Common MH disorders (anxiety and non-psychotic depression) are well associated to socioeconomic individual and neighborhood characteristics, but little is known about the influence of urban structure. We analyzed among a Turin  urban population the association at area level of different urban structure characteristics  and consumption of antidepressants. Estimates were adjusted by individual socio-demographic variables  and contextual social environment (SE) variables . Data was extracted from the Turin Longitudinal Study (TLS)—a census-based cohort study following up prospectively the mortality and morbidity of the population. As expected, individual characteristics show the strongest association with antidepressant drug consumption, while among built environment (BE) indicators accessibility by public transport and urban density only are associated to MH, being slightly protective factors. Results from this study, in agreement with previous literature, suggest that BE has a stronger effect on MH for people who spend more time in the neighborhood. Therefore, this research suggests that good accessibility to public transport, as well as a dense urban structure ( The urban built environment (BE) is one of the potential determinants of health and health inequalities to be considered in the Health in All Policies approach . The heaMental health (MH) might be considered one of the most responsive health targets of the urban structure. In recent years, studies on BE and MH have primarily focused on two measures: residents’ perceptions of their living environment ,3 and geetc.).According to their specific purpose, researchers have applied diverse definitions of BE. What is defined as BE encompasses physical indoor conditions, residential building characteristics and a fuzzy “neighborhood quality” that summarizes a vaguely understood neighborhood disorder. Few studies have clearly identified a pathway between urban BE features  elements, mainly related to neighborhood disorder and fear of crime, have been discovered to be related to MH ,17,18,19Depression is frequently reported in the literature as a MH outcome. As a result, antidepressants have been increasingly recommended in recent years for the treatment of both depressive and anxiety disorders ,22. A prIn conclusion, there is scanty evidence of the impact on and inequalities in MH from the different dimensions of the BE that define the urban structure. This limits the ability of urban planners to take into account the health and health equity impact of their decisions.The aim of this study is to test the hypothesis that the BE has an effect on MH, irrespective of the roles played by neighborhoods and individual social disadvantage, by looking at variations in antidepressant prescriptions depending on specific dimensions of the BE .Data was drawn from the Turin Longitudinal Study (TLS), which is based on the city’s historical population registry from 1971 to the present. Demographic information from the registry is individually linked to census variables and routinely registered health events ,30.In this study, adult Turin residents were followed up with regarding antidepressant medications prescribed from 1 January 2004 to 31 December 2006, adjusted by individual and contextual socio-demographic circumstances and their residential stability. Men  and women  aged between 20 and 64 years old, were enrolled and stratified by age ranges  in order to account for differences in exposure to neighborhood characteristics by life stage and gender.i.e., educational level (upper secondary education or higher versus second stage of basic education or lower (According to ISCED levels (ISCED 0–2 versus ISCED > 2)), activity status ; and population registry data: citizenship (native versus migrant) and residential stability (three or more years at the same address versus less than three years).Individual socio-demographic conditions were classified according to census data, BE and SE characteristics were measured at the neighborhood level . Some areas (excluded units 13) were excluded from the analysis as they showed extreme values due to their specificity and would invalidate the results. These areas included cemeteries and parks (no residents) and some hilly parts of the city with no services and few inhabitants due to the geographical conformation. We also excluded the wealthy, residential neighborhoods located in the hills of Turin because these areas have geographic characteristics that render them incomparable to the rest of the city in terms of distribution of public facilities and services.Data on the BE variables of neighborhoods was collected through the municipality administrative datasets and represent the two main aspects of the city’s profile that are relevant for urban policies, namely the structure of a neighborhood , represented in The green/pedestrian areas indicator represents the availability of parks, gardens and green facilities  that are within an accessible distance  and are 3/m2 for almost non-urban areas  to 3.96 m3/m2 as the maximum value, found in the core of the city and characterized by narrow streets with an average building height of six floors. The mean value for the city is 1.3 m3/m2, which is an average value common for cities in Italy and indicates an urban setting with a liveable balance of built volume and open space, comprised of a typical composition of blocks, inner courtyards, services and public spaces  , which hCultural and sport facilities is a composite index  which shows the availability at an accessible distance of facilities within the city that are related to free time leisure  and sports  .Accessibility by public transport refers to the amount of time (average in minutes) taken to reach each statistical area from a given one using only public transport. The values range from 23 minutes—the highest score for the best-served zone—to 74 minutes—the lowest value for the worst serviced zone of the city.Neighborhood SE variables refer to the occurrence among the resident population of urban safety and neighborhood perception, as measured through municipal administrative registries . Social Physical disorder refers to complaints made to municipal authorities for squalor, urban decay and acts of vandalism to garbage bins. This indicates a general carelessness in the area and could affect the sense of safety felt by residents due to the perception that the area is abandoned or of little interest to public authorities.Violent crimes refer to crimes involving physical aggression, such as homicide , fights, insults, assaults and battery, kidnapping and sexual violence (and related offenses). It is worth considering that most of these are reported to the police because they occurred in public .Vandalism refers to criminal offences committed against public goods that are reported to or discovered by the police. It includes criminal offences commonly falling under the definition of vandalism. It is worth noting that these offences may have varied definitions within the diverse legal systems of European countries.Each of these area-based variables was dichotomized using the median split procedure. This choice was suggested by the observed distribution, as linearity of covariates was not always respected, and it meets the need of simplification, as we could only estimate one parameter per variable due to model complexity. The literature did not offer useable solid cut-off values, consequently we opted for the median split. The values are reported in With regards to the health outcome, the adopted case definition was “at least one antidepressant prescription from the National Health Services during the observation period” (2004–2006). The antidepressants were identified in the DPR by their Anatomical Therapeutic Chemical (ATC) classification code (N06A) (WHO Collaborating Centre for Drug Statistics Methodology 2004) and included: monoamino-oxidase inhibitors (MAOI), selective serotonin uptake inhibitors (SSRI), tricyclic antidepressants (TCA) and others.Out-of-pocket purchases of drugs were not included in the database and are therefore excluded from the analyses.The outcome was tested as a function of individual socioeconomic variables , contextual BE variables  and contextual SE variables , in order to identify the BE dimensions affecting MH, irrespective of individual and contextual SE disadvantage. We used Poisson multilevel regression models  stratified by gender and age groups , with individuals nested within neighborhoods, to estimate Incidence Rate Ratios (IRR). We introduced in the models the individual socio-demographic set of variables and added one by one the BE predictors as variables of interest (Models A report results of separate regressions with just one BE covariate at a time); we selected the BE significant variables from Model A—and inserted them in Model B, where we added the SE indicators as control variables, leaving in the final model only the significant BE and SE predictors (Models B).Finally, in order to better highlight any potential social inequalities in vulnerability to the BE effect, we tested the interaction between the most significant variables from the individual socioeconomic set and from the BE set.Statistical analyses were performed using the STATA 10 software In In Models A, each BE indicator was adjusted for all individual socioeconomic indicators. Looking at the main individual predictors of prescriptions for antidepressants, employment status shows a stronger effect for men, with a peak for those aged between 35 and 49 years. Values for women are still significant, but the effect is weaker and comparable across ages. Low school attainment is associated with higher risk among younger men (20–34) and women (20–49), while it is a slightly protective factor for elderly individuals of both sexes. Immigrant status is associated with a consistently lower use of drugs in both sexes and all age groups, although the rates are somewhat higher among men. Residential stability is associated with a lower incidence of drug prescription for both sexes aged 35–65 years, which increases with age. Residential stability does not seem to have an impact on youth between the ages of 20 and 34 years.Among BE indicators for men, accessibility by public transport and urban density seem to influence the variations of antidepressant prescriptions only after age 50. For women, the protective impact of accessibility by public transport is statistically significant in each age group, and urban density only has a protective impact after the age of 50.The final Models B include the statistically significant BE and SE neighborhood variables adjusted for all individual characteristics. Due to their high collinearity (0.67), the specific effects of urban density and accessibility by public transport were nullified when jointly inserted in the model. As a result, we decided to undertake parallel analyses (models B.1 and B.2). The results are comparable for both indicators, demonstrating a significant protective effect of the BE covariate only for the elderly, accompanied by a statistically significant risk that is attributable to physical disorder.The interaction between employment status and accessibility by public transport  was tested and found to have insignificant results.urban density and of accessibility by public transport, with stronger effects evident among women and older adults. This association is true irrespective of the individual level of social disadvantage and the degree of challenges in the neighborhood.In Turin, the incidence of depressive symptoms among adults, as measured by any prescription of antidepressant drugs, decreases with the improvement of some specific