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Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.
Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.
Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.
This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.
Item 9 of the Patient Health Questionnaire-9 (PHQ-9) queries about thoughts of death and self-harm, but not suicidality. Although it is sometimes used to assess suicide risk, most positive responses are not associated with suicidality. The PHQ-8, which omits Item 9, is thus increasingly used in research. We assessed equivalency of total score correlations and the diagnostic accuracy to detect major depression of the PHQ-8 and PHQ-9.
We conducted an individual patient data meta-analysis. We fit bivariate random-effects models to assess diagnostic accuracy.
16 742 participants (2097 major depression cases) from 54 studies were included. The correlation between PHQ-8 and PHQ-9 scores was 0.996 (95% confidence interval 0.996 to 0.996). The standard cutoff score of 10 for the PHQ-9 maximized sensitivity + specificity for the PHQ-8 among studies that used a semi-structured diagnostic interview reference standard (N = 27). At cutoff 10, the PHQ-8 was less sensitive by 0.02 (−0.06 to 0.00) and more specific by 0.01 (0.00 to 0.01) among those studies (N = 27), with similar results for studies that used other types of interviews (N = 27). For all 54 primary studies combined, across all cutoffs, the PHQ-8 was less sensitive than the PHQ-9 by 0.00 to 0.05 (0.03 at cutoff 10), and specificity was within 0.01 for all cutoffs (0.00 to 0.01).
PHQ-8 and PHQ-9 total scores were similar. Sensitivity may be minimally reduced with the PHQ-8, but specificity is similar.
Background: Hereditary transthyretin-mediated (hATTR) amyloidosis is a multi-systemic, heterogenous, life-threatening disease. Patisiran resulted in significant improvement in neuropathy and QoL at 18-months compared to placebo, and was generally well-tolerated in the Phase 3 APOLLO study. Methods: Multi-center, OLE study to evaluate the efficacy and safety of long-term patisiran dosing for ≤ 5 years in hATTR amyloidosis patients with polyneuropathy who have completed the APOLLO study (NCT02510261). Endpoints include safety, tolerability and long-term efficacy of patisiran. Measures of clinical benefit are the same endpoints used in APOLLO including changes in mNIS+7 composite neuropathy impairment score and QoL (Norfolk QoL-DN) Results: As of December 2017, 184 of 186 (99%) patients who completed APOLLO and 25 patients from the Ph 2 OLE study enrolled in the Global OLE study. Baseline data for 211(APOLLO/placebo, n=49; APOLLO/patisiran, n=137 and patisiran Ph 2 OLE, n=25) patients included: median age 61 years (26-84); 74% males; 46% V30M. Interim safety data and 12-month efficacy results will be presented. Conclusions: The global OLE study includes a diverse population of hATTR amyloidosis patients. Interim data will include the long-term safety and maintenance of effect in patients continuing on patisiran, as well as the impact of treatment with patisiran on patients previously treated with placebo.
The proton beam from the 4 MV Van de Graaff at the University of Florida has been used in conjunction with a 5 mm thick lithium drifted silicon, Si (Li), x-ray detector to do elemental analysis of biomedical samples by proton-induced x-ray emission (PIXE). Several hundred samples, mostly autopsy organs ashed at high, temperature, have been analyzed by this method. The main object of the research is the correlation between human diseases and trace element levels. The target mass has been determined by monitoring the elastically scattered protons from the sample. This technique considerably reduces the target preparation time by eliminating careful weighings or doping of each individual sample.
The 3.8 MeV proton beam from the University of Florida Van de Graaff accelerator has been used to perform trace element analysis of approximately 1200 samples (mostly from autopsies) of human tissues by proton-induced X-ray emission analysis (PIXE). Fifteen different organs and a variety of diseases have been studied. Preliminary data are presented indicating the variations of various elements in human kidney as a function of age. Analysis of samples from infants also indicate essential and non-essential elements in human kidney. On the average twelve trace elements (with atomic number equal to or larger than nineteen) are observed in each organ. Quantitative measurements have been made on several elements including K, Ca, Mn, Fe, Cu, Zn, Pb, Br, Rb, Sr, Cd, and Ba.
