SAFE-clustering: Single-cell Aggregated (from Ensemble) clustering for single-cell RNA-seq data.

MOTIVATION: Accurately clustering cell types from a mass of heterogeneous cells is a crucial first step for the analysis of single-cell RNA-seq (scRNA-Seq) data. Although several methods have been recently developed, they utilize different characteristics of data and yield varying results in terms of both the number of clusters and actual cluster assignments. RESULTS: Here, we present SAFE-clustering, single-cell aggregated (From Ensemble) clustering, a flexible, accurate and robust method for clustering scRNA-Seq data. SAFE-clustering takes as input, results from multiple clustering methods, to build one consensus solution. SAFE-clustering currently embeds four state-of-the-art methods, SC3, CIDR, Seurat and t-SNE + k-means; and ensembles solutions from these four methods using three hypergraph-based partitioning algorithms. Extensive assessment across 12 datasets with the number of clusters ranging from 3 to 14, and the number of single cells ranging from 49 to 32, 695 showcases the advantages of SAFE-clustering in terms of both cluster number (18.2-58.1% reduction in absolute deviation to the truth) and cluster assignment (on average 36.0% improvement, and up to 18.5% over the best of the four methods, measured by adjusted rand index). Moreover, SAFE-clustering is computationally efficient to accommodate large datasets, taking <10 min to process 28 733 cells. AVAILABILITY AND IMPLEMENTATION: SAFEclustering, including source codes and tutorial, is freely available at https://github.com/yycunc/SAFEclustering. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The long-term effects of the Houston Child Advocates, Inc., program on children and family outcomes.

The objective of the study is to investigate the longitudinal effects of the Houston Child Advocates, Inc., program on children's outcomes. The treatment group consisted of children in the court system that were assigned Child Advocates volunteers, and the comparison children were chosen randomly from a similar population of children. The treatment group had significantly higher scores on the protective factor and family functioning measures and received more social services than those in the comparison group. Children in the treatment group also had significantly fewer placement changes and did better academically and behaviorally in school than children in the comparison group.

A multicenter, randomized, placebo controlled, multiple-dose, safety and pharmacokinetic study of AIT-082 (Neotrofin) in mild Alzheimer's disease patients.

A phase 1, randomized, double-blind, placebo-controlled, dose escalation study of the purine derivative, AIT-082 (Neotrofin, NeoTherapeutics) was conducted in mild Alzheimer's disease (AD) patients to evaluate multiple-dose safety, tolerability, and pharmacokinetics. Possible short-term effects of AIT-082 on cognition and memory were preliminarily investigated. AIT-082 is currently being developed as a potential treatment for Alzheimer's disease and other neurological disorders. Pre-clinical studies indicate that AIT-082 has memory enhancing properties, stimulates neuritogenesis and the production of neurotrophic factors. Patients received an oral dose of AIT-082 or placebo daily for one week. Thirty-six AD patients were divided into three dose cohorts; each dose cohort consisted of twelve patients with 8 patients randomized to AIT-082 and 4 to placebo. The 3 doses of AIT-082 evaluated in this study were 100 mg/day, 500 mg/day, and 2,000 mg/day. There were no serious adverse events at any dose and the drug was well tolerated without significant side effects. AIT-082 was orally and rapidly absorbed, resulting in peak serum concentrations within 2 hours with an elimination half-life of approximately 20 hours. Higher doses resulted in corresponding increases in peak concentrations and areas under the curve (AUC). There was an approximate 2-fold accumulation in AIT-082 with daily dosing (as reflected by the AUC) at steady state. There were no significant differences by treatment arm on the clinical or neuropsychological evaluations. AIT-082 was rapidly absorbed by the oral route with a half-life suitable for dosing once or twice daily. No problems with tolerability or safety were found. AIT-082 appears suitable for testing in larger clinical trials for the treatment of AD and other neurologic disorders.

Preserved color imagery in an achromatopsic.

