Test-Retest reliability and measurement error of the uncontrolled manifold analysis: A step towards the clinical translation.

The uncontrolled manifold (UCM) analysis has gained broad application in biomechanics and neuroscience for investigating the structure of motor variability in functional tasks. The UCM utilizes inter-trial analysis to partition the variance of elemental variables (e.g., finger forces, joint angles) that affect (VORT) and do not affect (VUCM) a performance variable (e.g., total force, end-effector position). However, to facilitate the translation of UCM into clinical settings, it is crucial to demonstrate the reliability of UCM estimates: VORT, VUCM, and their normalized difference, ΔV. This study aimed to determine the test-retest reliability using the intraclass correlation coefficient (ICC3,K), Bland-Altman plots, the standard error of measurement (SEM), and the minimal detectable change (MDC) of UCM estimate. Fifteen healthy individuals (24.8 ± 1.2 yrs old) performed a finger coordination task, with sessions separated by one hour, one day, and one week. Excellent reliability was found for VORT (ICC3,K = 0.97) and VUCM (ICC3,K = 0.92), whereas good reliability was observed for ΔV (ICC3,K = 0.84). Bland-Altman plots reveled no systematic differences. SEM% values were 24.57 %, 26.80 % and 12.49 % for VORT, VUCM and ΔV respectively, while the normalized MDC% values were 68.12 %, 74.30 % and 34.61 % for VORT, VUCM and ΔV respectively. Our results support the use of UCM as a reliable method for investigating the structure of movement variability. The excellent measurement properties make the UCM a promising tool for tracking changes in motor behavior over time (i.e., effects of interventions in prospective studies).

Simplifying Medication Regimens for People Receiving Community-Based Home Care Services: Outcomes of a Non-Randomized Pilot and Feasibility Study.

PURPOSE: Being able to manage a complex medication regimen is key to older people continuing to live at home. This study determined the feasibility of a multi-component intervention to simplify medication regimens for people receiving community-based home care services. PATIENTS AND METHODS: Research nurses recruited people receiving community-based home care services to participate in this non-randomized pilot and feasibility study (Australian New Zealand Clinical Trials Registry ACTRN12618001130257). Participants received a one-off clinical pharmacist intervention comprising medication reconciliation, assessment of capacity to self-manage medications, and application of a structured 5-step tool to identify medication simplification opportunities. A mixed-methods feasibility assessment with an explanatory design was undertaken to assess recruitment, protocol adherence and stakeholder acceptability. Data from interviews with 12 stakeholders were thematically analyzed. Secondary outcome measures, including medication discrepancies, and changes in number of medication administration times per day, quality of life, medication adherence and health service utilization, were determined over a 4-month follow-up. RESULTS: Twenty-five out of the target 50 participants were recruited. Initial recruitment was impacted by apparent uncertain role responsibilities in medication management, with some clients who declined to participate perceiving they would be unlikely to benefit or being reluctant to change regimens. However, with few exceptions, participants who received intervention did so with a high degree of protocol adherence and acceptability. Stakeholders valued the intervention and supported wider implementation. Discrepancies between the baseline medication history from the general medical practitioner and the pharmacist-compiled "best possible medication history" were identified for all participants' regimens (median of 6 per participant), with one-third resolved at follow-up. Simplification was possible for 14 participants (56%) and implemented for 7 (50%) at follow-up. No significant changes in other secondary outcomes were observed. CONCLUSION: The intervention was delivered as planned, and valued by stakeholders. Recruitment barriers should be addressed before wider implementation.

Quantitative Proteomics of Clinically Relevant Drug-Metabolizing Enzymes and Drug Transporters and Their Intercorrelations in the Human Small Intestine.

The levels of drug-metabolizing enzymes (DMEs) and transporter proteins in the human intestine are pertinent to determine oral drug bioavailability. Despite the paucity of reports on such measurements, it is well recognized that these values are essential for translating in vitro data on drug metabolism and transport to predict drug disposition in gut wall. In the current study, clinically relevant DMEs [cytochrome P450 (P450) and uridine 5'-diphospho-glucuronosyltransferase (UGT)] and drug transporters were quantified in total mucosal protein preparations from the human jejunum (n = 4) and ileum (n = 12) using quantification concatemer-based targeted proteomics. In contrast to previous reports, UGT2B15 and organic anion-transporting polypeptide 1 (OATP1A2) were quantifiable in all our samples. Overall, no significant disparities in protein expression were observed between jejunum and ileum. Relative mRNA expression for drug transporters did not correlate with the abundance of their cognate protein, except for P-glycoprotein 1 (P-gp) and organic solute transporter subunit alpha (OST-α), highlighting the limitations of RNA as a surrogate for protein expression in dynamic tissues with high turnover. Intercorrelations were found within P450 [2C9-2C19 (P = 0.002, R 2 = 0.63), 2C9-2J2 (P = 0.004, R 2 = 0.40), 2D6-2J2 (P = 0.002, R 2 = 0.50)] and UGT [1A1-2B7 (P = 0.02, R 2 = 0.87)] family of enzymes. There were also correlations between P-gp and several other proteins [OST-α (P < 0.0001, R 2 = 0.77), UGT1A6 (P = 0.009, R 2 = 0.38), and CYP3A4 (P = 0.007, R 2 = 0.30)]. Incorporating such correlations into building virtual populations is crucial for obtaining plausible characteristics of simulated individuals. SIGNIFICANCE STATEMENT: A number of drug transporters were quantified for the first time in this study. Several intercorrelations of protein abundance were reported. mRNA expression levels proved to be a poor reflection of differences between individuals regarding the level of protein expression in gut. The reported abundance of drug-metabolizing enzymes and transporters and their intercorrelations will contribute to better predictions of oral drug bioavailability and drug-drug interactions by linking in vitro observations to potential outcomes through physiologically based pharmacokinetic models.