The effects of growing pinto peanut mixed with elephant grass-based pastures are still little known. The aim of the current research was to evaluate the performance of herbage yield, nutritive value of forage and animal responses to levels of pinto peanut forage mass mixed with elephant grass in low-input systems. Three grazing systems were evaluated: (i) elephant grass-based (control); (ii) pinto peanut, low-density forage yield (63 g/kg of dry matter – DM) + elephant grass; and (iii) pinto peanut, high-density dry matter forage yield (206 g/kg DM) + elephant grass. The experimental design was completely randomized with the three treatments (grazing systems) and three replicates (paddocks) in split-plot grazing cycles. Forage samples were collected to evaluate the pasture and animal responses. Leaf blades of elephant grass and the other companion grasses of pinto peanut were collected to analyse the crude protein, in vitro digestible organic matter and total digestible nutrients. The pinto peanut, high-density dry matter forage yield + elephant grass treatment was found to give the best results in terms of herbage yield, forage intake and stocking rate, as well as having higher crude protein contents for both elephant grass and the other grasses, followed by pinto peanut with low-density forage yield + elephant grass and finally elephant grass alone. Better results were found with the grass–legume system for pasture and animal responses.
Major depressive disorder (MDD) is a highly heterogeneous condition in terms of symptom presentation and, likely, underlying pathophysiology. Accordingly, it is possible that only certain individuals with MDD are well-suited to antidepressants. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes of depression, such as neuroticism, anhedonia, and cognitive control deficits.
Within an 8-week multisite trial of sertraline v. placebo for depressed adults (n = 216), we examined whether the combination of machine learning with a Personalized Advantage Index (PAI) can generate individualized treatment recommendations on the basis of endophenotype profiles coupled with clinical and demographic characteristics.
Five pre-treatment variables moderated treatment response. Higher depression severity and neuroticism, older age, less impairment in cognitive control, and being employed were each associated with better outcomes to sertraline than placebo. Across 1000 iterations of a 10-fold cross-validation, the PAI model predicted that 31% of the sample would exhibit a clinically meaningful advantage [post-treatment Hamilton Rating Scale for Depression (HRSD) difference ⩾3] with sertraline relative to placebo. Although there were no overall outcome differences between treatment groups (d = 0.15), those identified as optimally suited to sertraline at pre-treatment had better week 8 HRSD scores if randomized to sertraline (10.7) than placebo (14.7) (d = 0.58).
A subset of MDD patients optimally suited to sertraline can be identified on the basis of pre-treatment characteristics. This model must be tested prospectively before it can be used to inform treatment selection. However, findings demonstrate the potential to improve individual outcomes through algorithm-guided treatment recommendations.
The authors developed a practical and clinically useful model to predict the risk of psychosis that utilizes clinical characteristics empirically demonstrated to be strong predictors of conversion to psychosis in clinical high-risk (CHR) individuals. The model is based upon the Structured Interview for Psychosis Risk Syndromes (SIPS) and accompanying clinical interview, and yields scores indicating one's risk of conversion.
Baseline data, including demographic and clinical characteristics measured by the SIPS, were obtained on 199 CHR individuals seeking evaluation in the early detection and intervention for mental disorders program at the New York State Psychiatric Institute at Columbia University Medical Center. Each patient was followed for up to 2 years or until they developed a syndromal DSM-4 disorder. A LASSO logistic fitting procedure was used to construct a model for conversion specifically to a psychotic disorder.
At 2 years, 64 patients (32.2%) converted to a psychotic disorder. The top five variables with relatively large standardized effect sizes included SIPS subscales of visual perceptual abnormalities, dysphoric mood, unusual thought content, disorganized communication, and violent ideation. The concordance index (c-index) was 0.73, indicating a moderately strong ability to discriminate between converters and non-converters.
