C2BAT: A Novel Method for Association Between Ge- netic Markers and Multiple Phenotypes

The purpose of this technical report is to describe a novel method developed to detect association between a genetic marker and multiple phenotypes. In order to obtain a one-degree of freedom test, a generalized principal component approach is suggested that aggregates the information about the genetic effect in the first prin- cipal component, while the remain principal components contain only environment noise. A limited simulation study is done validating the method. For scenarios in which the genetic effect is constant across all measurements and there is no envi- ronmental correlation between the measurements, preliminary results suggest that this method has similar power to standard methods of analysis. Since such setups favor the standard approach, the new method is expected to be efficient for many realistic alternative hypotheses, including those with varying genetic effect sizes across measurements and those accounting for environmental correlation

Using Canonical Correlation Analysis to Discover Genetic Regulatory Variants

Background: Discovering genetic associations between genetic markers and gene expression levels can provide insight into gene regulation and, potentially, mechanisms of disease. Such analyses typically involve a linkage or association analysis in which expression data are used as phenotypes. This approach leads to a large number of multiple comparisons and may therefore lack power. We assess the potential of applying canonical correlation analysis to partitioned genomewide data as a method for discovering regulatory variants. Methodology/Principal Findings: Simulations suggest that canonical correlation analysis has higher power than standard pairwise univariate regression to detect single nucleotide polymorphisms when the expression trait has low heritability. The increase in power is even greater under the recessive model. We demonstrate this approach using the Childhood Asthma Management Program data. Conclusions/Significance: Our approach reduces multiple comparisons and may provide insight into the complex relationships between genotype and gene expression

Converting GLX2-1 into an Active Glyoxalase II

Arabidopsis thaliana glyoxalase 2-1 (GLX2-1) exhibits extensive sequence similarity with GLX2 enzymes but is catalytically inactive with SLG, the GLX2 substrate. In an effort to identify residues essential for GLX2 activity, amino acid residues were altered at positions 219, 246, 248, 325, and 328 in GLX2-1 to be the same as those in catalytically active human GLX2. The resulting enzymes were overexpressed, purified, and characterized using metal analyses, fluorescence spectroscopy, and steady-state kinetics to evaluate how these residues affect metal binding, structure, and catalysis. The R246H/N248Y double mutant exhibited low level S-lactoylglutathione hydrolase activity, while the R246H/N248Y/Q325R/R328K mutant exhibited a 1.5−2-fold increase in kcat and a decrease in Km as compared to the values exhibited by the double mutant. In contrast, the R246H mutant of GLX2-1 did not exhibit glyoxalase 2 activity. Zn(II)-loaded R246H GLX2-1 enzyme bound 2 equiv of Zn(II), and 1H NMR spectra of the Co(II)-substituted analogue of this enzyme strongly suggest that the introduced histidine binds to Co(II). EPR studies indicate the presence of significant amounts a dinuclear metal ion-containing center. Therefore, an active GLX2 enzyme requires both the presence of a properly positioned metal center and significant nonmetal, enzyme−substrate contacts, with tyrosine 255 being particularly important

Clinical Effectiveness, Access to, and Satisfaction with Care Using a Telehomecare Substitution Intervention: A Randomized Controlled Trial

Background. Hospitalization accounts for 70% of heart failure (HF) costs; readmission rates at 30 days are 24% and rise to 50% by 90 days. Agencies anticipate that telehomecare will provide the close monitoring necessary to prevent HF readmissions. Methods and Results. Randomized controlled trial to compare a telehomecare intervention for patients 55 and older following hospital discharge for HF to usual skilled home care. Primary endpoints were 30- and 60-day all-cause and HF readmission, hospital days, and time to readmission or death. Secondary outcomes were access to care, emergency department (ED) use, and satisfaction with care. All-cause readmissions at 30 days (16% versus 19%) and over six months (46% versus 52%) were lower in the telehomecare group but were not statistically significant. Access to care and satisfaction were significantly higher for the telehomecare patients, including the number of in-person visits and days in home care. Conclusions. Patient acceptance of the technology and current home care policies and processes of care were barriers to gaining clinical effectiveness and efficiency

Associations between pre-surgical daily opioid use and short-term outcomes following knee or hip arthroplasty : a prospective, exploratory cohort study

