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Aptamers are functional nucleic acids that bind to a range of targets (small molecules, proteins or cells) with a high affinity and specificity. Chemically-modified aptamers are of interest because the incorporation of novel nucleobase components can enhance aptamer binding to target proteins, while fluorescent base analogues permit the design of functional aptasensors that signal target binding. However, since optimally modified nucleoside designs have yet to be identified, information about how to fine tune aptamer stability and target binding affinity is required. The present work uses molecular dynamics (MD) simulations to investigate modifications to the prototypical thrombin-binding aptamer (TBA), which is a 15-mer DNA sequence that folds into a G-quadruplex structure connected by two TT loops and one TGT loop. Specifically, we modeled a previously synthesized thymine (T) analog, namely 5-furyl-2'-deoxyuridine (5FurU), into each of the six aptamer locations occupied by a thymine base in the TT or TGT loops of unbound and thrombin bound TBA. This modification and aptamer combination were chosen as a proof-of-principle because previous experimental studies have shown that TBA displays emissive sensitivity to target binding based on the local environment polarity at different 5FurU modification sites. Our simulations reveal that the chemically-modified base imparts noticeable structural changes to the aptamer without affecting the global conformation. Depending on the modification site, 5FurU performance is altered due to changes in the local environment, including the modification site structural dynamics, degree of solvent exposure, stacking with neighboring bases, and interactions with thrombin. Most importantly, these changes directly correlate with the experimentally-observed differences in the stability, binding affinity and emissive response of the modified aptamers. Therefore, the computational protocols implemented in the present work can be used in subsequent studies in a predictive way to aid the fine tuning of aptamer target recognition for use as biosensors (aptasensors) and/or therapeutics.

Background: Late-life depression (LLD) is a disabling disorder and antidepressants are ineffective in as many as 60% of cases. Converging evidence shows a strong correlation between LLD and subsequent risk of cardiovascular disease. There is a need for new, well-tolerated, non-pharmacological augmentation interventions that can treat depressive symptoms as well as improve heart rate variability (HRV), an important prognostic marker for development of subsequent cardiovascular disease. Meditation-based techniques are of interest based on positive findings in other samples.AimsWe aimed to assess the efficacy of Sahaj Samadhi meditation (SSM), an underevaluated, standardised and manualised meditation intervention, on HRV and depressive symptoms., Method: Eighty-three men and women aged 60-85 years, with mild to moderate depression and receiving treatment as usual (TAU) were randomised to either the SSM or TAU arm. Those allocated to SSM attended 4 consecutive days of group meditation training, using personalised mantras followed by 11 weekly reinforcement sessions. HRV and Hamilton Rating Scale for Depression (HRSD; 17-item) score were measured at baseline and 12 weeks., Results: All time and frequency domain measures of HRV did not significantly change in either arm. However, there was significant improvement in the SSM arm, compared with TAU, on the HRSD (difference in mean, 2.66; 95% CI 0.26-5.05; P = 0.03)., Conclusions: Compared with TAU, SSM is associated with improvements in depressive symptoms but does not significantly improve HRV in patients with LLD. These results need to be replicated in subsequent studies incorporating a group-based, active control arm.Declaration of interestR.I.N. is the Director of Research and Health Promotion for the Art of Living Foundation, Canada and supervised the staff providing Sahaj Samadhi meditation. S.R. has received research funding from Satellite Healthcare for a mindfulness meditation trial in patients on haemodialysis. The remaining authors report no financial or other relationship relevant to the subject of this article.

Introduction: Targeted therapies, including tyrosine kinase inhibitors (TKIs) that target the sensitizing epidermal growth factor receptor (EGFR) gene are recommended for patients with non-small cell lung cancer (NSCLC). Most patients with NSCLC who test positive for the EGFR mutation and receive TKIs develop resistance to these drugs. Questions remain regarding which treatment sequence is optimal for patients with EGFR-mutant NSCLC, and few studies have evaluated patterns of TKI treatment use in NSCLC, irrespective of EGFR mutation status, in a real-world setting. This population-based study aimed to evaluate treatment patterns at a national level in the USA., Methods: This retrospective observational study used data from the US Oncology Network's iKnowMed database. Patients with advanced NSCLC who initiated first-line therapy with erlotinib and/or intravenous chemotherapy between January 1, 2012 and June 30, 2015 and met all other study criteria were included. Descriptive analyses assessed demographic and clinical characteristics and treatment patterns among the overall study cohort, as well as for specific erlotinib treatment subgroups, stratified by EGFR status., Results: Among the 3108 patients identified, 18.5% were EGFR positive, 49.8% were EGFR negative, and 31.7% were EGFR documented unknown. For the overall cohort, 18.4% received first-line erlotinib monotherapy, fewer than 1% received first-line combination therapy (erlotinib plus chemotherapy), 4.7% received second-line erlotinib monotherapy, and 3.3% received second-line combination therapy. First-line erlotinib monotherapy was used in 77.8% of all EGFR positive patients. Almost two-thirds of the overall cohort were not observed to have advanced to second-line therapy., Conclusions: As treatment options evolve, this study provides real-world treatment patterns that suggest concordance with NCCN guidelines and confirm the remaining need to understand sequencing of therapies and related outcomes., Funding: Eli Lilly and Company.

Objective: To determine the range of services and procedures offered by family physicians who define themselves as comprehensive practitioners and compare responses across 3 generations of alumni of a single family practice program., Design: Cross-sectional survey., Setting: Western University in London, Ont., Participants: All graduates of the family medicine program between 1985 and 2012., Main Outcome Measures: Self-reported provision of the following types of care: in-office care, in-hospital care, intrapartum obstetrics, housecalls, palliative care, after-hours care, nursing home care, minor surgery, emergency department care, sport medicine, and walk-in care. Sex, training site (urban or rural), size of community of practice, practice model, and satisfaction with practice were also reported., Results: Participants practised in 7 provinces and 1 territory across Canada, but principally in Ontario. A small number were located in the United States. There was a decline in the number of services provided across 3 generations of graduates, with newer graduates providing fewer services than the older graduates. Significant decreases across the 3 groups were observed in provision of housecalls ( P = .004), palliative care ( P = .028), and nursing home care ( P < .001). Non-significant changes were seen in provision of intrapartum obstetrics across the 3 alumni groups, with an initial decline and then increase in reported activity. Most respondents were in a family health organization or family health network practice model and those in such models reported offering significantly more services than those in family health group or salary models ( P < .001)., Conclusion: The normative definition of comprehensive care varies across 3 generations of graduates of this family medicine program, with newer physicians reporting fewer overall services and procedures than older graduates. Greater understanding of the forces (institutional, regulatory, economic, and personal) that determine the meaning of comprehensive primary care is necessary if this foundational element of family medicine is to be preserved., (Copyright© the College of Family Physicians of Canada.)

