Computerized Block Games for Automated Cognitive Assessment: Development and Evaluation Study.

BACKGROUND: Cognitive assessment using tangible objects can measure fine motor and hand-eye coordination skills along with other cognitive domains. Administering such tests is often expensive, labor-intensive, and error prone owing to manual recording and potential subjectivity. Automating the administration and scoring processes can address these difficulties while reducing time and cost. e-Cube is a new vision-based, computerized cognitive assessment tool that integrates computational measures of play complexity and item generators to enable automated and adaptive testing. The e-Cube games use a set of cubes, and the system tracks the movements and locations of these cubes as manipulated by the player. OBJECTIVE: The primary objectives of the study were to validate the play complexity measures that form the basis of developing the adaptive assessment system and evaluate the preliminary utility and usability of the e-Cube system as an automated cognitive assessment tool. METHODS: This study used 6 e-Cube games, namely, Assembly, Shape-Matching, Sequence-Memory, Spatial-Memory, Path-Tracking, and Maze, each targeting different cognitive domains. In total, 2 versions of the games, the fixed version with predetermined sets of items and the adaptive version using the autonomous item generators, were prepared for comparative evaluation. Enrolled participants (N=80; aged 18-60 years) were divided into 2 groups: 48% (38/80) of the participants in the fixed group and 52% (42/80) in the adaptive group. Each was administered the 6 e-Cube games; 3 subtests of the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV; Block Design, Digit Span, and Matrix Reasoning); and the System Usability Scale (SUS). Statistical analyses at the 95% significance level were applied. RESULTS: The play complexity values were correlated with the performance indicators (ie, correctness and completion time). The adaptive e-Cube games were correlated with the WAIS-IV subtests (r=0.49, 95% CI 0.21-0.70; P<.001 for Assembly and Block Design; r=0.34, 95% CI 0.03-0.59; P=.03 for Shape-Matching and Matrix Reasoning; r=0.51, 95% CI 0.24-0.72; P<.001 for Spatial-Memory and Digit Span; r=0.45, 95% CI 0.16-0.67; P=.003 for Path-Tracking and Block Design; and r=0.45, 95% CI 0.16-0.67; P=.003 for Path-Tracking and Matrix Reasoning). The fixed version showed weaker correlations with the WAIS-IV subtests. The e-Cube system showed a low false detection rate (6/5990, 0.1%) and was determined to be usable, with an average SUS score of 86.01 (SD 8.75). CONCLUSIONS: The correlations between the play complexity values and performance indicators supported the validity of the play complexity measures. Correlations between the adaptive e-Cube games and the WAIS-IV subtests demonstrated the potential utility of the e-Cube games for cognitive assessment, but a further validation study is needed to confirm this. The low false detection rate and high SUS scores indicated that e-Cube is technically reliable and usable.

Nail lichen planus: A review of clinical presentation, diagnosis and therapy.

Lichen planus is a multifaceted disease of complex etiopathogenesis. Nails are involved in up to 10% of patients with lichen planus. Although most cases are mild, serious consequences may occur due to rapid progression of the disease, the high risk of scarring, and the resulting irreversible damage to the nail structure. Permanent damage of at least one nail occurs in approximately 4-12% of patients with nail lichen planus. In this narrative review, we emphasize the pathophysiology of nail lichen planus, the emergent nature of the disease, and the spectrum of different clinical manifestations. Diagnosis of nail disease in general, and of nail lichen planus in particular, is rapidly evolving. This review provides a comprehensive account of the non-invasive and invasive diagnostic techniques and treatment options reported in the literature, with emphasis on the efficacy and safety of the drugs used, the associated evidence, and the factors to be taken into account in planning and providing adequate treatment. The role of aesthetic and camouflage options is also summarized.

Graft-versus-host disease after liver transplantation is associated with bone marrow failure, hemophagocytosis, and DNMT3A mutations.

