What is a clinical pathway? Refinement of an operational definition to identify clinical pathway studies for a Cochrane systematic review

Clinical pathways (CPWs) are a common component in the quest to improve the quality of health. CPWs are used to reduce variation, improve quality of care, and maximize the outcomes for specific groups of patients. An ongoing challenge is the operationalization of a definition of CPW in healthcare. This may be attributable to both the differences in definition and a lack of conceptualization in the field of clinical pathways. This correspondence article describes a process of refinement of an operational definition for CPW research and proposes an operational definition for the future syntheses of CPWs literature. Following the approach proposed by Kinsman et al. (BMC Medicine 8(1):31, 2010) and Wieland et al. (Alternative Therapies in Health and Medicine 17(2):50, 2011), we used a four-stage process to generate a five criteria checklist for the definition of CPWs. We refined the operational definition, through consensus, merging two of the checklist's criteria, leading to a more inclusive criterion for accommodating CPW studies conducted in various healthcare settings. The following four criteria for CPW operational definition, derived from the refinement process described above, are (1) the intervention was a structured multidisciplinary plan of care; (2) the intervention was used to translate guidelines or evidence into local structures; (3) the intervention detailed the steps in a course of treatment or care in a plan, pathway, algorithm, guideline, protocol or other 'inventory of actions' (i.e. the intervention had time-frames or criteria-based progression); and (4) the intervention aimed to standardize care for a specific population. An intervention meeting all four criteria was considered to be a CPW. The development of operational definitions for complex interventions is a useful approach to appraise and synthesize evidence for policy development and quality improvement

The development, implementation and evaluation of clinical pathways for chronic obstructive pulmonary disease (COPD) in Saskatchewan: protocol for an interrupted times series evaluation

Background: Chronic obstructive pulmonary disease (COPD) has substantial economic and human costs; it isexpected to be the third leading cause of death worldwide by 2030. To minimize these costs high qualityguidelines have been developed. However, guidelines alone rarely result in meaningful change. One method ofintegrating guidelines into practice is the use of clinical pathways (CPWs). CPWs bring available evidence to a rangeof healthcare professionals by detailing the essential steps in care and adapting guidelines to the local context.Methods/design: We are working with local stakeholders to develop CPWs for COPD with the aims of improvingcare while reducing utilization. The CPWs will employ several steps including: standardizing diagnostic training,unifying components of chronic disease care, coordinating education and reconditioning programs, and ensuringcare uses best practices. Further, we have worked to identify evidence-informed implementation strategies whichwill be tailored to the local context.We will conduct a three-year research project using an interrupted time series (ITS) design in the form of a multiplebaseline approach with control groups. The CPW will be implemented in two health regions (experimental groups) andtwo health regions will act as controls (control groups). The experimental and control groups will each contain an urbanand rural health region. Primary outcomes for the study will be quality of care operationalized using hospital readmissionrates and emergency department (ED) presentation rates. Secondary outcomes will be healthcare utilization andguideline adherence, operationalized using hospital admission rates, hospital length of stay and general practitioner (GP)visits. Results will be analyzed using segmented regression analysis.Discussion: Funding has been procured from multiple stakeholders. The project has been deemed exempt from ethicsreview as it is a quality improvement project. Intervention implementation is expected to begin in summer of 2017.This project is expected to improve quality of care and reduce healthcare utilization. In addition it will provide evidenceon the effects of CPWs in both urban and rural settings. If the CPWs are found effective we will work with allstakeholders to implement similar CPWs in surrounding health regions

Preexposure passive transfer predicts plasma antibody levels prevent HIV-I aquisition