features of the urban BE. This is primarily related to the protective effect of The association between social inequalities and the manifestation of depressive symptoms is well documented in epidemiological literature ,35,36,37In our data, a low level of education and inactivity shows the strongest effect on the incidence of first antidepressant prescriptions, particularly among unemployed men.SE covariates do not show any effect in our study population when adjusted by individual social position, apart from a small increase of risk evidenced among the elderly related to exposure to physical disorder. Physical disorder refers to a perception of urban decay as measured by complaints to local authorities and is strongly related to a sense of safety. This has been identified as one of the key determinants of health outcomes, particularly MH, in the literature . Since ietc.) without considering the complexity of the general urban structure.No previous study has specifically investigated the contribution of individual features of the BE, however, there has been general reporting that the BE has an effect on MH, both through direct and indirect pathways. Many studies have tried to shed a light on those pathways, but this has been primarily done by focusing on one determinant at a time , mixed et al. ,48, or tet al. . In our et al. [On the one hand, this is coherent with the latest research findings. Lee et al.  found thet al. , p. 134)On the other hand, and more specifically in connection with our study design, this absence of significant associations may be due to the fact that the effect of some urban features has been hidden by and included in the notions of density and accessibility. These are in turn mutually exclusive when inserted into the model. In other words, urban density—at least in European cities and particularly in Turin—is associated with a variety of uses, urban vitality and a pleasant BE. This primarily coincides with city centers which are often characterized by high accessibility due to the availability of reliable connections and easy access to any services.In our results, the younger population—especially men—seem to be less reactive to their neighborhood environments, both social and structural. On average, women and the elderly tend to pass longer periods of time at home. Some scholars ,50 suggeIn fact, the transportation system enables individuals to access a wider variety of activities. Even if services cannot be distributed within the close proximity of every resident, public transport helps to close the gap by giving individuals the opportunity to easily and quickly reach the needed service. Car use increases as we move further outside the city center toward the suburbs . Public From the point of view of health inequalities, the protective effect of accessibility is evenly distributed across the population by educational level and employment status. This means that these two coefficients are independent determinants of health inequalities in the population.The MH could have been better measured by means of psychometric questionnaires, but it would have reduced the analysis to a sample. The TLS, however, by relying on census and administrative data, aims at surveying the whole population and therefore provides a stronger statistical power.Only prescriptions issued through the National Health System were considered in the study and out-of-pocket purchases were excluded. It is recognized that this could lead to an underestimation of consumption by those who are economically privileged, as we may suppose that this group can more easily afford private medical expenses. In addition, a bias could also be identified in the issuance of NHS prescriptions as antidepressants are surely an inconclusive indicator of the full extent of depressive symptoms, given that seeking care (or not) is frequently influenced by various social and cultural factors, while receiving a prescription for an antidepressant will vary greatly in accordance with physicians’ attitudes. Depression is severely underdiagnosed and undertreated, even in developed countries ,57. Theri.e., income) and at the area level  could have improved the validity of our estimates. The small protective effect of some BE variables, however, appears so strongly independent of individual and area social conditions that a better measure is unlikely to change the direction of the association. Some other important aspects of the physical urban health context are missing, which could have helped explain indirect pathways, such as environmental stressors ; however, reliable up-to-date data on air quality and noise pollution was unavailable at the neighborhood level.We have previously mentioned some omitted variables in the control of confounding factors, More specifically, better measures of social disadvantage both at the individual level , particularly among the elderly and women. The BE seems unable to modify the effect of some socioeconomic characteristics, that is to say, to influence the capacity and resilience of the most vulnerable to confront social and economic distress.In order to address health inequalities, urban policies should invest in the delivery of services that enhance resilience factors, above all a good public transport network, in a careful and equal manner, throughout the city. Attention must be paid to more vulnerable groups, such as the elderly and particularly women. Accessibility and transport services could be easily modified by policymakers as a compensation measure when it is impossible to provide proximity to services for everyone.Such efforts could contribute to the improvement of MH in the city in relation to urban policies. It should also be remembered that the main responsibility for the promotion of MH remains with the social policy sector, to foster equity in the distribution of social determinants.


The role of Home Care (HC) services for the elderly will be increasingly important in meeting populations’ future needs for care. HC services include Home Health Care (HHC) and Homemaking/Personal Support (HMPS), distinction rarely seen in the literature. This paper argues that it is important to distinguish between these types of HC, since the factors that drive the likelihood of the receipt of each type of care may differ, and also to investigate the interrelationship between them. We explored the interrelationship between receipt of publicly funded HMPS and HHC, and the determinants of the receipt of each type of services. A Panel Two-Stage Residual Inclusion approach was applied to estimate the likelihood of the receipt of HC services using data for those aged 65 and over from 9 biannual waves of the Canadian National Population Health Survey (1994-95 to 2010-11). We found that there are in fact differences in the determinants of the likelihood of HHC and HMPS receipt. Moreover, receipt of publicly funded HMPS was found to be complementary with receipt of publicly funded HHC services after adjusting for functional and health status. Dependence on help with activities of daily living, health status, household arrangement, and income were found to be determinants of the propensity to receive both publicly funded HHC and HMPS services. This study aims to contribute to the existent literature by taking a step toward explicitly modelling the potential interaction between the determinants of the receipt of different types of HC services simultaneously, as a system. Our methodological approach, a Panel Two-Stage Residual Inclusion method, seems to effectively address problems that are known to be a source of bias in the literature. One anticipated consequence of the aging of societies around the world is an increase in the prevalence of chronic conditions and disability and a higher demand for long-term care, including home care (HC) services. The need for long-term care services is expected to dramatically increase worldwide, at least during the coming four decades , 2. By 2In this study, the distinction between Home Health Care (HHC) services and Homemaking/Personal Support (HMPS) services is made. HHC services include nursing care, physiotherapy, nutritional counselling, and other health care services delivered by professional health care staff. In contrast, HMPS services help people with daily tasks, such as meal preparation, eating, toileting, personal hygiene, medication reminders, laundry, light housekeeping, shopping, and transportation –7. TheseDespite the differences between HHC and HMPS services, distinctions are often not made in the literature. The distinction may be an important one however, since there are likely to be differences in the determinants of the demand for these two types of services. For example, an early discharge from hospital may be supported by post-acute nursing care at home, while a senior suffering from dementia will mostly require help with ADL/IADL. Equally important is the different potential for substitution for informal care. While a functional spouse will provide support with personal care, he or she will hardly be able to replace the role of providers of more medically intensive services. The need, access, availability of subsidies, and the potential for substitution among public, private, and informal care within each service type are all expected to differ.There is also the issue that once an individual has received either HHC or HMPS services that this may influence the likelihood that they receive the other type of service. Most jurisdictions in North America and Europe allocate HC services primarily based on users’ need. However, it might be the case, as with other health and social services, that once seniors enter the system, the likelihood of receipt of additional services is higher at lower levels of need. This represents not only an issue of inequitable allocation of scarce resources; with capped budgets and overall service volume constraints , receiptThe primary objectives of this study were to explore the determinants of the receipt of publicly funded HHC and HMPS; and by modelling the types of services jointly, to determine whether publicly funded HHC and HMPS services are complements or substitutes in the Canadian context. The analysis also pays particular attention to whether socio-economic factors affect the likelihood of the receipt of publicly funded HC services.Age and dependence on help with ADLs/IADLs have been consistently reported as factors that increase the receipt of HC services of any type and from any source –23 and, It is worth noting that all the studies cited in relation to the effect of income on HC made no distinction between HHC and HMPS services, with the exception of Meinow et al.’s , which oU.S.