An investigation of handwriting legibility and pencil use tasks in healthy older adults

This project explores handwriting legibility and pencil use tasks in 120 healthy older Australian adults, aged 60 to 99 years. A cross sectional study design was used. The aim of these studies was to explore if handwriting legibility or pencil use performance deteriorated as people aged. This is important to help therapists determine if handwriting difficulties following stroke, or other medical conditions, are more likely a consequence of condition-related impairments or due to ‘normal ageing’. Tasks performed under standardised test conditions included writing copied and self-composed sentences, shopping lists, transcribing a telephone message and completing the ‘lines’ and ‘dots’ pencil use Motor Assessment Scale (MAS) subtests. Handwriting legibility was scored using the Modified Four Point Scale-version 2. The first study explored the distribution of handwriting legibility scores in healthy older adults, relationships between handwriting legibility, age and writing task and reliability of rating procedures. Results indicated that handwriting generally remained legible in older adults, regardless of increasing age. The second study explored the performance of older adults without stroke on the ‘lines’ and ‘dots’ tasks, the relationship between age and task performance, and the relationship between writing speed and performance on the ‘lines’ task. Results indicated that many older adults failed the ‘lines’ task and many over 90 years of age failed the ‘dots’ task. Results suggest that impaired handwriting legibility in older adults who have had a stroke (or other medical condition) is likely due to the effects of the medical condition (or the complexity of the task) rather than ‘normal ageing’. However, failure to pass the ‘lines’ and ‘dots’ tasks is likely related to a combination of age and individual skill level and not solely due to condition-related impairment. A revised method for rating performance on the ‘lines’ and ‘dots’ tasks is also proposed

Untangling a Cat’s Cradle: Diphacinone, Acetaminophen, Trauma, and Multiple Deaths in a Kentucky Cat Colony

This manuscript describes an animal cruelty investigation in which several cats from a feral colony were suspected of having been poisoned. Three of the cats were submitted for complete postmortem examination by a qualified veterinary pathologist, and appropriate toxicologic analyses were selected and interpreted by a qualified veterinary toxicologist. Diagnosis in poisoning cases requires communication and collaboration between the pathologists and the toxicologist. A truly definitive diagnosis is not always possible in poisoning cases, particularly in a forensic investigation – a court of law requires a higher standard to establish a cause of death than do routine diagnostic cases. This case series illustrates the importance of a thorough diagnostic workup in forensic animal death investigations

Estimation of Short-Term Effects of Air Pollution on Stroke Hospital Admissions in Wuhan, China

Background and Objective:High concentrations of air pollutants have been linked to increased incidence of stroke in North America and Europe but not yet assessed in mainland China. The aim of this study is to evaluate the association between stroke hospitalization and short-term elevation of air pollutants in Wuhan, China.Methods:Daily mean NO2, SO2 and PM10 levels, temperature and humidity were obtained from 2006 through 2008. Data on stroke hospitalizations (ICD 10: I60-I69) at four hospitals in Wuhan were obtained for the same period. A time-stratified case-crossover design was performed by season (April-September and October-March) to assess effects of pollutants on stroke hospital admissions.Results:Pollution levels were higher in October-March with averages of 136.1 μg/m3 for PM10, 63.6 μg/m3 for NO2 and 71.0 μg/m3 for SO2 than in April-September when averages were 102.0 μg/m3, 41.7 μg/m3 and 41.7 μg/m3, respectively (p<.001). During the cold season, every 10 μg/m3 increase in NO2 was associated with a 2.9% (95%C.I. 1.2%-4.6%) increase in stroke admissions on the same day. Every 10 ug/m3 increase in PM10 daily concentration was significantly associated with an approximate 1% (95% C.I. 0.1%-1.4%) increase in stroke hospitalization. A two-pollutant model indicated that NO2 was associated with stroke admissions when controlling for PM10. During the warm season, no significant associations were noted for any of the pollutants.Conclusions:Exposure to NO2 is significantly associated with stroke hospitalizations during the cold season in Wuhan, China when pollution levels are 50% greater than in the warm season. Larger and multi-center studies in Chinese cities are warranted to validate our findings. © 2013 Xiang et al