The loss of color vision secondary to central nervous system disease (achromatopsia) is thought to preclude visual imagery of colors. We report a patient with achromatopsia, secondary to bilateral temporo-occipital infarcts inclusive of the lingual and fusiform gyri, with preserved color imagery. Our findings, in conjunction with previous cases in the literature, are consistent with a single neural network for color processing in which a disconnection of internal activation from stored color representations produces impaired color imagery with preserved color perception, whereas a disconnection of visual input to these representations produces achromatopsia with preserved color imagery.

The differential effects of simulating malingering, closed head injury, and other CNS pathology on the Wisconsin Card Sorting Test: support for the "pattern of performance" hypothesis.

We investigated the effects of faking bad on the Wisconsin Card Sorting Test, comparing the performance of simulating malingerers (M; n = 24) to controls (C; n = 21), closed head-injured patients (CHI, n = 70), and patients with mixed CNS pathology other than CHI alone (CNS; n = 89). Stepwise discriminant functions achieved good accuracy (91-96%), sensitivity (58-100%), and specificity (92-100%) in differentiating simulating malingerers from these groups. The Categories score was a consistent significant independent discriminating variable. Categories alone could differentiate between the M and C groups. However, in discriminating between simulating malingerers and both CHI or CNS patients, more complex patterns of performance emerged, consisting of relatively poorer performance ratios on Categories compared to Perseverative Errors. This supported the Pattern of Performance theory of the effects of simulating malingering on neuropsychological tests, which holds that people simulating malingering do more poorly on obvious vs. subtle tasks compared to people with verified brain damage. Due to the difficulty of tracking one's performance on several different indices simultaneously, known patterns of performance for patients with verified brain dysfunction should be very difficult to fake, even with coaching.

Repetition and the arcuate fasciculus.

According to the traditional model of language organization, repetition deficits arise following damage to the arcuate fasciculus of the dominant hemisphere (conduction aphasia). Conduction aphasia may result from lesions that spare the arcuate fasciculus. However, these patients have atypical language organization. We describe a man with normal language architecture who underwent a resection of the anterior portion of his arcuate fasciculus and retained his ability to repeat words and sentences. We propose that the arcuate fasciculus is not necessary for speech repetition by the lexical route.

Discriminating between simulated malingering and closed head injury on the Wechsler Memory Scale-Revised.

We tested the hypothesis that malingering is distinguished by poorer performance on recognition relative to recall tasks by evaluating the ability of discriminant functions to distinguish between 89 subjects simulating malingering and 44 subjects with a history of closed head injury (CHI) on the Wechsler Memory Scale - Revised (WMS-R). Functions with good accuracy in discriminating between simulated malingerers and controls in prior studies did not have adequate specificity when applied to the CHI group. A newly derived discriminant function achieved overall classification accuracy of 79% for the malingering versus CHI groups on cross-validation, with 79% sensitivity (true positives for malingering) and 80% specificity (true negatives for closed head injured). A complex performance pattern on seven WMS-R subtests distinguished malingering subjects from those with CHI, but did not support the recognition versus recall hypothesis. The malingering pattern involved: (a) power performance on two relatively (but inconspicuously) easy tasks dependent on immediate recall (Visual Reproduction I and Visual Memory Span); (b) better performance on two relatively (but inconspicuously) easy tasks dependent on immediate recall (Visual Paired Associates I and Digit Span); (c) poorer performance on two relatively difficult delayed tasks (Logical Memory II and Visual Paired Associates II); and (d) better performance on another difficult task involving delayed recall (Visual Reproduction II).

Sri Lankan cleft lip and palate study model analysis: clefts of the secondary palate.

The study models of a group of adult Sri Lankan patients with clefts of the secondary palate were investigated. Tooth-size and arch-dimension comparisons were made with a comparable control group. Significant differences were found between the cleft and control groups in tooth sizes, chord lengths, and arch widths. The cleft group dimensions were generally smaller than those of the control group. Overjets were larger in the cleft group.

Malingering on neuropsychological memory tests: potential objective indicators.