Drivers Advancing Oral Health in a Large Group Dental Practice Organization.

UNLABELLED: Three change drivers are being implemented to high standards of patient centric and evidence-based oral health care within the context of a large multispecialty dental group practice organization based on the commitment of the dental hygienist chief operating officer and her team. BACKGROUND AND PURPOSE: A recent environmental scan elucidated 6 change drivers that can impact the provision of oral health care. Practitioners who can embrace and maximize aspects of these change drivers will move dentistry forward and create future opportunities. This article explains how 3 of these change drivers are being applied in a privately held, accountable risk-bearing entity that provides individualized treatment programs for more than 417,000 members. To facilitate integration of the conceptual changes related to the drivers, a multi-institutional, multidisciplinary, highly functioning collaborative work group was formed. METHODS AND APPROACH: The document Dental Hygiene at a Crossroads for Change(1) inspired the first author, a dental hygienist in a unique position as chief operating officer of a large group practice, to pursue evidence-based organizational change and to impact the quality of patient care. This was accomplished by implementing technological advances including dental diagnosis terminology in the electronic health record, clinical decision support, standardized treatment guidelines, quality metrics, and patient engagement to improve oral health outcomes at the patient and population levels. The systems and processes used to implement 3 change drivers into a large multi-practice dental setting is presented to inform and inspire others to implement change drivers with the potential for advancing oral health. CONCLUSIONS: Technology implementing best practices and improving patient engagement are excellent drivers to advance oral health and are an effective use of oral health care dollars. Improved oral health can be leveraged through technological advances to improve clinical practice.

Medium-Chain Acyl-CoA Dehydrogenase Deficiency in Adulthood: A Potential Diagnosis in a Patient with Mental Status Changes Suspected of Drug Toxicity.

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a rare but important component of the differential diagnosis for adults with a history of premortem mental status changes and the postmortem finding of hepatic steatosis. This case report describes a 30-year-old white man who, following a period of nausea and vomiting, was admitted to the hospital with sudden mental status deterioration followed rapidly by clinical deterioration and death. Treating physicians in this case suspected acute illicit drug toxicity with synthetic cathinones based on social history. Clinicians and medical examiners should be aware that the presentation, signs, and symptoms described may indicate an underlying inborn error of metabolism such as MCAD deficiency and take action accordingly.

Markers of feline leukaemia virus infection or exposure in cats from a region of low seroprevalence.

Molecular techniques have demonstrated that cats may harbour feline leukaemia virus (FeLV) provirus in the absence of antigenaemia. Using quantitative real-time polymerase chain reaction (qPCR), p27 enzyme-linked immunosorbent assay (ELISA), anti-feline oncornavirus-associated cell-membrane-antigen (FOCMA) antibody testing and virus isolation (VI) we investigated three groups of cats. Among cats with cytopenias or lymphoma, 2/75 were transiently positive for provirus and anti-FOCMA antibodies were the only evidence of exposure in another. In 169 young, healthy cats, all tests were negative. In contrast, 3/4 cats from a closed household where FeLV was confirmed by isolation, had evidence of infection. Our results support a role for factors other than FeLV in the pathogenesis of cytopenias and lymphoma. There was no evidence of exposure in young cats. In regions of low prevalence, where the positive predictive value of antigen testing is low, qPCR may assist with diagnosis.

Personalized genomic medicine: lessons from the exome.

While genomic sequencing methods are powerful tools in the discovery of the genetic underpinnings of human disease, incidentally-revealed novel genomic risk factors may be equally important, both scientifically, and as relates to direct patient care. We performed whole-exome sequencing on a child with VACTERL association who suffered severe post-surgical neonatal pulmonary hypertension, and identified a potential novel genetic risk factor for this complication: a heterozygous mutation in CPSI. Newborn screening results from this patient's monozygotic twin provided evidence that this mutation, in combination with an environmental trigger (in this case, surgery), may have resulted in pulmonary artery hypertension due to inadequate nitric oxide production. Identification of this genetic risk factor allows for targeted medical preventative measures in this patient as well as relatives with the same mutation, and illustrates the power of incidental medical information unearthed by whole-exome sequencing.