Background: It is widely appreciated that effective human vaccines directed against viral pathogens elicit neutralizing antibodies (NAbs). During the past four years, a new generation of potent broadly reacting neutralizing monoclonal antibodies (mAbs) have been isolated from HIV-I infected individuals. These mAbs typically exhibit great breadth and potency against heterologous HIV isolates when assayed for neutralization in vitro. The passive transfer of anti-HIV l neutralizing antibodies conferring sterilizing immunity to macaques has been used to determine the plasma neutralization titers, which must be present at the time of exposure to prevent acquisition of SIV/HIV chimeric virus (SHIV) infections. Methods: In this study, five recently isolated potent and broadly acting anti-HIV neutralizing mAbs, interacting with the HIV l gp 120 CD4 binding site (VRCO I, 45-46 m^2 and 3BNC 117) or dependent on the gp120 N332 glycan, (10-1074 and PGTl2l) were individually administered to 60 rhesus monkeys, which were challenged intrarectally 24 hours later with either of two different R5-tropic SHIVs. Results: Of the 5 neutralizing mAbs evaluated, PGT121 was clearly the most effective against both viruses. In addition to measuring the plasma concentrations of the different mAbs at the time of challenge and their respective in vivo half lives, the corresponding protective neutralization titers were also determined. By combining the results obtained from 60 challenged animals, we determined that the protective neutralization titer in plasma preventing virus acquisition in 50% of the exposed monkeys was approximately 1:100. Conclusion: These results are informative for establishing a threshold level of protective neutralizing activity to be induced by a prophylactic HIV I vaccine

Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques

It is widely appreciated that effective human vaccines directed against viral pathogens elicit neutralizing antibodies (NAbs). The passive transfer of anti–HIV-1 NAbs conferring sterilizing immunity to macaques has been used to determine the plasma neutralization titers, which must be present at the time of exposure, to prevent acquisition of SIV/HIV chimeric virus (SHIV) infections. We administered five recently isolated potent and broadly acting anti-HIV neutralizing monoclonal antibodies (mAbs) to rhesus macaques and challenged them intrarectally 24 h later with either of two different R5-tropic SHIVs. By combining the results obtained from 60 challenged animals, we determined that the protective neutralization titer in plasma preventing virus infection in 50% of the exposed monkeys was relatively modest (∼1:100) and potentially achievable by vaccination

Early antibody therapy can induce long-lasting immunity to SHIV

Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques, and humans(1-12). In immunotherapy experiments, administration of bNAbs to chronically infected animals transiently suppresses virus replication, which invariably returns to pre-treatment levels and results in progression to clinical disease. Here we show that early administration of bNAbs in a macaque simian/human immunodeficiency virus (SHIV) model is associated with very low levels of persistent viraemia, which leads to the establishment of T-cell immunity and resultant longterm infection control. Animals challenged with SHIVAD8-EO by mucosal or intravenous routes received a single 2-week course of two potent passively transferred bNAbs (3BNC117 and 10-1074 (refs 13, 14)). Viraemia remained undetectable for 56-177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. Four additional animals maintained their counts of T cells carrying the CD4 antigen (CD4+) and very low levels of viraemia persisted for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4(+) T cells in the six controller macaques. Infusion of a T-cell-depleting anti-CD8 beta monoclonal antibody to the controller animals led to a specific decline in levels of CD8(+) T cells and the rapid reappearance of plasma viraemia. In contrast, macaques treated for 15 weeks with combination anti-retroviral therapy, beginning on day 3 after infection, experienced sustained rebound plasma viraemia when treatment was interrupted. Our results show that passive immunotherapy during acute SHIV infection differs from combination anti-retroviral therapy in that it facilitates the emergence of potent CD8(+) T-cell immunity able to durably suppress virus replication

Transfer of neutralizing IgG to macaques 6 h but not 24 h after SHIV infection confers sterilizing protection: Implications for HIV-1 vaccine development

Passive transfer of high-titered antiviral neutralizing IgG, known to confer sterilizing immunity in pig-tailed monkeys, has been used to determine how soon after virus exposure neutralizing antibodies (NAbs) must be present to block a simian immunodeficiency virus (SIV)/HIV chimeric virus infection. Sterilizing protection was achieved in three of four macaques receiving neutralizing IgG 6 h after intravenous SIV/HIV chimeric virus inoculation as monitored by PCR analyses of and attempted virus isolations from plasma, peripheral blood mononuclear cell, and lymph node specimens. In the fourth animal, the production of progeny virus was suppressed for >4 weeks. A delay in transferring NAbs until 24 h after virus challenge resulted in infection in two of two monkeys. These results suggest that even if a vaccine capable of eliciting broadly reactive NAbs against primary HIV-1 were at hand, the Abs generated must remain at, or rapidly achieve, high levels within a relatively short period after exposure to virus to prevent the establishment of a primate lentivirus infection