Revisiting Ophidiomycosis (Snake Fungal Disease) After a Decade of Targeted Research.

Emerging infectious diseases (EIDs) are typically characterized by novelty (recent detection) and by increasing incidence, distribution, and/or pathogenicity. Ophidiomycosis, also called snake fungal disease, is caused by the fungus Ophidiomyces ophidiicola (formerly "ophiodiicola"). Ophidiomycosis has been characterized as an EID and as a potential threat to populations of Nearctic snakes, sparking over a decade of targeted research. However, the severity of this threat is unclear. We reviewed the available literature to quantify incidence and effects of ophidiomycosis in Nearctic snakes, and to evaluate whether the evidence supports the ongoing characterization of ophidiomycosis as an EID. Data from Canada remain scarce, so we supplemented the literature review with surveys for O. ophidiicola in the Canadian Great Lakes region. Peer-reviewed reports of clinical signs consistent with ophidiomycosis in free-ranging, Nearctic snakes date back to at least 1998, and retrospective molecular testing of samples extend the earliest confirmed record to 1986. Diagnostic criteria varied among publications (n = 33), confounding quantitative comparisons. Ophidiomycosis was diagnosed or suspected in 36/121 captive snakes and was fatal in over half of cases (66.7%). This result may implicate captivity-related stress as a risk factor for mortality from ophidiomycosis, but could also reflect reporting bias (i.e., infections are more likely to be detected in captive snakes, and severe cases are more likely to be reported). In contrast, ophidiomycosis was diagnosed or suspected in 441/2,384 free-ranging snakes, with mortality observed in 43 (9.8 %). Ophidiomycosis was only speculatively linked to population declines, and we found no evidence that the prevalence of the pathogen or disease increased over the past decade of targeted research. Supplemental surveys and molecular (qPCR) testing in Ontario, Canada detected O. ophidiicola on 76 of 657 free-ranging snakes sampled across ~136,000 km2. The pathogen was detected at most sites despite limited and haphazard sampling. No large-scale mortality was observed. Current evidence supports previous suggestions that the pathogen is a widespread, previously unrecognized endemic, rather than a novel pathogen. Ophidiomycosis may not pose an imminent threat to Nearctic snakes, but further research should investigate potential sublethal effects of ophidiomycosis such as altered reproductive success that could impact population growth, and explore whether shifting environmental conditions may alter host susceptibility.

Electronically monitored dosing histories can be used to develop a medication-taking habit and manage patient adherence.

Nonadherence to prescribed medications can lead to medical complications, disease progression, hospitalizations, overestimated dosing requirements, impaired quality of life, and death, as well as incurring substantive costs for the healthcare system from suboptimal dosing during ambulatory pharmacotherapy. Adherence can be improved by helping patients build habits of taking prescribed medications, impacting day-to-day implementation of and persistence with rationally prescribed drug dosing regimens. Accurate, easily understood and personally relevant feedback is clearly relevant to many patients in this process. There is a clear-cut need for studies specifically designed to investigate interventions aimed at improving adherence, taking into account the sometimes complex nature of these interventions. Implementation of results from such studies can be expected to improve outcomes. For scientific progress to be maintained in this field, there is also a clear need for consistent use of a sound taxonomy for the dosing errors that comprise poor adherence (distinguishing between initiation, implementation and discontinuation), and for interventions performed to improve adherence.

Identification and assessment of adherence-enhancing interventions in studies assessing medication adherence through electronically compiled drug dosing histories: a systematic literature review and meta-analysis.