Objective: Determine the effect of complete malleus removal during canal wall up tympanomastoidectomy for cholesteatoma on ossiculoplasty success and rate of residual cholesteatoma., Methods: We reviewed the operative, audiogram, and clinical reports of patients who underwent canal wall up tympanomastoidectomy for cholesteatoma between 2009 and 2016 at a tertiary academic medical center with at least 8 months of follow-up after surgery. To control for extent of disease, we independently catalogued the subsites of the middle ear and mastoid that cholesteatoma involved from each operation. We performed multivariate logistic regression to determine the independent effect of complete removal of the malleus on the rate of residual disease and success of ossiculoplasty., Results: One hundred eighty surgeries were included in the analysis. For ossiculoplasty success, the adjusted odds ratio of complete malleus removal was 1.7 (95% CI, 0.43-7.0, P = .43), which was not statistically significant. For residual disease, the adjusted odds ratio of complete malleus removal versus not was 0.29 (95% CI, 0.074-1.1, P = .076), which approached but did not meet statistical significance., Conclusion: Though complete malleus removal does not independently decrease the rate of residual cholesteatoma, it may be a safe technique as it did not compromise ossiculoplasty success.

Aim: To assess the cost-effectiveness of first-line pemetrexed/platinum and other commonly administered regimens in a representative US elderly population with advanced non-squamous non-small cell lung cancer (NSCLC)., Materials and Methods: This study utilized the Surveillance Epidemiology and End Results (SEER) cancer registry linked to Medicare claims records. The study population included all SEER-Medicare patients diagnosed in 2008-2009 with advanced non-squamous NSCLC (stages IIIB-IV) as their only primary cancer and who started chemotherapy within 90 days of diagnosis. The study evaluated the four most commonly observed first-line regimens: paclitaxel/carboplatin, platinum monotherapy, pemetrexed/platinum, and paclitaxel/carboplatin/bevacizumab. Overall survival and total healthcare cost comparisons as well as incremental cost-effectiveness ratios (ICERs) were calculated for pemetrexed/platinum vs each of the other three. Unstratified analyses and analyses stratified by initial disease stage were conducted., Results: The final study population consisted of 2,461 patients. Greater administrative censorship of pemetrexed recipients at the end of the study period disproportionately reduced the observed mean survival for pemetrexed/platinum recipients. The disease stage-stratified ICER analysis found that the pemetrexed/platinum incurred total Medicare costs of $536,424 and $283,560 per observed additional year of life relative to platinum monotherapy and paclitaxel/carboplatin, respectively. The pemetrexed/platinum vs triplet comparator analysis indicated that pemetrexed/platinum was associated with considerably lower total Medicare costs, with no appreciable survival difference., Limitations: Limitations included differential censorship of the study regimen recipients and differential administration of radiotherapy., Conclusions: Pemetrexed/platinum yielded either improved survival at increased cost or similar survival at reduced cost relative to comparator regimens in the treatment of advanced non-squamous NSCLC. Limitations in the study methodology suggest that the observed pemetrexed survival benefit was likely conservative.

Background: The cost of cancer care is increasing, and tools are needed to understand the economic impact of new drugs on the hospital pharmacy budget., Objective: To develop an interactive budget impact model (BIM) through a collaborative effort of industry, academia, and modeling experts to evaluate the use of a new agent in non-small cell lung cancer (NSCLC); this BIM included an institutional module specific to the needs of practices that purchase medications for use in institutional settings., Methods: Treatment regimens, doses, duration of therapy, toxicity, and cost data are from published sources. All input data may be modified to match the local population. Outputs include cost of care, reimbursement, and margin overall and by treatment regimen., Results: The base case assumes 20 NSCLC patients progressing after initial therapy (3 receiving ramucirumab+docetaxel, 2 bevacizumab+erlotinib, 3 docetaxel, 6 erlotinib, and 6 pemetrexed), wholesale acquisition cost (WAC) purchase price, and reimbursement at WAC+4.3%. The model estimated the total cost and reimbursement for the institutional oncology pharmacy to be $699,413 and $729,487, respectively, resulting in a margin of $30,075 (difference due to rounding) for the year for regimens utilized in the treatment of NSCLC in the post-progression setting. Results will vary depending on the input data., Conclusions: There is an increasing need for institutional pharmacies to plan ahead and anticipate the impact of new drugs on their oncology budgets. This interactive Excel-based institutional BIM may provide evidence-based support for pharmacy decision making.

Late-life depression affects 2-6% of seniors aged 60 years and above. Patients are increasingly embracing non-pharmacological therapies, many of which have not been scientifically evaluated. This study aimed to evaluate a category of meditation, automatic self-transcending meditation (ASTM), in alleviating symptoms of depression when augmenting treatment as usual (NCT02149810). The preliminary results of an ongoing single-blind randomised controlled trial comparing a training programme involving ASTM with a wait-list control indicate that a 12-week ASTM programme may lead to significantly greater reductions in depression and anxiety severity. As such, ASTM may be an effective adjunctive therapy in the treatment of late-life depression., Declaration of Interest: R.I.N. is Director of Research and Health Promotion for the Art of Living Foundation, Canada and supervised the staff providing ASTM training., Copyright and Usage: © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

Background: The prevalence and socioeconomic cost of late life depression (LLD) is on the rise, while the response rate to antidepressant trials remains poor. Various mind-body therapies are being embraced by patients as they are considered safe and potentially effective, yet little is known regarding the effectiveness of such therapies to improve LLD symptoms. Among the mind-body therapies currently in practice, the results of our pilot study have shown that a particular meditation technique called Sahaj Samadhi Meditation, which belongs to the category of meditation termed automatic self-transcending meditation (ASTM) may have some promise in improving cardiovascular autonomic disturbances associated with LLD as well as ameliorating symptoms of depression and anxiety., Methods/design: Patients between the ages of 60 and 85 with LLD will be randomized either to ASTM plus treatment as usual (TAU) or TAU alone to assess changes in cardiovascular autonomic parameters, neuropsychological symptoms of depression and anxiety as well as quality of life. The instructional phase of the intervention consists of 4 consecutive days of meditation training, after which participants are encouraged to meditate twice daily for twenty minutes each time at home. The intervention also includes once weekly follow up sessions for the subsequent 11 weeks. The planned study has one and a half year recruitment period. Participants will be assessed at baseline and at 4, 8, 12 and 24 weeks post intervention., Discussion: This study should provide a unique data source from a randomized, controlled, longitudinal trial to investigate the effects of a form of ASTM on cardiovascular autonomic and neuropsychological health in LLD., Trial Registration: Clinicaltrials.gov NCT02149810, date registered: 05/28/2014.

