ABSTRACT
The striatum comprises two neurochemical compartments: striosomes and the matrix. Striosomal and matrix compartments receive inputs from limbic system‐related and sensorimotor cortices, ...respectively. Here, we investigate the impact on the corticostriosomal pathway in the valproic acid (VPA)‐induced autism spectrum disorder mouse model. VPA administration during the neurogenesis time windows of striosomes, but not the matrix, resulted in aberrant compartmentation i.e., maternal VPA injections at embryonic day (E)12.75 decreased μ‐opioid receptor–positive striosomes, but increased calbindin‐positive matrix in the rostral striatum. VPAE12.75 treatment also impaired the aggregation of cells pulse labeled with 5‐bromo‐2′‐deoxyuridine at E12.75 into striosomal cell clusters, which suggests defective segregation of striosomal cells from matrix cells. This possibility was supported by our findings that VPAE12.75 treatment altered the expression of ephrinA5 and EphA4, two molecules that are related to compartmental segregation. In the VPAE12.75 neocortex, Foxp2‐positive neurons were decreased in layer VI, but increased in layer V, which projects to the striosomal compartment. We also investigated VPA effects on the corticostriosomal pathway. VPAE12.75 treatment decreased the putative corticostriosomal synapses of striosomal neurons and induced an aberrant pattern of isolation stress–induced ultrasonic vocalizations. Of interest, risperidone treatments conjointly improved ultrasonic vocalizations and restored the striosomal compartment in VPAE12.75 pups. Collectively, dysfunctional corticostriatal pathways, particularly via the aberrant striosomal compartment, may be involved in autism spectrum disorder pathophysiology.—Kuo, H.‐Y., Liu, F.‐C. Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder. FASEB J. 31, 4458–4471 (2017). www.fasebj.org
A biosimilar is a biological product that is highly similar to an existing approved reference drug and has no clinically meaningful difference from it. Biosimilars are composed of or derived from ...living cells or organisms. Therefore, they are often sensitive to slight variations in the manufacturing process. Consequently, in demonstrating biosimilarity, it might be inappropriate to focus solely on the mean difference, or ratio of means, while ignoring the variabilities associated with the test and reference products. It is important to account for the entire population of clinical outcomes. Thus, we propose using the concept of tolerance intervals and related hypothesis testing for assessing biosimilarity. Our approach has the advantage of considering entire populations associated with both groups. A real example is used to illustrate our proposed method, and our approach is more stringent than those that employ confidence intervals. This is specifically the case when the mean difference of two drugs is not sufficiently large, but the biosimilar has a higher variability than that in the reference drug.
Tolerance intervals have been recommended for simultaneously validating both the accuracy and precision of an analytical procedure. However, statistical inferences for the corresponding hypothesis ...testing are scarce. The aim of this study is to establish a whole statistical inference for tolerance interval testing, including sample size determination, power analysis, and calculation of p-value. More specifically, the proposed method considers the bounds of a tolerance interval as random variables so that a bivariate distribution can be derived. Simulations confirm the theoretical properties of the method. Furthermore, an example is used to illustrate the proposed method.
Bayesian hierarchical models for adaptive basket trial designs Chen, Chian; Hsiao, Chin‐Fu
Pharmaceutical statistics : the journal of the pharmaceutical industry,
May/June 2023, 2023 May-Jun, 2023-05-00, 20230501, Letnik:
22, Številka:
3
Journal Article
Recenzirano
Basket trials evaluate a single drug targeting a single genetic variant in multiple cancer cohorts. Empirical findings suggest that treatment efficacy across baskets may be heterogeneous. Most modern ...basket trial designs use Bayesian methods. These methods require the prior specification of at least one parameter that permits information sharing across baskets. In this study, we provide recommendations for selecting a prior for scale parameters for adaptive basket trials by using Bayesian hierarchical modeling. Heterogeneity among baskets attracts much attention in basket trial research, and substantial heterogeneity challenges the basic assumption of exchangeability of Bayesian hierarchical approach. Thus, we also allowed each stratum‐specific parameter to be exchangeable or nonexchangeable with similar strata by using data observed in an interim analysis. Through a simulation study, we evaluated the overall performance of our design based on statistical power and type I error rates. Our research contributes to the understanding of the properties of Bayesian basket trial designs.
Smoking tobacco is the major risk factor for developing lung cancer. However, most Han Chinese women with lung cancer are nonsmokers. Chinese cooking methods usually generate various carcinogens in ...fumes that may inevitably be inhaled by those who cook the food, most of whom are female. We investigated the associations of cooking habits and exposure to cooking fumes with lung cancer among non-smoking Han Chinese women. This study was conducted on 1,302 lung cancer cases and 1,302 matched healthy controls in Taiwan during 2002-2010. Two indices, "cooking time-years" and "fume extractor use ratio," were developed. The former was used to explore the relationship between cumulative exposure to cooking oil fumes and lung cancer; the latter was used to assess the impact of fume extractor use for different ratio-of-use groups. Using logistic models, we found a dose-response association between cooking fume exposure and lung cancer (odds ratios of 1, 1.63, 1.67, 2.14, and 3.17 across increasing levels of cooking time-years). However, long-term use of a fume extractor in cooking can reduce the risk of lung cancer by about 50%. Furthermore, we provide evidence that cooking habits, involving cooking methods and oil use, are associated with risk of lung cancer.