BACKGROUND: Non-adherence to medications is prevalent across all medical conditions that include ambulatory pharmacotherapy and is thus a major barrier to achieving the benefits of otherwise effective medicines. OBJECTIVE: The objective of this systematic review was to identify and to compare the efficacy of strategies and components thereof that improve implementation of the prescribed drug dosing regimen and maintain long-term persistence, based on quantitative evaluation of effect sizes across the aggregated trials. DATA SOURCES: MEDLINE, EMBASE, CINAHL, the Cochrane Library, and PsycINFO were systematically searched for randomized controlled trials that tested the efficacy of adherence-enhancing strategies with self-administered medications. The searches were limited to papers in the English language and were included from database inception to 31 December 2011. STUDY SELECTION: Our review included randomized controlled trials in which adherence was assessed by electronically compiled drug dosing histories. Five thousand four hundred studies were screened. Eligibility assessment was performed independently by two reviewers. A structured data collection sheet was developed to extract data from each study. STUDY APPRAISAL AND SYNTHESIS METHODS: The adherence-enhancing components were classified in eight categories. Quality of the papers was assessed using the criteria of the Cochrane Handbook for Systematic Reviews of Interventions guidelines to assess potential bias. A combined adherence outcome was derived from the different adherence variables available in the studies by extracting from each paper the available adherence summary variables in a pre-defined order (correct dosing, taking adherence, timing adherence, percentage of adherent patients). To study the association between the adherence-enhancing components and their effect on adherence, a linear meta-regression model, based on mean adherence point estimates, and a meta-analysis were conducted. RESULTS: Seventy-nine clinical trials published between 1995 and December 2011 were included in the review. Patients randomized to an intervention group had an average combined adherence outcome of 74.3 %, which was 14.1 % higher than in patients randomized to the control group (60.2 %). The linear meta-regression analysis with stepwise variable selection estimated an 8.8 % increase in adherence when the intervention included feedback to the patients of their recent dosing history (EM-feedback) (p < 0.01) and a 5.0 % increase in adherence when the intervention included a cognitive-educational component (p = 0.02). In addition, the effect of interventions on adherence decreased by 1.1 % each month. Sensitivity analysis by selecting only high-quality papers confirmed the robustness of the model. The random effects model in the meta-analysis, conducted on 48 studies, confirmed the above findings and showed that the improvement in adherence was 19.8 % (95 % CI 10.7-28.9 %) among patients receiving EM-feedback, almost double the improvement in adherence for studies that did not include this type of feedback [10.3 % (95 % CI 7.5-13.1 %)] (p < 0.01). The improvement in adherence was 16.1 % (95 % CI 10.7-21.6 %) in studies that tested cognitive-educational components versus 10.1 % (95 % CI 6.6-13.6 %) in studies that did not include this type of intervention (p = 0.04). Among 57 studies measuring clinical outcomes, only 8 reported a significant improvement in clinical outcome. LIMITATIONS: Despite a common measurement, the meta-analysis was limited by the heterogeneity of the pooled data and the different measures of medication adherence. The funnel plot showed a possible publication bias in studies with high variability of the intervention effect. CONCLUSIONS: Notwithstanding the statistical heterogeneity among the studies identified, and potential publication bias, the evidence from our meta-analysis suggests that EM-feedback and cognitive-educational interventions are potentially effective approaches to enhance patient adherence to medications. The limitations of this research highlight the urgent need to define guidelines and study characteristics for research protocols that can guide researchers in designing studies to assess the effects of adherence-enhancing interventions.

Young adult preventive health care guidelines: there but can't be found.

OBJECTIVES: To (1) identify adolescent and adult clinical preventive services guidelines relevant to the young adult age group; (2) review, compare, and synthesize these guidelines, with emphasis on the extent to which professional guidelines are consistent with evidence-based guidelines developed by the US Preventive Services Task Force; and (3) recommend the next steps in the establishment and integration of preventive care guidelines for young adults. DESIGN: Nonexperimental: an Internet search was conducted to identify relevant preventive care guidelines for the young adult group. SETTING: The search included federal agencies and professional organizations that focus on health areas linked to the care of young adults or that provide health care to adolescents and young adults. PARTICIPANTS: National organizations, federal agencies, health professional associations, and medical societies. MAIN OUTCOME MEASURES: Preventive services guidelines for adolescents and adults that intersect with the age range of 18 to 26 years. RESULTS: When the ages of 18 to 26 years are carved out of established professional guidelines across specialty groups, there is a broad number of recommendations, with many supported by sufficient evidence to receive a US Preventive Services Task Force grade of A or B that can inform the care of young adults. CONCLUSIONS: We recommend the establishment of young adult preventive health guidelines that reflect the current evidence-based recommendations that overlap with the young adult age group; we suggest clinician and health care system supports to facilitate the delivery of preventive services to young adults; and we emphasize prioritizing research in prevention areas in which sufficient evidence does not exist.