The prediction model performed well in classifying converters and non-converters and revealed SIPS measures that are relatively strong predictors of conversion, comparable with the risk calculator published by NAPLS (c-index = 0.71), but requiring only a structured clinical interview. Future work will seek to externally validate the model and enhance its performance with the incorporation of relevant biomarkers.
Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.
To evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics.
Data collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit.
A total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15–3.87). Compared with semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores ≤6) as having major depression (OR = 3.13; 95% CI = 0.98–10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7–15) (OR = 0.96; 95% CI = 0.56–1.66) and significantly less likely for high-level symptoms (PHQ-9 scores ≥16) (OR = 0.50; 95% CI = 0.26–0.97).
The MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.
Declaration of interest
Drs Jetté and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.
Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.
Buried surface hoar and near-surface faceted crystals are known to lead to deadly avalanches. Over the course of three winter seasons a field investigation detailing the environmental conditions leading to the formation of these crystals was performed. Weather stations on north- and south-facing aspects were established. The weather data were accompanied by detailed daily observations and grain-scale photographs of the snow surface. During the three seasons, 35 surface hoar and 47 near-surface facets events were recorded. The mean weather conditions for the entire dataset (all three seasons and both stations) were compared to the nights when surface hoar formed. The comparison yielded five parameters that were statistically linked to the formation of surface hoar: incoming longwave radiation, snow surface temperature, wind velocity, relative humidity and the air/snow temperature difference. A similar comparison between the daytime mean values for all days with near-surface facet events revealed three parameters with statistically significant differences. Thus, these parameters (short- and longwave radiation and relative humidity) could be statistically linked to facet formation. This research also suggests that environmental conditions in the daytime hours before and after surface hoar formation are statistically similar to the conditions causing near-surface facet formation.
To determine the scope, source, and mode of transmission of a multifacility outbreak of extensively drug-resistant (XDR) Acinetobacter baumannii.
SETTING AND PARTICIPANTS
Residents and patients in skilled nursing facilities, long-term acute-care hospital, and acute-care hospitals.
A case was defined as the incident isolate from clinical or surveillance cultures of XDR Acinetobacter baumannii resistant to imipenem or meropenem and nonsusceptible to all but 1 or 2 antibiotic classes in a patient in an Oregon healthcare facility during January 2012–December 2014. We queried clinical laboratories, reviewed medical records, oversaw patient and environmental surveillance surveys at 2 facilities, and recommended interventions. Pulsed-field gel electrophoresis (PFGE) and molecular analysis were performed.
We identified 21 cases, highly related by PFGE or healthcare facility exposure. Overall, 17 patients (81%) were admitted to either long-term acute-care hospital A (n=8), or skilled nursing facility A (n=8), or both (n=1) prior to XDR A. baumannii isolation. Interfacility communication of patient or resident XDR status was not performed during transfer between facilities. The rare plasmid-encoded carbapenemase gene blaOXA-237 was present in 16 outbreak isolates. Contact precautions, chlorhexidine baths, enhanced environmental cleaning, and interfacility communication were implemented for cases to halt transmission.
Interfacility transmission of XDR A. baumannii carrying the rare blaOXA-237 was facilitated by transfer of affected patients without communication to receiving facilities.
Although the use of donor sperm as a treatment modality for male infertility has become common place, the health outcomes for those conceived has been poorly studied. A structured search of the literature using PubMed, EMBASE and Cochrane Reviews was performed to investigate the health outcomes of offspring conceived from donor sperm. Eight studies were eligible and included in the review, and of these, three were included in a meta-analysis. Meta-analysis of clinical outcomes showed that donor sperm neonates are not at increased risk of being born of low birth weight (<2500 g), preterm (<37 weeks) or with increased incidences of birth defects, than spontaneously conceived neonates.
