Revealing mammalian evolutionary relationships by comparative analysis of gene clusters

Many software tools for comparative analysis of genomic sequence data have been released in recent decades. Despite this, it remains challenging to determine evolutionary relationships in gene clusters due to their complex histories involving duplications, deletions, inversions, and conversions. One concept describing these relationships is orthology. Orthologs derive from a common ancestor by speciation, in contrast to paralogs, which derive from duplication. Discriminating orthologs from paralogs is a necessary step in most multispecies sequence analyses, but doing so accurately is impeded by the occurrence of gene conversion events. We propose a refined method of orthology assignment based on two paradigms for interpreting its definition: by genomic context or by sequence content. X-orthology (based on context) traces orthology resulting from speciation and duplication only, while N-orthology (based on content) includes the influence of conversion events

Absence of system xc⁻ on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis

Background: Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System x(c)- or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration. Methods: Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system x(c)-, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT(-/-)) mice and irradiated mice reconstituted in xCT(-/-) bone marrow (BM), to their proper wild type (xCT(+/+)) controls. Results: xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT(+/+) mice, xCT(-/-) mice were equally susceptible to EAE, whereas mice transplanted with xCT(-/-) BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected. Conclusions: Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system x(c)- on immune cells invading the CNS participates to EAE. Since a total loss of system x(c)- had no net beneficial effects, these results have important implications for targeting system x(c)- for treatment of MS

What are the unmet supportive care needs of men and their partner/caregivers living with and beyond penile cancer?

Globally, cancer of the penis is an uncommon malignancy with reported incidence in Western countries of 1 per 100,000 in Europe. More recently, epidemiological data in United Kingdom (UK) has identified a 21% increase in cases of penile cancer incidence over recent years. An existing systematic review, identified that 50% of men affected by penile cancer experienced psychological problems, 40% reported a negative impact on quality of life, and 70% of patients experienced difficulties with sexual function. This review does not identify the lived experienced of penile cancer, the impact that penile cancer can have on partner/caregivers, or importantly, the areas of unmet supportive care needs in care delivery. Gaining more knowledge of the experiences of men and their loved ones affected by penile cancer will provide additional insights for healthcare providers to create a holistic model of care and clinical practice guidelines. Therefore, this systematic review will address the following research questions: 1. What are the different domains of unmet supportive care needs of men and their partner/caregivers affected by penile cancer? 2. What are the most frequently reported individual domains of unmet need in the current available literature? This review will be conducted using the systematic review methodology provided by the European Association of Urology for clinical guidelines practice

Gene × Physical Activity Interactions in Obesity: Combined Analysis of 111,421 Individuals of European Ancestry

Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age2, sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, Pinteraction = 0.014 vs. n = 71,611, Pinteraction = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction = 0.003) and the SEC16B rs10913469 (Pinteraction = 0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal

THE EFFECT OF A NOVEL REHABILITATION PROGRAM ON WALKING PERFORMANCE IN PERSONS WITH MULTIPLE SCLEROSIS

The current study examined the effects of the NewGait™ device on walking performance in persons with multiple sclerosis (MS). Eight MS patients participated in this study. Pre- and post-testing assessed kinematic gait variables (step width, length, and speed), ankle range of motion, and rating of perceived exertion (RPE). Participants completed an 8-week physical therapy (PT) protocol aimed to improve gait and balance, with the experimental group wearing the NewGait™ device. Repeated measures mixed ANOVA showed no main effects between the gait variables or between groups. Post-hoc paired t-tests indicated that the NewGait™ device elicited meaningful change in left and right step length and speed. The NewGait™ device may be a promising rehabilitation device to help induce positive walking performance changes in persons with MS

