Effects of a Remote Multimodal Intervention Involving Diet, Walking Program, and Breathing Exercise on Quality of Life Among Newly Diagnosed People with Multiple Sclerosis: A Quasi-Experimental Non-Inferiority Pilot Study.

Background: Interventions involving diet, physical activity, and breathing exercises are shown to be beneficial in managing both fatigue and quality of life (QoL) related to MS; however, the impact of such interventions among people newly diagnosed with clinically isolated syndrome (CIS) or relapsing-remitting multiple sclerosis (RRMS) who decline disease-modifying therapies (DMTs) is unknown. Methods: A 12-month prospective quasi-experimental non-inferiority trial recruited people newly diagnosed with CIS or RRMS who voluntarily declined DMTs (health behavior group; HB, n = 29) or followed standard of care (SOC, n = 15). Participants in the HB group were remotely coached on the study diet, moderate-intensity walking, and breathing exercises. All participants completed questionnaires validated to assess MS symptoms, including perceived mental and physical QoL (MSQOL54); fatigue (Fatigue Severity Scale, FSS; and Modified Fatigue Impact Scale, MFIS); mood (Hospital Anxiety and Depression Scale, HADS); and cognitive function (Perceived Deficits Questionnaire, PDQ). Results: During the 12 months, the HB group experienced improvement in scores for mental QoL (MSQOL54 - Mental, 0.24, 95% CI 0.01, 0.47; p = 0.04), fatigue (Total MFIS, -7.26, 95% CI -13.3,-1.18; p = 0.02), and perceived cognitive function (Total PDQ, PDQ-Attention, PDQ-Promemory, and PDQ-Planning, p ≤ 0.03 for all). A between-group difference was observed only for PDQ-Planning (p = 0.048). Non-inferiority analysis revealed that the 12-month changes in means for the HB group were not worse than those for the SOC group with respect to fatigue (FSS, p = 0.02), mood (HDS-Anxiety, p = 0.02; HADS-Depression, p < 0.0001), physical QoL (MSQOL54 - Physical, p = 0.02), or cognitive dysfunction (Total PDQ, p = 0.01). Conclusion: The multimodal lifestyle intervention for individuals newly diagnosed with CIS or RRMS, who voluntarily decline DMTs, did not yield patient-reported outcomes worse than those observed in the SOC group regarding perceived mental quality of life, mood, fatigue, and cognitive function. Trial Registration: clinicaltrials.gov identifier: NCT04009005.

Trends in Early Graft Failure Leading to Regrafting After Endothelial Keratoplasty in the United States.

PURPOSE: The purpose of this study was to report trends in the prevalence of early graft failure after endothelial keratoplasty in the United States. METHODS: Descemet membrane endothelial keratoplasty (DMEK) and Descemet stripping automated endothelial keratoplasty (DSAEK) graft volumes were collected from records maintained by 6 major eye banks in the United States from January 1, 2013, to December 31, 2018. The prevalence and presumed cause of early graft failures (defined as a graft with persistent edema or regrafted within 8 weeks after keratoplasty) each year were sourced from surgeon-reported adverse events. Failed graft cases from the 3 eye banks were compared with nonfailures at the donor and recipient levels to perform subset analysis of factors associated with early graft failure. RESULTS: A total of 51,887 endothelial keratoplasty tissues were distributed during the study period; 72% were DSAEK grafts. The total number of early graft failures reported was 168 of 14,284 (1.18%) for DMEK and 322 of 37,603 (0.86%) for DSAEK. Early DMEK failures decreased from 2013 (7.69%) to 2018 (0.68%). In generalized linear mixed model analyses adjusting for donor tissue characteristics, recipient age, and diagnosis, an association of borderline significance was found between higher donor age and early failure [odds ratio (95% confidence interval): 1.03 (1.00-1.05); unit change of 1 yr] and DSAEK [odds ratio 1.02 (1.00-1.04); unit of change 1 yr] cases. CONCLUSIONS: The proportion of early graft failures in DMEK decreased over time and was comparable with failure rates in DSAEK at the end of the study period. The surgical learning curve might have played a role.

Change in Micronutrient Intake among People with Relapsing-Remitting Multiple Sclerosis Adapting the Swank and Wahls Diets: An Analysis of Weighed Food Records.

The low-saturated fat (Swank) and modified Paleolithic elimination (Wahls) diets have shown promise for MS symptoms; however, due to their restriction of specific foods, inadequate intake of micronutrients is concerning. Therefore, as part of a randomized trial, weighed food records were collected on three consecutive days and were used to evaluate the intake of micronutrients among people with relapsing remitting MS adapting these diets. After randomization to either the Swank or Wahls diets, diet education and support was provided by registered dietitians at baseline and throughout the first 12 weeks of the intervention. Usual intake of each micronutrient was estimated and then evaluated with the EAR-cut point method. At 12 weeks, the Swank group had significant reductions in the proportion with inadequate intake from food for vitamins C, D, and E, while the Wahls group had significant reductions for magnesium and vitamins A, C, D, and E. However, the proportion with inadequate intake significantly increased for calcium, thiamin, and vitamin B12 in the Wahls group and for vitamin A in the Swank group. Inclusion of intake from supplements reduced the proportion with inadequate intake for all micronutrients except calcium among the Wahls group but increased the proportion with excessive intake for vitamin D and niacin among both groups and magnesium among the Swank group. Both diets, especially when including intake from supplements, are associated with reduced inadequate intake compared to the normal diet of people with relapsing remitting MS.

