of delivery was more favorable in adolescents (half rate of caesarean sections, shorter duration of membrane ruptures). Nevertheless, adolescents presented a higher risk of severe prematurity (<32 Weeks gestation, incidence 3.6% vs 1.6%, OR 2.3, p = 0.008). CONCLUSION: With optimal prenatal care (more than 90% of our cohort), primiparous adolescents present globally a favorable course of their pregnancies and have better deliveries than their young (18-29 years) counterparts. However, there is a significant risk of severe prematurity requiring special care for these pregnancies.

[Endometriosis with ascites and pleural effusion: a case report]. / Endométriose avec ascite et épanchement pleural: à propos d'un cas.

Massive ascites associated with pelvic endometriosis is an uncommon combination. Pleural effusion may rarely occur. Fourteen cases are reported in the literature. We report the case of a black nulligravida woman followed for a primary infertility. Endometriosis was suspected in presence of increasing dysmenorrhea, cystic adnexal masse, umbilical nodes and ascites. The diagnosis was confirmed at exploratory laparoscopy. The patient had been followed for assisted procreation for six years and had undergone a conservative laparoscopic surgery never described. After several ascites recurrences, the pathology was resolved by Gonadotropin-releasing hormone agonist therapy. But a right pleural effusion with ascites occurred following a bad therapeutic observance. This complication reveals an early pregnancy never reported for this exceptional pathology. A conservative management allowed this unique case of well outcoming pregnancy. The possible pathogenesis of ascites and pleural effusion are explored and recommendations for diagnosis and treatment options are discussed.

[Isolated torsion of the Fallopian tube in a 15-year old adolescent. About one case]. / Torsion tubaire isolée chez une adolescente de 15 ans. A propos d'un cas.

Isolated torsion of the Fallopian tube is an uncommon event. Surgery is often necessary to establish the diagnosis. This report focuses on a 15-year old female who presented with acute pelvic pain. Pelvic ultrasound showed an adnexal mass. The laparoscopy performed confirmed the diagnosis of isolated tubal torsion. Based on this experience as well as on other similar reported cases, characteristics of isolated torsion of the Fallopian tube are discussed. This pathology should be considered in the differential diagnosis of acute pelvic pain in the female patient. Prompt surgical intervention may allow for preservation of the tube.

Pedigree analysis of French Canadian families with T14484C Leber's hereditary optic neuropathy.

We analyzed the clinical phenotype and determined the recurrence risks to relatives of patients with T14484C Leber's hereditary optic neuropathy (LHON). LHON is a maternally inherited optic neuropathy that primarily affects adolescent males. It is usually associated with one of three mtDNA mutations: G3460A, G11778A, or T14484C. Definition of recurrence risks for the T14484C mutation previously has not been possible due to the relative scarcity of families with this mutation. We obtained blood samples from index patients and their consenting family members, all of whom were of French Canadian ancestry and screened for LHON mutations in mtDNA. Referring ophthalmologists furnished clinical summaries and patients provided pedigree data. T14484C was the most common mutation in the pedigrees analyzed and was always homoplasmic. In these pedigrees, the ratio of affected males to females was 8:1. Median age at onset for males was 19 years (95th percentile, 40.8 years; range, 6 to 48 years). Some improvement of vision was observed in 58% of patients. Recurrence risks to brothers were 28%, sisters 5%, nephews 30%, nieces 3%, male matrilineal first cousins 19%, and female matrilineal first cousins 4%. Recurrence risks to brothers and nephews were not different; however, recurrence risks to brothers and male cousins and to nephews and male cousins were significantly different. There were no differences in recurrence risks to sisters and nieces or to either group compared with their female cousins. Affected females did not have more affected children than unaffected females. The clinical characteristics of French Canadian patients with T14484C LHON were strikingly similar to those in previous reports, suggesting that recurrence risks are generalizable to other T14484C LHON populations for genetic counseling of T14484C LHON families.

Safety, infectivity, transmissibility and immunogenicity of rhesus rotavirus vaccine (MMU 18006) in infants.

In an attempt to evaluate the immunogenicity, infectivity, transmissibility and safety of rhesus rotavirus vaccine (RRV) MMU 18006, 27 infants ages 5 to 20 months participated in two randomized, double-blind placebo controlled trials, one in a day care setting to allow for child to child contact and close surveillance and the other on an outpatient basis. Fourteen infants (mean age, 8.3 months) received 10(5) plaque-forming units of RRV and 13 (mean age, 11.1 months) received placebo. In the eight infants who participated in the vaccine trial in the day care setting, there was no evidence of transmissibility of RRV, by either stool excretion or seroconversion. The data from both trials showed RRV to be 100% infective and immunogenic in the vaccinees. There were no gastrointestinal side effects although there was an association between vaccine administration and fever occurring on Days 3 and 4. Based on these encouraging preliminary results, further work is proceeding to evaluate this vaccine at lower doses in this age group of infants.

Mössbauer spectroscopy and perturbed angular correlation studies of the rare-and alkaline-earth bone uptake.

Emission Mössbauer spectra and Perturbed Angular Correlation measurements have been performed on samples of mineral bone powder labelled with 161Tb3+ or 133Ba2+ ions after either in vitro absorption or uptake by metabolic pathway. The study of these hyperfine spectra, compared with those carried out when 161Tb or 133Ba are situated in either hydroxyde lattice or phosphate one, shows that the uptake modes of rare-and alkaline-earth ions on the bone matrix are different. The rare earth ion seems to be absorbed on the surface bone in an environment of hydroxyl groups similar to the structure of a rare earth hydroxyde. The alkaline earth ion bone uptake appears more complicated and would make according to the following process : at first, surface absorption on the hydroxylapatite in a hydroxyde environment and then cationic exchange with the calcium phosphate groups into bone crystals.