Background: Retrospective studies have found that daily opioid use pre-arthroplasty predicts worse longer-term service, clinical and patient-reported outcomes. Prospective studies are needed to confirm these observations. This prospective, exploratory study aimed to determine: the proportion of total knee or hip arthroplasty (TKA, THA) patients who use opioids regularly (daily) pre-surgery; if opioid use pre-surgery is associated with acute and sub-acute outcomes to 12-weeks post-surgery. Methods: Consecutive patients undergoing primary TKA or THA were prospectively enrolled pre-surgery and followed-up by telephone to 12-weeks post-surgery. Acute-care (oral morphine equivalent dosage (OMED), length of stay, discharge to inpatient rehabilitation, complications) and 12-week outcomes (Oxford Knee or Hip Score, Euroqol 'today' health score, current use of opioids, and complications including readmissions) were monitored. Unadjusted and adjusted Odds Ratios (ORs) (95% Confidence Interval, CI), Rate Ratios and β coefficients (standard error) were calculated. Results: Five Hundred Twenty-One patients were included (TKA n = 381). 15.7% (95%CI 12.6 to 18.9) used opioids regularly pre-surgery. 86.8% (452/521) were available for follow-up at 12-weeks. In unadjusted analyses, pre-surgical opioid use was significantly associated with higher average acute daily OMED [β 0.40 (0.07), p < 0.001], presence of an acute complication [OR 1.75 (1.02 to 3.00)], and ongoing use of opioids at 12-weeks [OR 5.06 (2.86 to 8.93)]. After adjusting for covariates, opioid use pre-surgery remained significantly associated with average acute daily OMED [β 0.40 (0.07), p < 0.001] and ongoing use at 12-weeks [OR 5.38 (2.89 to 9.99)]. Conclusion: People who take daily opioids pre-surgery have significantly greater odds for greater opioid consumption acutely and ongoing use post-surgery. Adequately powered prospective studies are required to confirm whether pre-surgical opioid use is or is not associated with poorer joint and quality of life scores or a complication in the short-term

Salmonellosis in Calves by Serovar Dublin in Paraná State, Brazil - Clinicopathological Aspects

Background: Calf diarrhea remains one of the main diseases affecting the cattle industry. Persistence of this significant problem is associated with the complexity of factors that may be involved (infectious, environmental). An accurate diagnosis is essential for confirming the cause and helping clinicians and cattle producers to apply appropriate strategies in a timely manner. This report describes the histological changes according to the degree of salmonellosis severity, which is a contagious infectious disease caused by Salmonella enterica subsp. enterica, a Gram-negative bacterium, in two beef calves in northern Paraná State, southern Brazil. Cases: Two 90-day-old crossbred Angus and Nellore calves from a beef farm in northern Paraná State were referred to a Veterinary Hospital. Animal 1- developed acute clinical signs (enteritis, ataxia, and muscle rigidity) and died the day after the signs began. Gross findings included heavy and non-collapsed lungs, pulmonary oedema, hepatomegaly, enteritis, and severe diffuse typhlitis. Microscopic analysis revealed severe diffuse necrotic enteritis, typhlitis, severe diffuse interstitial pneumonia, moderate centrilobular hepatic necrosis, mild multifocal nephritis, and severe spleen and lymph node necrosis. Paratyphoid nodules were evidenced on the liver, spleen, and mesenteric lymph nodes. Animal 2- presented apathy, green fibrinous diarrhea, and died three days after the onset of clinical signs. The macroscopic examination showed moderate diffuse enteritis and hepatosplenomegaly. At the microscopic examination, many paratyphoid nodules were observed on the liver, spleen, kidneys, and Peyer's patches, which were associated with intralesional and intravascular bacilli. Additional findings included severe diffuse fibrinous necrotic enteritis with intralesional bacilli, diffuse interstitial pneumonia, multifocal splenic necrosis, lymphoid depletion, and moderate multifocal to coalescent lymphocytic nephritis. Histological Gram staining was performed on selected samples, revealing intralesional Gram-negative bacilli in the liver and intestine. Thus, liver and intestine fragments were used for the microbiological examination. Microbiological culture, isolation and biochemical tests identified the genus Salmonella spp. Then, the colonies were subjected to serological tests for serovar identification, according to ISO/TR 6579-3, which determined the serovar Dublin. After identifying the disease etiological agent, the outbreak was controlled by appropriate antibiotic therapy combined with the correction of sanitary measures.Discussion: Enteritis is a frequent disease in calves, posing a diagnostic challenge in identifying the etiological agent. In the present case, the histological, microbiological, and serological results confirmed a disseminated Salmonella spp. infection. The microscopic findings, such as interstitial pneumonia, fibrinous necrotic enteritis markedly in ileum and paratyphoid nodules in various organs, are the most common aspects of the disease. However, fibrinous cholecystitis, which is considered pathognomonic for salmonellosis, was not observed in this study. Therefore, the absence of such a lesion should not exclude the disease in sick animals. A microscopic injury score was used to determine lesion severity by assigning values from 1 to 4, wherein: 1 = no apparent lesions, 2 = mild lesions, 3 = moderate lesions, and 4 = severe lesions. Both calves were scored as 4. Multiple predisposing factors for the condition were identified in this farm such as different age animals in the same paddock and no specific paddock for sick animals, given that the infectious agent remains in feces, saliva, and nasal discharge. The serovar Dublin induces several clinical signs such as septicemic, respiratory, and enteric manifestations, making a clinical diagnosis a challenge. Keywords: dysbiosis, calf diarrhea, infection, paratyphoid nodules, septicemia.Descritores: disbiose, diarreia neonatal, infecção, nódulos paratifoides, septicemia.Título:  Salmonelose em bezerros pelo sorovar Dublin no estado do Paraná, Brasil - aspectos clínico-patológicos

