OBJECTIVE: Conventional randomized controlled trials (RCTs) have long served as the foundation of research in clinical psychology; however, most treatments for eating disorders show only modest effects on reduction of symptoms and maintenance of long-term remission. New options for psychotherapy treatment development research, beyond continuing to pursue additive or subpopulation approaches, are needed.
METHODS: One option is to apply dose-response designs, which are commonplace in studies of pharmacology, toxicology, and medical research, and characterized by the evaluation of the amount of exposure (dose) to an intervention, and the resulting changes in body function or health (response).
RESULTS: Eating disorder interventions are particularly well-suited for dose-response treatment designs. The deadly nature of eating disorders makes it imperative that patients are not turned away for not being \"ready\" to engage with treatment. By identifying optimal doses, research will likely yield a more parsimonious course of treatment, which will lend itself to reduced costs, greater uptake, and reduced drop-out.
CONCLUSIONS: Limited use of within-subject designs in trials for patients with eating disorders has produced fast-track efficacy studies and omitted key elements in the treatment development pathway. To decrease reliance on RCT\'s, dose-response methods should be applied as an alternative study design.
UNASSIGNED: Eating disorders are associated with medical and psychiatric comorbidities, poor quality of life, and high mortality. Access to evidence-based services for patients with eating disorders is limited, and identifying additional effective treatment options can be difficult because of challenges inherent to randomized-controlled trials. This manuscript describes an alternative trial methodology to maximize the information that can be gathered prior to utilizing a standard large-scale efficacy design.

UNASSIGNED: Eccentric exercise may trigger mechanical stress, resulting in muscle damage that may decrease athletic performance. L-citrulline potentially prevents skeletal muscle damage after acute eccentric exercise. This study aimed to assess the dose-response effect of L-citrulline as a preventive therapy for skeletal muscle damage in mice after acute eccentric exercise.
UNASSIGNED: This is a controlled laboratory in vivo study with a post-test-only design. Male mice (BALB/c, n = 25) were randomized into the following groups: a normal control (C1) (n = 5); a negative control (C2) with downhill running and placebo intervention (n = 5); treatment groups: T1 (n = 5), T2 (n = 5), and T3 (n = 5), were subjected to downhill running and 250, 500, and 1,000 mg/kg of L-citrulline, respectively, for seven days. Blood plasma was used to determine the levels of TNNI2 and gastrocnemius muscle tissue NOX2, IL-6, and caspase 3 using ELISA. NF-κB and HSP-70 expressions were determined by immunohistochemistry.
UNASSIGNED: Skeletal muscle damage (plasma TNNI2 levels) in mice after eccentric exercise was lower after 250 and 500 mg/kg of L-citrulline. Further, changes in oxidative stress markers, NOX2, were reduced after a 1,000 mg/kg dose. However, a lower level of change has been observed in levels of cellular response markers (NF-κB, HSP-70, IL-6, and caspase 3) after administration of L-citrulline doses of 250, 500, and 1,000 mg/kg.
UNASSIGNED: L-citrulline may prevent skeletal muscle damage in mice after acute eccentric exercise through antioxidant effects as well as inflammatory and apoptotic pathways. In relation to dose-related effects, it was found that L-citrulline doses of 250, 500, and 1,000 mg/kg significantly influenced the expression of NF-κB and HSP-70, as well as the levels of IL-6 and caspase 3. Meanwhile, only doses of 250 and 500 mg/kg had an impact on TNNI2 levels, and the 1,000 mg/kg dose affected NOX2 levels.

UNASSIGNED: The local hemodynamic response after cupping therapy has been considered as a contributing factor for improving muscle tissue health; however, the effects of cupping pressure and duration on the spatial hemodynamic response have not been investigated.
UNASSIGNED: The objective of this study was to investigate the hemodynamic response inside and outside the cupping cup under various pressures and durations of cupping therapy.
UNASSIGNED: A 3-way factorial design with repeated measures was used to investigate the main and interaction effects of the location (areas inside and outside the cup), pressure (-225 and -300 mmHg) and duration (5 and 10 min) on the hemodynamic response of the biceps muscle. A functional near-infrared spectroscopy was used to assess hemodynamic changes in 18 participants.
UNASSIGNED: A significant three-way interaction of the location, pressure, and duration factors was observed in oxyhemoglobin (p= 0.023), deoxy-hemoglobin (p= 0.013), and blood volume (p= 0.013). A significant increase was observed in oxyhemoglobin, blood volume, and oxygenation compared to pre-cupping (p< 0.05) in the area outside the cup.
UNASSIGNED: Our findings indicate that an appropriate combination of cupping pressure and duration can effectively affect the spatial hemodynamic response of the biceps.

