Flour exposure, sensitization and respiratory health among Alberta trainee bakers.

BACKGROUND: Sensitization to allergens encountered in baking, and allergic disease including asthma and rhinitis, is recognized. Attempts to reduce this risk have been instituted in some workplaces, but awareness remains low. This study aimed to quantify the current risk among Alberta bakers. AIMS: To estimate the onset of sensitization to bakery allergens and allergic disease among trainee bakers at the outset of their career. METHODS: Trainees attending one of the two bakery programmes were recruited between 2015 and 2018. At entry, an interview was held and spirometry and skin prick tests were performed. Participants were contacted every 6 months by telephone or online interview for 3 years to update work and health information. An exit interview was completed between 2018 and 2019 for all who could be contacted. Exposure was estimated using collected work history and a job exposure matrix was prepared for this study. RESULTS: A total of 220 individuals participated in the entry interview, 204 completed one or more periodic interviews and 113 completed the exit interview. Six who completed exit testing developed new sensitization to bakery antigens, an incidence of 2.49/100 person-years. Positive skin prick tests for bakery antigens were associated with bread making. Rhinitis symptoms were associated with total flour dust and new-onset rhinitis to months in trade. New-onset asthma was related to cumulative exposure to flour improvers. CONCLUSIONS: Trainee bakers in Alberta remain at risk of sensitization and occupational respiratory disease.

Respiratory health, occupation and the healthy worker effect.

BACKGROUND: Workers are exposed to physical, chemical and other hazards in the workplace, which may impact their respiratory health. AIMS: To examine the healthy worker effect in the Canadian working population and to identify the association between occupation and respiratory health. METHODS: Data from four cycles of the Canadian Health Measures Survey were utilized. The current occupation of employed participants was classified into 10 broad categories based on National Occupation Category 2011 codes. Data relating to 15 400 subjects were analysed. RESULTS: A significantly lower proportion of those in current employment than those not in current employment reported respiratory symptoms or diseases or had airway obstruction. Similarly, those currently employed reported better general health and had greater mean values for percent-predicted forced vital capacity (FVC), forced expiratory volume in one second (FEV1), forced expiratory flow between 25% and 75% of FVC (FEF25-75%) and FEV1/FVC ratio. Among males, females and older age groups, significant differences were observed for almost all the respiratory outcomes for those in current employment. Those in 'Occupations unique to primary industry' had a significantly greater likelihood of regular cough with sputum and ever asthma and had lower mean values of percent-predicted FEV1/FVC and FEF25-75% than those in 'Management occupations'. Those in 'Health occupations' had the highest proportion of current asthma. CONCLUSIONS: Participants in current employment were healthier than those not in current employment providing further support for the healthy worker effect. Those in 'Occupations unique to primary industry' had an increased risk of adverse respiratory outcomes and reducing workplace exposures in these occupations has the potential to improve their respiratory health.

Course participation and the recognition and reporting of occupational ill-health.

BACKGROUND: The Foundation Course in Occupational Medicine for community-based physicians was started in Alberta in 2012 and has since been implemented across Canada. As part of the evaluation of the first 4 years, two studies were initiated to assess the impact of the course on assessment of work-relatedness and case-reporting. AIMS: To determine whether assessment of work-relatedness, intention to report cases and number of cases reported to the Workers' Compensation Board (WCB) changed during/after the course. METHODS: In study 1, course participants were asked to rate scenarios describing ill-health potentially resulting from work. They rated work-relatedness on a visual analogue scale and recorded whether they would report to the WCB. Assessments were made before the course started, after course completion or both. In study 2, numbers of reports to the WCB were documented for physicians giving consent, both for Foundation Course participants and a comparison group of community-based physicians. Multilevel regression models were fitted to allow for potential confounders and clustering within respondent. RESULTS: Among 102 physicians completing at least one set of scenario assessments, ratings of work-relatedness (ß = 6.5; 95% CI 2.6-10.4) and likelihood of reporting to the WCB (OR = 1.9; 95% CI 1.2-3.1) increased significantly post-course. The mean annual number of cases reported to the WCB increased from 91.8 to 125.7 among the 35 Alberta physicians included in study 2. This change was only significant (P < 0.05) on a one-sided test. CONCLUSION: The two evaluative studies showed good evidence of changes in perceptions and intentions but only weak evidence of behavioural change.

Workers' recovery from concussions presenting to the emergency department.