-based studies generally do not make the distinction between HHC services and HMPS services, and they usually use the term “home health care” to refer to both health care and social services delivered at home. The main reason for this seems to be that Medicare and Medicaid fund both HHC and HMPS services for eligible users. In contrast, several European studies acknowledge this distinction , 21, 24.Two recent European studies using 2004 data from the Survey of Health, Ageing and Retirement in Europe (SHARE), which includes data from 18 European countries, supports the importance of making the distinction between HHC and HMPS, since informal care was found to be a substitute for HMPS yet a complement to HHC  and to aIn Canada, a number of studies have made the distinction between HHC and HMPS services, but only for descriptive purposes , 26–28. Up to this point, the literature has treated HC as one homogenous type of services or has explored HHC and HMPS separately. However, in addition to the evident difference between these types of services, as we noted above, there is potentially a system of interactions between them that has not yet been explored. In order to effectively understand the determinants of the receipt of HC services, modeling the simultaneous effect of the receipt of different types of services is required. This study represents a step toward trying to explicitly model this interaction in an effort to address this research gap in the literature.At the beginning of the 2000s, estimates suggested that approximately 20 % of formal HC services in Canada were privately financed, with the remaining 80 % financed by the public sector , 29. TheCanada Health Act, with the exception of physicians’ services, all services provided at the hospital without any cost to the patient are potentially subject to fees in ambulatory settings. Availability of and eligibility for publicly funded services varies across the 10 Canadian provinces and other national subsystems for nonhospital-based services. This situation generates a conflict when services are transferred from hospitals to homes and community settings.Under to the Across provinces, regional organizations provide a single access point where applicants’ needs and eligibility criteria are assessed and matched to appropriate services, including home care, supportive living, or long-term care facilities . Until AWe used a household home care decision model previously developed by the authors , in whicThe first component of the model that will be addressed in this study is the relationship between publicly funded HMPS and HHC services. Receipt of one is not expected to serve as a substitute for receipt of the other. Indeed, seniors receiving one kind of service are also expected to receive the other more intensively, given the fact that the main determinants of receipt of both HMPS and HHC services are similar and related mostly to age, dependence on help with ADLs/IADLs, and health status. However, when they are adjusted by these variables, they will not necessarily be complementary in their effects. This represents the first testable hypothesis in the model. If receipt of publicly funded HMPS services and receipt of publicly funded HHC services are complements, then receipt of one will be positively associated with receipt of the other, even after adjustments by functional and health status.The second testable component comes from the model’s assumption that households fully exhaust their allocation of publicly funded HC services. The effect of receipt of informal care on publicly funded HMPS receipt, after adjustment for variables reflecting need, will be driven by the impact of this care on supply rather than on demand. Whether the dependent senior lives with other family members may influence his or her likelihood of receiving publicly funded HMPS services. For example, if help is needed for meal preparation, the possibility of being included in a “meals on wheels” program is higher if a person lives alone than if he or she lives with a functional partner. The probability of receiving help with household chores is also likely to be lower if the dependent senior is coresiding with children. Consequently, the availability of informal care from a coresident family member is expected to negatively affect the likelihood of receiving publicly funded HMPS services. A care receiver’s living arrangement will be closely related to the availability of help with ADLs/IADLs. Therefore, household arrangement may be considered a proxy for informal care from coresident caregivers and may be used to test this hypothesis. If informal HMPS services from coresident family members substitute for publicly funded HMPS services, living in a shared household arrangement will be negatively associated with the likelihood of receiving publicly funded HMPS services.Another testable hypothesis is that allocation of publicly funded HC services is expected to be determined mostly by variables that reflect need . However, income is a constraint in the theoretical model, and so an effect of income on the likelihood of receiving publicly funded HMPS services is expected, due to scaled out-of-pocket contributions based on income assessments implemented in Canada over the study period.Data for this study were derived from the household component of the National Population Health Survey (NPHS) held by Statistics Canada. The NPHS is a nationally representative longitudinal survey that collected data biennially from a panel of approximately 17,000 people for 18 years . All ninThe study population was defined as people 65 years of age and older, who were residing in a community dwelling in one of the 10 Canadian provinces for at least one year during the study’s time frame. Individuals who turned 65 years of age during the course of the 16 years of observation were included for the waves in which they met the inclusion criteria. Individuals with incomplete follow-up information or who died were included in the waves in which data were available. This was therefore an unbalanced panel data set.The outcome variables of the study were the probability of receipt of publicly funded HMPS, and the probability of receipt of HHC services. The NPHS also inquires about the type of services received and allows for more than one positive answer. The variables of the study are presented and described in Table The inclusion of variables in the model was guided by the elements contained in the conceptual framework and grouping criteria were guided by frequency distribution. Alternative variable types and their different impacts on the model, and also interaction terms and collinearity were explored. For model selection criteria, an Akaike’s Information Criterion (AIC) was used.Simultaneous eligibility for HHC and HMPS services may possibly produce a problem of endogeneity when modelling the effect of one on the other, causing biased results due to the correlation of these predictors with the error term. Given these concerns, an instrumental variable (IV) approach was used.Given the presence of binary outcome variables in this analysis, usual two-stage least square methods are unsuitable. Instead, a Two-Stage Residual Inclusion method was adopted. This approach has been used in health economics to address endogeneity issues through the use of IVs in nonlinear models , 36, 37.To address this problem, an original approach was used, referred to as the Panel Two-Stage Residual Inclusion model. We first specified a reduced form, first-step equation for each wave of the data set separately. Using logistic regression, we predicted the values of the endogenous variable, HMPS, as a function of its lagged values, and a set of explanatory variables:for t = waves {3, 4, 5, 6, 7, 8, 9} of the NPHS1HMPS is receipt of publicly funded HMPS and z represents exogenous predictors . The IVs used exclusively for HMPS were second lagged values of HMPS receipt, dementia, and social support. From this regression, we obtained the residuals predicted for each wave where Next we estimated an equation for likelihood of receipt of HHC, as a function of its second lagged values and other explanatory variables including whether the individual had cancer or had been hospitalized along with the same set of variables contained in z above:for t = waves {3, 4, 5, 6, 7, 8, 9} of the NPHSWe generated the predicted residuals from this equation for each wave receipt of HHC: second lagged values of HHC receipt, cancer, and hospital admission.For The following IVs were selected and exclusively used in one of the two first-step equations for the identification of each endogenous predictor separately:Aging at Home and Home First in Ontario [b)receipt of HMPS: second lagged values of HMPS receipt, dementia, and social support.For Receipt of publicly funded HHC services in previous cycles is expected to affect current HHC receipt yet not current HMPS. Regarding hospital admission, post-acute HC is prescribed after in-hospital stays to allow an early discharge through health services that can be delivered safely at home. Even though post-acute HMPS is also prescribed, these services are only provided concurrently with HHC after a hospital discharge. Canadian examples of these programs are  Ontario , 39. Simsocial support, as previously described, captures elements of emotional and social support exclusively related to HMPS.Similarly, past HMPS receipt is expected to affect current HMPS receipt yet not the current receipt of HHC. In addition, home care services for dementia patients are mostly directed to provide support and respite to family caregivers  rather tFor the second-stage equations, panel logistic regression (“xtlogit” in Stata) with random-effects was used to specify receipt of HHC as a function of HMPS and other explanatory variables, and the residuals from the first stage HMPS equation described above were included to correct for the potential endogeneity of HMPS. We also specified HMPS as a function of HHC and other explanatory variables, including the residuals from the first stage HHC equation. Standard errors were estimated by bootstrapping. The second-stage HHC and HMPS equations were estimated as follows:The significance of residual terms included in the second-stage equations was taken as a test for endogeneity . To testTo assess the robustness of the model the results were compared with an equivalent analysis using panel probit and Generalized Estimating Equations (GEE)All statistical analyses were performed using STATA 12.0 . Ethics approval for this research was granted by the Health Sciences Research Ethics Board of the University of Toronto .Descriptive statistics are presented in Tables p < 0.001; Table p = 0.062), meaning that receipt of HHC was endogenous to receipt of HMPS services. The strength of the instruments was tested, and the average value of the chi-square test was 29.54 . However, the included residuals were nonsignificant at the 10 % level (p = 0.595). Given the simultaneous effect between receipt of HMPS and HHC services, and the significant evidence of endogeneity in the previous model, the instrumented model was preferred in both cases. Notwithstanding, the coefficients on the other variables in the model were, in general, stable when the residuals were included compared to when they were dropped out, as can be observed in Table p < 0.001) and the standard error of the correlation coefficient for the instrumented HHC predictor was 0.91 times larger than the noninstrumented variable, which was considered adequate.There was a positive and significant association between HHC receipt and the propensity to receive HMPS services . Living with a partner was found to be nonsignificant in general ; however, the interaction term between sex  and living with partner was found to be significantly negative *partner”: OR = 0.23; p < 0.001), a finding that may be interpreted as a substitution effect in relation to informal care provision only by a female partner for a male dependent. As expected on the basis of the conceptual framework, the availability of informal care was nonsignificant in affecting HHC receipt.Household arrangement was a proxy for receipt of informal care in this analysis. In line with the hypothesis, living with other adult family members was associated with a significant decrease in the likelihood of receipt of publicly funded HMPS services , as compared with the middle income-adequacy category, and with no observed significant difference between low- and middle-income seniors. Unexpectedly, high-income seniors reported a significantly lower likelihood of HHC receipt , and low-income seniors reported a significantly higher likelihood of HHC receipt .The income