Objective: To determine patient satisfaction with care provided at a family medicine teaching clinic., Design: Mailed survey., Setting: Victoria Family Medical Centre in London, Ont., Participants: Stratified random sample of 600 regular patients of the clinic aged 18 years or older; 301 responses were received., Main Outcome Measures: Patient satisfaction with overall care, wait times for appointments, contact with physicians, and associated demographic factors. Logistic regression analysis and analysis were used to determine the significance of factors associated with satisfaction., Results: The response rate was 50%. Overall, 88% of respondents were fairly, very, or completely satisfied with care. Older patients tended to be more satisfied. Patients who were less satisfied had longer wait times for appointments (P < .001) and reduced continuity with specific doctors (P = .004). More satisfied patients also felt connected through other members of the health care team., Conclusion: Patients were generally satisfied with the care provided at the family medicine teaching clinic. Older patients tended to be more satisfied than younger patients. Points of dissatisfaction were related to wait times for appointments and continuity with patients' usual doctors. These findings support the adoption of practices that reduce wait times and facilitate continuity with patients' usual doctors and other regular members of the health care team.

Objective: Many parents of preschool-age children have concerns about how to discipline their child but few receive help. We examined the effects of a brief treatment along with usual care, compared with receiving usual care alone. Patients. Parents (N = 178) with concerns about their 2- to 5-year olds' discipline were recruited when they visited their family physician at 1 of 24 practices., Methods: After completing mailed baseline measures, parents were randomly assigned to receive usual care or the Parenting Matters intervention along with usual care. Parenting Matters combined a self-help booklet with two calls from a telephone coach during a 6-week treatment period. Follow-up assessments were completed at 7 weeks post-randomization, and 3 and 6 months later., Results: Behaviour problems (Eyberg Child Behaviour Inventory) decreased significantly more in the Parenting Matters condition compared with Usual Care alone, based on a significant time by treatment group effect in intent-to-treat, growth curve analyses (P = 0.033). The Parenting Matters group also demonstrated greater and more rapid improvement than in usual care alone in terms of overall psychopathology (Child Behaviour Checklist, P = 0.02), but there were no group differences in parenting. The overall magnitude of group differences was small (d = 0.15 or less)., Conclusion: A brief early intervention combining a self-help booklet and telephone coaching is an effective way to treat mild behaviour problems among young children. This minimal-contact approach addresses the need for interventions in primary health care settings and may be a useful component in step-care models of mental health.

Objective: To develop and describe observable evaluation objectives for assessing competence in professionalism, which are grounded in the experience of practising physicians., Design: Modified nominal group technique., Setting: The College of Family Physicians of Canada in Mississauga, Ont., Participants: An expert group of 7 family physicians and 1 educational consultant, all of whom had experience in assessing competence in family medicine. Group members represented the Canadian context with respect to region, sex, language, community type, and experience., Methods: Using an iterative process, the expert group defined a list of observable behaviours that are indicative of professionalism, or not, in the family medicine setting. Themes relate to professional behaviour in family medicine; specific observable behaviours are those that family physicians believe are indicative of professionalism for each theme., Main Findings: The expert group identified 12 themes and 140 specific observable behaviours to assist in the observation and discussion of professional behaviour in family medicine workplace settings., Conclusion: Competency-based education literature emphasizes the importance of formative evaluation and feedback. Such feedback is particularly challenging in the domain of professionalism because of its personal nature and the potential for emotional reactions. Effective dialogue between learners and teachers begins with clear expectations and reference to descriptions of relevant, specific behaviour. This research has generated a competency-based resource to assist the assessment of professional behaviour in family medicine educational programs.

Objective: To develop evaluation objectives for assessing competence in procedure skills using a key-features approach. This was part of a multiyear project to develop competency-based evaluation objectives for Certification in Family Medicine., Design: Nominal group technique., Setting: The College of Family Physicians of Canada in Mississauga, Ont., Participants: An expert group of 7 family physicians and 1 educational consultant, all of whom had experience in assessing competence in family medicine. Group members represented the Canadian context with respect to region, sex, language, community type, and experience., Methods: Using a nominal group technique, the expert group developed the general key features for procedure skills. The expert group also linked the key features to already established skill dimensions in the domain of competence, to the 4 principles of family medicine, and to the CanMEDS roles., Main Findings: The general key features were developed after 5 iterations. Ten key features were outlined and were shown to reflect all the essential skill dimensions in the domain of competence for family medicine. The key features were linked to 2 of the 4 principles of family medicine and to 4 of the CanMEDS roles., Conclusion: The general key features for procedure skills were developed to assess competence in procedure skills in family medicine.

Objective: To provide a pragmatic approach to the evaluation of communication skills using observable behaviours, as part of a multiyear project to develop competency-based evaluation objectives for Certification in family medicine., Design: A nominal group technique was used to develop themes and subthemes and to identify positive and negative observable behaviours that demonstrate competence in communication in family medicine., Setting: The College of Family Physicians of Canada in Mississauga, Ont., Participants: An expert group of 7 family physicians and 1 educational consultant, all of whom had experience in assessing competence in family medicine. Group members represented the Canadian context with respect to region, sex, language, community type, and experience., Methods: The group used the nominal group technique to derive a list of observable behaviours that would constitute a detailed operational definition of competence in communication skills; multiple iterations were used until saturation was achieved. The group met several times a year, and membership remained unchanged during the 4 years in which the work was conducted. The iterative process was undertaken twice--once for communication with patients and once for communication with colleagues., Main Findings: Five themes, 5 subthemes, and 106 positive and negative observable behaviours were generated. The subtheme of charting skills was defined using a key-features analysis., Conclusion: Communication skills were defined in terms of themes and observable behaviours. These definitions were intended to help assess family physicians' competence at the start of independent practice.