BACKGROUND: The emergency department (ED) is the first point of care for many patients with concussion, and post-concussion syndrome can impact vocational outcomes like successful return to work. Evaluation of concussion in general adult populations is needed. AIMS: To document the occurrence and outcomes of work-related concussion presenting to the ED for treatment. METHODS: This study enrolled adults presenting with concussion to three urban Canadian EDs. Baseline ED interviews, physician questionnaires and patient phone interviews at 30 and 90 days documented work-related events, ED management, discharge advice, patient adherence and symptom severity. Work-related injury and return to work were modelled using logistic or linear regression, as appropriate. RESULTS: Overall, 172 enrolled workers completed at least one follow-up. Work-related concussions were uncommon (n = 28). Most employees (80%) missed at least 1 day of work (median = 7; interquartile range: 3-14). Most (91%) employees returned to work within 90 days, while 41% reported persistent symptoms. Manual labour and self-reported history of attention deficit hyperactivity disorder were associated with work-related concussion, while days of missed work increased with marital status (divorced), history of sleep disorder and physician's advice to avoid work. CONCLUSION: Work-related concussions are infrequent; however, most workers who sustain a concussion will miss work, and many return while still experiencing symptoms. Work-related concussion and days of missed work are mainly affected by non-modifiable factors. Workers, employers and the workers' compensation system should take necessary precautions to ensure that workers return to work safely and successfully following a concussion.

Developing a tool for identifying high-risk employers for inspection.

BACKGROUND: Workers' Compensation Board (WCB) data and other information are sometimes used to calculate an 'Occupational Health and Safety (OHS) index' as a way of identifying businesses considered 'high risk' to be inspected as part of enforcement work. However, no evidence on the validity of this index exists. AIMS: To evaluate the performance of the Alberta OHS index, a 'score' based largely on WCB claims data, and to see if an index calculated using different information could perform better. METHODS: Data from the Alberta Compliance Management Information System database, 2011-2015, and WCB claim database, 2007-2014, were retrieved. Issuing 'stop work' or 'stop use' orders in inspections was defined as a proxy of high-risk outcome. The performance of the current and a modified OHS index were assessed using receiver operating characteristics (ROC) and regression analyses. RESULTS: In large employers, neither the current nor the modified OHS index was particularly effective in identifying 'high risk' employers with the area under the ROC curve (AROC) of 0.55 (95% confidence interval [CI] 0.52-0.57; P < 0.001) and 0.59 (95% CI 0.57-0.62; P < 0.001), respectively. In small employers, neither index seemed very effective with an AROC of 0.54 (95% CI 0.53-0.56; P < 0.001) and 0.55 (95% CI 0.53-0.56; P < 0.001), respectively. These results were consistent in subgroup analyses of assignments without specific initiatives, both in large and small employers. CONCLUSIONS: Neither the current nor a modified OHS index seemed to effectively identify high-risk employers. Heterogeneous results in large and small employers suggest that approaches to different-sized employers are appropriate.

Systematic review: plantar fasciitis and prolonged weight bearing.

BACKGROUND: Plantar fasciitis (PF) is one of the most common causes of foot pain. Work can involve factors that may predispose to foot pain. AIMS: To systematically review the evidence of the association between weight bearing (walking or standing) and PF among workers. METHODS: Literature search of relevant indexing databases from inception to May 2012, grey literature, websites of relevant organizations and reference lists for all identified articles. Two reviewers independently selected studies for full review, assessed methodological quality and graded evidence. Findings were summarized qualitatively. RESULTS: Four studies were included; all were assessed as high or unclear risk of bias. Three studies were case-control studies; two used clinic populations and one used volunteers. The other study was cross-sectional involving the workforce of an assembly plant. A number of associations between PF and risk factors were identified including sex, obesity, foot biomechanics and job factors (e.g. job tenure). Two case-control studies and the cross-sectional study found an association with weight bearing, but the assessment of weight bearing varied (e.g. time on feet, time walking or standing). There was low-quality evidence to confirm a causal relationship (Royal College of General Practitioners (RCGP) * grade). CONCLUSIONS: This systematic review found low-quality evidence of an association between PF and weight-bearing tasks such as walking and standing on hard surfaces. The only occupations specifically identified as having higher risk were those associated with the engine assembly plant. Further research is required to fully determine the association between weight bearing and PF.

Effectiveness of safety-engineered devices in reducing sharp object injuries.