variable had a significant effect on the propensity to receive HMPS services, with significantly fewer services for higher-income people (OR = 0.54, Age, disability, and dependency were strong predictors of publicly funded HMPS receipt, while stroke, incontinence, cancer, dependency and hospitalization were associated with a higher likelihood of HHC receipt. The analysis showed an increased likelihood of HMPS and HHC receipt by male seniors. Immigrant status was found to be associated with a significantly lower likelihood of HMPS receipt, in spite of the fact that the average time since immigration in our sample was 43.9 years. In contrast, ethnic minority was not a significant predictor in any of the analyses.Among other demographic variables, urban seniors did not report a significantly different likelihood of the receipt of HC services. All provinces showed a lower likelihood of HC receipt as compared to Ontario. However, the sample sizes were limited for the small provinces. Among the four provinces that had higher representation in the sample, residents of Quebec and Alberta had a significantly lower likelihood of HMPS receipt in the adjusted analysis, and residents of British Columbia had a significantly lower likelihood of HHC receipt, as compared to Ontario residents.The proportion of seniors reporting receipt of public HMPS services decreased significantly over the study’s time frame in the adjusted analysis. Receipt of HHC, in contrast, did not show a significant variation.Even though the trends in the association between predictors and HC receipt did not change after the inclusion of residuals, there were some changes in the significance of variables, as shown in the second and fourth columns of Table The results from the preferred model were entirely comparable in terms of the magnitude and direction of effects with those obtained using a panel probit model and weighted GEE analysis in the second-stage equation, although significance levels showed some differences. These results are available upon request.The HC literature, up to this point, most frequently treats HHC and HMPS as one homogeneous type of service. Findings in our study support the existence of important differences among them. This research provides robust empirical evidence to confirm part of the hypotheses in our conceptual framework, which translates into a number of important policy implications. In addition, this study is the first attempt to explore and model the potential system of interactions between HC services of different types.We found that receipt of publicly funded HHC was complementary to the receipt of publicly funded HMPS services. This finding supports the assumption that, once a senior accesses the HC system, the probability of being deemed eligible or being offered additional services is higher. The receipt of HMPS was also a strong predictor of HHC receipt, although weaker than the effect of HHC as a predictor of HMPS receipt. This finding partially departed from the expectation that receipt of HMPS would be a weak predictor of HHC receipt. A certain level of qualification is required for assessment of the need for health services, and this type of care is specialized, as compared with HMPS services.In terms of patient care, the consequence of this complementary effect is an increased gap between care recipients and non-recipients, who are at equivalent levels of functional and health status. This element raises concerns about equitable access to HC services in Canada, especially given that provincial HC programs are characterized by capped budgets and overall service volume constraints . This fiConsistent with the theoretical model, we found that the availability of informal care was a negative and significant determinant of the receipt of publicly funded HMPS services, when such care was included in the analysis through the use of household arrangement variables. However, living with a partner only significantly reduced the likelihood of receipt of HMPS when the caregiver partner was a female. Living with other adult family members significantly reduced the likelihood of receipt of HMPS. These findings confirm the reliance on family caregiving when allocating publicly funded HC services, even if eligibility criteria are not explicit in this regard; gender differences are also confirmed. Living arrangement variables were not significant predictors of HHC receipt, which represent additional evidence to the importance of analyzing different types of HC services separately. These observations were concurrent with the interactions in the conceptual framework. Observed differences in the determinants of the receipt of HHC and HMPS may translate into unattended needs in systems where eligibility to HC services is bundled for health and social care, such as the US Medicare system –a hypothesis worth exploring further.Income was an important determinant of HMPS receipt, with fewer services for high-income seniors, as compared with those in the middle- and low-income categories. These findings were expected because all Canadian provinces charged copayments for HMPS services until 2007, payments that were graduated by income . In addiThe study has several limitations, mostly related to the data source. First, the NPHS asks if subjects received services at home or not, but does not inquire about the intensity of services received, i.e., total amount of hours of care received. Second, receipt of informal care from a coresident family member was only inferred from its availability in terms of living arrangement, since specific information on the actual receipt of informal care was not available at this point. In addition, the NPHS has a reduced number of questions specific to HC receipt, which limited the scope of questions to be addressed with this data set.Among the contributions, this study uses 18 years of longitudinal data, which represent an extraordinary opportunity to explore the determinants and interactions in the receipt of HC services. The results suggest that there are important differences between the drivers of HHC and HMPS service receipt. As regards, the second aim—to explore the potential interactions between the likelihood of receipt of the two types of services, this study represents a first attempt to model the determinants of types of publicly funded HC receipt as a system. We argued that failure to address the potential for interactive effects in the existing literature may have biased findings to date. The challenge in this study was that the set of potential instruments in the data were few and necessitated use of lagged variables. We explored various specifications to test the robustness of our results and tested the instruments for strength and validity.Our results remained consistent across the instrumented and noninstrumented approaches, confirming our main research hypotheses. Therefore, the policy implications discussed deserve careful consideration from health care providers and policy makers, to ensure equitable and fair access to health and social support in the home and community settings for the frail elders. Nevertheless, future research should further explore the questions posed within the framework presented in this paper using data that offer a wider set of potentially strong instruments.The original methodological approach proposed in this study, a Panel Two-Stage Residual Inclusion approach, seems to have yielded sensible results and to have effectively addressed problems that are known to be a source of bias in the literature.A conclusion of this study is that the distinction between receipt of HHC and HMPS services matters, given the fact that we found differences in the determinants of the likelihood of HHC and HMPS receipt.We found a complementary interrelationship between receipt of publicly funded HMPS and HHC services, after adjusting for functional and health status. The consequence of this complementary effect may be an increased gap between care recipients and non-recipients, who are at equivalent levels of functional and health status.Dependence on help with activities of daily living, health status, household arrangement, and income were significant determinants of the propensity to receive both publicly funded HHC and HMPS services.Our results suggest that the determinants of receipt of HC services of different types are more complex than has been acknowledge so far, and that this complexity should be taken into greater consideration in the empirical literature.


Although stroke is a significant public health challenge and the need for palliative care has been emphasized for these patients, there is limited data on end-of-life care for patients dying from stroke.To study the end-of-life care during the last week of life for patients who had died of stroke in terms of registered symptom, symptom management, and communication, in comparison with patients who had died of cancer.This study is a retrospective, comparative registry study.A retrospective comparative registry study was performed using data from a Swedish national quality register for end-of-life care based on WHO`s definition of Palliative care. Data from 1626 patients who had died of stroke were compared with data from 1626 patients who had died of cancer. Binary logistic analyses were used to calculate odds ratios, with 95% CI.Compared to patients who was dying of cancer, the patients who was dying of stroke had a significantly higher prevalence of having death rattles registered, but a significantly lower prevalence of, nausea, confusion, dyspnea, anxiety, and pain. In addition, the stroke group had significantly lower odds ratios for health care staff not to know whether all these six symptoms were present or not. Patients who was dying of stroke had significantly lower odds ratio of having informative communication from a physician about the transition to end-of-life care and of their family members being offered bereavement follow-up.The results indicate on differences in end-of-life care between patients dying of stroke and those dying from cancer. To improve the end-of-life care in clinical practice and ensure it has consistent quality, irrespective of diagnosis, education and implementation of palliative care principles are necessary. Stroke is a significant public health challenge, and accounts for 10% of all deaths globally. Although there has been a decline in stroke mortality over the past decades , which mAlthough there are international, specific, and detailed guidelines for the management of stroke, they usually focus on the acute phase and the rehabilitation phase, and only briefly mention palliative care for those patients who will not recover despite medical treatment , 7. The Outside specialist palliative care clinics, there are contradictions and confusions around the term “palliative care”, 9, evenSymptom management is essential in palliative care , and patDespite the medical improvement in the treatment of stroke, a significant proportion of patients die in the acute phase, 21% within the first 30 days . AccordiAlthough it is well known that stroke patients suffer from a range of symptoms and that communication near the end of life with health care staff may ameliorate the situation for patients and their families , there aTo improve end of life in the stroke context and reduce suffering for the afflicted and their families , it is iThis study is a retrospective, comparative registry study.SRPC received the status of a national quality registry in 2006 and has been evaluated, validated, and revised , 27. In The registry includes 30 questions, of which 24 were analyzed, concerning the place of death, main cause of death, symptoms, symptom