We have carried out lunar occultation observations at λ = 2.2μm at the WHT and Calar Alto telescopes of young stellar objects both in the Taurus and the Ophiuchus star forming regions. We report the discovery of 4 new binary systems: IW Tau and HK Tau/G2 in Taurus as well as GSS 35 and VSSG 14 in Ophiuchus; the projected separations are about 70 milliarcseconds (mas) for each of the Taurus objects, while for the Ophiuchus sources they are about 20 and 100 mas, respectively (20 mas correspond to 3 AU).
We analyzed birth order differences in means and variances of height and body mass index (BMI) in monozygotic (MZ) and dizygotic (DZ) twins from infancy to old age. The data were derived from the international CODATwins database. The total number of height and BMI measures from 0.5 to 79.5 years of age was 397,466. As expected, first-born twins had greater birth weight than second-born twins. With respect to height, first-born twins were slightly taller than second-born twins in childhood. After adjusting the results for birth weight, the birth order differences decreased and were no longer statistically significant. First-born twins had greater BMI than the second-born twins over childhood and adolescence. After adjusting the results for birth weight, birth order was still associated with BMI until 12 years of age. No interaction effect between birth order and zygosity was found. Only limited evidence was found that birth order influenced variances of height or BMI. The results were similar among boys and girls and also in MZ and DZ twins. Overall, the differences in height and BMI between first- and second-born twins were modest even in early childhood, while adjustment for birth weight reduced the birth order differences but did not remove them for BMI.
Donated oocytes are a treatment modality for female infertility which is also associated with increased risks of preeclampsia. Subsequently it is important to evaluate if there is concomitant increased risks for adverse neonatal events in donated oocyte neonates. A structured search of the literature using PubMed, EMBASE and Cochrane Reviews was performed to investigate the perinatal health outcomes of offspring conceived from donor oocytes compared with autologous oocytes. Meta-analysis was performed on comparable outcomes data. Twenty-eight studies were eligible and included in the review, and of these, 23 were included in a meta-analysis. Donor oocyte neonates are at increased risk of being born with low birth weight (<2500 g) [risk ratio (RR): 1.18, 95% confidence interval (CI): 1.14–1.22, P-value (P)<0.00001], very low birth weight (<1500 g) (RR: 1.24, CI: 1.15–1.35, P<0.00001), preterm (<37 weeks) (RR: 1.26, CI: 1.23–1.30, P<0.00001), of lower gestational age (mean difference −0.3 weeks, CI: −0.35 weeks to −0.25 weeks, P<0.00001), and preterm with low birth weight (RR: 1.24, CI: 1.19–1.29, P<0.00001), when compared with autologous oocyte neonates. Conversely, low birth weight outcomes were improved in term donor oocyte neonates (RR: 0.86, CI: 0.8–0.93, P=0.0003). These negative outcomes remained significant when controlling for multiple deliveries. The donor oocyte risk rates are higher than those found in general ART outcomes, are important considerations for the counselling of infertile patients and may also influence the long term health of the offspring.
In November 2013, national public health agencies in England and Scotland identified an increase in laboratory-confirmed Salmonella Mikawasima. The role of proton pump inhibitors (PPIs) as a risk factor for salmonellosis is unclear; we therefore captured information on PPI usage as part of our outbreak investigation. We conducted a case-control study, comparing each case with two controls. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. Thirty-nine of 61 eligible cases were included in the study. The median age of cases was 45 years; 56% were female. Of these, 33% were admitted to hospital and 31% reported taking PPIs. We identified an association between PPIs and non-typhoidal salmonellosis (aOR 8·8, 95% CI 2·0–38·3). There is increasing evidence supporting the existence of an association between salmonellosis and PPIs; however, biological studies are needed to understand the effect of PPIs in the pathogenesis of Salmonella. We recommend future outbreak studies investigate PPI usage to strengthen evidence on the relevance of PPIs in Salmonella infection. These findings should be used to support the development of guidelines for patients and prescribers on the risk of gastrointestinal infection and PPI usage.
A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.