We evaluated five potential indicators of malingering on the Rey Memory Test (RMT), Hebb's Recurring Digits (HRD), the Wechsler Memory Scale-Revised (WMS-R), the Complex Figure Test (CFT), and the Auditory Verbal Learning Test (AVLT). Fifty-seven subjects were assigned randomly to either a control group or a simulated malingering group. Two indicators-discriminant functions derived from the WMS-R and from the CFT/AVLT-achieved classification accuracy of 88% and 86%, respectively, without misidentifying controls as malingerers. Among the remaining indicators, there were problems with the recommended RMT cut-off, but it and the HRD show some promise. Subjects who simulated malingering did so by suppressing performance on tasks that involve recall as well as recognition memory and are relatively easy, but not obviously so.

The effect of mechanical deformation on the distribution of potassium ions across the cell membrane of sutural cells.

Ionic concentrations of potassium, sodium, and chloride were determined in osteocytes of the rat calvarium. The values were determined by fluorescent microscopy of both intra- and extracellular concentrations. Following the baseline determination, the calvaria were placed in tension by retraction of a microelectrode manipulator, and the fluorescence of the cells were measured again. A statistically significant change in the derived ion distribution was found. Thus, the tensile forces affected the distribution of ions across the cell membranes, increasing intracellular sodium and decreasing intracellular potassium. This would have an effect on the resting cell membrane potential with a change of potential of 8 mV. This has implications in the interpretation of clinical findings.

Correcting performance-rating errors in oral examinations.

Although oral examinations are widely used for making decisions regarding an individual's level of competence, they are frequently of limited reliability. A significant part of the error in oral performance ratings is due to the tendency for some evaluators to be lenient and others to be stringent in their assignment of ratings. This article describes and evaluates a simple method to identify and correct for errors of leniency and stringency. The method, which is based on a regression model recommended by Wilson (1988), extends and simplifies the procedures recommended by Cason and Cason (1984, 1985). The method provides an estimate of each individual's performance that has been corrected for errors of leniency and stringency. In addition, it produces for each rater an index of leniency or stringency and several other statistics useful in evaluating the properties of rating data. The regression method is applied to performance ratings from three separate administrations of an oral examination in a medical specialty. The results indicate modest but significant levels of leniency and stringency error; correcting for such errors would change the pass/fail decisions for about 6% of the examinees. Limitations of the procedure, as well as the need for additional research, are discussed.

Bases for the analysis of cephalometric radiographs: intracranial reference structures or natural head position.

The inherent variability of intracranial cephalometric reference structures makes analysis based upon them potentially misleading with serious implications for orthodontic and orthognathic surgical treatment planning. These problems can be avoided by using natural head position and relating measurement to the true horizontal. The lack of suitable norms has been a barrier to this approach. This paper demonstrates that norms can be derived from existing data, enabling the clinical application of analyses related to the true horizontal.

An in vivo assessment of muscular activity and the importance of electrical phenomena in bone remodelling.

Modified orthopaedic pins were placed close to the medial and distal epiphyses of the tibia in 4 anaesthetised rabbits, in order to allow the application of controlled external loading cycles. Rosette strain gauges were placed at midshaft level, where the greatest compressive and tensile strains were expected during loading. Two weeks later, following stabilisation of the pins by bone healing, the animals were anaesthetised again and silver-silver chloride electrodes were attached close to the strain gauges in order to measure the changes in electrical potential difference. A sinusoidal load cycle was exerted between the pins with peak levels of 100 N or 250 N depending on the age of the animal. A fluctuation in potential difference, in synchrony with the strain recorded by the strain gauges, was recorded. The maximum potential difference was 2.2 mV, and it was not possible to exceed this with increased bone strain. After demonstration of the piezoelectric effect, repeated stimuli were applied to the sciatic nerve, producing a twitch in the muscles adjacent to the tibia. The electric potential difference from the muscles completely overwhelmed the local potential difference at the bone surface. A further two animals were prepared as previously described, and one electrode was placed on the endosteal surface. The electrical events mirror the changes found across the limb. The stimulus to bone remodeling, as distinct from growth, is usually loading in association with muscular activity. The fact that the changes in electrical fields at the bone surface are predominantly those originating in the muscles indicates that local electrical phenomena generated by bone strain cannot be the factors initiating the cellular response that is responsible for bone remodeling.