BACKGROUND: Sharps injuries remain a common factor in occupational exposure of healthcare workers to blood-borne viruses. The extent to which the introduction of safety-engineered devices has been effective in reducing such injuries among healthcare workers is unclear. AIMS: To investigate the incidence of sharp object injury among healthcare workers in the Capital Health Region of Alberta, Canada and to determine the effectiveness of the introduction of safety- engineered devices in preventing these. METHODS: All reports of sharp object injuries to Capital Region Workplace Health and Safety offices from healthcare workers 2003-10 were analysed. Rates of sharp object injury were compared before (2006), during (2007-08) and after (2009-10) the introduction of safety-engineered devices, adjusting for other potential risk factors using Poisson regression and log-linear models. RESULTS: Between 2003 and 2010, a total of 4707 sharp object injuries were reported from 15 healthcare facilities. The sharp object injury rate per 1000 full-time equivalent employees per year declined from 35 before the introduction period to 30 during the introduction period (rate ratio [RR]: 0.88, 95% confidence interval [CI]: 0.78, 0.99) among most healthcare workers, but then rebounded again slightly after the intervention. Physician risks showed little change during the period of introduction (odds ratio [OR]: 0.99, 95% CI: 0.85, 1.14) but decreased significantly after the intervention (OR: 0.83, 95% CI: 0.71, 0.97). CONCLUSIONS: The introduction of safety-engineered devices was associated with a modest reduction in reported sharp object injuries but this appeared to be relatively short-lived for most workers.

Association of vitamin D with respiratory outcomes in Canadian children.

BACKGROUND/OBJECTIVES: Vitamin D modifies airway inflammation and appears to be important in building immunity against respiratory infections, and so is potentially beneficial in asthma. However, to date results from studies investigating the relationship of vitamin D with respiratory outcomes are inconsistent. The objective of this study was to determine the association of vitamin D with current wheeze, ever asthma and lung function. SUBJECTS/METHODS: Data on 1213 children aged 6-12 years, from the Canadian Health Measures Survey, were considered for the study. Serum 25-hydroxy vitamin D (25(OH)D) levels were categorized into three categories: ⩽49 nmol/l (low); 50-74 nmol/l (moderate); and ⩾75 nmol/l (high). RESULTS: Children in the low and high 25(OH)D categories were more likely to report current wheeze in comparison to those in the moderate category (odds ratio (OR): 3.26, 95% confidence interval (CI): 1.16-9.17 and OR: 2.14, 95% CI: 1.07-4.28, respectively). The results for the association between 25(OH)D levels and ever asthma were similar to those observed for current wheeze, except that a significant association was observed only in the lower category. The rate of increase in forced expiratory volume in one second and forced vital capacity with age was greater in the moderate category. CONCLUSIONS: Children in both low and high 25(OH)D categories had increased risk of current wheeze and reduced rate of change in lung function with age in comparison to the moderate category, raising the possibility of a U-shaped association between vitamin D levels and respiratory health. Clearer guidelines for optimal vitamin D levels are required to improve respiratory health in children.

Validation study of the Self-Assessment Goal Achievement (SAGA) questionnaire for lower urinary tract symptoms.

BACKGROUND: Patients' treatment goals for overactive bladder (OAB) and other lower urinary tract symptoms (LUTS) may not be aligned with their healthcare provider's goals. Successful management of OAB symptoms is improved by individualised treatment plans with attainable treatment goals. Goal attainment setting may facilitate patient-provider interaction and the development of a personalised treatment plan based on realistic, individual goals, thereby increasing patient satisfaction and therapeutic outcomes. The purpose of this study was to validate the utility of the Self-Assessment Goal Achievement (SAGA) questionnaire for LUTS in helping patients identify and achieve realistic treatment goals. METHODS: The 2-module SAGA questionnaire consists of nine prespecified (fixed) items and five open-ended items for goal identification and ranking (baseline module) and goal achievement rating (follow-up module). Adult patients in the United States (n = 104) seeking treatment for LUTS, including symptoms of OAB, completed the SAGA baseline module, micturition diary, other patient-reported outcome measures (PROs), and discussed their urinary goals with a clinician at baseline. The SAGA follow-up module was completed 2-4 months later. SAGA was validated based on analyses of face, concurrent, known-groups, and convergent validity and item distribution. RESULTS: Among the nine fixed goals of SAGA, four were ranked as very important by > 50% of patients (i.e. reduce night-time frequency, daytime frequency, urine leakage, urgency). Most patients did not change the importance level of their goals after discussion with their healthcare provider. Pearson correlations between SAGA, diary variables and PRO scores were generally of low to moderate strength. The global mean (SD) follow-up SAGA T-score was 32.54 (12.54), indicating that overall goal attainment was not achieved after 3 months. The goal attainment score was significantly different between groups differing in symptom severity, health-related quality of life, bladder control and continence status. CONCLUSIONS: The results support the validity of SAGA as a measure of patients' goals and goal achievement for the treatment of LUTS, including symptoms of OAB. SAGA may improve healthcare provider-patient interactions and treatment outcomes in clinical practice.