The efficacy of low-carbohydrate, high-fat diets, such as ketogenic diets, for cancer patients is of research interest. We previously demonstrated the efficacy of the ketogenic diet in a case study in which medium-chain triglycerides (MCTs) or MCT-containing formula (ketogenic formula) was used as a supplement to increase blood ketone bodies. However, little is known about the amounts needed to induce ketogenic effects and about the usefulness of monitoring of breath acetone. To investigate the pharmacokinetics of MCTs and their metabolites, blood ketone bodies and breath acetone, 24 healthy subjects received one of four single oral doses of the ketogenic formula (equivalent to 0, 10, 20, and 30 g of MCTs) under fasting conditions. Total blood ketone bodies, β-hydroxybutyrate, octanoic acid, and decanoic acid were increased in a dose-dependent manner. The ketogenic effect was considered to depend on octanoic and decanoic acids, because a positive correlation was observed between them. A strong positive correlation was also observed between total serum ketone bodies and breath acetone at each time points. Therefore, monitoring breath acetone levels seems a less invasive method to predict blood concentrations of ketone bodies during ketogenic diet therapy. Clinical trial registration:https://rctportal.niph.go.jp/en/detail?trial_id=UMIN000032634, UMIN-CTR UMIN000032634.

The present paper identifies a critical factor that leads to false negative results (i.e., failing to indicate efficacy when beneficial results did occur) in randomized human drug trials. The paper demonstrates that human performance can only be enhanced by a maximum of 30-60% as described by the hormetic dose response which defines the limits of biological plasticity. However, human epidemiological/clinical trials typically contain such extensive variability that often requires responses greater than 2-3 times control group responses to show statistical significance. Thus, many potentially beneficial agents may be missed because the clinical trial fails to recognize and take into consideration the limits of biological plasticity. The paper proposes that this hormesis-biological plasticity-clinical trial conundrum can be addressed successfully via the use of a weight-of-evidence methodology similar to that used by regulatory agencies such as EPA in environmental assessment of chemical toxicity.

Among chronically-ill older adults, the benefits of moderate-to-vigorous physical activity (MVPA) are established. Comorbid depressive symptoms and Major Depression are prevalent among the chronically-ill, but how different doses of MVPA may protect against depression remains understudied. Thus, using 10 years of data from The Irish Longitudinal Study on Ageing, we quantified longitudinal associations between MVPA doses and depressive symptoms and Major Depression among chronically-ill older adults living with type 2 diabetes (T2DM). Continuous MVPA (MET.min.week-1), three dose and five dose MVPA categories were examined. Depressive symptoms and Major Depression were measured using the center for Epidemiological Studies Depression and the Composite International Diagnostic Interview for Major Depressive Episode. Negative binomial regression and logistic models, adjusted for covariates, quantified associations across time. Among the 2,262 participants, those adhering to the WHO guidelines of 600-<1,200 MET.min.week-1 had 28% lower odds of Major Depression compared to those not achieving the guidelines (OR: 0.72; 95%CI: 0.53-0.98). For depressive symptoms, a higher MVPA dose was required with a 13% (IRR: 0.87; 95%CI: 0.82-0.93) lower rate of symptoms among those exceeding recommendations (1200-<2,400 MET.min.week-1). Interventions should focus on enhancing achievability of and compliance with these MVPA doses among the chronically-ill, including T2DM, to protect against depression.