In this study, we evaluated the efficacy of hydroxychloroquine (HCQ) against coronavirus disease 2019 (COVID-19) via a randomized controlled trial (RCT) and a retrospective study.
Subjects admitted ...to 11 designated public hospitals in Taiwan between April 1 and May 31, 2020, with COVID-19 diagnosis confirmed by pharyngeal real-time RT-PCR for SARS-CoV-2, were randomized at a 2:1 ratio and stratified by mild or moderate illness. HCQ (400 mg twice for 1 d or HCQ 200 mg twice daily for 6 days) was administered. Both the study and control group received standard of care (SOC). Pharyngeal swabs and sputum were collected every other day. The proportion and time to negative viral PCR were assessed on day 14. In the retrospective study, medical records were reviewed for patients admitted before March 31, 2020.
There were 33 and 37 cases in the RCT and retrospective study, respectively. In the RCT, the median times to negative rRT-PCR from randomization to hospital day 14 were 5 days (95% CI; 1, 9 days) and 10 days (95% CI; 2, 12 days) for the HCQ and SOC groups, respectively (p = 0.40). On day 14, 81.0% (17/21) and 75.0% (9/12) of the subjects in the HCQ and SOC groups, respectively, had undetected virus (p = 0.36). In the retrospective study, 12 (42.9%) in the HCQ group and 5 (55.6%) in the control group had negative rRT-PCR results on hospital day 14 (p = 0.70).
Neither study demonstrated that HCQ shortened viral shedding in mild to moderate COVID-19 subjects.
There have been a variety of constant on-time (COT) controllers for dc power converter applications reported in recent years 1-5 . In this paper, a novel adaptive quasi-constant on-time current-mode ...control scheme is proposed and implemented in buck converters. While preserving the advantages of the conventional COT current-mode converters, this scheme allows fast transient response to step-load that is a critical requirement of a computer load with smart management. A small-signal model of the proposed circuit is also developed. Experimental results are also provided. This scheme is well suited for the next-generation dc converters for power management central-processor-unit devices.
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with a high prevalence rate. The core symptoms of ASD patients are impaired social communication and repetitive behavior. ...Genetic and environmental factors contribute to pathophysiology of ASD. Regarding environmental risk factors, it is known that valproic acid (VPA) exposure during pregnancy increases the chance of ASD among offspring. Over a decade of animal model studies have shown that maternal treatment with VPA in rodents recapitulates ASD-like pathophysiology at a molecular, cellular and behavioral level. Here, we review the prevailing theories of ASD pathogenesis, including excitatory/inhibitory imbalance, neurotransmitter dysfunction, dysfunction of mTOR and endocannabinoid signaling pathways, neuroinflammation and epigenetic alterations that have been associated with ASD. We also describe the evidence linking neuropathological changes to ASD-like behavioral abnormalities in maternal VPA-treated rodents. In addition to obtaining an understanding of the neuropathological mechanisms, the VPA-induced ASD-like animal models also serve as a good platform for testing pharmacological reagents that might be use treating ASD. We therefore have summarized the various pharmacological studies that have targeted the classical neurotransmitter systems, the endocannabinoids, the Wnt signal pathway and neuroinflammation. These approaches have been shown to often be able to ameliorate the ASD-like phenotypes induced by maternal VPA treatments.
Globalized drug development studies, such as multiregional clinical trials (MRCTs), have attracted much attention due to their ability to expedite drug development and shorten the time lag of drug ...release. While observing the overall effect of a new drug, the region‐specific effects to support drug registration in constituent regions can also be evaluated. Several challenges arise in conducting MRCTs, such as the heterogeneity in the variability of the primary endpoint across regions. However, most of the existing statistical methods assume a common variability, which may not be valid in practice due to differences across regions (eg, diversities in ethnicity or disparities in medical culture/practice). We present a statistical method for the design and evaluation of MRCTs to consider the heterogeneous variability across regions. We assessed the overall sample size requirement and addressed the region‐specific sample size determination to establish the consistency of treatment effects between the specific region and the entire group. We demonstrate the proposed approach with numerical examples.
The striatum comprises a mosaic structure of striosomal and matrix compartments. Imbalanced neuronal activity between striosomes and matrix is implicated in neurological deficits in psychomotor and ...limbic functions. Because patients with autism spectrum disorder (ASD) are impaired in social communication and psychomotor function, it raises the possibility that abnormal striatal compartments may contribute to ASD pathogenesis. Here, we provide pathological evidence from human postmortem brains to support this hypothesis. Because ASD is a neurodevelopmental disease that emerges early in childhood, we analyzed juvenile and adolescent brains. Distinct patterns of PRODYNORPHIN-positive and calbindin-poor striosomes were detected in the caudate nucleus of control brains by in situ hybridization and immunohistochemistry. By contrast, PRODYNORPHIN-positive and calbindin-poor striosomes were decreased in the caudate nucleus of young ASD brains. Moreover, calbindin, a matrix marker, was aberrantly increased in the striosomal compartment, obscuring the boundaries between calbindin-poor striosomes and calbindin-rich matrix in ASD caudate nucleus. Calbindin-positive cells were decreased in the ASD matrix compartment. Collectively, our study has uncovered for the first time that aberrant striatal compartments occur in the caudate nucleus of human ASD brains, which suggests abnormal striatal compartmentation as a pathological signature that has previously been underestimated in ASD pathogenesis.
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