patients with PPF.TCM treatments are typically diverse and individualized,requiring urgent development of efficient and precise design strategies to identify effective treatment options.We designed an innovative Bayes...patients with PPF.TCM treatments are typically diverse and individualized,requiring urgent development of efficient and precise design strategies to identify effective treatment options.We designed an innovative Bayesian adaptive two-stage trial,hoping to provide new ideas for the rapid evaluation of the effectiveness of TCM in PPF.An open-label,two-stage,adaptive Bayesian randomized controlled trial will be conducted in China.Based on Bayesian methods,the trial will employ response-adaptive randomization to allocate patients to study groups based on data collected over the course of the trial.The adaptive Bayesian trial design will employ a Bayesian hierarchical model with“stopping”and“continuation”criteria once a predetermined posterior probability of superiority or futility and a decision threshold are reached.The trial can be implemented more efficiently by sharing the master protocol and organizational management mechanisms of the sub-trial we have implemented.The primary patient-reported outcome is a change in the Leicester Cough Questionnaire score,reflecting an improvement in cough-specific quality of life.The adaptive Bayesian trial design may be a promising method to facilitate the rapid clinical evaluation of TCM effectiveness for PPF,and will provide an example for how to evaluate TCM effectiveness in rare and refractory diseases.However,due to the complexity of the trial implementation,sufficient simulation analysis by professional statistical analysts is required to construct a Bayesian response-adaptive randomization procedure for timely response.Moreover,detailed standard operating procedures need to be developed to ensure the feasibility of the trial implementation.展开更多
Painful stimuli elicit first-line reflexive defensive reactions and,in many cases,also evoke second-line recuperative behaviors,the latter of which reflects the sensing of tissue damage and the alleviation of sufferin...Painful stimuli elicit first-line reflexive defensive reactions and,in many cases,also evoke second-line recuperative behaviors,the latter of which reflects the sensing of tissue damage and the alleviation of suffering.The lateral parabrachial nucleus(lPBN),composed of external-(elPBN),dorsal-(dlPBN),and central/superior-subnuclei(jointly referred to as slPBN),receives sensory inputs from spinal projection neurons and plays important roles in processing affective information from external threats and body integrity disruption.However,the organizational rules of lPBN neurons that provoke diverse behaviors in response to different painful stimuli from cutaneous and deep tissues remain unclear.In this study,we used region-specific neuronal depletion or silencing approaches combined with a battery of behavioral assays to show that slPBN neurons expressing substance P receptor(NK1R)(lPBNNK1R)are crucial for driving pain-associated self-care behaviors evoked by sustained noxious thermal and mechanical stimuli applied to skin or bone/muscle,while elPBN neurons are dispensable for driving such reactions.Notably,lPBNNK1R neurons are specifically required for forming sustained somatic pain-induced negative teaching signals and aversive memory but are not necessary for fear-learning or escape behaviors elicited by external threats.Lastly,both lPBNNK1R and elPBN neurons contribute to chemical irritant-induced nocifensive reactions.Our results reveal the functional organization of parabrachial substrates that drive distinct behavioral outcomes in response to sustained pain versus external danger under physiological conditions.展开更多
基金supported by National Natural Science Foundation of China(No.81973713)。
文摘patients with PPF.TCM treatments are typically diverse and individualized,requiring urgent development of efficient and precise design strategies to identify effective treatment options.We designed an innovative Bayesian adaptive two-stage trial,hoping to provide new ideas for the rapid evaluation of the effectiveness of TCM in PPF.An open-label,two-stage,adaptive Bayesian randomized controlled trial will be conducted in China.Based on Bayesian methods,the trial will employ response-adaptive randomization to allocate patients to study groups based on data collected over the course of the trial.The adaptive Bayesian trial design will employ a Bayesian hierarchical model with“stopping”and“continuation”criteria once a predetermined posterior probability of superiority or futility and a decision threshold are reached.The trial can be implemented more efficiently by sharing the master protocol and organizational management mechanisms of the sub-trial we have implemented.The primary patient-reported outcome is a change in the Leicester Cough Questionnaire score,reflecting an improvement in cough-specific quality of life.The adaptive Bayesian trial design may be a promising method to facilitate the rapid clinical evaluation of TCM effectiveness for PPF,and will provide an example for how to evaluate TCM effectiveness in rare and refractory diseases.However,due to the complexity of the trial implementation,sufficient simulation analysis by professional statistical analysts is required to construct a Bayesian response-adaptive randomization procedure for timely response.Moreover,detailed standard operating procedures need to be developed to ensure the feasibility of the trial implementation.
基金supported by the Shenzhen Key Laboratory of Drug Addiction (ZDSYS20190902093601675)CAS Key Laboratory of Brain Connectome and Manipulation (2019DP173024)+2 种基金National Natural Science Foundation of China (82274358)Shenzhen-Hong Kong Institute of Brain ScienceGuangdong Basic and Applied Basic Research Foundation (2023B1515040009)
文摘Painful stimuli elicit first-line reflexive defensive reactions and,in many cases,also evoke second-line recuperative behaviors,the latter of which reflects the sensing of tissue damage and the alleviation of suffering.The lateral parabrachial nucleus(lPBN),composed of external-(elPBN),dorsal-(dlPBN),and central/superior-subnuclei(jointly referred to as slPBN),receives sensory inputs from spinal projection neurons and plays important roles in processing affective information from external threats and body integrity disruption.However,the organizational rules of lPBN neurons that provoke diverse behaviors in response to different painful stimuli from cutaneous and deep tissues remain unclear.In this study,we used region-specific neuronal depletion or silencing approaches combined with a battery of behavioral assays to show that slPBN neurons expressing substance P receptor(NK1R)(lPBNNK1R)are crucial for driving pain-associated self-care behaviors evoked by sustained noxious thermal and mechanical stimuli applied to skin or bone/muscle,while elPBN neurons are dispensable for driving such reactions.Notably,lPBNNK1R neurons are specifically required for forming sustained somatic pain-induced negative teaching signals and aversive memory but are not necessary for fear-learning or escape behaviors elicited by external threats.Lastly,both lPBNNK1R and elPBN neurons contribute to chemical irritant-induced nocifensive reactions.Our results reveal the functional organization of parabrachial substrates that drive distinct behavioral outcomes in response to sustained pain versus external danger under physiological conditions.