Implementing early mobilisation after knee or hip arthroplasty to reduce length of stay : a quality improvement study with embedded qualitative component

Background: Models of care for managing total knee or hip arthroplasty (TKA, THA) incorporating early mobilisation are associated with shorter acute length-of-stay (LOS). Few studies have examined the effect of implementing early mobilisation in isolation, however. This study aimed to determine if an accelerated mobilisation protocol implemented in isolation is associated with a reduced LOS without undermining care. Method: A Before-After (quasi-experimental) study was used. Standard practice pre-implementation of the new protocol was physiotherapist-led mobilisation once per day commencing on post-operative Day 1 (Before phase). The new protocol (After phase) aimed to mobilise patients four times by end of Day 2 including an attempt to commence on Day 0; physiotherapy weekend coverage was necessarily increased. Poisson regression modelling was used to determine associations between study period and LOS. Additional outcomes to 12 weeks post-surgery were monitored to identify unintended consequences of the new protocol. Time to first mobilisation (hours) and proportion mobilising Day 0 were monitored to assess protocol compliance. An embedded qualitative component captured staff perspectives of the new protocol. Results: Five hundred twenty consecutive patients (n = 278, Before; n = 242, After) were included. The new protocol was associated with no change in unadjusted LOS, a small reduction in adjusted LOS (8.1%, p = 0.046), a reduction in time to first mobilisation (28.5 (10.8) vs 22.6 (8.1) hrs, p < 0.001), and an increase in the proportion mobilising Day 0 (0 vs 7%, p < 0.001). Greater improvements were curtailed by an unexpected decrease in physiotherapy staffing (After phase). There were no significant changes to the rates of complications or readmissions, joint-specific pain and function scores or health-related quality of life to 12 weeks post-surgery. Qualitative findings of 11 multidisciplinary team members highlighted the importance of morning surgery, staffing, and well-defined roles. Conclusion: Small reductions in LOS are possible utilising an early mobilisation protocol in isolation after TKA or THA although staff burden is increased likely undermining both sustainability and the magnitude of the change. Simultaneous incorporation of other changes within the pathway would likely secure larger reductions in LOS

Identifying Distinct Risk Profiles to Predict Adverse Events among Community-Dwelling Older Adults

Preventing adverse events among chronically ill older adults living in the community is a national health priority. The purpose of this study was to generate distinct risk profiles and compare these profiles in time to: hospitalization, emergency department (ED) visit or death in 371 community-dwelling older adults enrolled in a Medicare demonstration project. Guided by the Behavioral Model of Health Service Use, a secondary analysis was conducted using Latent Class Analysis to generate the risk profiles with Kaplan Meier methodology and log rank statistics to compare risk profiles. The Vuong-Lo-Mendell-Rubin Likelihood Ratio Test demonstrated optimal fit for three risk profiles (High, Medium, and Low Risk). The High Risk profile had significantly shorter time to hospitalization, ED visit, and death (p \u3c 0.001 for each). These findings provide a road map for generating risk profiles that could enable more effective targeting of interventions and be instrumental in reducing health care costs for subgroups of chronically ill community-dwelling older adults

Recruitment and baseline data of the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) study: A randomized trial of a hearing loss intervention for reducing cognitive decline

INTRODUCTIONHearing loss is highly prevalent among older adults and independently associated with cognitive decline. The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) study is a multicenter randomized control trial (partially nested within the infrastructure of an observational cohort study, the Atherosclerosis Risk in Communities [ARIC] study) to determine the efficacy of best-practice hearing treatment to reduce cognitive decline over 3 years. The goal of this paper is to describe the recruitment process and baseline results.METHODSMultiple strategies were used to recruit community-dwelling 70–84-year-old participants with adult-onset hearing loss who were free of substantial cognitive impairment from the parent ARIC study and de novo from the surrounding communities into the trial. Participants completed telephone screening, an in-person hearing, vision, and cognitive screening, and a comprehensive hearing assessment to determine eligibility.RESULTSOver a 24-month period, 3004 telephone screenings resulted in 2344 in-person hearing, vision, and cognition screenings and 1294 comprehensive hearing screenings. Among 1102 eligible, 977 were randomized into the trial (median age = 76.4 years; 53.5% female; 87.8% White; 53.3% held a Bachelor's degree or higher). Participants recruited through the ARIC study were recruited much earlier and were less likely to report hearing loss interfered with their quality of life relative to participants recruited de novo from the community. Minor differences in baseline hearing or health characteristics were found by recruitment route (i.e., ARIC study or de novo) and by study site.DISCUSSIONThe ACHIEVE study successfully completed enrollment over 2 years that met originally projected rates of recruitment. Substantial operational and scientific efficiencies during study startup were achieved through embedding this trial within the infrastructure of a longstanding and well-established observational study.HighlightsThe ACHIEVE study tests the effect of hearing intervention on cognitive decline.The study is partially nested within an existing cohort study.Over 2 years, 977 participants recruited and enrolled.Eligibility assessed by telephone and in-person for hearing, vision, and cognitive screening.The ACHIEVE study findings will have significant public health implications