Objective: To develop key features for priority topics previously identified by the College of Family Physicians of Canada that, together with skill dimensions and phases of the clinical encounter, broadly describe competence in family medicine., Design: Modified nominal group methodology, which was used to develop key features for each priority topic through an iterative process., Setting: The College of Family Physicians of Canada., Participants: An expert group of 7 family physicians and 1 educational consultant, all of whom had experience in assessing competence in family medicine. Group members represented the Canadian family medicine context with respect to region, sex, language, community type, and experience., Methods: The group used a modified Delphi process to derive a detailed operational definition of competence, using multiple iterations until consensus was achieved for the items under discussion. The group met 3 to 4 times a year from 2000 to 2007., Main Findings: The group analyzed 99 topics and generated 773 key features. There were 2 to 20 (average 7.8) key features per topic; 63% of the key features focused on the diagnostic phase of the clinical encounter., Conclusion: This project expands previous descriptions of the process of generating key features for assessment, and removes this process from the context of written examinations. A key-features analysis of topics focuses on higher-order cognitive processes of clinical competence. The project did not define all the skill dimensions of competence to the same degree, but it clearly identified those requiring further definition. This work generates part of a discipline-specific, competency-based definition of family medicine for assessment purposes. It limits the domain for assessment purposes, which is an advantage for the teaching and assessment of learners. A validation study on the content of this work would ensure that it truly reflects competence in family medicine.

Objectives: To compare the accuracy and precision of a manufacturer-supplied dropper versus a pharmacy-supplied syringe when measured by a trained student pharmacist and to evaluate patients' ability to accurately measure a prescribed amount of medication with these devices before and after counseling on their use., Methods: This was a two-phased study with a pretest/posttest design of 125 community pharmacy patrons of Virginia community pharmacies. Deliverable volume was measured by a student pharmacist for nystatin suspension and digoxin elixir using the manufactured-supplied device. Patients at pharmacies were asked to complete a short survey, then asked to measure a specified dose of nystatin suspension and digoxin elixir (using the manufacturer-supplied administration device). The patients repeated this a second time after a student provided education on how to properly use each administration device. The main outcomes measure was whether education on an administration device would provide more measurement accuracy using medications with different physical properties., Results: For nystatin, 88% and 85.6% of patients measured with an error of greater than or equal to 20% before and after counseling, respectively. For digoxin, the totals were 24.8% before counseling and 4% after. A statistically significant (P < 0.05) difference was observed in the percent measurement error before and after counseling for nystatin and digoxin both for patients who had been educated before the study and for those who had not been counseled., Conclusion: In general, the accuracy of medication dosage devices seems to be most affected by viscosity of the liquid being measured. With education on proper use, the oral syringe provides a statistically and clinically significant improvement in dosing accuracy for viscous medications compared with the manufacturer-supplied dropper. Pharmacists must review with patients the proper way to use a manufacturer- or pharmacy-supplied oral delivery device for appropriate dosing measurements.

In North America, zebra mussels (Dreissena polymorpha) are notoriously known as invasive species. The abundance of naked amoebae sampled from the shells of zebra mussels was compared with abundances from rock scrapings at approximately monthly intervals for 1 year. The sites were 2 km apart along the same shoreline. No significant difference in abundance of naked amoebae (F = 1.44; P

Peptide mimics containing spirocyclic glucosyl-(3'-hydroxy-5'-hydroxymethyl)proline hybrids (Glc3'(S)-5'(CH(2)OH)HypHs) with a polar hydroxymethyl substituent at the C-5' position, such as C-terminal ester Ac-Glc3'(S)-5'(CH(2)OH)Hyp-OMe and C-terminal amide Ac-Glc3'(S)-5'(CH(2)OH)Hyp-N'-CH(3), were synthesized. C-Terminal esters exhibit increased cis population (23-53%) relative to Ac-3(S)HyPro-OMe (17%) or Ac-Pro-OMe (14%) in D(2)O. The prolyl amide cis population is further increased to 38-74% in the C-terminal amide form in D(2)O. Our study shows that the stereochemistry of the hydroxymethyl substituent at the C-5' position of proline permits tuning of the prolyl amide cis/trans isomer ratio. Inversion-magnetization transfer NMR experiments indicate that the stereochemistry of the hydroxymethyl substituent has a dramatic effect on the kinetics of prolyl amide cis/trans isomerization. A 200-fold difference in the trans-to-cis (k(tc)) isomerization and a 90-fold rate difference in the cis-to-trans (k(ct)) isomerization is observed between epimeric C-5' 3 and 4. When compared to reference peptide mimics Ac-Pro-OMe and Ac-3(S)Hyp-OMe, our study demonstrates that a (13-16)-fold decrease in k(tc) and k(ct) is observed for the C-5'(S), while a (5-24)-fold acceleration is observed for the C-5'(R) epimer. DFT calculations indicate that the pyrrolidine ring prefers a C(beta) exo pucker in both Ac-Glc3'(S)-5'(CH(2)OH)Hyp-OMe diastereoisomers. Computational calculations and chemical shift temperature coefficient (Delta delta/Delta T) experiments indicate that the hydroxymethyl group at C-5' in Ac-Glc3'(S)-5'(CH(2)OH)Hyp-OMe forms a stabilizing intramolecular hydrogen bond to the carbonyl of the N-acetyl group in both epimeric cis isomers. However, a competing intramolecular hydrogen bond between the hydroxymethyl groups in the pyrrolidine ring and pyran ring stabilizes the trans isomer in the C-5'(S) diastereoisomer. The dramatic differences in the kinetic properties of the diastereoisomeric peptide mimics are rationalized by the presence or absence of an intramolecular hydrogen bond between the hydroxymethyl substituent located at C-5' and the developing lone pair on the nitrogen atom of the N-acetyl group in the transition state.