199 Baricitinib in patients with systemic lupus erythematosus: results from a phase 2, randomized, double-blind, placebo-controlled study

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JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies

BACKGROUND. Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment

The evolution of non-small cell lung cancer metastases in TRACERx

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relaps

Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop

<p>Abstract</p> <p>Background</p> <p>Envenomation by crotaline snakes (rattlesnake, cottonmouth, copperhead) is a complex, potentially lethal condition affecting thousands of people in the United States each year. Treatment of crotaline envenomation is not standardized, and significant variation in practice exists.</p> <p>Methods</p> <p>A geographically diverse panel of experts was convened for the purpose of deriving an evidence-informed unified treatment algorithm. Research staff analyzed the extant medical literature and performed targeted analyses of existing databases to inform specific clinical decisions. A trained external facilitator used modified Delphi and structured consensus methodology to achieve consensus on the final treatment algorithm.</p> <p>Results</p> <p>A unified treatment algorithm was produced and endorsed by all nine expert panel members. This algorithm provides guidance about clinical and laboratory observations, indications for and dosing of antivenom, adjunctive therapies, post-stabilization care, and management of complications from envenomation and therapy.</p> <p>Conclusions</p> <p>Clinical manifestations and ideal treatment of crotaline snakebite differ greatly, and can result in severe complications. Using a modified Delphi method, we provide evidence-informed treatment guidelines in an attempt to reduce variation in care and possibly improve clinical outcomes.</p

Induction of APOBEC3 exacerbates DNA replication stress and chromosomal instability in early breast and lung cancer evolution

APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when APOBEC3 expression is induced during cancer development remains to be defined. Here we show that specific APOBEC3 genes are upregulated in breast DCIS, and in pre-invasive lung cancer lesions coincident with cellular proliferation. We observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from TRACERx pre-invasive to invasive NSCLC lesions. We find that APOBEC3B exacerbates DNA replication stress and chromosomal instability through incomplete replication of genomic DNA, manifested by accumulation of mitotic ultrafine bridges and 53BP1 nuclear bodies in the G1 phase of the cell cycle. Analysis of TRACERx NSCLC clinical samples and mouse lung cancer models, revealed APOBEC3B expression driving replication stress and chromosome missegregation. We propose that APOBEC3 is functionally implicated in the onset of chromosomal instability and somatic mutational heterogeneity in pre-invasive disease, providing fuel for selection early in cancer evolution

The western painted turtle genome, a model for the evolution of extreme physiological adaptations in a slowly evolving lineage

Background: We describe the genome of the western painted turtle, Chrysemys picta bellii, one of the most widespread, abundant, and well-studied turtles. We place the genome into a comparative evolutionary context, and focus on genomic features associated with tooth loss, immune function, longevity, sex differentiation and determination, and the species' physiological capacities to withstand extreme anoxia and tissue freezing.Results: Our phylogenetic analyses confirm that turtles are the sister group to living archosaurs, and demonstrate an extraordinarily slow rate of sequence evolution in the painted turtle. The ability of the painted turtle to withstand complete anoxia and partial freezing appears to be associated with common vertebrate gene networks, and we identify candidate genes for future functional analyses. Tooth loss shares a common pattern of pseudogenization and degradation of tooth-specific genes with birds, although the rate of accumulation of mutations is much slower in the painted turtle. Genes associated with sex differentiation generally reflect phylogeny rather than convergence in sex determination functionality. Among gene families that demonstrate exceptional expansions or show signatures of strong natural selection, immune function and musculoskeletal patterning genes are consistently over-represented.Conclusions: Our comparative genomic analyses indicate that common vertebrate regulatory networks, some of which have analogs in human diseases, are often involved in the western painted turtle's extraordinary physiological capacities. As these regulatory pathways are analyzed at the functional level, the painted turtle may offer important insights into the management of a number of human health disorders