management during the last week of life, and communication with the patient and the family about transition to end of life care . The questions regarding symptoms were followed with a question on whether the specific symptom was relieved . There were three questions concerning the presence of decubitus, satisfaction with the care provided by health staff, and whether the patient`s ability to self-determine was retained until the final days. These were answered on an ordinal scale (graded 0–5).Using the SRPC data, the inclusion criteria for this study were: diseased patients who had stroke as the main cause of death; who had died in hospital or in a nursing home; and whose death was expected. Data were collected during November 2011 to October 2012. A statistician matched each stroke patient with a registered patient who had died of cancer in the same period, according to the place of death, sex and age . A totalThis study was carried out in accordance with the principles of the Helsinki Declaration  and the Descriptive statistics were calculated for the individual variables with means and SD for continuous variables, and frequencies and percentages for categorical data. All data were dichotomized and binary logistic regression analyses were used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) in univariate models. A p-value of <0.05 was considered to be statistically significant. IBM SPSS Statistics version 23 was used to perform the statistical analysis.All six assessed symptoms were prevalent in both studied groups (on one occasion or more during the last week). Compared to the patients with cancer, the patients dying of stroke had significantly higher OR for having death rattles , but lower ORs for registering the symptoms of pain, nausea, confusion, anxiety and dyspnea Tables –3. HowevCompared to the cancer group the stroke group had a significantly lower OR of having informative communication from a physician about the transition to end of life,  . The heaThis study is unique as it identified what kind of palliative care at the end of life patients dying of stroke receive in comparison to patients dying of cancer.All six studied symptoms were reported as prevalent in the stroke group, from nausea at 7.6% to death rattles at 60.7%. One of the assessed symptoms was pain, which approximately 43% of the stroke patients suffered from during their last week of life, and 5% were registered having severe pain (NRS > 6 on one occasion or more during the last week). Mazzocato et al.`study of patients cared for by an organized palliative care consulting team showed an even higher prevalence of pain in dying stroke patients, namely, 69%.Although the stroke group had a lower registered prevalence for most of the studied symptoms compared with the cancer group, the dying stroke patients suffered more often from death rattles during the last week of life. However, there were no significant difference if death rattles was fully relieved between the groups. Death rattles can be very distressing for family members to listen to, and successful palliation of this symptom has been shown to provide a positive experience for the family . There iAnother noteworthy result is that, the stroke group had a significantly higher odds ratio than the cancer group for the staff members not to know whether the patient was suffering from all the studied symptoms or not, with ORs ranging from 1.95 for death rattles to 8.84 for pain. Symptom management is essential in palliative care [In the statement from the American Stroke Association, the understanding of the considerable unmet needs of symptom management for patients dying from stroke is obvious . The useThe results of this study also indicate that stroke patients received nutrition supply significantly more often than the cancer patients on the last day of life. This could constitute adequate care, but could also be an expression of decision-making problems concerning how to diagnose impending death and provide optimal end of life care , 23. TodAnother essential part of palliative care is communication with patients and families and within the team . In the The results of the current study also relate to another significant aspect of palliative care  namely, The results of the present study raise questions if there is a need of improvement in stroke care the last week in life. We cannot be sure, as our results does not necessarily present the reality, but the results indicate differences in assessment for all studied symptoms. Does this mean that there is a need of a development and implementation of palliative care skills within the health care structure that has previously been suggested by other authors ? SettingFurther studies are needed concerning whether an educational intervention would influence end of life care for stroke team members and affect patients’ end of life care. However, family members’ perspectives on the care provided during the last week of life are also important.A few issues ought to be raised in terms of the limitations of this study. First of all, there were six symptoms registered in the questionnaire; other possible symptoms that might occur were not reported in this study. Secondly, it seems worth noting that the questionnaires were completed retrospectively, so recall bias could have affected the results. There might be selection bias in the units that are registered in the SPRC, namely, units particularly interested in palliative care. In addition, to avoid confounders regarding age, sex and caregivers the groups were matched. Finally, the validity of the questionnaire has been continually evaluated , 27.This study has identified differences in palliative care at the end of life between patients dying of stroke compared with patients dying of cancer especially regarding symptoms, symptom management, communication with the patient, and offering a bereavement follow-up to the family. The results may have implications for clinical practice. Does health care staff need to pay more attention to the palliative care needs of patients dying of stroke and to their family members? Further studies in this area are needed to determine this.


As explained by the World Health Organization (WHO) in 2000, the concept of health system responsiveness is one of the core goals of health systems. Since 2000, further efforts have been made to measure health system responsiveness and the factors affecting responsiveness, yet few studies have applied responsiveness concepts to the evaluation of mental health systems. The present study aims to measure responsiveness and its related domains in the mental health-care system of Tehran. Utilizing the same method used by the WHO for its responsiveness survey, responsiveness for outpatient mental health care was evaluated using a validated Farsi questionnaire. A sample of 500 public mental health service users in Tehran participated and subsequently completed the questionnaire. On average, 47% of participants reported experiencing poor responsiveness. Among responsiveness domains, confidentiality and dignity were the best performing factors while autonomy, access to care, and quality of basic amenities were the worst performing. Respondents who reported their social status as low were more likely to experience poor responsiveness overall. Attention and access to care were responsiveness dimensions that performed poorly but were considered to be highly important by study participants. In summary, the study suggests that measuring responsiveness could provide guidance for further development of mental health-care systems to become more patient orientated and provide patients with more respect. The Universal Declaration of Human Rights and its related conventions and guidelines, which have been ratified by governments globally, contain a wide range of health-related rights. These include the right to health and health care, and particularly the right of individuals with physical and mental disabilities to the highest quality health services . When goResponsiveness becomes particularly relevant when considering the mental health-care system . CompareBeginning in the late 1980s, in order to achieve the highest attainable level of mental health care, the Islamic Republic of Iran began integrating mental health services into primary health care. At the village or neighborhood level in urban areas, community health workers are in charge of mental health-care responsibilities, including active case finding and referral. At primary care centers, trained general practitioners provide mental health care as part of their general health-care responsibilities. In case of complex mental health problems, general practitioners refer patients to district or provincial health centers, which are supported by university mental health hospitals  Are the perceptions of responsiveness different by sociodemographic characteristics? and (ii) Which responsiveness domains are most important to service users? Is it those with good or poor performance?In some ways, the health system structure and organization in the Islamic Republic of Iran is unique. At the national level, the Ministry of Health and Medical Education (MoHME) is responsible for health service delivery through planning, designing, and implementing health policies as well as monitoring and supervising health-related activities for the public and private sectors . Yet, thAs in many large cities, the provision of mental health care in Tehran is complex. A combination of public, private, and special services such as military hospitals and clinics as well as services related to semi-private schools of medicine  are involved in mental health-care provision. Most people, especially those from poor neighborhoods, depend on public mental health services because of the high costs of private care.The survey was conducted in Tehran, the capital of Iran, between January and April 2013. In Tehran, mental health services are organized in terms of catchment areas. Each of the four public medical universities provides inpatient and outpatient mental health services for a defined catchment area. These services are provided through mental hospitals and nine affiliated outpatient clinics. However, service users can freely choose to be referred to any of the mental health services.A non-random sample of 500 mentally ill patients referring to 27 mental health service providers in nine public outpatient clinics distributed in different city regions  was selected. Private psychiatric clinics were excluded. The number of participants assigned to each clinic was proportional to the total number of patients attending the clinics during the previous 3 months.Service users diagnosed as mentally ill based on a psychiatric evaluation record (the psychiatrists were blinded to the study). The study participants were recruited after being initially approached by the interviewers with regard to their willingness to participate. Inclusion criteria were (1) being an adult (18–65 years old), (2) receiving outpatient care during the past 12 months, and (3) being mentally capable of following the interview according to their clinical record. Type of mental disorder was not considered an inclusion criterion since experiences that mental health patients have with services relate more to the services functioning than to the patient’s current diagnosis , 14. SerTrained external interviewers with a bachelor degree in psychology conducted face-to-face interviews. Interviewers explained the procedure of the interview to the participants and obtained their written consent. Participants were asked about the outpatient mental health-care services that they had experienced during the last 12 