Adherence to medications: insights arising from studies on the unreliable link between prescribed and actual drug dosing histories.

Satisfactory adherence to aptly prescribed medications is essential for good outcomes of patient care and reliable evaluation of competing modes of drug treatment. The measure of satisfactory adherence is a dosing history that includes timely initiation of dosing plus punctual and persistent execution of the dosing regimen throughout the specified duration of treatment. Standardized terminology for initiation, execution, and persistence of drug dosing is essential for clarity of communication and scientific progress. Electronic methods for compiling drug dosing histories are now the recognized standard for quantifying adherence, the parameters of which support model-based, continuous projections of drug actions and concentrations in plasma that are confirmable by intermittent, direct measurements at single time points. The frequency of inadequate adherence is usually underestimated by pre-electronic methods and thus is clinically unrecognized as a frequent cause of failed treatment or underestimated effectiveness. Intermittent lapses in dosing are potential sources of toxicity through hazardous rebound effects or recurrent first-dose effects.

[Compliance, concordance, adherence]. / Compliance, Konkordanz, Adhärenz.

Ambulatory pharmacotherapy is marked by many deviations, mostly downward, in drug dosing from prescribed instructions. Soundly compiled dosing histories date from 1977, based on electronic time-stamping of medication 'events': package entry times, done first with eyedrop dispensers for glaucoma drugs. Electronically monitored packages for oral dosage forms date from 1988. Since then, expanding data have brought many surprises, as evidence has replaced eminence in clinical views regarding discrepancies between prescription and reality. Key features of electronic monitoring are: automaticity of time-stamping, inviolable data, and high rates of data-sampling (60/hr vs 2 - 12/yr with older methods), revealing time-of-day, day-of-week, and white coat effects that facilitate medication management, opening new ways to improve care.

Living history: F. Eugene Yates.

In 2005, the American Physiological Society (APS) initiated the Living History of Physiology Archival Program to recognize senior members who have made significant contributions during their career to the advancement of the discipline and the profession of physiology. During 2008, the APS Cardiovascular Section selected Francis Eugene Yates to be profiled in Advances in Physiology Education.

Historical vicariance and male-mediated gene flow in the toad-headed lizards Phrynocephalus przewalskii.

Using mitochondrial and microsatellite DNA data and a population genetic approach, we tested male-mediated gene flow in the toad-headed lizards Phrynocephalus przewalskii. The mitochondrial DNA (ND2 gene), on the one hand, revealed two major lineages and a strong population genetic structure (F(ST) = 0.692; F(ST)' = 0.995). The pairwise differences between the two lineages ranged from 2.1% to 6.4% and the geographical division of the two lineages coincided with a mountain chain consisting of the Helan and Yin Mountains, suggesting a historical vicariant pattern. On the other hand, the nuclear microsatellite DNA revealed a significant but small population genetic structure (F(ST) = 0.017; F(ST)' = 0.372). The pairwise F(ST) among the nine populations examined with seven microsatellite DNA loci ranged from 0.0062 to 0.0266; the assignment test failed to detect any naturally occurring population clusters. Furthermore, the populations demonstrated a weak isolation by distance and a northeast to southwest clinal variation, rather than a vicariant pattern. A historical vicariant event followed by male-mediated gene flow appears to be the best explanation for the data. Approximately 2-5 Ma, climatic change may have created an uninhabitable zone along the Helan-Yin mountain chain and initiated the divergence between the two mitochondrial lineages. With further climatic changes, males were able to disperse across the mountain chain, causing sufficient gene flow that eventually erased the vicariant pattern and drastically reduced the population genetic structure, while females remained philopatric and maintained the mitochondrial DNA (mtDNA) divergence. Although polygyny mating system and female philopatry may partially contribute to the reduced movement of females, other hypotheses, such as female intrasexual aggression, should also be explored.

Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories.

OBJECTIVE: To describe characteristics of dosing history in patients prescribed a once a day antihypertensive medication. DESIGN: Longitudinal database study. SETTING: Clinical studies archived in database for 1989-2006. PARTICIPANTS: Patients who participated in the studies whose dosing histories were available through electronic monitoring. MAIN OUTCOME MEASURES: Persistence with prescribed antihypertensive treatment and execution of their once a day drug dosing regimens. RESULTS: The database contained dosing histories of 4783 patients with hypertension. The data came from 21 phase IV clinical studies, with lengths ranging from 30 to 330 days and involving 43 different antihypertensive drugs, including angiotensin II receptor blockers (n=2088), calcium channel blockers (n=937), angiotensin converting enzyme inhibitors (n=665), beta blockers (n=195), and diuretics (n=155). About half of the patients who were prescribed an antihypertensive drug had stopped taking it within one year. On any day, patients who were still engaged with the drug dosing regimen omitted about 10% of the scheduled doses: 42% of these omissions were of a single day's dose, whereas 43% were part of a sequence of several days (three or more days-that is, drug "holidays"). Almost half of the patients had at least one drug holiday a year. The likelihood that a patient would discontinue treatment early was inversely related to the quality of his or her daily execution of the dosing regimen. CONCLUSIONS: Early discontinuation of treatment and suboptimal daily execution of the prescribed regimens are the most common facets of poor adherence with once a day antihypertensive drug treatments. The shortfalls in drug exposure that these dosing errors create might be a common cause of low rates of blood pressure control and high variability in responses to prescribed antihypertensive drugs.

Estimation of the comparative therapeutic superiority of QD and BID dosing regimens, based on integrated analysis of dosing history data and pharmacokinetics.

Once-daily dosing almost invariably shows a slightly higher percentage of prescribed doses taken than does twice-daily dosing. Many pharmaceutical scientists, regulators, and prescribers have considered this finding to signify the therapeutic superiority of once-daily dosing. The therapeutically more relevant question, however, is not the percentage of prescribed doses taken but the comparative impact of missed doses on the pharmacologic effects of a drug under the two dosing regimens. A key point in this regard is that the pharmacokinetic equivalent of a single missed once-daily dose is 2-3 sequentially omitted twice-daily doses. Thus, an important parameter in comparing the two regimens is the probability of two or three twice-daily doses being sequentially omitted, versus the probability of missing a single once-daily dose. Our data indicate that the probability of sequential omission of 2-3 twice daily doses is half the probability of omission of a single once-daily dose. For that reason, a twice-daily regimen could prove to be superior to a once-daily regimen in maintaining drug concentrations within a therapeutically desirable range. A more important consideration, however, is to maintain not just the concentration of drug in plasma, but the drug's therapeutic action. The duration of therapeutic drug action following a last-taken dose is not only drug-specific, but also, for some drug, dependent on the pharmacodynamic properties. Judging the comparative superiority of one dosing regimen over another requires knowledge of the drug's duration action after a last-taken dose, plus knowledge of the comparative probabilities of the various patterns of dose omission. When applied to HIV protease inhibitors, a twice-daily regimen appears to be better than an once-daily regimen in maintaining therapeutically effective drug actions.

Modelling the association between adherence and viral load in HIV-infected patients.