The Vascularity of Ayurvedic Leech Therapy: Sensory Translations and Emergent Agencies in Interspecies Medicine.

This article offers vascularity as a multi-dimensional imaginary for the interspecies entanglements constituting Ayurvedic leech therapy. Whether, when, where, and how a leech decides to bite, suck, and release comprise pivotal junctures in leech therapy as practiced in southern Kerala, India. In the course of leech-human intra-actions, leeches translate matter, providing sensory mediation, relief, and amusement. Enmeshed in social and ecological relations inflected by gender, religion, class, and caste, this analysis of Ayurvedic leech therapy reframes questions of agencies starting with and from the viewpoint of the vascular capacities of leeches in their interactions with humans. This image of vascularity provides an analytic for the emergent agencies of humans and leeches constituted by sensory intra-actions at branching points in this multispecies clinical practice.

Facilitators and Barriers Surrounding the Role of Administration in Employee Job Satisfaction in Long-Term Care Facilities: A Systematic Review.

Previous literature has shown how associate engagement has positively impacted on productivity, job satisfaction, safety, retention, consumer sentiment, and financial performance in hospitals and healthcare systems. However, a lack of research showing the relationship between associate engagement and job satisfaction within the long-term care environment has existed. Our objective was to investigate characteristics within the long-term care environment that promote and detract from associate job satisfaction and extrapolate the best practices in maintaining job satisfaction and engagement. This systematic review queried CINAHL, PubMed (MEDLINE), and Academic Search Ultimate databases for peer-reviewed publications for facilitators and barriers commensurate with employee job satisfaction in long-term care facilities using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and the Kruse Protocols. The authors identified 11 facilitators for job satisfaction and 18 barriers to job satisfaction in the 60 selected articles. The top four facilitators were Supportive Leadership, Capable and Motivated Employees, Positive Organizational Values, and Social Support Mechanisms. The top four barriers were condescending management style, high job demands, lack of self-care, and lack of training with medically complex patients. The systematic review revealed the importance of maintaining satisfied employees in the long-term care workplace through am emphasis leadership and on the facilitators identified to best serve their associates and improve care for residents.

A global reference for human genetic variation.

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.

ClinGen--the Clinical Genome Resource.

On autopsy, a patient is found to have hypertrophic cardiomyopathy. The patient's family pursues genetic testing that shows a "likely pathogenic" variant for the condition on the basis of a study in an original research publication. Given the dominant inheritance of the condition and the risk of sudden cardiac death, other family members are tested for the genetic variant to determine their risk. Several family members test negative and are told that they are not at risk for hypertrophic cardiomyopathy and sudden cardiac death, and those who test positive are told that they need to be regularly monitored for cardiomyopathy on echocardiography. Five years later, during a routine clinic visit of one of the genotype-positive family members, the cardiologist queries a database for current knowledge on the genetic variant and discovers that the variant is now interpreted as "likely benign" by another laboratory that uses more recently derived population-frequency data. A newly available testing panel for additional genes that are implicated in hypertrophic cardiomyopathy is initiated on an affected family member, and a different variant is found that is determined to be pathogenic. Family members are retested, and one member who previously tested negative is now found to be positive for this new variant. An immediate clinical workup detects evidence of cardiomyopathy, and an intracardiac defibrillator is implanted to reduce the risk of sudden cardiac death.

Human genomic regions with exceptionally high levels of population differentiation identified from 911 whole-genome sequences.

BACKGROUND: Population differentiation has proved to be effective for identifying loci under geographically localized positive selection, and has the potential to identify loci subject to balancing selection. We have previously investigated the pattern of genetic differentiation among human populations at 36.8 million genomic variants to identify sites in the genome showing high frequency differences. Here, we extend this dataset to include additional variants, survey sites with low levels of differentiation, and evaluate the extent to which highly differentiated sites are likely to result from selective or other processes. RESULTS: We demonstrate that while sites with low differentiation represent sampling effects rather than balancing selection, sites showing extremely high population differentiation are enriched for positive selection events and that one half may be the result of classic selective sweeps. Among these, we rediscover known examples, where we actually identify the established functional SNP, and discover novel examples including the genes ABCA12, CALD1 and ZNF804, which we speculate may be linked to adaptations in skin, calcium metabolism and defense, respectively. CONCLUSIONS: We identify known and many novel candidate regions for geographically restricted positive selection, and suggest several directions for further research.

Characterizing genetic variants for clinical action.