months; interviews lasted between 45 and 50 min and were strictly anonymous. To ensure subjects were not interviewed twice, each record was labeled with a code. The Ethical Committee and Research Council of the University of Social Welfare and Rehabilitation Sciences in Iran approved the study. In addition, administrative permission was obtained from the Medical Universities in the study area. All study participants were evaluated by a psychiatrist prior to the interview. Based on the psychiatrist-written clinical reports, participants were in the remission phase of their mental disorder and capable of making a decision. The nature and purpose of the study was explained to each participant; then, individual informed consent was confirmed by participants with a signature or a left thumbprint. Before the interview, participants were informed that the completion of the questionnaire was voluntary and their identification would be protected, as the data files were anonymous. Participants were informed of their right to withdraw from the study at any time. Participants gave permission to audiotape the interview session.The responsiveness concept developed by the WHO was applied in this study . In a prIn accordance with the WHO health system responsiveness questionnaire  and the very good and good responses) and poor responsiveness  , we scored responsiveness in each domain based on the “rating” question, which was asked only after participants had answered a series of detailed “report” questions related to the relevant domain. For the rating questions, the responses were categorized as 5 (very bad), 4 (bad), 3 (moderate), 2 (good), and 1 (very good). A further summary score for “overall responsiveness” was obtained by calculating the average scores across all the eight domains. The responsiveness outcomes were then dichotomized into good responsiveness (combining the sponses) . Multivanificant .A total of 500 participants aged 18–65 years  were enrolled in the study. Among them, 38% were females and 62% males. Approximately 24% had 5 years or less of formal education and 28.7% were unemployed. All participants revealed that they used the services more than once during the past 6 months, and 96% had used services more than twice in the last 6 months. The majority of participants (52.7%) indicated that they belonged to the middle social status, and 92.8% of participants had access to medical insurance. Details of the sociodemographic characteristics of the study participants are presented in Table poor responsiveness. Table poor responsiveness among the different sociodemographic groups. Youngest participants (53.7%) reported worst responsiveness than did older participants (31.7%). In addition, more participants with low SSS scored responsiveness as poor compared to those with high and middle SSS. Approximately half of the participants with intermediate educations or who were unemployed reported poor responsiveness for services.On average, 47% of participants reported experiencing very bad, bad, moderate, good, and very good in all domains. The best-performing domains (very good and good) were confidentiality (92.4%) and dignity (81.8%). The worst performing  domains were autonomy (42.7%), access to care (31.9%), and quality of basic amenities (31.3%).Figure In order to examine the relationship between the poor responsiveness rating and the sociodemographic characteristics of participants, a multivariable logistic regression analysis was performed. Overall, as well per domain, SSS was the only characteristic that showed differences in rating responsiveness Table . RespondThe importance of the responsiveness domains in relation to domain performance is presented in Figure To our knowledge, this is the first study exploring the responsiveness of the mental health-care system in Iran. Previously, only one study from Germany focused on the responsiveness of the mental health-care system . HoweverOur study showed that confidentiality was the best-performing domain in outpatient mental health care. This result is in line with the German study on mental health responsiveness as well as the studies from Tehran , 23. ThiDignity was the second best-performing domain in our study. This finding is also supported in previous responsiveness studies , 23, 25.Autonomy, access to care, and quality of basic amenities were poor-performing domains. It is noteworthy that in our study, autonomy combines the domains of choice and autonomy used in the WHO questionnaire. In this respect, our findings are very similar to the German study on mental health responsiveness. In mental health care, there are indeed fewer opportunities for free choice and service user autonomy. This may be due to the fact that some mentally ill patients may have poor insight into their disorder and also suffer from some degree of impairments in their rational thinking. Therefore, for these patients, active participation in the process of decision making is difficult and complex. On the other hand, there is a specific desire among mental health service users to participate in mental health-care decisions, and the more they recover, the more they want to participate , 27. FurAccess to care was the second poor-performing domain. The definition of this domain in our study was very similar to the domain of prompt attention used in the WHO questionnaire. In this regard, our results are different from the German study  but veryRegarding perceptions of responsiveness among different sociodemographic groups, the German study reported that outpatient care was perceived differently depending on respondents’ income and education . HoweverThere is no statistically significant difference in responsiveness between males and females and between different age groups. This finding is consistent with the result of studies in health system responsiveness in Iran and the German study on mental health system responsiveness –25. ThisIn terms of the importance of the responsiveness domains, attention, dignity, and access to care received higher scores. This finding is also similar to a study among mentally handicapped children in Tehran  and a stPerformance of responsiveness domains in relation to the importance given to them in our study showed that attention and access to care do not perform well despite their importance for service users. Access to care seems to be a core expectation in general health care as well as mental health care , 23. TheThis is the first time that mental health system responsiveness has been measured in Iran. It represents the actual experiences of the service users when they come in contact with the mental health system. In conclusion, this study showed that dignity and confidentiality were well-performing domains, while autonomy, quality of basic amenities, and access were poor-performing domains. Improvement of all these poor-performing domains is dependent on resources. In addition, attention and access to care, which were rated high in importance and poor in performance, could be priority areas for intervention and reengineering of referral systems and admission processes. The role of the SSS in responsiveness should be further studied.The need to assess responsiveness and its domains in the delivery of mental health services is not only important for good health practice but also for the provision of health and health-care rights . The finOur study had a few limitations. The cross-sectional study design did not permit investigation of the cause and effect relationship between our independent variables and responsiveness. In addition, this study did not include inpatient service users. Access to social support could not be measured either. Finally, although a different dichotomization of the responsiveness outcome might have resulted in other associations, we decided to follow the guidelines provided by WHO.SF: contributions to the conception or design of the work, analysis and interpretation of data, drafting the work, revising it critically, final approval of the version to be published, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. MP: analysis and interpretation of data, revising it critically, final approval of the version to be published, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. HR, MG, and MD: contributions to the conception or design of the work, revising it critically, final approval of the version to be published, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. MS: contributions to the conception or design of the work, interpretation of data, drafting the work, revising it critically, final approval of the version to be published, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Nonsteroidal anti-inflammatory drugs (NSAIDs) act upon peripheral tissues and upon the central nervous system to produce analgesia. A major central target of NSAIDs is the descending pain control system. The rostral structures of the descending pain control system send impulses towards the spinal cord and regulate the transmission of pain messages. Key structures of the descending pain control system are the periaqueductal gray matter (PAG) and the rostral ventromedial region of the medulla (RVM), both of which are critical targets for endogenous opioids and opiate pharmaceuticals. NSAIDs also act upon PAG and RVM to produce analgesia and, if repeatedly administered, induce tolerance to themselves and cross-tolerance to opioids. Experimental evidence shows that this is due to an interaction of NSAIDs with endogenous opioids along the descending pain control system. Analgesia by NSAIDs along the descending pain control system also requires an activation of the CB1 endocannabinoid receptor. Several experimental approaches suggest that opioids, NSAIDs and cannabinoids in PAG and RVM cooperate to decrease GABAergic inhibition and thus enhance the descending flow of impulses that inhibit pain. The intensity of these reactions serves as an indicator of the degree to which pain messages are being transmitted and would eventually reach the brain and give rise to the conscious experience of pain. Another indicator is the discharge of action potentials by postsynaptic nociceptive neurons, e.g., in the spinal dorsal horn, when a standardized stimulus is applied to a peripheral tissue. Defensive reflexes and behaviors, and neuronal action potential discharges, are of course only surrogates of the real experience of pain, but they have greatly served to investigate the mechanisms of pain and the action of analgesics, so much so that frequently (if erroneously) increases in reflexes, behaviors or neuronal firing are referred to as “hyperalgesia” while their attenuation is referred to as “analgesia”.The conscious experience of pain is one of the functional products of a set of neural structures in charge of detecting tissue damage and reacting to it. Tissue damage is detected by the distal terminals of peripheral neurons known as nociceptive primary afferents, which conduct this information up to their proximal axon terminals. These excitatory synaptic terminals are located in the dorsal horn of the spinal cord or in other neuronal groups in the central nervous system. Here information processing by second and further order nociceptive neurons, as well as by excitatory and inhibitory interneurons, may give rise to pain messages aimed at further targets. Some of these targets are neuronal circuits whose functional products are autonomic reflexes or somatic defensive reflexes and behaviors. Researchers purposely elicit in animals such defensive reflexes and more complex behaviors by applying standardized noxious stimuli to peripheral tissues, e.g., a hind paw, the colon, Beyond the spinal cord, pain messages