Objective: This guideline provides evidence-based recommendations on managing cerumen impaction, defined as an accumulation of cerumen that causes symptoms, prevents assessment of the ear, or both. We recognize that the term "impaction" suggests that the ear canal is completely obstructed with cerumen and that our definition of cerumen impaction does not require a complete obstruction. However, cerumen impaction is the preferred term since it is consistently used in clinical practice and in the published literature to describe symptomatic cerumen or cerumen that prevents assessment of the ear. This guideline is intended for all clinicians who are likely to diagnose and manage patients with cerumen impaction., Purpose: The primary purpose of this guideline is to improve diagnostic accuracy for cerumen impaction, promote appropriate intervention in patients with cerumen impaction, highlight the need for evaluation and intervention in special populations, promote appropriate therapeutic options with outcomes assessment, and improve counseling and education for prevention of cerumen impaction. In creating this guideline the American Academy of Otolaryngology-Head and Neck Surgery Foundation selected a panel representing the fields of audiology, family medicine, geriatrics, internal medicine, nursing, otolaryngology-head and neck surgery, and pediatrics., Results: The panel made a strong recommendation that 1) clinicians should treat cerumen impaction that causes symptoms expressed by the patient or prevents clinical examination when warranted. The panel made recommendations that 1) clinicians should diagnose cerumen impaction when an accumulation of cerumen is associated with symptoms, or prevents needed assessment of the ear (the external auditory canal or tympanic membrane), or both; 2) clinicians should assess the patient with cerumen impaction by history and/or physical examination for factors that modify management, such as one or more of the following: nonintact tympanic membrane, ear canal stenosis, exostoses, diabetes mellitus, immunocompromised state, or anticoagulant therapy; 3) the clinician should examine patients with hearing aids for the presence of cerumen impaction during a healthcare encounter (examination more frequently than every three months, however, is not deemed necessary); 4) clinicians should treat the patient with cerumen impaction with an appropriate intervention, which may include one or more of the following: cerumenolytic agents, irrigation, or manual removal other than irrigation; and 5) clinicians should assess patients at the conclusion of in-office treatment of cerumen impaction and document the resolution of impaction. If the impaction is not resolved, the clinician should prescribe additional treatment. If full or partial symptoms persist despite resolution of impaction, alternative diagnoses should be considered. The panel offered as an option that 1) clinicians may observe patients with nonimpacted cerumen that is asymptomatic and does not prevent the clinician from adequately assessing the patient when an evaluation is needed; 2) clinicians may distinguish and promptly evaluate the need for intervention in the patient who may not be able to express symptoms but presents with cerumen obstructing the ear canal; 3) the clinician may treat the patient with cerumen impaction with cerumenolytic agents, irrigation, or manual removal other than irrigation; and 4) clinicians may educate/counsel patients with cerumen impaction/excessive cerumen regarding control measures., Disclaimer: This clinical practice guideline is not intended as a sole source of guidance in managing cerumen impaction. Rather, it is designed to assist clinicians by providing an evidence-based framework for decision-making strategies. It is not intended to replace clinical judgment or establish a protocol for all individuals with this condition, and may not provide the only appropriate approach to diagnosing and managing this problem.

Objective: To further knowledge of diabetes management in family practice. DESIGN Retrospective, observational chart audit study., Setting: Southwestern Ontario., Participant: A random sample of non-academic family physicians and a random selection of their patients with type 2 diabetes mellitus., Main Outcome Measures: Glycemic control as measured by HbA1c and adherence to recommendations in clinical practice guidelines (CPGs)., Results: Eighty-four percent of patients had at least one HbA1c test ordered in the previous year. Overall mean HbA1c was 0.079 and half-the patients had levels deemed acceptable by 1992 CPGs. Screening for microvascular complications was disappointing; only 28% were tested for microalbuminuria, and 15% were examined for diabetes-related foot conditions. Screening for macrovascular complications was more comprehensive; blood pressure was measured in 88%, and lipid profiles documented in 48%, of patient charts., Conclusion: Management of glycemic control and screening for microvascular and macrovascular disease in family practice can be improved.

Background: Few studies have explored the contextual dimensions and subsequent interactions that contribute to a lack of adherence in the application of guidelines for diabetes management., Objective: The purpose of this qualitative study was to explore family physicians' issues and perceptions regarding the barriers to and facilitators of the management of patients with type 2 diabetes mellitus (DM)., Methods: Four focus groups composed of family physicians (n= 30) explored the participants' experiences in the management of patients with type 2 DM. A semi-structured interview guide began with questions on family physicians' experience of providing care and included specific probes to stimulate discussion about the various barriers to and facilitators of the management of type 2 DM in family practice., Results: Participants clearly identified type 2 DM as a chronic disease most often managed by family physicians. The findings revealed distinct barriers and facilitators in managing patients with type 2 DM which fell into three domains: patient factors; physician factors; and systemic factors. There was a dynamic interplay among the three factors. The important role of education was common to each., Conclusions: The interactions of patient, physician and systemic factors have implications for the implementation of a diabetes management model. The care of patients with type 2 DM exemplifies the ongoing challenges of caring for patients with a chronic disease in family practice. The findings, while specific to the management of type 2 DM, have potential transferability to other chronic illnesses managed by family physicians.

Ab initio molecular orbital theory is used to investigate 1,2-amino shifts catalyzed by aminomutases, coenzyme B12, and vitamin B6 (in the form of pyridoxal 5'-phosphate or PLP). Our calculations suggest essential catalytic roles for each of B12, B6, and the enzyme in aminomutase-catalyzed reactions. In the first place, coenzyme B12 provides a source of abstracting radicals, allowing the rearrangement reaction to take place on the radical surface. The involvement of radicals is supported by comparison of experimental and theoretical electron paramagnetic resonance parameters. Next, B6 allows the enzyme to lower the barrier height by introducing a double bond (allowing a low-energy intramolecular rearrangement pathway) and by providing a suitable site for partial protonation (preventing overstabilization of the reaction intermediate which could lead to enzyme inactivation). The PLP hydroxyl group is also identified as an important participant in these reactions. Finally, the enzyme holds the various reaction components in place and is the source of acidic functional groups that can provide partial protonation.