Graft-versus-host disease after liver transplantation (LT-GVHD) is rare, frequently fatal, and associated with bone marrow failure (BMF), cytopenias, and hyperferritinemia. Given hyperferritinemia and cytopenias are present in hemophagocytic lymphohistiocytosis (HLH), and somatic mutations in hematopoietic cells are associated with hyperinflammatory responses (clonal hematopoiesis of indeterminate potential, CHIP), we identified the frequency of hemophagocytosis and CHIP mutations in LT-GVHD. We reviewed bone marrow aspirates and biopsies, quantified blood/marrow chimerism, and performed next-generation sequencing (NGS) with a targeted panel of genes relevant to myeloid malignancies, CHIP, and BMF. In all, 12 marrows were reviewed from 9 LT-GVHD patients. In all, 10 aspirates were evaluable for hemophagocytosis; 7 had adequate DNA for NGS. NGS was also performed on marrow from an LT cohort (n = 6) without GVHD. Nine of 10 aspirates in LT-GVHD patients showed increased hemophagocytosis. Five (71%) of 7 with LT-GVHD had DNMT3A mutations; only 1 of 6 in the non-GVHD LT cohort demonstrated DNMT3A mutation (p = .04). Only 1 LT-GVHD patient survived. BMF with HLH features was associated with poor hematopoietic recovery, and DNMT3A mutations were over-represented, in LT-GVHD patients. Identification of HLH features may guide prognosis and therapeutics. Further studies are needed to clarify the origin and impact of CHIP mutations on the hyperinflammatory state.

Enteral myiasis causing acute dysentery: A case report.

Enteral myiasis or intestinal myiasis is acquired by ingesting food or water contaminated with dipteran fly eggs or larvae. Here, we describe a patient with intestinal myiasis presenting with acute dysentery caused by the larva of Hermetia illucens. The larva was identified morphologically, and its species confirmed through molecular analysis using polymerase chain reaction and sequencing based on mitochondrial cytochrome c oxidase subunit I gene (COI).

Increasing Contrast Improves Object Perception in Parkinson's Disease with Visual Hallucinations.

BACKGROUND: Deficits in basic vision are associated with visual hallucinations in Parkinson's disease. Of particular interest is contrast sensitivity loss in this disorder and its effect on object identification. OBJECTIVES: Evaluate whether increased contrast improves object perception in persons with Parkinson's disease and visual hallucinations, without dementia. METHODS: We assessed 26 individuals with mild to moderate idiopathic Parkinson's disease, half of whom reported one or more episodes of hallucinations/unusual perceptual experiences in the past month, with a letter-identification task that determined the contrast level required to achieve 80% accuracy. Contrast sensitivity was further assessed with a chart that presented stimuli at multiple spatial frequencies. The groups were closely matched for demographic and clinical characteristics except for experience of hallucinations. RESULTS: Relative to participants without visual hallucinations, those with hallucinations had poorer spatial frequency contrast sensitivity and required significantly greater contrast to correctly identify the letters on the identification task. Specifically, participants with hallucinations required a mean contrast of 52.8%, whereas participants without hallucinations required 35.0%. When given sufficient contrast, the groups with and without hallucinations were equally accurate in letter identification. CONCLUSIONS: Compared to those without hallucinations, individuals with Parkinson's disease and hallucinations without dementia showed poorer contrast sensitivity. Once contrast was individually enhanced, the groups were equally accurate at object identification. These findings suggest the potential of visual perception tests to predict, and perception-based interventions to reduce, hallucinations in Parkinson's disease.

Enteral myiasis causing acute dysentery: A case report

@#Enteral myiasis or intestinal myiasis is acquired by ingesting food or water contaminated with dipteran fly eggs or larvae. Here, we describe a patient with intestinal myiasis presenting with acute dysentery caused by the larva of Hermetia illucens. The larva was identified morphologically, and its species confirmed through molecular analysis using polymerase chain reaction and sequencing based on mitochondrial cytochrome c oxidase subunit I gene (COI).

American Geriatrics Society and National Institute on Aging Bench-to-Bedside Conference: Sensory Impairment and Cognitive Decline in Older Adults.

This article summarizes the presentations and recommendations of the tenth annual American Geriatrics Society and National Institute on Aging Bench-to-Bedside research conference, "Sensory Impairment and Cognitive Decline," on October 2-3, 2017, in Bethesda, Maryland. The risk of impairment in hearing, vision, and other senses increases with age, and almost 15% of individuals aged 70 and older have dementia. As the number of older adults increases, sensory and cognitive impairments will affect a growing proportion of the population. To limit its scope, this conference focused on sensory impairments affecting vision and hearing. Comorbid vision, hearing, and cognitive impairments in older adults are more common than would be expected by chance alone, suggesting that some common mechanisms might affect these neurological systems. This workshop explored the mechanisms and consequences of comorbid vision, hearing, and cognitive impairment in older adults; effects of sensory loss on the aging brain; and bench-to-bedside innovations and research opportunities. Presenters and participants identified many research gaps and questions; the top priorities fell into 3 themes: mechanisms, measurement, and interventions. The workshop delineated specific research questions that provide opportunities to improve outcomes in this growing population. J Am Geriatr Soc 66:2052-2058, 2018.