reach further targets along the ascending pain pathway—neuronal groups in the medulla, the pons, the midbrain, the hypothalamus and the thalamus—until the forebrain is reached—the amygdala and the insular, somatosensory and cingulate cortices. Here the neurons of the so-called “pain matrix” finally bring to consciousness the presence of damage in some specific somatic or visceral tissue.This was pretty much the picture of the “pain system” until about 1970 . In the One very important structure of the descending pain control system  is the gBoth the PAG and the RVM are well endowed with opioid receptors  and are The aim of the present review is to propose that non-opioid analgesics share common mechanisms for analgesia by the descending pain control system with endogenous opioids and, probably, endocannabinoids.The analgesics known as nonsteroidal anti-inflammatory drugs (NSAIDs) have, with reason, traditionally been considered to be different from the opiates . Yet welInhibition of nocifensive reflexes in these experiments is interpreted as caused by inhibition of nociceptive neurons. But it might also be due to inhibition of motor neuronal circuits without alteration of ascending pain messages. Motor inhibition would have the unwanted consequence of leaving pain undiminished while preventing limb withdrawal from the noxious stimulus. Therefore, in order to be certain of an effect upon pain sensory pathways, action potentials from nociceptive neurons were recorded in the spinal dorsal horn of rats. Action potential discharges elicited by peripheral noxious stimuli applied to a hind paw were severely attenuated when metamizol was microinjected into the PAG . FurtherRepeated administration of a drug can lead to a progressive loss of its effect. This is known as tolerance, and is particularly notorious for opiates. The PAG is crucial for tolerance to opiates ,39,40,41These findings were in agreement with the fact that tolerance to NSAIDs in humans had been suspected for a long time ,45,46,47Tolerance to opiates is to some extent mediated by cholecystokinin, an endogenous peptide , and tolAs already mentioned, the action of either opioid or non-opioid analgesics in the PAG leads to an excitation of PAG output neurons and this causes an activation of RVM off-cells and an inhibition of RVM on-cells, thus leading to “analgesia”. When tolerance develops, PAG microinjections of morphine  or metamThese results show further mechanistic relationships between opioid and non-opioid analgesics as regards the descending pain control system.Cannabis sativa). The best known cannabinoid receptor types are called CB1 and CB2, and both of them mediate inhibition of cellular processes [Cannabinoids are lipid molecules that activate metabotropic, G-protein coupled membrane receptors also activated by some derivatives of marihuana (rocesses ,61. The rocesses ,61. The rocesses  and seemrocesses . CB1 andInjection of cannabinoids into the cerebral ventricles , the latAn involvement of endocannabinoids in the analgesic effects of NSAIDs has been shown at a systemic level ,70,71 anThe most widely demonstrated mechanism for the analgesic action of NSAIDs is the inhibition of cyclooxygenases ,23,24,252 and thereby increase the availability of arachidonic acid [i.e., an increase in the activity of off-cells, which are output neurons that mediate spinal nociceptive inhibition [The fact that the action of NSAIDs in the PAG is related to opioids could be explained if NSAIDs increased the release of endogenous opioids, but this has never been investigated. Nonetheless there is experimental evidence for other types of interaction. Opioids in the PAG, by way of the µ receptor activate phospholipase Anic acid . Also NSnic acid . Thus, inic acid , and attnic acid . It thushibition . This mihibition .As with opioids, one possible mechanism for the analgesic action of NSAIDs could be their induction of endocannabinoid release. Again, at least as far as the PAG and the RVM are concerned, this has not been investigated. Once more, a plausible link between NSAIDs and endocannabinoids may be related to the fact that NSAIDs inhibit the cyclooxygenases and the FAAH , and thaIn the lateral-ventrolateral PAG and in the RVM, cannabinoids via the CB1 receptor inhibit the presynaptic release of GABA and thus enhance the activity of postsynaptic neurons, like opioids do ,88. TherAs with all models, the model proposed to describe the interactions between NSAIDs, endogenous opioids and endocannabinoids  does notThus, in spite of some uncertainties, the bulk of experimental evidence indicates that disinhibition by endogenous opioids and endocannabinoids of brain stem neurons that mediate descending inhibition of nociception ,14 is thExperiments in laboratory animals have shown that NSAIDs, in addition to their actions at peripheral tissues and the spinal cord, exert their analgesic effects by activating the descending pain control system at the PAG and the RVM. Like the opioids and cannabinoids, NSAIDs act at the descending pain control system by activating RVM pain-inhibiting neurons and inhibiting RVM pain-facilitating neurons whose axons descend onto the spinal dorsal horn. The analgesic effects of NSAIDs at the PAG are at least partly related to endogenous opioids and cannabinoids and in the end indirectly result in an attenuation of GABAergic synapses, thus increasing the activity of output neurons responsible for descending inhibition. Repeated administration of NSAIDs progressively leads to tolerance to the NSAID, cross-tolerance to morphine and the risk of a withdrawal syndrome. These findings are important for human and animal medicine.


The traditional view of the medial temporal lobe (MTL) focuses on its role in episodic memory. However, some of the underlying functions of the MTL can be ascertained from its wider role in supporting spatial cognition in concert with parietal and prefrontal regions. The MTL is strongly implicated in the formation of enduring allocentric representations (e.g., O'Keefe,  The precise role of the hippocampus in memory has been the subject of much debate. A large body of evidence points toward a crucial role for this structure in the formation of allocentric spatial representations, based on rodent and non-human primate hippocampal place cell recordings, as well as studies of humans with hippocampal lesions and implanted electrode hippocampal recordings  model of spatial memory  were associated with activation of the precucneus, parieto-occipital sulcus/retrosplenial cortex and hippocampus , a pure rotation of viewpoint (ROT), and  and allocentric representation of objects  and object configurations (hippocampus). We further predicted that JRD would most strongly activate this circuit, since it requires the most complex transformation (involving both the transformation required in ROT as well as a translation).The study was approved by the ethics review boards at McMaster University and St. Joseph's Healthcare Hamilton. All participants gave written consent to participate in the behavioral selection experiment, written notice of interest to be considered for scanning, and additional written consent to take part in the fMRI scan on the day of scanning.Fifteen participants were included in the final analysis after six were rejected due to excess motion in the scanner and technical issues with scanning, and one elected to withdraw from the study during scanning. All participants were male right-handed McMaster University students  with normal or corrected vision and were classified as gamers (minimum of 10 h a week playing video games). Gamers were chosen due to their experience with operating and navigating in virtual environments, and males were preferred to avoid sex differences in spatial cognition and navigation  and second, within the scanner 3–5 weeks later. The initial selection experiment, used to select participants for the scanning session, was run in a quiet testing room on a Lenovo Thinkpad E430 laptop with a 14″ 1366 × 768 resolution display.During the selection experiment, each participant performed three rounds, each involving a block of each task. A single round included five consecutive blocks of Collect and Replace for learning, followed by one block each of VIS, INVIS, REF, ROT, and JRD, in order (these tasks are defined in detail below). Final JRD accuracy was used to determine whether a participant was invited for a follow-up scanning session so as to select only those who could learn the arena map and infer object-to-object relationsihps well. Participants were required to have either an average JRD error less than one standard deviation below the mean on the final round of the experiment, or average JRD errors less that one standard deviation below the mean on each of the first two rounds of the experiment.The scanning experiment was conducted at St. Joseph's Hospital in Hamilton, Ontario, Canada. Prior to scanning, each participant performed two complete rounds outside the scanner as done in the selection experiment to refresh their memory of the arena map and instructions for each task. Only the last four pointing tasks  were performed in the scanner.A virtual environment was built in the open-source simulation platform OpenSimulator  or pointing to objects using an arrow. When navigating , participants controlled an avatar  from a third-person view using the keyboard's directional arrows. When pointing, the participants rotated an arrow, presented in the fronto-parallel plane, to identify the direction of the cued object. In the scanner, participants made pointing responses using buttons on a gamepad-like device that was safe for operation within the scanner. The pointing arrow was rotated clockwise or counter-clockwise in the fronto-parallel plane using two buttons, and a response was made with the third button. On all pointing trials, the initial direction of the arrow was randomized to avoid the interference of proprioceptive memory over visuospatial memory.During the scanning portion of the experiment, participants were cued using pictorial instructions in a heads-up display to inform them of the task that was starting and the goal of each trial. Prior to each trial onset, a blank screen was displayed for 3 s. Afterwards, the cue was overlaid on the blank screen for another 3 s , followed by another blank screen for 3 s. Following this second blank gray screen, the pointing response arrow appeared on the blank screen to indicate that a response could be made. Other than the differences in the cues visually and temporally, all trials across all tasks were presented identically. Cues and the arrow used for pointing response are presented in Figure Participants performed the tasks at their own pace, though trials which lasted longer than 25 s were rejected, as it was deemed likely that the participant had not been sufficiently engaged during the trial. Since each trial required the participant to imagine and reason about the spatial relationships of the objects in the arena before making a response, no strict response time could be imposed. Therefore, response time varied from trial to trial, as evident in Table Each round contained a block each of REF, ROT, and JRD  with four randomly generated trials in each block. In REF, each object was pointed to once in each block in a random order, but in ROT and JRD, trials were completely randomly generated, i.e., the viewpoint direction and/or position was resampled on each trial. Each round ended with a screen indicating the end of the round, and participants were able to start the next round at their own pace by pressing a button on their input device. On average, 13.6 REF trials, 12.0 ROT trials, and 10.8 