Using a symptom diary to investigate work-related urticaria.

BACKGROUND: The strategy of keeping a diary may not be considered by many treating clinicians, but this approach has been recommended for occupational asthma and proved useful in this case of chronic urticaria associated with work. AIMS: To report a case of a health care worker who had significant allergic reactions that were found to be associated with exposure to test allergens while working in an asthma clinic. METHODS: The patient, a nurse working in a paediatric asthma clinic, was known to be allergic to common allergens that were used to test patients in the clinic. She developed reactions including swelling of the eyelids and urticarial reactions on the forehead, torso and upper and lower limbs on different occasions. A symptom diary was used to collect information on the reactions and the activity performed at the time they occurred. RESULTS: She recorded symptoms that were mainly urticarial, with additional rhinitis or wheeze on occasion, on 20 (74%) working days and only 5 (28%) non-work days, indicating a significant association (P < 0.01) between her symptoms and working days. CONCLUSIONS: Medical management had not controlled her symptoms, which improved on removal from the work activity and was confirmed by further diary recording.

Factors affecting work-related shoulder pain.

BACKGROUND: Work-related shoulder pain is a common problem. Ergonomic factors in the workplace are thought to be important but a number of other factors have also been associated with shoulder pain. AIMS: To identify risk factors for work-related shoulder pain in Alberta, focusing particularly on ergonomic risk factors. METHODS: A case referent design was used to compare individuals who made a Workers' Compensation Board (WCB) claim for work-related shoulder pain with individuals who made a claim for other types of injury. Data were collected using a postal questionnaire and analysed by logistic regression. RESULTS: There were 1263 participants (562 cases, 701 referents). The participation rate was 25% among cases and 21% among referents (P < 0.01). Factors associated with an increased likelihood of claim for shoulder injury included lifting ≥10 kg above shoulder height for ≥15 min per day, shoulder pain in the month prior to injury, working in the 'Government, education, and health services' industry sector and being occasionally/never satisfied with support from colleagues. CONCLUSIONS: These results support the importance of ergonomic factors in work-related shoulder pain claims, particularly the lifting of weights above shoulder level for even short periods. Relatively simple ergonomic measures, such as restricting above shoulder lifting, could be adopted with the aim of reducing the risk of shoulder injury at work.

Mental health in Alberta grain farmers using pesticides over many years.

BACKGROUND: Exposure to organophosphates and certain other pesticides has been related to symptoms of mental ill-health. There is particular interest in whether exposure over many years may result in chronic ill-health. AIMS: To relate lifetime history of pesticide exposure to symptoms and medical records of mental ill-health in elderly grain farmers in Alberta. METHODS: Two populations of grain farmers were identified for study: cohort A (n = 5986), members of an Alberta farm organization in 1983; cohort B (n = 4781), grain farmers registered with the provincial department of agriculture. In 2002-03 both groups completed a questionnaire on lifetime history of pesticide use, physician diagnosed disease and recent neuropsychological symptoms. Durations of exposure to seven pesticide components were calculated and a factor score extracted from responses to the symptom questionnaire. For a sub-cohort surviving to 2009 medical records for mental ill-health were identified. Records and symptom scores were related to pesticide exposures allowing for confounding. RESULTS: From cohort A, 1348 and cohort B, 1078 were alive and interviewed (median age 63 years; median duration in farming 40 years): 1371 were linked to the medical records database. Mental ill-health symptom scores were related to duration of exposure to phenoxy compounds (but not to other pesticides) and to mental ill-health in medical records. Those with mental ill-health in hospital discharge records were more likely to have been exposed to phenoxy compounds for ≥35 years. CONCLUSIONS: The relationship of long-term exposure to phenoxy herbicides and neuropsychiatric symptoms was unexpected but not explained by measured confounders.

How physicians allocate causation: a scenario study with factorial design.