Long-term stability of the lower labial segment relative to the A-Pog line.

Cephalometric records of 47 cases treated with the Begg technique were examined with a view to assessing both the effects of treatment and long-term change. The cases were treated by a single operator (Dr H. Brouwer) whose long-term records were taken on average over 10 years out of retention. Special reference was made of the use of A-Pog line as a guide to lower incisor stability. There was marked individual variation in both response to treatment and long-term change. Though all the results were clinically stable the A-Pog line was not found to be a reliable guide to lower incisor stability. In 62 per cent of the cases examined, the lower incisors tended to return towards their original positions after retention, whilst in the remaining cases the changes were extremely variable.

A study model analysis of adult unoperated Sri Lankans with unilateral cleft lip and palate.

The maxillary arch-form of 41 Sri Lankan adults with unoperated complete unilateral cleft lip and palate (8 female and 33 male) were compared to a control group of 100 normal Sri Lankan adults (45 female and 55 male). The teeth in the cleft group were smaller than their equivalents in the control group, the most marked difference being found in the central and lateral incisors. Arch widths of the cleft groups were reduced, more anteriorly than posteriorly, resulting in more V-shaped arches. No differences were found in the arch length or chord lengths between the groups. Crossbites occurred in 19.5 percent of the cleft group as compared to none of the controls. The overjet was greater in the cleft group than in the controls. A higher percentage of missing teeth was recorded in the cleft group.

Stimulation of human rheumatoid synovial cells by non-lethal complement membrane attack.

The effects of non-lethal complement attack on cultured human rheumatoid synovial cells have been investigated by measuring a variety of parameters. Within 3-4 min of initiating non-lethal complement membrane attack there was a rise in reactive oxygen metabolite release from cultured synovial cells, which slowly returned to basal levels over a period of 45 min. The response was dependent on the formation of the complete C5b-9 complex. Prostaglandin E2 was also released during non-lethal attack in a biphasic manner, an early phase of release occurring within the first hour and a second, larger phase commencing at 4 hr and rising to levels of over 1000 ng/10(6) cells at 24 hr, compared to control levels at this time of less than 100 ng/10(6) cells. This response was dependent on the formation of the C5b-8 complex but did not require C9. Removal of extracellular calcium reduced release of prostaglandin E2 to background levels, and inclusion of an inhibitor of protein synthesis abolished the second phase of release but not the first phase. Non-lethal attack caused release of small amounts of leukotriene B4 but no detectable release of tumour necrosis factor.

A preliminary study of facial growth and morphology in unoperated male unilateral cleft lip and palate subjects over 13 years of age.

This paper investigates the effects of surgery on facial growth and morphology in Sri Lankan males with unilateral cleft lip and palate who were over 13 years of age at the time of study with cephalometry and dental study models. Three separate subgroups were analyzed: those who had totally unrepaired cleft lip and palate, those who received lip repair in infancy but not palatal repair, and those who had lip and palate repair in infancy. Twenty-three healthy noncleft Sri Lankan males over 13 years formed a control group from the same racial background. The results show that subjects who had no surgery had a potential for normal maxillary growth. Subjects who have had lip repair in early infancy show relatively normal maxillary growth, but maxillary hypoplasia is common when the palate has also been repaired early.

The prevention of softball injuries: the experience at Yokota.

Softball injuries occur in a predictable pattern. Review of Emergency Room records at Yokota AB Hospital for three summers showed a high incidence of ankle injuries. Sliding is the cause of many of these injuries. Common sense interventions should reduce the incidence of softball injury. Use of low profile bases or the outlawing of sliding are reasonable interventions that should be considered by policy makers.