Mathematical modelling methods and adaptive trial design are likely to be effective for optimising vaccine dose but are not yet commonly used. This may be due to uncertainty with regard to the correct choice of parametric model for dose-efficacy or dose-toxicity. Non-parametric models have previously been suggested to be potentially useful in this situation. We propose a novel approach for locating optimal vaccine dose based on the non-parametric Continuous Correlated Beta Process model and adaptive trial design. We call this the \'Correlated Beta\' or \'CoBe\' dose optimisation approach. We evaluated the CoBe dose optimisation approach compared to other vaccine dose optimisation approaches using a simulation study. Despite using simpler assumptions than other modelling-based methods, we found that the CoBe dose optimisation approach was able to effectively locate the maximum efficacy dose for both single and prime/boost administration vaccines. The CoBe dose optimisation approach was also effective in finding a dose that maximises vaccine efficacy and minimises vaccine-related toxicity. Further, we found that these modelling methods can benefit from the inclusion of expert knowledge, which has been difficult for previous parametric modelling methods. This work further shows that using mathematical modelling and adaptive trial design is likely to be beneficial to locating optimal vaccine dose, ensuring maximum vaccine benefit and disease burden reduction, ultimately saving lives.

Inter-patient and intra-tumour heterogeneity (ITH) have prompted the need for a more personalised approach to cancer therapy. Although patient-derived xenograft (PDX) models can generate drug response specific to patients, they are not sustainable in terms of cost and time and have limited scalability. Tumour Organ-on-Chip (OoC) models are in vitro alternatives that can recapitulate some aspects of the 3D tumour microenvironment and can be scaled up for drug screening. While many tumour OoC systems have been developed to date, there have been limited validation studies to ascertain whether drug responses obtained from tumour OoCs are comparable to those predicted from patient-derived xenograft (PDX) models. In this study, we established a multiplexed tumour OoC device, that consists of an 8 × 4 array (32-plex) of culture chamber coupled to a concentration gradient generator. The device enabled perfusion culture of primary PDX-derived tumour spheroids to obtain dose-dependent response of 5 distinct standard-of-care (SOC) chemotherapeutic drugs for 3 colorectal cancer (CRC) patients. The in vitro efficacies of the chemotherapeutic drugs were rank-ordered for individual patients and compared to the in vivo efficacy obtained from matched PDX models. We show that quantitative correlation analysis between the drug efficacies predicted via the microfluidic perfusion culture is predictive of response in animal PDX models. This is a first study showing a comparative framework to quantitatively correlate the drug response predictions made by a microfluidic tumour organ-on-chip (OoC) model with that of PDX animal models.

Family socioeconomic position (SEP) in childhood is an important factor to predict some chronic diseases. However, the association between family SEP in childhood and the risk of lung cancer is not clear.
A systematic search was performed to explore their relationship. We selected education level, socioeconomic positions of parents and childhood housing conditions to represent an individual family SEP. Hazard ratios (HRs) of lung cancer specific-mortality were synthesized using a random effects model. Two-sample Mendelian randomization (MR) was carried out with summary data from published genome-wide association studies of SEP to assess the possible causal relationship of SEP and risk of lung cancer.
Through meta-analysis of 13 studies, we observed that to compared with the better SEP, the poorer SEP in the childhood was associated with the increased lung cancer risk in the adulthood (HR: 1.25, 95% CI: 1.10 to 1.43). In addition, the dose-response analysis revealed a positive correlation between the poorer SEP and increased lung cancer risk. Same conclusion was reached in MR [(education level) OR 0.50, 95% CI: 0.39 to 0.63; P < 0.001].
This study indicates that poor family socioeconomic position in childhood is causally correlated with lung cancer risk in adulthood.
identifier: 159082.

This paper demonstrates that the dissertation research of Ray-Chaudhuri (1939, 1944) that was used by Hermann Muller to support his radiation induced gene mutation hypothesis and linear non-threshold (LNT) dose response model during his Nobel Prize Lecture is \"uninterpretable\" with respect to these issues. The research failed to include essential research design information, resulting in reporting flaws that have never been previously identified. These observations are historically important because this dissertation was used to blunt powerful criticism of Muller\'s gene mutation research and strongly promoted his advocacy of the LNT model in radiation risk assessment.