Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Service components of case management that reduce in-patient care use

Case management is expected to fill the gap between the needs of the seriously mentally ill and the care system. The findings from previous research on case management are inconsistent with respect to its impact on hospitalization, ambulatory service use, and clinical improvement. This study compared the effectiveness of two types of case management: traditional case management (CM) which included the function of service coordination, and Intensive Case Management (ICM) which consisted of both the coordination function and the provision of direct support to the client in the community. Secondary data on public clients using the Philadelphia mental health system were used. Clients selected for the study were Medicaid eligible adults, with a diagnosis of schizophrenia or affective disorder and had at least 60 inpatient days one year prior to the end of the inpatient episode. The ICM sample consisted of 80 clients who were linked to ICM immediately following discharge. The CM sample consisted of 84 clients who received CM instead of ICM while they waited for the registration for ICM. The demographic characteristics and the prior mental health service use patterns showed that the two groups had similar characteristics. Over the follow-up year, 65% of the ICM clients and 76% of the CM clients were rehospitalized. Among the clients who were rehospitalized, the time in the community prior to the rehospitalization was significantly longer for the ICM clients (M = 148, SD = 104) than for the CM clients (M = 94, SD = 93). There was no significant difference between the two groups in continuity of care variables. The ICM clients had significantly more contacts with case managers than the CM clients on average. These findings suggest that the connection to the existing mental health services is not a significant factor in explaining the difference in rehospitalization outcome between ICM and CM. It appears that the provision of non-treatment, direct support services may make a significant difference

Effects of Antipsychotic Medication on Psychiatric Service Utilization and Cost

Background: Based on randomized clinical trials, consensus has been emerging that the first line of treatment for individuals with psychotic disorders should be the newer atypical or second generation antipsychotic medications rather than the older neuroleptics. Given that acquisition costs of atypical antipsychotics are generally higher than typical antipsychotics, uncertainty exists whether the newer atypicals are cost effective alternatives when used in ordinary practice settings. Aims of the Study: The introduction of newer atypical antipsychotic agents has prompted evaluation of their overall effectiveness in reducing health care costs given their higher acquisition costs. This paper focuses on the effects of differing classes of atypical versus typical antipsychotic medications on psychiatric service utilization and cost for persons with serious mental illness treated in usual practice settings. Methods: Descriptive statistics are used to compare patient characteristics, service rates and costs across psychotropic medication groups. Prediction equations employing ordinary least squares regression models are used to explain variation in cost due to pharmacy group membership controlling for demographics, clinical diagnoses and symptoms. Subjects were 338 Medicaid clients with serious mental illness from Florida, Pennsylvania and Oregon treated in ordinary clinical settings. Resource utilization and costs were operationalized using administrative databases to measure consumption of treatment services and pharmaceuticals for a six month period. Results: Inpatient service use was significantly higher for individuals on atypical only and combination atypical/typical medications compared to those on typical medications only, Background: Based on randomized clinical trials, consensus has been emerging that the first line of treatment for individuals with psychotic disorders should be the newer atypical or second generation antipsychotic medications rather than the older neuroleptics. Given that acquisition costs of atypical antipsychotics are generally higher than typical antipsychotics, uncertainty exists whether the newer atypicals are cost effective alternatives when used in ordinary practice settings. Aims of the Study: The introduction of newer atypical antipsychotic agents has prompted evaluation of their overall effectiveness in reducing health care costs given their higher acquisition costs. This paper focuses on the effects of differing classes of atypical versus typical antipsychotic medications on psychiatric service utilization and cost for persons with serious mental illness treated in usual practice settings. Methods: Descriptive statistics are used to compare patient characteristics, service rates and costs across psychotropic medication groups. Prediction equations employing ordinary least squares regression models are used to explain variation in cost due to pharmacy group membership controlling for demographics, clinical diagnoses and symptoms. Subjects were 338 Medicaid clients with serious mental illness from Florida, Pennsylvania and Oregon treated in ordinary clinical settings. Resource utilization and costs were operationalized using administrative databases to measure consumption of treatment services and pharmaceuticals for a six month period. Results: Inpatient service use was significantly higher for individuals on atypical only and combination atypical/typical medications compared to those on typical medications only, Background: Based on randomized clinical trials, consensus has been emerging that the first line of treatment for individuals with psychotic disorders should be the newer atypical or second generation antipsychotic medications rather than the older neuroleptics. Given that acquisition costs of atypical antipsychotics are generally higher than typical antipsychotics, uncertainty exists whether the newer atypicals are cost effective alternatives when used in ordinary practice settings. Aims of the Study: The introduction of newer atypical antipsychotic agents has prompted evaluation of their overall effectiveness in reducing health care costs given their higher acquisition costs. This paper focuses on the effects of differing classes of atypical versus typical antipsychotic medications on psychiatric service utilization and cost for persons with serious mental illness treated in usual practice settings. Methods: Descriptive statistics are used to compare patient characteristics, service rates and costs across psychotropic medication groups. Prediction equations employing ordinary least squares regression models are used to explain variation in cost due to pharmacy group membership controlling for demographics, clinical diagnoses and symptoms. Subjects were 338 Medicaid clients with serious mental illness from Florida, Pennsylvania and Oregon treated in ordinary clinical settings. Resource utilization and costs were operationalized using administrative databases to measure consumption of treatment services and pharmaceuticals for a six month period. Results: Inpatient service use was significantly higher for individuals on atypical only and combination atypical/typical medications compared to those on typical medications only,whereas outpatient use was highest for those on typicals. Furthermore, six-month costs for both pharmacy and psychiatric services were significantly greater for persons in the atypical only ($6528) and combination typical/atypical groups ($6589) compared to those on typicals only ($3463). There were still significantly higher costs associated with atypical only and the combination typical/atypical users after multivariate controls were used. Discussion: This study showed that Medicaid clients in community settings using atypical only and typical/atypical combination medications had the highest costs both in pharmacy and service use when compared to those on typical only medications. However, this study design does not allow us to ascribe a causal relationship between medication group and service costs. Given that olanzapine was the most recent medication in the compendium of available drugs at the time of this study, it is possible that those in the olanzapine only group were failing on other drugs. Caution must be used in drawing policy implications regarding cost effectiveness of newer medications since individuals who are getting the newer atypical or combination medications in community mental health center settings may be unstable on the older medications. Implications for Future Research: A longer follow-up period is needed to determine if the cohort remaining on current atypical medications stabilize over time while those taking the newest drug on the market become the most costly population