Search

The present study examined punishment of responding with histamine injection, and its potential to generate avoidance of punishment. Sprague–Dawley rats were trained under concurrent schedules in which responses on one lever (the punishment lever) produced food under a variable‐interval schedule, and under some conditions intermittent injections of histamine, which suppressed behavior. Responses on a second (avoidance) lever prevented histamine injections scheduled on the punishment lever. After stabilization of punished responding, a variable‐interval 15‐s schedule of cancellation of histamine (avoidance) was added for responding on the second/avoidance lever, without subsequent acquisition of responding on that lever. Progressive decreases in the length of the punishment variable‐interval schedule increased suppression on the punishment lever without increases in response rates on the avoidance lever. Exchanging contingencies on the levers ensured that response rates on the avoidance lever were sufficiently high to decrease the histamine injection frequency; nonetheless response rates on the avoidance lever decreased over subsequent sessions. Under no condition was responding maintained on the avoidance lever despite continued punishing effectiveness of histamine throughout. The present results suggest that avoidance conditioning is not a necessary condition for effective punishment, and confirm the importance of empirical rather than presumed categorization of behavioral effects of stimulus events. [ABSTRACT FROM AUTHOR]

Simple Summary: We conducted a systematic review using 16 trials (RCTs and NRCTs) across eight countries and three continents; which included 672 patients with high-grade CIN associated with HPV. To the best of our knowledge, this is the first synthesis related to the safety, efficacy, and immunogenicity of therapeutic vaccines for the treatment of patients with high-grade CIN associated with HPV. The findings from the trials revealed that therapeutic vaccines can be considered promising for these injuries. However, there are still only a few phase III RCTs, and a better understanding of the specificities of different vaccine compositions and delivery systems and pathways to prevent viral escape mechanisms are needed. Overall, the results of this systematic review indicate that the therapeutic vaccines that are being developed for the treatment of CIN 2/3 are safe and well tolerated and that most trigger only systemic symptoms classified as mild or moderate that improve spontaneously in a short period of time. Considering the inconsistent results among phase I and II trials involving different therapeutic vaccines, our findings provide some clarification and have implications for multiple stakeholders. Despite the knowledge that HPV is responsible for high-grade CIN and cervical cancer, little is known about the use of therapeutic vaccines as a treatment. We aimed to synthesize and critically evaluate the evidence from clinical trials on the safety, efficacy, and immunogenicity of therapeutic vaccines in the treatment of patients with high-grade CIN associated with HPV. A systematic review of clinical trials adhering to the PRISMA 2020 statement in MEDLINE/PubMed, Embase, CENTRAL Cochrane, Web of Science, Scopus, and LILACS was undertaken, with no data or language restrictions. Primary endpoints related to the safety, efficacy, and immunogenicity of these vaccines were assessed by reviewing the adverse/toxic effects associated with the therapeutic vaccine administration via histopathological regression of the lesion and/or regression of the lesion size and via viral clearance and through the immunological response of individuals who received treatment compared to those who did not or before and after receiving the vaccine, respectively. A total of 1184 studies were identified, and 16 met all the criteria. Overall, the therapeutic vaccines were heterogeneous regarding their formulation, dose, intervention protocol, and routes of administration, making a meta-analysis unfeasible. In most studies (n = 15), the vaccines were safe and well tolerated, with clinical efficacy regarding the lesions and histopathological regression or viral clearance. In addition, eleven studies showed favorable immunological responses against HPV, and seven studies showed a positive correlation between immunogenicity and the clinical response, indicating promising results that should be further investigated. In summary, therapeutic vaccines, although urgently needed to avoid progression of CIN 2/3 patients, still present sparse data, requiring greater investments in a well-designed phase III RCT. [ABSTRACT FROM AUTHOR]