Genome-wide association studies, DNA sequencing studies, and other genomic studies are finding an increasing number of genetic variants associated with clinical phenotypes that may be useful in developing diagnostic, preventive, and treatment strategies for individual patients. However, few variants have been integrated into routine clinical practice. The reasons for this are several, but two of the most significant are limited evidence about the clinical implications of the variants and a lack of a comprehensive knowledge base that captures genetic variants, their phenotypic associations, and other pertinent phenotypic information that is openly accessible to clinical groups attempting to interpret sequencing data. As the field of medicine begins to incorporate genome-scale analysis into clinical care, approaches need to be developed for collecting and characterizing data on the clinical implications of variants, developing consensus on their actionability, and making this information available for clinical use. The National Human Genome Research Institute (NHGRI) and the Wellcome Trust thus convened a workshop to consider the processes and resources needed to: (1) identify clinically valid genetic variants; (2) decide whether they are actionable and what the action should be; and (3) provide this information for clinical use. This commentary outlines the key discussion points and recommendations from the workshop.

An integrated map of genetic variation from 1,092 human genomes.

By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million single nucleotide polymorphisms, 1.4 million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations.

A map of human genome variation from population-scale sequencing.

The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother-father-child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10(-8) per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research.

ECG response of koalas to tourists proximity: a preliminary study.

Koalas operate on a tight energy budget and, thus, may not always display behavioral avoidance reaction when placed in a stressful condition. We investigated the physiological response of captive koalas Phascolarctos cinereus in a conservation centre to the presence of tourists walking through their habitat. We compared, using animal-attached data-recorders, the electrocardiogram activity of female koalas in contact with tourists and in a human-free area. One of the koalas in the tourist zone presented elevated heart rate values and variability throughout the recording period. The remaining female in the exhibit area showed a higher field resting heart rates during the daytime than that in the isolated area. In the evening, heart rate profiles changed drastically and both the koalas in the exhibit and in the tourist-free zones displayed similar field resting heart rates, which were lower than those during the day. In parallel, the autonomic nervous systems of these two individuals evolved from sympathetic-dominant during the day to parasympathetic-dominant in the evening. Our results report ECG of free-living koalas for the first time. Although they are preliminary due to the difficulty of having sufficient samples of animals of the same sex and age, our results stress out the importance of studies investigating the physiological reaction of animals to tourists.

A HapMap harvest of insights into the genetics of common disease.

The International HapMap Project was designed to create a genome-wide database of patterns of human genetic variation, with the expectation that these patterns would be useful for genetic association studies of common diseases. This expectation has been amply fulfilled with just the initial output of genome-wide association studies, identifying nearly 100 loci for nearly 40 common diseases and traits. These associations provided new insights into pathophysiology, suggesting previously unsuspected etiologic pathways for common diseases that will be of use in identifying new therapeutic targets and developing targeted interventions based on genetically defined risk. In addition, HapMap-based discoveries have shed new light on the impact of evolutionary pressures on the human genome, suggesting multiple loci important for adapting to disease-causing pathogens and new environments. In this review we examine the origin, development, and current status of the HapMap; its prospects for continued evolution; and its current and potential future impact on biomedical science.

New models of collaboration in genome-wide association studies: the Genetic Association Information Network.

The Genetic Association Information Network (GAIN) is a public-private partnership established to investigate the genetic basis of common diseases through a series of collaborative genome-wide association studies. GAIN has used new approaches for project selection, data deposition and distribution, collaborative analysis, publication and protection from premature intellectual property claims. These demonstrate a new commitment to shared scientific knowledge that should facilitate rapid advances in understanding the genetics of complex diseases.

Mammaglobin as a novel breast cancer biomarker: multigene reverse transcription-PCR assay and sandwich ELISA.

BACKGROUND: The aim of this study was to examine the potential usefulness of a mammaglobin multigene reverse transcription-PCR (RT-PCR) assay and a mammaglobin sandwich ELISA as diagnostic tools in breast cancer. METHODS: We studied peripheral blood samples from 147 untreated Senegalese women with biopsy-confirmed breast cancer and gathered patient information regarding demographic, and clinical staging of disease. The samples were tested for mammaglobin and three breast cancer-associated gene transcripts by a multigene real-time RT-PCR assay and for serum mammaglobin protein by a sandwich ELISA assay. RESULTS: In 77% of the breast cancer blood samples, a positive signal was obtained in the multigene RT-PCR assay detecting mammaglobin and three complementary transcribed genes. Fifty samples from healthy female donors tested negative. Significant correlations were found between mammaglobin protein in serum, presence of mammaglobin mRNA-expressing cells in blood, stage of disease, and tumor size. Circulating mammaglobin protein was detected in 68% of the breast cancer sera, and was increased in 38% in comparison with a mixed control population. The RT-PCR assay and the ELISA for mammaglobin produced a combined sensitivity of 84% and specificity of 97%. CONCLUSION: The ELISA and RT-PCR for mammaglobin and mammaglobin-producing cells could be valuable tools for diagnosis and prognosis of breast cancer.