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1.
《Drug discovery today》2022,27(3):705-729
The successful regulatory authority approval rate of drug candidates in the drug development pipeline is crucial for determining pharmaceutical research and development (R&D) efficiency. Regulatory authorities include the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceutical and Food Safety Bureau Japan (PFSB), among others. Optimal drug metabolism and pharmacokinetics (DMPK) properties influence the progression of a drug candidate from the preclinical to the clinical phase. In this review, we provide a comprehensive assessment of essential concepts, methods, improvements, and challenges in DMPK science and its significance in drug development. This information provides insights into the association of DMPK science with pharmaceutical R&D efficiency.  相似文献   
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背景 颈肩痛的全球疾病经济总负担排名第21名,及时采取规范性的干预措施,可有效治疗疾病,缓解患者的疼痛。运用目标成就评量法可以更加针对性地进行干预效果评估。 目的 基于目标成就评量法分析杭州市社区卫生服务中心中医健康管理综合干预措施在慢性颈肩痛人群中的实施效果及影响因素。 方法 于2020年8—9月,采用典型抽样方法抽取杭州市3家社区卫生服务中心共262例慢性颈肩痛患者作为研究对象,采用自编的调查问卷进行调查,调查内容包括一般情况、长海痛尺表及基于目标成就评量法的调查表。将纳入的调查对象随机分成对照组(n=131)和干预组(n=131)。对照组接受单纯针灸治疗,干预组在此基础上增加综合中医健康管理措施,两组干预时间均为1个月。2020年11月,进行干预效果评估调查。 结果 干预组和对照组均失访9例,最终干预组和对照组各纳入122例颈肩痛患者。两组干预后GAS得分分别为(51.20±7.81)、(42.94±7.57)分,两组比较,差异有统计学意义(P<0.05)。干预后,两组分别有92例(75.4%)、44例(36.1%)患者达到或超过预期目标,两组比较,差异有统计学意义(P<0.05)。干预组不同文化程度、婚姻状况、就业情况、中医体质、自评健康状况的颈肩痛患者干预后GAS得分比较,差异有统计学意义(P<0.05)。多元线性逐步回归分析结果显示,中医体质、自评健康状况、饮酒情况是干预组颈肩痛患者综合干预后GAS得分的影响因素(P<0.05)。 结论 中医健康管理综合干预措施在慢性颈肩痛患者中应用效果显著,提示可在基层医疗卫生机构实施以健康管理为基础的中医综合干预措施。  相似文献   
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《Clinical therapeutics》2019,41(5):943-960.e4
PurposePatients’ perceptions of benefit–risk are essential to informing the regulatory process and the context in which potential therapies are evaluated. To bring this critical information to regulators, Cure SMA launched a first-ever Benefit-Risk Survey for spinal muscular atrophy (SMA) to characterize decision-making and benefit–risk trade-offs in SMA associated with a potential therapy. We hypothesized that risk tolerance would be correlated with SMA type/severity and disease progression. This article presents the results of a benefit–risk survey to enhance understanding of how patients with SMA and caregivers evaluate specific benefits and risks associated with potential therapies.MethodsAffected adults, representing all SMA types (I–IV) within the Cure SMA database, and caregivers of affected individuals of all ages/types were invited via e-mail to participate. Best–worst scaling (BWS) was used to assess participants’ priorities on benefit–risk trade-offs, as it provides higher discrimination and importance scaling among tested attributes. Twelve potentially clinically meaningful treatment benefits and 11 potential risks (ranging in severity and immediacy) were tested. Multiple factors were correlated with individual responses, including: SMA type/disease severity, stage of disease, respondent type, sex, and quality of life/level of independence (current and expected). Survey respondents were also evaluated for "risk-taking attitudes."FindingsA total of 298 responses were evaluated (28% affected adults and 72% caregivers, mostly parents). Most respondents were diagnosed >5 years ago (67.3%), with 22.1% SMA type I, 45.6% SMA type II, and 27.9% SMA type III. No strong correlation was found between risk tolerance and SMA type, stage of disease progression, respondent type, sex, quality of life assessment, or rated levels of independence. Irrespective of SMA type, respondents consistently rated the following risks, associated with a potential treatment, as "least tolerable": life-threatening allergic reactions; 1 in 1000 risk of life-threatening side effects leading to possible organ failure; or worsening quality of life. Furthermore, all SMA type respondents rated these risks as "most tolerable": invasive mode of treatment administration (including need for general anesthesia); side effect of dizziness; and other common side effects such as nausea, vomiting, loss of appetite, headaches, back pain, or fatigue.ImplicationsWith the approval of the first SMA treatment, these findings offer a unique opportunity to assess and characterize baseline risk-tolerance in SMA against which to evaluate future SMA treatment options. Although differences had been expected in risk tolerance among respondents based on disease baseline and certain patient attributes, this was not observed. Survey results should inform future SMA drug development and benefit–risk assessments.  相似文献   
4.