BACKGROUND: Causation is a complex concept but important in suspected work-related disease. Physicians routinely make initial assessments of causation as part of their work, but the factors contributing to these assessments are not well understood. AIMS: To determine which factors influence a family physician's assessment of causation when seeing patients with suspected work-related injury or illness. METHODS: Four groups of family physicians with differing levels of prior reporting (zero, low, medium, high) to the Workers Compensation Board received a questionnaire including four randomly allocated case scenarios. For each scenario there were four versions with either strong or weak causal features suggesting work or non-work factors were important causes or contributors. Responses to questions were made on a series of visual analogue scales. RESULTS: The nature of the condition and scenario type (i.e. strength of the causal information about workplace and non-workplace factors) were associated with the physicians' opinion on work-relatedness. Understanding the nature of the patient's work, the timing of symptoms and the patients' opinion about work-relatedness were viewed by the physicians as important. A decision that a condition was not work related was influenced primarily by the strength of potential causes outside work. Prior reporting history of the physician was not associated with opinions on work-relatedness, nor the factors considered in reaching this decision. CONCLUSIONS: The characteristics of the case scenario were more important in determining a physician's opinion about work-relatedness than the characteristics of the physician.

Physician diagnosed mental ill-health in male and female workers.

BACKGROUND: Although there have been many studies of work demands and self-reported job strain, few have examined incident physician-diagnosed mental ill-health (MIH) by detailed occupational group. AIMS: To investigate whether linkage of occupation from worker compensation claims to diagnoses from administrative health records can give credible information on occupation and incidence of MIH by diagnostic group and gender. METHODS: Information on occupation from all worker compensation claims 1995-2004 in Alberta, Canada were linked to administrative health records of MIH diagnoses. Relative risks for affective, substance use and psychotic disorders by four digit occupational codes were calculated for men and women aged 18-65 years in a log-binomial regression adjusting for age and stratifying by sex. RESULTS: There were 327883 male and 88483 female compensation claims available for the analysis of incident cases. Affective disorders (5.2% men, 11.5% women) were much more common than substance use disorders or psychotic disorders (both ≤1%) in this population of working people. In men, the type of work appeared to either protect from or precipitate affective disorders, but no protective effect was seen for women. Substance use disorders clustered mainly in physically demanding occupations typically involving employment outside the urban areas. New onset psychotic disease was rare but seen in excess in painters, boilermakers and chefs. CONCLUSIONS: Data linkage of occupation close to the time of new onset MIH can provide important insight into the relation between work and physician-diagnosed MIH and indicate areas in which intervention might be appropriate.

Mental ill-health and second claims for work-related injury.

BACKGROUND: There is some evidence that mental ill-health (MIH) is associated with injury at work, but data are sparse. AIMS: To examine, within a cohort of workers with a first workers' compensation claim, whether those with a history of MIH had a higher than expected number of second claims. METHODS: All Workers' Compensation Board (WCB) records from January 1995 to December 2004 were linked to administrative health records, and a physician diagnosis of MIH in the 48 months prior to the first WCB claim extracted. The first and second (if any) claim for each worker were identified and time to second claim calculated. Survival time to second claim was estimated by Cox regression with history of MIH as a covariate. RESULTS: Results were available for 389 903 WCB first claimants. Of these 53% of men and 38% of women had a second claim, with a mean time between claims of 768 days (men) and 785 days (women). Those with a history of MIH were somewhat more likely to make a second claim and, in the survival analysis, to make this claim sooner. Type of injury at first claim did not appear to modify this effect. CONCLUSIONS: Workers with a recent history of MIH at the time of making a first WCB claim for a work injury are at greater risk of a second injury, leading to a new claim. Strategies to get workers back to work after the first injury/claim should include management of MIH to reduce the risk of further injury.

Transdermal permeation of novel n-acetyl-glucosamine/NSAIDs mutual prodrugs.

The current investigation reports skin permeation of three novel mutual prodrugs (MP) which couple n-acetyl-glucosamine with an NSAID, either ketoprofen or ibuprofen. They were evaluated for transdermal permeation using shed snakeskin, and to our knowledge represent the first MPs synthesized for this purpose, although they also could be used for subcutaneous delivery. MPs are defined as two active drug compounds usually connected by an ester linkage. Glucosamine administration has been linked to damaged cartilage repair, and pain relief in joints afflicted with osteoarthritis. NSAIDs are commonly used orally in transdermal creams or gels for joint pain relief. Two novel compounds we report (MP1 and MP2) covalently link ibuprofen and ketoprofen directly to the amide nitrogen of n-acetyl-glucosamine (NAG); the other compound (MP3) covalently links ibuprofen to the amide nitrogen, using a short chain acetyl linker. Permeability studies show that the ketoprofen mutual prodrug (MP2) permeates shed snakeskin more than three times greater than either ibuprofen derivative, while ethanol markedly increases the permeation for all three. The ketoprofen mutual prodrug appears the most likely candidate for transdermal administration; all three mutual prodrugs may be candidates for subcutaneous injection.