The primary objective of this paper is to investigate the effect of adherence to prescribed antiretroviral therapy on virologic response measured repeatedly over time in HIV-infected patients. To this end observations on plasma viral load (HIV RNA) assessed in copies/ml are categorized into four clinically meaningful states, [0--50[, [50--400[, [400--2000[, [2000 and up. A time-dependent continuation ratio model is used to analyse longitudinal ordinal responses. The main challenge lies in modelling dependencies over time and using information contained in the data efficiently to establish a dynamic relation between observed patient adherence and viral load. Among the several measures of adherence investigated, two specifically account for long periods of time without intake. One is derived from the third moment of the inter-dose interval distribution, while the second reflects internal drug exposure using pharmacokinetic parameters. The approach is applied to a clinical trial involving 35 patients who were followed over 12 months. Results demonstrate a significant relation between patient adherence and virologic response.

Successful projection of the time course of drug concentration in plasma during a 1-year period from electronically compiled dosing-time data used as input to individually parameterized pharmacokinetic models.

Pharmacokinetic studies rely on blood sampling at times relative to predefined dosing intervals. Intensive sampling is often done under direct observation of dose taking, which, though costly, virtually eliminates uncertainty about actual dosing times. In contrast, the sparse sampling done in population pharmacokinetic studies relies on patient-reported times of dosing, the accuracy of which the authors sought to assess by adding electronic monitoring to the usual patient reporting of dosing times. The study involved 35 antiretroviral-naive, human immunodeficency virus-infected patients and was designed to assess the safety, tolerability, pharmacokinetics, and antiviral activity of prescribed lopinavir/ritonavir (800/200 mg qd or 400/100 mg bid), stavudine, and lamivudine. The present research reports the pharmacokinetic analysis that results from taking into account the patients' actual dosing histories. Intensive sampling for plasma lopinavir concentrations was done at week 3, and 4 additional predose (trough) concentrations were measured during the next 12 months. Convergence was achieved by fitting a simple 1-compartment pharmacokinetic model, with first-order absorption and elimination, to the sparse sampling data, using electronic monitoring-reported times. In contrast, convergence was not achieved using the simple model when steady state was assumed, and the times for the last qd dose or the last 2 bid doses, as reported by the patient, were used as model input. Estimated individual pharmacokinetic parameters were then combined with electronic dosing histories to project each patient's internal drug exposure over long periods of time. This strategy may provide a basis for greatly increasing the informational yield and utility of conventional therapeutic drug monitoring.

Patient adherence to prescribed antimicrobial drug dosing regimens.

The aim of this article is to review current knowledge about the clinical impact of patients' variable adherence to prescribed anti-infective drug dosing regimens, with the aim of renewing interest and exploration of this important but largely neglected area of therapeutics. Central to the estimation of a patient's adherence to a prescribed drug regimen is a reliably compiled drug dosing history. Electronic monitoring methods have emerged as the virtual 'gold standard' for compiling drug dosing histories in ambulatory patients. Reliably compiled drug dosing histories are consistently downwardly skewed, with varying degrees of under-dosing. In particular, the consideration of time intervals between protease inhibitor doses has revealed that ambulatory patients' variable execution of prescribed dosing regimens is a leading source of variance in viral response. Such analyses reveal the need for a new discipline, called pharmionics, which is the study of how ambulatory patients use prescription drugs. Properly analysed, reliable data on the time-course of patients' actual intake of prescription drugs can eliminate a major source of unallocated variance in drug responses, including the non-response that occurs and is easily misinterpreted when a patient's complete non-execution of a prescribed drug regimen is unrecognized clinically. As such, reliable compilation of ambulatory patients' drug dosing histories has the promise of being a key step in reducing unallocated variance in drug response and in improving the informational yield of clinical trials. It is also the basis for sound, measurement-guided steps taken to improve a patient's execution of a prescribed dosing regimen.