Discrete choice experiments (DCEs) are frequently used in health economics to measure preferences for nonmarket goods. Best–worst discrete choice experiment (BWDCE) has been proposed as a variant of the traditional “pick the best” approach. BWDCE, where participants choose the best and worst options, is argued to generate more precise preference estimates because of the additional information collected. However, the validity of the approach relies on two necessary conditions: (a) best and worst decisions provide similar information about preferences and (b) asking individuals to answer more than one choice question per task does not reduce data quality. Whether these conditions hold in empirical applications remains under researched. This is the first study to compare participants' choices across three experimental conditions: (a) BEST choices only, (b) WORST choices only, and (c) BEST and WORST choices (BWDCE). We find responses to worst choices are noisier. Implied preferences from the best only and worst only choices are qualitatively different, leading to different WTP values. Responses to BWDCE tasks have lower consistency, and respondents are more likely to use simplifying decision heuristics. We urge caution in using BWDCE as an alternative to the traditional “pick the best” DCE.  相似文献   
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BackgroundThe effect of tibiofemoral geometry on musculoskeletal function is important to movement biomechanics.Research questionWe hypothesised that tibiofemoral geometry determines tibiofemoral motion and musculoskeletal function. We then aimed at 1) modelling tibiofemoral motion during normal activity as a function of tibiofemoral geometry in healthy adults; and 2) quantifying the effect of tibiofemoral geometry on musculoskeletal function.MethodsWe used motion data for six activity types and CT images of the knee from 12 healthy adults. Geometrical variation of the tibia and femoral articular surfaces were measured in the CT images. The geometry-based tibiofemoral motion was calculated by fitting a parallel mechanism to geometrical variation in the cohort. Matched musculoskeletal models embedding the geometry-based tibiofemoral joint motion and a common generic tibiofemoral motion of reference were generated and used to calculate joint angles, net joint moments, muscle and joint forces for the six activities analysed. The tibiofemoral model was validated against bi-planar fluoroscopy measurements for walking for all the six planes of motion. The effect of tibiofemoral geometry on musculoskeletal function was the difference between the geometry-based model and the model of reference.ResultsThe geometry-based tibiofemoral motion described the pattern and the variation during walking for all six motion components, except the pattern of anterior tibial translation. Tibiofemoral geometry had moderate effect on cohort-averages of musculoskeletal function (R2 = 0.60–1), although its effect was high in specific instances of the model, outputs and activities analysed, reaching 2.94 BW for the ankle reaction force during stair descent. In conclusion, tibiofemoral geometry is a major determinant of tibiofemoral motion during walking.SignificanceGeometrical variations of the tibiofemoral joint are important for studying musculoskeletal function during normal activity in specific individuals but not for studying cohort averages of musculoskeletal function. This finding expands current knowledge of movement biomechanics.  相似文献   
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Background: There is emerging evidence that gait variability outcomes provide unique insights regarding the status of an individual’s locomotor control system; however, there is currently limited evidence on the within-day reliability of stride time variability (STV) outcomes, or whether they demonstrate diurnal variation, when measured during continuous, overground walking in healthy young adults.Research Questions: 1) Are STV outcomes measured in the morning and afternoon during continuous, overground walking significantly different in healthy young adults? 2) What is the within-day reliability of STV outcomes measured during continuous, overground walking in healthy young adults?.Methods: Thirty-one healthy young adults (20.8 ± 3.7 years) completed two 10-minute continuous, overground walking trials on the same day (9:00-11:00am and 3:00-5:00pm) at their preferred walking speed. Data from a waist-mounted tri-axial accelerometer were used to determine the series of consecutive stride times for each trial.Results: There were no significant differences between sessions for average walking speed, average stride time, or STV. The within-day reliability was excellent for average walking speed and stride time, and generally poor to fair for STV.Significance: Healthy young adults do not appear to demonstrate diurnal variation in STV outcomes during continuous, overground walking; however, the development of a protocol to improve their reliability, as well as the establishment of normative ranges for such outcomes, would be beneficial to improve their application and interpretation in research and clinical settings.  相似文献   