PlGF enhances TLR-dependent inflammatory responses in human mononuclear phagocytes.

PROBLEM: Levels of placental growth factor (PlGF) peak during third trimester of pregnancy, a time when women are at increased risk of virus-induced morbidity. We hypothesized PlGF might contribute to an exaggerated inflammatory response to Toll-like receptor (TLR) activation. METHOD OF STUDY: Primary human adult and cord blood CD14+ cells were cultured in the presence of TLR ligands and/or PlGF. RESULTS: PlGF significantly enhanced the magnitude and duration of TNF messenger RNA and protein production by TLR-7/8-activated monocytes, and increased subsequent production of TNF-independent inflammatory cytokines. This PlGF/TLR effect involved multiple inflammatory cytokines/chemokines and was seen with the majority of TLR agonists. PlGF enhanced phosphorylation of IkappaB kinase (IKK) in monocytes stimulated with the TLR-7/8 agonist R848, and IKK inhibition completely suppressed the PlGF effect. CONCLUSION: PlGF enhances TLR-signaling upstream of IKK and contributes to an exaggerated pathologic pro-inflammatory state in response to activation of maternal and fetal mononuclear phagocytes by specific TLR agonists.

Role of nail bed methotrexate injections in isolated nail psoriasis: conventional drug via an unconventional route.

Nail psoriasis can be a debilitating condition; however, in patients with isolated nail involvement, the use of toxic systemic therapies such as methotrexate may not be justified. We report on 4 patients (30 involved nails between them), who were treated with injections of methotrexate (0.1 mL of a 25 mg/mL solution) into the nail bed at 3-weekly intervals. Mean baseline Nail Psoriasis Severity Index (NAPSI) was 4.77 (range 2-8, cumulative score 143; n = 30); dropping successively at each visit to 2.43 (range 0-4, cumulative score 73; n = 30) at 15 weeks. The decline in mean NAPSI from 4.87 to 2.17 was statistically significant (P < 0.001; Friedman analysis). Reported adverse effects were pain, injection site pigmentation and nail bed haemorrhage. Administration of specific targeted therapy to the nail bed may help manage nail psoriasis effectively.

Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia.

Secreted proteins in the bone marrow microenvironment play critical roles in acute myeloid leukemia (AML). Through an ex vivo functional screen of 94 cytokines, we identified that the pro-inflammatory cytokine interleukin-1 (IL-1) elicited profound expansion of myeloid progenitors in ∼67% of AML patients while suppressing the growth of normal progenitors. Levels of IL-1ß and IL-1 receptors were increased in AML patients, and silencing of the IL-1 receptor led to significant suppression of clonogenicity and in vivo disease progression. IL-1 promoted AML cell growth by enhancing p38MAPK phosphorylation and promoting secretion of various other growth factors and inflammatory cytokines. Treatment with p38MAPK inhibitors reversed these effects and recovered normal CD34+ cells from IL-1-mediated growth suppression. These results highlight the importance of ex vivo functional screening to identify common and actionable extrinsic pathways in genetically heterogeneous malignancies and provide impetus for clinical development of IL-1/IL1R1/p38MAPK pathway-targeted therapies in AML.

Entire nucleotide sequences of Gossypium raimondii and G. arboreum mitochondrial genomes revealed A-genome species as cytoplasmic donor of the allotetraploid species.

Cotton (Gossypium spp.) is commonly grouped into eight diploid genomic groups, designated A-G and K, and an allotetraploid genomic group, AD. Gossypium raimondii (D5 ) and G. arboreum (A2 ) are the putative contributors to the progenitor of G. hirsutum (AD1 ), the economically important fibre-producing cotton species. Mitochondrial DNA from week-old etiolated seedlings was extracted from isolated organelles using discontinuous sucrose density gradient method. Mitochondrial genomes were sequenced, assembled, annotated and analysed in orderly. Gossypium raimondii (D5 ) and G. arboreum (A2 ) mitochondrial genomes were provided in this study. The mitochondrial genomes of two diploid species harboured circular genome of 643,914 bp (D5 ) and 687,482 bp (A2 ), respectively. They differ in size and number of repeat sequences, both contain illuminating triplicate sequences with 7317 and 10,246 bp, respectively, demonstrating dynamic difference and rearranged genome organisations. Comparing the D5 and A2 mitogenomes with mitogenomes of tetraploid Gossypium species (AD1 , G. hirsutum; AD2 , G. barbadense), a shared 11 kbp fragment loss was detected in allotetraploid species, three regions shared by G. arboreum (A2 ), G. hirsutum (AD1 ) and G. barbadense (AD2 ), while eight regions were specific to G. raimondii (D5 ). The presence/absence variations and gene-based phylogeny supported that A-genome is a cytoplasmic donor to the progenitor of allotetraploid species G. hirsutum and G. barbadense. The results present structure variations and phylogeny of Gossypium mitochondrial genome evolution.