The interconversion of (S)-glutamate and (2S,3S)-3-methylaspartate catalyzed by B(12)-dependent glutamate mutase is discussed using results from high-level ab initio molecular orbital calculations. Evidence is presented regarding the possible role of coenzyme-B(12) in substrate activation and product formation via radical generation. Calculated electron paramagnetic resonance parameters support experimental evidence for the involvement of substrate-derived radicals and will hopefully aid the future detection of other important radical intermediates. The height of the rearrangement barrier for a fragmentation-recombination pathway, calculated with a model that includes neutral amino and carboxylic acid substituents in the migrating glycyl group, supports recent experimental evidence for the interconversion of (S)-glutamate and (2S,3S)-3-methylaspartate through such a pathway. Our calculations suggest that the enzyme may facilitate the rearrangement of (S)-glutamate through (partial) proton-transfer processes that control the protonation state of substituents in the migrating group.

Clostridium difficile-induced diarrhea and colitis are common complications of therapeutic courses of antibiotics in the hospital setting. We report a case of Clostridium difficile colitis following antibiotic prophylaxis for endocarditis prior to dental procedures in the community setting. The infection necessitated hospital admission and a prolonged hospital stay. Dental practitioners must be aware of the significance of the disease and the risk associated with antibiotics, whether they are used for prophylaxis or treatment.

Background: Orange juice-a rich source of vitamin C, folate, and flavonoids such as hesperidin-induces hypocholesterolemic responses in animals., Objective: We determined whether orange juice beneficially altered blood lipids in subjects with moderate hypercholesterolemia., Design: The sample consisted of 16 healthy men and 9 healthy women with elevated plasma total and LDL-cholesterol and normal plasma triacylglycerol concentrations. Participants incorporated 1, 2, or 3 cups (250 mL each) of orange juice sequentially into their diets, each dose over a period of 4 wk. This was followed by a 5-wk washout period. Plasma lipid, folate, homocyst(e)ine, and vitamin C (a compliance marker) concentrations were measured at baseline, after each treatment, and after the washout period., Results: Consumption of 750 mL but not of 250 or 500 mL orange juice daily increased HDL-cholesterol concentrations by 21% (P: < 0.001), triacylglycerol concentrations by 30% (from 1.56 +/- 0.72 to 2.03 +/- 0.91 mmol/L; P: < 0.02), and folate concentrations by 18% (P: < 0.01); decreased the LDL-HDL cholesterol ratio by 16% (P: < 0.005); and did not affect homocyst(e)ine concentrations. Plasma vitamin C concentrations increased significantly during each dietary period (2.1, 3.1, and 3.8 times, respectively)., Conclusions: Orange juice (750 mL/d) improved blood lipid profiles in hypercholesterolemic subjects, confirming recommendations to consume >/=5-10 servings of fruit and vegetables daily.

Objective: To determine family physicians' perceptions of how available respite care is and how easy it is to refer chronically ill older people to it, and to examine their opinions of respite care., Design: Mailed survey to family physicians on the Thames Valley Family Practice Research Unit's mailing list., Setting: London, Ont, and surrounding area., Participants: Of the 448 surveys mailed to eligible physicians, 288 were completed and returned for a response rate of 64.3%., Main Outcome Measures: Respondents' perceptions of how available respite care is and how easy it is to refer chronically ill older people to it and their opinions on the effectiveness of respite care., Results: More than half the respondents reported that outpatient respite care is always available, but how available depended on practice location. Inpatient respite care was reported as less available. More than half the respondents found referral to respite care difficult. Respondents were very positive about the role of respite services in long-term care and in lowering caregiver stress. Respondents' perceptions varied according to where they had attended medical school. Their perceptions of respite care's role in long-term care and in helping patients remain at home were influenced by whether they thought respite care was available., Conclusion: Family physicians need education in the value of respite services for their chronically ill older patients and their families. Physicians also need information on the respite services available and strategies for accessing them. Our findings suggest a need for greater attention to regional discrepancies in availability of services.

Build-up of high nitrate concentrations in closed seawater systems where primary productivity is undesirable and water changes are impractical presents unique problems. Nitrate concentration in Ocean Tank at the New Jersey State Aquarium reached 9500 microM after 6 years of operation. A biological denitrification system was installed in 1998 and nitrate concentration in the aquarium decreased to 7000 microM within the first 100 days of operation. The system offers additional benefits by increasing the pH and alkalinity of seawater and providing a reducing environment to balance the oxidizing disinfection environment in the aquarium. The initial performance of the denitrification system was monitored and two semi-empirical models were developed: one based on the actual methanol additions, and another based on the daily amounts of nitrogen gas removed. The first model predicts a net nitrate decrease of 39 microM/day in the aquarium. The second model predicts a net decrease of 25 microM/day, in good agreement with the empirical value of 23 microM/day. This indicates that nitrogen gas removal is the controlling factor during denitrification in this facility, and the second model can be used to predict and optimize the operation of the system.

Sixty-three children aged 4 to 17 years were examined by tympanometry, pure-tone audiometry, transient-evoked otoacoustic emissions (TEOAEs), and otoscopy to evaluate the effects of middle ear pathologies and the associated hearing loss on TEOAEs. TEOAE measures were highly specific (93.8%) in identifying normal ears that passed both audiometric and tympanometric criteria. The sensitivity for identifying abnormal ears was also reasonable (83. 3%). The effects of the middle ear abnormality were most significant, regardless of the degree of hearing loss, when the tympanogram was type B with normal volume measures, which is associated with reduced eardrum mobility and middle ear fluid. The middle ear conditions producing the greater negative pressure, which in turn led to more conductive hearing loss, also produced more TEOAE failures. The mere presence of an open ventilation tube was not a determining factor for absent TEOAEs because 60% of the open ventilation tubes had normal TEOAEs. Provided that the clinician understands the effects of middle ear pathologies on otoacoustic emissions, TEOAEs can be a great asset for diagnosis of both otologic and audiologic disorders.

Objective: To review the principles of use, common techniques, and effectiveness of cryosurgery for common skin lesions that can be treated by family physicians in their offices., Quality of Evidence: MEDLINE and the Cochrane Database controlled trials register (1998 version) were searched. Much of the evidence for the effectiveness of cryosurgery or cryotherapy is based on of cryosurgery for treating common warts, external genital warts, lentigines, and basal cell carcinomas. Many of the trials reviewed were conducted in specialty clinics and, therefore, the results might not apply accurately to family practice., Main Message: Evidence from case report and series suggests that cryosurgery is effective for actinic keratoses, seborrheic keratoses, dermatofibroma, keloids, molluscum contagiosum, and benign nevi. Randomized comparative trials show that, for external genital warts, cryosurgery is more effective than podophyllin treatment, better than or equal to trichloroacetic acid, but less effective than electrodesiccation or surgical removal. Prospective randomized trials of cryosurgery for common warts showed that weekly cryotherapy produced more rapid cures, but the overall cure rate depended on number of treatments. Two freeze-thaw cycles and paring before freezing improved the cure rate for plantar warts.