THE EFFECT OF A NOVEL REHABILITATION DEVICE ON MUSCLE ACTIVATION DURING GAIT IN PERSONS WITH MULTIPLE SCLEROSIS

This study examined the acute effect of a novel rehabilitation device, NewGait™, on muscle activation in persons with Multiple Sclerosis. Through electromyography, muscle activation of the vastus medialis (VM), gastrocnemius lateralis (GL) and tibialis anterior (TA) was measured in seventeen patients (n=17). Three trials were conducted in each condition: a 10-meter control walk and 10-meter NewGait™ walk. Results showed a non-significant change in muscle activity with moderate effect sizes in the right VM (increase of 39.72% MVC, p=0.082, d=0.626) and right TA (decrease of 12.71% MVC, p=0.069, d=0.427). In general, no change in muscle activation was noted when wearing the NewGait™ device. Future research should include a larger sample size and differentiation between the stance phases to accurately measure the outcomes of the NewGait™ device on muscle activation

CHANGES IN GAIT AND COORDINATION VARIABILITY IN PERSONS WITH MULTIPLE SCLEROSIS FOLLOWING A REHABILITATION PROGRAM

This study investigated changes in gait and coordination variability in persons with Multiple Sclerosis (MS) after an 8-week rehabilitation intervention. Data for eight participants (Control: 4, Intervention: 4) were analyzed via Cortex Motion Analysis software and Visual 3D to calculate knee and ankle joint angles as well as discrete spatiotemporal parameters. The knee and ankle joint angles were further analyzed using a vector coding technique to quantify coordination between these joints and how they produce a functional gait pattern. No significant changes in gait or coordination variability were found after rehabilitation, but some meaningful changes with large and moderate effect sizes were present. This study demonstrated a comprehensive overview of the relationship between process and outcome variability in a clinical population

Comparing genotyping algorithms for Illumina's Infinium whole-genome SNP BeadChips

Background: Illumina's Infinium SNP BeadChips are extensively used in both small and large-scale genetic studies. A fundamental step in any analysis is the processing of raw allele A and allele B intensities from each SNP into genotype calls (AA, AB, BB). Various algorithms which make use of different statistical models are available for this task. We compare four methods (GenCall, Illuminus, GenoSNP and CRLMM) on data where the true genotypes are known in advance and data from a recently published genome-wide association study.Results: In general, differences in accuracy are relatively small between the methods evaluated, although CRLMM and GenoSNP were found to consistently outperform GenCall. The performance of Illuminus is heavily dependent on sample size, with lower no call rates and improved accuracy as the number of samples available increases. For X chromosome SNPs, methods with sex-dependent models (Illuminus, CRLMM) perform better than methods which ignore gender information (GenCall, GenoSNP). We observe that CRLMM and GenoSNP are more accurate at calling SNPs with low minor allele frequency than GenCall or Illuminus. The sample quality metrics from each of the four methods were found to have a high level of agreement at flagging samples with unusual signal characteristics.Conclusions: CRLMM, GenoSNP and GenCall can be applied with confidence in studies of any size, as their performance was shown to be invariant to the number of samples available. Illuminus on the other hand requires a larger number of samples to achieve comparable levels of accuracy and its use in smaller studies (50 or fewer individuals) is not recommended

Does Screening for Pain Correspond to High Quality Care for Veterans?

Routine numeric screening for pain is widely recommended, but its association with overall quality of pain care is unclear. To assess adherence to measures of pain management quality and identify associated patient and provider factors. A cross-sectional visit-based study. One hundred and forty adult VA outpatient primary care clinic patients reporting a numeric rating scale (NRS) of moderate to severe pain (four or more on a zero to ten scale). Seventy-seven providers completed a baseline survey regarding general pain management attitudes and a post-visit survey regarding management of 112 participating patients. We used chart review to determine adherence to four validated process quality indicators (QIs) including noting pain presence, pain character, and pain control, and intensifying pharmacological intervention. The average NRS was 6.7. Seventy-three percent of charts noted the presence of pain, 13.9% the character, 23.6% the degree of control, and 15.3% increased pain medication prescription. Charts were more likely to include documentation of pain presence if providers agreed that “patients want me to ask about pain” and “pain can have negative consequences on patient’s functioning”. Charts were more likely to document character of pain if providers agreed that “patients are able to rate their pain”. Patients with musculoskeletal pain were less likely to have chart documentation of character of pain. Despite routine pain screening in VA, providers seldom documented elements considered important to evaluation and treatment of pain. Improving pain care may require attention to all aspects of pain management, not just screening