Medication education program for Indian children with asthma: A feasibility stud.

OBJECTIVE: It is postulated that children with asthma who receive an interactive, comprehensive, culturally relevant education program would improve their asthma knowledge (AK), asthma control, and adherence compared with children receiving usual care. The aim of this study was to develop, implement, and evaluate the efficacy of a culturally relevant asthma education intervention for children with asthma and their parents in India. METHODS: Children with asthma (7-12 years) and their parents were recruited from an outpatient clinic in a Chest Diseases Hospital in New Delhi, and were randomly assigned to either an intervention or usual care group. At baseline, outcome data collected included pediatric asthma caregiver quality of life (PACQL, primary outcome), AK, asthma control, adherence, inhaler technique, action plan ownership, and goal achievement. These data were collected again at 1 and 6 months after baseline. Outcomes were compared within and between groups using ANOVA techniques. RESULTS: Forty parent-child pairs were recruited. Of these, 24 pairs of children with asthma and their parents received the educational intervention. The PACQL significantly improved from baseline to 6 months in the intervention (5.87 ± 0.94-7.00 ± 0.03) versus the usual care group (5.90 ± 0.52-6.34 ± 0.56) (P < 0.001). Other outcomes such as the parents' and child's AK, child's asthma control and inhaler technique were significantly improved in the intervention group across the study. All the participants possessed a written asthma action plan at the end of the intervention. Eighty-five goals were set by children with asthma across all the visits and were achieved by completion. CONCLUSION: An asthma educator delivered interactive program simultaneously involving children with asthma and their parents, improved quality of life, empowered and promoted better self-management skills.

Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages.

The Fanconi anemia proteins participate in a canonical pathway that repairs cross-linking agent-induced DNA damage. Cells with inactivated Fanconi anemia genes are universally hypersensitive to such agents. Fanconi anemia-deficient hematopoietic stem cells are also hypersensitive to inflammatory cytokines, and, as importantly, Fanconi anemia macrophages overproduce such cytokines in response to TLR4 and TLR7/8 agonists. We questioned whether TLR-induced DNA damage is the primary cause of aberrantly regulated cytokine production in Fanconi anemia macrophages by quantifying TLR agonist-induced TNF-α production, DNA strand breaks, crosslinker-induced chromosomal breakage, and Fanconi anemia core complex function in Fanconi anemia complementation group C-deficient human and murine macrophages. Although both M1 and M2 polarized Fanconi anemia cells were predictably hypersensitive to mitomycin C, only M1 macrophages overproduced TNF-α in response to TLR-activating signals. DNA damaging agents alone did not induce TNF-α production in the absence of TLR agonists in wild-type or Fanconi anemia macrophages, and mitomycin C did not enhance TLR responses in either normal or Fanconi anemia cells. TLR4 and TLR7/8 activation induced cytokine overproduction in Fanconi anemia macrophages. Also, although TLR4 activation was associated with induced double strand breaks, TLR7/8 activation was not. That DNA strand breaks and chromosome breaks are neither necessary nor sufficient to account for the overproduction of inflammatory cytokines by Fanconi anemia cells suggests that noncanonical anti-inflammatory functions of Fanconi anemia complementation group C contribute to the aberrant macrophage phenotype and suggests that suppression of macrophage/TLR hyperreactivity might prevent cytokine-induced stem cell attrition in Fanconi anemia.

Mutant calreticulin-expressing cells induce monocyte hyperreactivity through a paracrine mechanism.