The goals of this study were to develop a mouse model for virally induced otitis media, and to study the immune response to infection. Intranasal inoculation of mice by reovirus was used to induce otitis media. Immunohistochemical evidence for the presence of reovirus in the nasopharynx, eustachian tubes, and middle ears and the amount of infiltrating B-cells and T-cells in those sites were serially evaluated by painlessly sacrificing animals over a 21 -day period. Reovirus antigen was detected in the middle ear mucosa by day 4 in 75% of infected animals, and histologic evidence for otitis media was found in 54% of all infected animals. A significant increase in B-cells in the nasopharynx and eustachian tubes was noted 7 to 10 days following infection. The number of infiltrating T-cells did not vary significantly from that in the control animals at any of the sites. These results provide a basis for further investigations of the immune response in otitis media.

Objectives: To determine whether, in individuals with hypercholesterolemia, substituting dietary soybean products for cows' milk products improves the plasma lipid profile and whether any change in the profile is due partially to soy oil., Design: Randomized 3-treatment crossover trial., Setting: Family practice clinics and an outpatient clinic in London, Ont., Participants: Seventeen healthy men and 17 healthy women with elevated plasma levels of total and low-density-lipoprotein (LDL) cholesterol and with normal plasma levels of triglycerides., Interventions: Participants incorporated into their normal diet either 2% cows' milk products, soybean products or a combination of skim milk products and soy oil, each over period of 4 weeks, with 22-week wash-out periods. Plasma lipid profile, blood pressure and body weight were assessed after each dietary and wash-out period., Outcome Measures: Plasma levels of total and lipoprotein cholesterol, plasma levels of triglycerides, apolipoprotein B and A1 levels, blood pressure and plasma lipid peroxidation., Results: The change in diet had no effect on body mass index, levels of apolipoproteins B and A1 and most plasma lipids. During the soybean period, the subjects' mean level of high-density-lipoprotein (HDL) cholesterol increased 9% (p < 0.04) and their mean LDL/HDL cholesterol ratio decreased 14% (p < 0.007). These effects were less pronounced during the skim milk/soy oil period. In the 24 subjects with the highest initial LDL cholesterol level and LDL/HDL cholesterol ratio, the mean LDL cholesterol level decreased 11% after the soybean period. In all subjects, changes in the LDL/HDL cholesterol ratio induced by a soybean diet were negatively correlated with the initial LDL/HDL cholesterol ratio and positively correlated with the initial HDL cholesterol level., Conclusions: In people with hypercholesterolemia, the plasma lipid profile improved after treatment with a soybean-product diet, and this improvement was partially due to soy oil. The degree of responsiveness was associated with initial risk factors for coronary artery disease.

Management of patients with cerebrospinal fluid rhinorrhea (CSF) remains controversial. Most studies recommend either an endoscopic or an external extracranial approach, depending on the surgeon's preference. Eighteen patients with CSF rhinorrhea have been managed at our institution since 1990. The causes of the CSF rhinorrhea consisted of functional endoscopic sinus surgery (7), lateral rhinotomy with excision of a benign nasal tumor (3), spontaneous rhinorrhea (7), and secondary repair after intranasal ethmoidectomy (1). In 11 patients the CSF leak was recognized at the time of surgery; in 10 of these patients it was repaired during the primary surgery, whereas one patient underwent secondary repair after failure of conservative management of his CSF fistula. Seven patients underwent exploration for spontaneous CSF rhinorrhea. Four patients had computer tomography scans that showed the leak, and two patients had cisternography to localize the leak. One patient underwent magnetic resonance cisternography. Both of these leaks were identified with cisternography and were then confirmed intraoperatively. Repair methods included a pedicled septal mucosal flap (4), a free mucosal graft from the septum (7), and a middle turbinate (5). Two patients had obliteration of the sinus with muscle/fascia and fibrin glue. Eight patients were repaired endoscopically. The remainder underwent repair through external approaches. Seventeen patients (at a minimum 1 year follow-up) remain free from leakage. One patient required a second repair 8 months after surgery. Iatrogenic trauma remains the most common cause of CSF rhinorrhea. Management at the initial setting is the least morbid approach and is successful in 95% of cases. Whether an endoscopic or external approach is used depends on surgical expertise and experience.

The aim of this study is to investigate the role of adenovirus and respiratory syncytial virus in the cause of chronic otitis media with effusion by use of the polymerase chain reaction for detection. The polymerase chain reaction has proved to be more sensitive and specific than viral cultures and immunoassays in the detection of viruses in other specimens. Adenovirus and respiratory syncytial virus were chosen because these viruses have been the most commonly isolated viruses in middle ear effusions in studies using other techniques. The effusions (132 total) were sterilely collected from 88 children undergoing myringotomy and ventilation tube placement for chronic otitis media with effusion. Nine (6.8%) specimens were positive for adenovirus by the polymerase chain reaction, and 13 (9.9%) were positive for respiratory syncytial virus by the polymerase chain reaction. Only one specimen was positive for adenovirus and respiratory syncytial virus by viral culture and immunofluorescence, respectively. Our results show that the polymerase chain reaction can be used to detect adenovirus and respiratory syncytial virus in chronic middle ear effusions and that PCR is more sensitive than viral culture and immunofluorescence techniques.