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Synaptic scaling is a form of homeostatic plasticity that stabilizes neuronal firing in response to changes in synapse number and strength. Scaling up in response to action-potential blockade is accomplished through increased synaptic accumulation of GluA2-containing AMPA receptors (AMPAR), but the receptor trafficking steps that drive this process remain largely obscure. Here, we show that the AMPAR-binding protein glutamate receptor-interacting protein-1 (GRIP1) is essential for regulated synaptic AMPAR accumulation during scaling up. Synaptic abundance of GRIP1 was enhanced by activity deprivation, directly increasing synaptic GRIP1 abundance through overexpression increased the amplitude of AMPA miniature excitatory postsynaptic currents (mEPSCs), and shRNA-mediated GRIP1 knockdown prevented scaling up of AMPA mEPSCs. Furthermore, knockdown and replace experiments targeting either GRIP1 or GluA2 revealed that scaling up requires the interaction between GRIP1 and GluA2. Finally, GRIP1 synaptic accumulation during scaling up did not require GluA2 binding. Taken together, our data support a model in which activity-dependent trafficking of GRIP1 to synaptic sites drives the forward trafficking and enhanced synaptic accumulation of GluA2-containing AMPAR during synaptic scaling up.Proper development of neuronal circuits, as well as efficient information storage during learning and memory, are thought to depend upon the presence of homeostatic mechanisms that stabilize neuronal excitability (13). One such mechanism is synaptic scaling, which compensates for perturbations in average firing by scaling up or down the postsynaptic strength of all of a neuron’s excitatory synapses (4). Synaptic scaling is a cell-autonomous process in which neurons detect changes in their own firing through a set of calcium-dependent sensors that then regulate receptor trafficking to increase or decrease the accumulation of AMPA receptors (AMPAR) at synaptic sites and thus increase or decrease synaptic strength (46). Despite great recent interest, the AMPA receptor-trafficking events that underlie synaptic scaling remain largely obscure. Defects in synaptic scaling have been postulated to contribute to disorders as diverse as Alzheimer’s disease (7) and epilepsy (8), so illuminating the underlying AMPAR trafficking steps could shed light into the genesis of a wide range of neurological disorders.Most neocortical AMPAR are heteromeric receptors composed of both GluA1 and GluA2 subunits, which have unique phosphorylation sites and interact with distinct trafficking proteins (9). During synaptic scaling up in response to action potential blockade, synaptic strength is increased through enhanced synaptic accumulation of GluA1 and GluA2-containing AMPAR (5, 1013) and requires the C-terminal domain of the GluA2 subunit (12), but which subunit-specific interactions underlie synaptic scaling remain controversial (12, 14). Several trafficking proteins are known to interact with the GluA2, but not the GluA1, C-tail, including glutamate receptor interacting protein-1 (GRIP1) (15) and protein interacting with C-kinase-1 (PICK1) (16). Many studies have examined the role of GRIP1 and PICK1 in AMPAR trafficking and surface accumulation (15, 1722), but little is known about their potential roles in regulating AMPAR synaptic accumulation during synaptic scaling. It was recently shown that deletion of PICK1, which competes with GRIP1/2 for binding to GluA2, enhances AMPAR accumulation and occludes synaptic scaling up (23), suggesting GRIP/PICK1-GluA2 interactions as possible critical players in synaptic scaling.GRIP1 was one of the first AMPAR-binding proteins identified (15), and yet its exact function in synaptic transmission and plasticity remains controversial. GRIP1 is an abundant multi-PDZ domain-containing protein that interacts with GluA2 through its fourth and fifth PDZ domains (15) and has known interactions with several other signaling and trafficking proteins, including itself (24), ABP (25), EphB receptors (26); the rasGEF GRASP-1 (27), the scaffold protein liprin-α (28), and the microtubule motor protein KIF5, or kinesin 1 (29). The role of GRIP1 in AMPAR trafficking is complicated and may involve AMPAR trafficking to and stabilization at synapses (17), as well as microtubule-based transport into dendrites (29) and the regulation of AMPAR movement between intracellular recycling compartments and the cell surface (22, 30). How GRIP1 influences basal AMPAR trafficking is not entirely clear. Overexpression of GRIP1 or gain-of-function GRIP1 mutants have been consistently observed to enhance surface AMPAR levels (21, 31), but knockout or dominant-negative GRIP1 constructs have had inconsistent effects, with slower synaptic AMPAR accumulation observed in one study (17) but no effects on basal AMPAR recycling and transmission in others (22, 32). Interestingly, GRIP1 and -2 are critical for the expression of cerebellar long-term depression (LTD), where they play redundant roles in regulated AMPAR endocytosis (33, 34). Currently no direct role for GRIP1 in activity-dependent synaptic strengthening or homeostatic plasticity has been established.Here, we show that the GRIP1–GluA2 interaction plays an essential role in the activity-dependent synaptic AMPAR accumulation and enhanced excitatory synaptic strength that underlies synaptic scaling up. Activity blockade with TTX increased the accumulation of GRIP1 at synaptic sites, whereas directly enhancing synaptic GRIP1 accumulation through overexpression (OE) was sufficient to mimic synaptic scaling. GRIP1 was necessary for synaptic scaling, because scaling up was prevented by shRNA-mediated knock down (KD) of endogenous GRIP1 and rescued by replacement with an RNAi-insensitive (RNAiI) GRIP1 but not a GRIP1 mutant that lacks the GluA2 interaction domain. We showed previously that GluA2 KD blocks synaptic scaling (12). Here, we show that synaptic scaling after GluA2 KD can be rescued by wild-type (RNAiI) GluA2 or point mutants that do not interfere with GRIP1 binding but not by GluA2 point mutants (Y876E and S880E) that reduce GluA2- GRIP1 binding, strongly suggesting that GRIP1 mediates synaptic scaling through interactions with GluA2. Finally, TTX still induced GRIP1 synaptic accumulation even when AMPAR accumulation was prevented by expression of GluA2 Y876E; thus, during synaptic scaling GluA2 synaptic accumulation depends on GRIP1 binding, but GRIP1 translocation and synaptic accumulation occur independently of GluA2 binding. Together our data show that activity-dependent regulation of synaptic GRIP1 abundance is critical for the forward trafficking and accumulation of AMPA receptors at synapses during synaptic scaling.  相似文献   
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