Mutations in the calreticulin gene (CALR) were recently identified in approximately 70-80% of patients with JAK2-V617F-negative essential thrombocytosis and primary myelofibrosis. All frameshift mutations generate a recurring novel C-terminus. Here we provide evidence that mutant calreticulin does not accumulate efficiently in cells and is abnormally enriched in the nucleus and extracellular space compared to wildtype calreticulin. The main determinant of these findings is the loss of the calcium-binding and KDEL domains. Expression of type I mutant CALR in Ba/F3 cells confers minimal IL-3-independent growth. Interestingly, expression of type I and type II mutant CALR in a nonhematopoietic cell line does not directly activate JAK/STAT signaling compared to wildtype CALR and JAK2-V617F expression. These results led us to investigate paracrine mechanisms of JAK/STAT activation. Here we show that conditioned media from cells expressing type I mutant CALR exaggerate cytokine production from normal monocytes with or without treatment with a toll-like receptor agonist. These effects are not dependent on the novel C-terminus. These studies offer novel insights into the mechanism of JAK/STAT activation in patients with JAK2-V617F-negative essential thrombocytosis and primary myelofibrosis.

Oxymetholone therapy of fanconi anemia suppresses osteopontin transcription and induces hematopoietic stem cell cycling.

Androgens are widely used for treating Fanconi anemia (FA) and other human bone marrow failure syndromes, but their mode of action remains incompletely understood. Aged Fancd2(-/-) mice were used to assess the therapeutic efficacy of oxymetholone (OXM) and its mechanism of action. Eighteen-month-old Fancd2(-/-) mice recapitulated key human FA phenotypes, including reduced bone marrow cellularity, red cell macrocytosis, and peripheral pancytopenia. As in humans, chronic OXM treatment significantly improved these hematological parameters and stimulated the proliferation of hematopoietic stem and progenitor cells. RNA-Seq analysis implicated downregulation of osteopontin as an important potential mechanism for the drug's action. Consistent with the increased stem cell proliferation, competitive repopulation assays demonstrated that chronic OXM therapy eventually resulted in stem cell exhaustion. These results expand our knowledge of the regulation of hematopoietic stem cell proliferation and have direct clinical implications for the treatment of bone marrow failure.

At the interface of sensory and motor dysfunctions and Alzheimer's disease.

Recent evidence indicates that sensory and motor changes may precede the cognitive symptoms of Alzheimer's disease (AD) by several years and may signify increased risk of developing AD. Traditionally, sensory and motor dysfunctions in aging and AD have been studied separately. To ascertain the evidence supporting the relationship between age-related changes in sensory and motor systems and the development of AD and to facilitate communication between several disciplines, the National Institute on Aging held an exploratory workshop titled "Sensory and Motor Dysfunctions in Aging and AD." The scientific sessions of the workshop focused on age-related and neuropathologic changes in the olfactory, visual, auditory, and motor systems, followed by extensive discussion and hypothesis generation related to the possible links among sensory, cognitive, and motor domains in aging and AD. Based on the data presented and discussed at this workshop, it is clear that sensory and motor regions of the central nervous system are affected by AD pathology and that interventions targeting amelioration of sensory-motor deficits in AD may enhance patient function as AD progresses.

A snapshot of stroke from miri hospital.

UNLABELLED: Our objective was to study the profile of cerebrovascular accidents and proportion of cerebral haemorrhage (CH) among stroke patients. This project was designed after we observed higher incidence of CH in Miri hospital as compared to conventionally reported data. METHODS: This was a prospective observational study conducted from 1st June 2008 to 31st May 2009. All patients admitted in both male and female wards of the Medical Unit with the first incidence of a stroke were recruited for analysis. CT scan brain was done in all patients. RESULTS: Total admissions in one year in the medical department were 3204 patients, both male and female together, out of which 215 were due to a first incidence of stroke; Stroke accounted for 6.7% of admissions and 16.8% of deaths in medical unit. 139 (64.7%) were ischaemic strokes and 76 (35.3%) were cerebral haemorrhages. The incidence of CH (35.3%) was high compared to regional data. 71.7% (154) patients had preexisting hypertension. Higher incidence of hypertension, diabetes mellitus and aspirin intake was noted in the ischaemic group. Also compliance to treatment for hypertension was better in the Ischaemic group with more defaults in CH category (P<0.01). Significantly more deaths were noted in patients with higher systolic blood pressure on presentation, poor Glasgow Coma Scale (GCS) and those with dysphagia. CONCLUSION: Every third stroke was due to cerebral hemorrhage; CH patients were largely unaware of their hypertension or were altogether treatment naïve or defaulters while compliance was far better in ischaemic stroke category.