JRD trials were completed within the 25 s rejection threshold by each participant.For each round of the experiment, REF, ROT and JRD were performed in the same order. It was required that REF come first in order to re-establish the reference viewpoint for the ROT condition, which must follow REF in order make use of this freshly re-established viewpoint since ROT uses the same position, albeit a different heading direction. Since the JRD breaks away from this reference viewpoint, it may interfere with performance of the ROT trials if it were to be interposed between REF and ROT. Therefore, there was no counterbalancing of the task order in this experiment. The order during the selection experiment was Collect and Replace, VIS, INVIS, REF, ROT, and JRD, while the order for the scanning eperiment was INVIS, REF, ROT, and JRD.Participants performed five rounds of collecting the objects and returning them to their original locations in order to learn the layout of the arena and distal landmarks. Participants were cued to collect each object in the arena one by one in a random order and each object was collected simply by walking to the object. Participants were instructed that they would need to replace each object during the next task and that no visual information aside from the distal landmarks would be avialable during that time, implying that these landmarks should be carefully observed during the collect phase. Only the cued object was visible during each collect trial so that participants were less able to encode the spatial relationships between the objects themselves and were needed to rely on the distal landmarks. All other potential cues were minimized by ensuring the shape and textures of the ground, arena, and sky were consistent throughout.After each object had been collected, the avatar was teleported to a random location within the arena with a viewpoint in a random direction. With none of the objects visible, the participant was next required to walk close to the cued object's original location in order to replace it. The object appeared for 1 s when the avatar was close enough to the location  to provide feedback for learning, and disappeared again before the next object was cued. After all of the objects were replaced, the avatar was randomly teleported and the collect phase repeated. After the fifth collect and replace round was completed, the next task was initiated.Pointing While Visible (VIS) was a calibration task that simply asked the participant to point to each successively cued object using the black pointing arrow . This served the purpose of allowing the participant to establish a familiar viewpoint and to become accustomed to the pointing controls. It also provided an indication of the baseline pointing error, in degrees, for that participant. These errors were checked to ensure that the participant correctly performed the task and that performance was higher on this task than on any of the other more challenging pointing tasks.Pointing while invisible (INVIS) was identical to pointing while visible except that the objects were not visible . The participant was required to point to the location of each object from memory and was provided feedback after each response by the brief reappearance of the target object. Note that this reference viewpoint, used for VIS, INVIS, and REF, had all objects in the field of view, so visual feedback was always possible.During scanning, VIS was only used as a means to orient the participant to viewing the screen and operating the controls within the scanner, and to check that they were still able to perform the trials with similar accuracy as outside of the scanner. INVIS was used in a similar way, but also for comparison to REF, since the task is similar but without as much reliance on mental imagery. For the remainder of the paper, INVIS will generally be referred to as the baseline task.reference viewpoint). However, the entire virtual environment was now occluded and only the pointing arrow and cues were visible. Pointing necessarily took place purely from memory without the assistance of distal landmarks and was done with a black arrow on a gray background occluding the entire arena (the same black arrow over a gray background was used for the ROT and JRD tasks as well).Pointing from imagery required the participant to point to the objects from the same viewpoint as in the previous pointing tasks . As seen in Figure The final task was a judgment of relative direction (JRD). This was almost identical to ROT except that a translation was added. Participants were required to imagine standing at the location of one object, facing a second object, and then to point to a third object. A third line of images was added to the cue to illustrate all three components of the instructions Figure . This cuTE = 2.2 ms; TR = 7.7 ms; 80 slices; slice thickness = 2 mm, no skip.Scans were performed with a 3 Tesla General Electric fMRI scanner. A T1-weighted anatomical scan in the axial orientation was obtained prior to functional imaging. The scanning parameters for the anatomical image series were: 3D SPGR pulse; fast IRP sequence; prep time = 450; flip angle = 12; FOV = 240 mm; TR of 2600 ms, totalling 500 volumes and a functional scan time of 21 min and 48 s. The TE was 25 ms and the flip angle was 90°.Functional images were were collected in interleaved axial slices with a GRE-EPI pulse sequence. The field of view was 21 cm with a slice thickness of 2.9 mm and a slice gap of 0.1 mm There were 40 slices per volume with a Image processing and statistical analysis were performed using BrainVoyager QX 2.6   was used to model each participant's data individually. Due to the self-paced nature of each trial and the various possible strategies participants may have used for producing their responses , we used the time window from cue onset to response input to measure brain activation. For the ROT and JRD conditions, a parametric model was built by using the standardized pointing errors as an additional regressor. This weighted the brain activity by trial accuracy . The unweighted brain activity was subtracted from the performance-weighted activity  to find performance-related activations and to reduce the loss of information when averaging across strategy differences, individual skill differences, and trial-by-trial changes in attention, effort, strategy, and performance. This included the added benefit of filtering brain activations that may have been a result of superfluous processing not contributing to task performance, including processing on-screen visuals. Data from all participants were combined in a random-effects GLM using a participant-averaged mask and an averaged anatomical.FDRp < 0.05, which is usually thought of as a stricter correction than the alternatives when activation is sparse, and less conservative if activated areas are large  of To investigate the accuracy of the representations used by participants to perform the JRD and Rotation tasks, we examined participants' average absolute pointing errors from the true object location (denoted by the center of the object) and their response times from cue offset. Participants were highly accurate in both the REF and INVIS conditions, and less accurate in the Rotation task than the JRD task . Brain areas having significant task-related activations (a simple contrast with no parametric modeling) for REF vs. baseline , and performance-related activity for the JRD task and the ROT task are given in Tables For both the JRD and the ROT tasks when parameterized by performance, we found significant performance-related activations in the hippocampus Figure , the parFDRp < 0.05).We also assessed the difference in performance-related activation between the JRD task and the ROT task Figure . When thFDRp < 0.05). Therefore, the regions identified by the BBB model were more activated by the JRD task than the ROT task.There was greater activity in the ROT task contrasted with the JRD task in the superior temporal gyrus, the postcentral gyrus, the left middle temporal gyrus, the middle frontal gyrus, the medial frontal gyrus, the cuneus, and the anterior cingulate gyrus  in the right hippocampus, parahippocampal gyrus (left for JRD and right and left for ROT), right retrosplenial cortex, and right precuneus as predicted by the BBB model, as well as activity in the middle frontal gyrus (left and right), the anterior cingulate (left), and the superior and middle temporal gyri (left). Visual comparisons between ROT and REF and JRD and REF are shown in Figures The brain regions predicted by the BBB model to be involved in transforming between egocentric and allocentric representations , parahippocampal cortex and hippocampus) were active during our mental transformation tasks. Importantly, these activations correlated with task performance, consistent with our hypothesis that this neural circuit subserves the transformation between egocentric and allocentric representations. Moreover, as predicted, this circuit was more strongly activated in imagined transformations involving both rotation and translation of viewpoint (JRD) relative to transformations involving only a rotation of viewpoint (ROT). Our results in the JRD condition are consistent with those of two other recent studies that asked participants to perform spatial memory tasks after imagined viewpoint changes that included both a rotation of viewpoint and a translation of the observers location , and would keep learning time to a minimum, as gamers tend to show greater facility at traversing and learning VR layouts. The choice of right-handed males was made to minimize variability in functional activation due to sex differences and lateralization of functions. These benefits come at a cost to the generalizability of our results. One of the most well-documented sex differences is in spatial cognition . While activations due to the pointer itself are likely to be mostly filtered out by averaging and parametric modeling, it is possible that how the cues were processed mentally was correlated to some degree with the accuracy of the responses, introducing some interference. However, since surveys showed that participants generally began imagining their cued position, direction, and objects while the cue was present, this interference is unavoidable with the current visual paradigm and setup.Due to the limitation in the scanning time available for each participant to perform a sufficient number of trials, we were not able to accommodate an additional task, pointing from a fixed viewing direction with a translation only . Though this task does not directly address the questions we have posed for this study, it would shed light on interesting and related questions on the differences between rotation-only and translation-only processing, and their relative contributions to the JRD task. Future work is required to tease apart the independent contributions of rotation vs. translation vs. rotation plus translation to behavioral performance in the tasks reported here, as well as the effects of rotation and translation magnitude on performance and brain activity.We have focused in this paper on the effects of task demands such as rotation and translation on the neural circuits involved in imagined pointing responses. Other potential sources of variability in participants' responses in the ROT and JRD tasks are the degree of imagined heading disparity and object-target disparity. For example, a well established finding is that tasks requiring a rotation of imagined perspective incur a reaction time cost in proportion to the degree of heading direction disparity (e.g., Rieser, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.