Background: Carcinoma of the paranasal sinuses is rare. The majority of these originate in the maxillary sinus with primary ethmoid carcinomas occurring in up to 20% of cases. Adenocarcinomas comprise up to 50% of the ethmoid malignancy. The relative rarity of tumors originating in this area has led to their inclusion in series that consist mainly of maxillary antral tumors., Methods: A retrospective chart review of all patients presenting with primary ethmoid adenocarcinoma at West Virginia University Hospitals between 1988 and 1993 was undertaken. Only patients whose epicenter was believed to be in the ethmoids were included in this analysis. CT scans, MRIs, operative notes, pathology, and final outcome were all analyzed., Results: Eight patients with primary ethmoid adenocarcinoma were treated during this time span. The male to female ratio was 1:1 with a mean age of 50 years. Symptoms had been present from 3 to 18 months (mean 8 months). All patients underwent craniofacial resection with 5 patients receiving postoperative radiotherapy. Pathologically 4 patients had cribriform plate erosion, 2 had dural involvement, and 1 had extension into the sphenoid sinus. With a mean follow-up of 45 months (9-71 months) 7 patients are disease free and 1 patient has died of disease., Conclusions: Obtaining clear margins by craniofacial resection is essential to the management of adenocarcinoma of the ethmoid sinuses. Radiotherapy is reserved for positive margins, cribriform plate penetration, dural invasion, and high-grade lesions that are close to the cribriform plate. Local control was obtained in 87% of our patients.

The American Academy of Otolaryngology-Head and Neck Surgery recently developed a questionnaire called the "Five-Minute Hearing Test" and distributed it to many primary care physicians. Our literature review suggests that the test characteristics (i.e., sensitivity and specificity) of this screening instrument have not been published. The purpose of this study was to examine the validity of the test by correlating the "Five-Minute Hearing Test" results to various audiologic results obtained for the same patients and to analyze the test characteristics with pure-tone measures as a standard criterion. An original version of the "Five-Minute Hearing Test" was administered to 70 patients older than 55 years, and a revised version of the test was administered to additional 74 elderly patients. The "Five-Minute Hearing Test" scores in both original and revised versions significantly correlated with all audiologic measures, especially with the pure-tone measures. However, the American Academy of Otolaryngology-Head and Neck Surgery's recommended cutoff score for a referral yielded a high false-positive rate. If the cutoff score were changed, the "Five-Minute Hearing Test" would be a reliable hearing screening tool for identification of hearing loss among the elderly population. Specific recommendations include adjustment of the cutoff score to at least 15 and revision of a few selected test items.

Purpose: This study was designed to determine the effects of long-term perioperative pentoxifylline administration on random skin flap survival in an appropriate animal model. A secondary objective was to document bioavailability of pentoxifylline in the animal model by measuring blood levels of parent compound and metabolites at regular intervals and comparing these to levels measured in humans., Materials and Methods: A randomized control study of the effects of oral pentoxifylline on the survival of "random" skin flaps was conducted at the animal care facility of an academic tertiary referral center on six randomly selected Yorkshire pigs. Oral pentoxifylline was administered daily to four pigs for 3 months, and two pigs received placebo. Pentoxifylline blood levels for each experimental animal were measured after 4, 8, and 12 weeks of daily dosing. Blood viscosity, fibrinogen, and hematocrit were measured for each of the six animals on day 1, day 30, day 60, and day 91. On day 91, 12 surgical random skin flaps were elevated on each of the six animals and immediately sewn back in the donor bed. Pentoxifylline dosing was continued for 2 weeks, and placebo was continued in control animals. On postoperative day 15, all animals were killed and all flaps were measured individually for area of viability. The outcome measure was the detection of statistically significant increase in survival area in skin flaps of those animals administered perioperative pentoxifylline., Results: No significant augmentation of flap survival was noted in experimental animals when compared with those in the control group; no significant difference was noted between or within groups of experimental animals. Pentoxifylline and metabolite blood levels in all experimental animals at every interval were noted to be comparable to those documented in human studies; metabolite concentrations conformed to expected patterns as observed in humans. No significant alterations of blood viscosity, fibrinogen, or hematocrit were measured in the experimental animals when compared with those in the control group. The only animal showing mean flap survival outside the 95% confidence interval was one in the control group., Conclusion: No augmentation of random skin flap survival could be shown in the pig model after a 3 month regimen of daily oral pentoxifylline. Blood levels of pentoxifylline in experimental animals were compared with those documented in humans. No alteration of blood viscosity, fibrinogen, or hematocrit was noted in any of the experimental animals when compared with each other or with those in the control group.

Shy-Drager syndrome consists of progressive autonomic nervous system failure with Parkinson's disease-like symptoms and orthostatic hypotension. It can also result in airway compromise from bilateral vocal cord paralysis. Fewer than 30 cases of severe bilateral vocal cord paresis or paralysis associated with the Shy-Drager syndrome have been reported in the English literature. We present a case of a 72-year-old man who had a 2-year history of orthostatic hypotension, neurogenic bladder, impotence, anhydrosis, and extremity weakness and paresthesias. Hoarseness and dyspnea with stridor developed as a result of bilateral vocal cord paralysis in the median position and required an emergency tracheotomy. This combination of symptoms resulted in the diagnosis of Shy-Drager syndrome. We present the case along with literature review of bilateral vocal cord paralysis with the Shy-Drager syndrome.

Epistaxis is a common condition as well as a frequent otolaryngologic emergency, with up to 60% of people experiencing one episode in their lifetime and 6% seeking medical attention. Treatment is controversial, with many options being available. We retrospectively reviewed the hospital course and management of 65 patients who experienced epistaxis from January 1, 1986, to October 31, 1991, to compare medical and surgical treatment methods. Fifty-one patients were managed medically. Of these, 36 patients required one treatment (group 1), 10 required multiple treatments (group 2), and seven required multiple admissions (group 3). The mean lengths of hospitalization were 3.27, 4.90, and 5.57 days respectively. Fourteen patients were managed surgically. The preoperative stay of nine patients who underwent unsuccessful medical management at our institution (group 4) was 3.9 days, with an average postoperative stay of 7.3 days. The difference in length of stay was statistically significant between surgical and medical groups and the postoperative stay of group 4 was different from the length of stay of group 1 patients. The remaining five patients were initially treated elsewhere (group 5). Seventeen (33.3%) medical and only 1 (7%) surgical patients underwent unsuccessful initial therapy. Complication rates were not statistically different for each group. Transfusion requirements were evaluated as a possible predictive factor. Eighteen patients (35.3%) in the medically managed group required transfusions, compared with 11 patients (78.6%) treated surgically (p < 0.01). The medical group received an average of 0.91 units, compared to the surgical group that received 2.93 units preoperatively (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

There seems to be a consensus in the surgical literature that wound infections after surgery for cancer have a favorable effect on the course of certain malignant diseases. In a review of laryngeal cancer during a 10-year period, the recurrence rate was statistically lower in the group that suffered wound infections than in the group that did not have a wound infection.