Neuroprotective effects and mechanism of cognitive-enhancing choline analogs JWB 1-84-1 and JAY 2-22-33 in neuronal culture and Caenorhabditis elegans.

BACKGROUND: Our previous work indicated that novel analogs of choline have cytoprotective effects in vitro that might be useful in neurodegenerative conditions such as Alzheimer's disease (AD). Furthermore, two lead compounds (JWB1-84-1 and JAY2-22-33) from a library of more than 50 improved cognitive performances in a transgenic mouse model of AD. The purpose of these experiments was to more specifically investigate the neuroprotective capabilities of these lead compounds both in vitro and in vivo. RESULTS: We used N2a cells which express a Swedish mutation in the amyloid precursor protein and presenilin 1 genes to investigate the effect of JWB1-84-1 and JAY2-22-33 on ß-amyloid (Aß) levels and found that both compounds significantly reduced Aß levels. JWB1-84-1 and JAY2-22-33 also protected rat primary cortical neurons from Aß toxicity. Subsequently, we utilized the nematode Caenorhabditis elegans (C. elegans) as an in vivo model organism to identify potential molecular targets of these compounds. In the C. elegans model of Aß toxicity, human Aß is expressed intracellularly in the body wall muscle. The expression and subsequent aggregation of Aß in the muscle leads to progressive paralysis. CONCLUSION: We found that JAY2-22-33 (but not JWB1-84-1) significantly reduced Aß toxicity by delaying paralysis and this protective effect required both the insulin signaling pathway and nicotinic acetylcholine receptors (nAChRs).

Explaining Alberta's rising mesothelioma rates.

Although mesothelioma rates have been rising worldwide, little is known about mesothelioma trends in Alberta. This population-based descriptive study used Alberta Cancer Board Registry data from 1980 to 2004 to develop an age-period-cohort model of male pleural mesothelioma incidence rates over time. Both age and cohort effects are associated with incidence rates. The highest-risk cohort comprised men born between 1930 and 1939, reflecting widespread asbestos use and exposure beginning in the 1940s in Canada. We predict that 1393 Albertan men 40 years and older will die of pleural mesothelioma between 1980 and 2024; 783 (56.2%) of these deaths will occur between 2010 and 2024. The total number of mesothelioma deaths in Alberta will be higher when all age groups, both sexes, and all disease sites are included, with numbers likely peaking sometime between 2015 and 2019. In addition to the ongoing efforts that focus on eliminating asbestos-related disease in Alberta, the challenge is to implement surveillance systems to prevent future epidemics of preventable occupational cancers in Alberta.

Desensitization of nicotinic acetylcholine receptors as a strategy for drug development.

The specific pharmacological response evoked by a nicotinic acetylcholine receptor (nAChR) agonist is governed by the anatomical distribution and expression of each receptor subtype and by the stoichiometry of subunits comprising each subtype. Contributing to this complexity is the ability of agonists that bind to the orthosteric site of the receptor to alter the affinity state of the receptor and induce desensitization and the observation that, at low doses, some nAChR antagonists evoke agonist-like nicotinic responses. Brain concentrations of nicotine rarely increase to the low-mid micromolar concentrations that have been reported to evoke direct agonist-like responses, such as calcium influx or neurotransmitter release. Low microgram per kilogram doses of nicotine administered to humans or to nonhuman primates to improve cognition and working memory probably result only in low nanomolar brain concentrations--more in line with the ability of nicotine to induce receptor desensitization. Here we review data illustrating that nicotine, its major metabolite cotinine, and two novel analogs of choline, JWB1-84-1 [2-(4-(pyridin-3-ylmethyl)piperazin-1-yl)ethanol] and JAY2-22-33, JWB1-84-1 [2-(methyl(pyridine-3-ylmethyl)amino)-ethanol], improve working memory in macaques. The effectiveness of these four compounds in the task was linearly related to their effectiveness in producing desensitization of the pressor response to ganglionic stimulation evoked by a nAChR agonist in rats. Only nicotine evoked an agonist-like action (increased resting blood pressure). Therefore, it is possible to develop new chemical entities that have the ability to desensitize nAChRs without an antecedent agonist action. Because these "silent desensitizers" are probably acting allosterically, an additional degree of subtype specificity could be attained.