Optimal Dose-response Relationship Research Articles

Effects of exercise training on bone health in adults living with HIV: a systematic review with meta-analysis

ABSTRACT We investigated the effects of exercise training on bone mineral density (BMD) in people living with Human Immunodeficiency Virus (PLHIV). Pubmed, Scopus, Cochrane Library, and ScienceDirect databases were searched for trials investigating exercise training-induced changes in BMD of PLHIV at baseline vs. post-intervention assessed by dual-energy X-ray absorptiometry (DXA). Hedge effect sizes (ES) were calculated incorporating fixed effects for BMD variation assumptions. Disaggregated comparisons were performed for trials with more than one intervention or BMD site assessment. Seven trials included 210 PLHIV and 35 non-HIV-infected controls. Methodological quality evaluated using the Physiotherapy Evidence Database (PEDro) scale ranged from poor to moderate. Interventions applied isolated resistance, combined aerobic and resistance, and multimodal exercise protocols performed 3 d/wk for 12-to 104 week. One controlled and another uncontrolled trial presented significant effects, reporting improvements at the femoral neck and total (ES 2.14 and 0.49, respectively). Magnitude of those specific ES influenced the overall effect (controlled and uncontrolled trials), which was small but significant (k = 12, ES 0.277, 95% confidence interval 0.120-0.434). Resistance training may promote favorable adaptations in BMD of PLHIV, particularly in femur. Future research should elucidate the optimal dose-response relationship and physiological mechanisms underlying exercise-induced adaptations on the BMD of PLHIV.

Stanford Hypnosis Integrated with Functional Connectivity-targeted Transcranial Stimulation (SHIFT): a preregistered randomized controlled trial

AbstractHypnotizability, one’s ability to experience cognitive, emotional, behavioral and physical changes in response to suggestions in the context of hypnosis, is a stable neurobehavioral trait associated with improved treatment outcomes from hypnosis-based therapy. Increasing hypnotizability in people who are low-to-medium hypnotizable individuals could improve both the efficacy and effectiveness of therapeutic hypnosis as a clinical intervention. Hypnotizability is associated with dorsolateral prefrontal cortex (DLPFC) functions and connectivity with the salience network, yet there is conflicting evidence as to whether unilateral inhibition of the DLPFC changes hypnotizability. We hypothesized that using personalized neuroimaging-guided targeting to non-invasively stimulate the left DLPFC with transcranial magnetic stimulation (TMS) would temporarily increase hypnotizability. In a preregistered, double-blinded, randomized controlled trial, we recruited a sample of 80 patients with fibromyalgia syndrome, a functional pain disorder for which hypnosis has been a demonstrated beneficial non-pharmacological treatment option. All participants were TMS-naive. Participants were randomly assigned to active or sham continuous theta-burst stimulation over a personalized neuroimaging-derived left-DLPFC target, a technique termed SHIFT (Stanford Hypnosis Integrated with Functional Connectivity-targeted Transcranial Stimulation). We tested our hypothesis using the hypnotic induction profile scores, a standardized measure of hypnotizability. Pre-to-post SHIFT change in the hypnotic induction profile scores was significantly greater in the active versus sham group after 92 s of stimulation (P = 0.046). Only the active SHIFT group showed a significant increase in hypnotizability following stimulation (active: P < 0.001; sham: P = 0.607). As such, modulation of trait hypnotizability is possible in humans using non-invasive neuromodulation. Our findings support a relationship between the inhibition of the left DLPFC and an increase in hypnotizability. Dose–response optimization of spaced SHIFT should be explored to understand the optimal dose–response relationship. ClinicalTrials.gov registration: NCT02969707.

The Impact of Regular Physical Exercise on Psychopathology, Cognition, and Quality of Life in Patients Diagnosed with Schizophrenia: A Scoping Review.

The presence of less healthy lifestyle habits among individuals diagnosed with schizophrenia which can contribute to the escalation of physical disorders and exacerbation of psychological symptoms is well documented. The present scoping review aims to synthesize and evaluate the available evidence regarding the impact of regular physical exercise on psychopathology, cognition, and quality of life (QoL) in patients diagnosed with schizophrenia. A literature search was performed across Web of Science, SCOPUS, PubMed, and SPORTDiscus for randomized control trials published up to April 2022. Two independent reviewers applied the selection criteria and a third reviewer resolved discrepancies. A total of twelve studies were included, of which nine used endurance training and three used concurrent training (one of these additionally used resistance training). The results reveal benefits of various modalities of supervised regular exercise in the psychopathology of schizophrenia. Furthermore, regular endurance training seems to improve cognitive function in patients with schizophrenia and promote their QoL; however, results are inconclusive with respect to this last variable. The assessment of methodological quality in the reviewed articles indicates a high overall risk of bias, particularly in relation to deviations from intended interventions and the selection of reported results. Furthermore, an assessment of exercise reporting revealed that only 5 out of 19 items were fulfilled in more than 50% of the articles. Future research is needed to evaluate the effects of different training modalities and the optimal dose-response relationship in patients diagnosed with schizophrenia.

Dose-Response Relationships of Resistance Training in Adults With Knee Osteoarthritis: A Systematic Review and Meta-analysis.

To determine the effects of resistance training (RT) on symptoms, function, and lower limb muscle strength in patients with knee osteoarthritis (KOA), and to determine the optimal dose-response relationships. We searched the PubMed, MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and ClinicalTrials.gov databases from inception to January 23, 2022. Randomized controlled trials that examined the effects of RT in KOA patients (mean age ≥50 years) were included. We applied Hedges' g of the random-effects model to calculate the between-subject standardized mean difference (SMDbs). A random-effects metaregression was calculated to explain the influence of key training variables on the effectiveness of RT. We used the Grading of Recommendations Assessments, Development and Evaluation (GRADE) method to appraise the certainty of evidence. A total of 46 studies with 4289 participants were included. The analysis revealed moderate effects of RT on symptoms and function (SMDbs =-0.52; 95% CI: -0.64 to -0.40), and lower limb muscle strength (SMDbs = 0.53; 95% CI: 0.42 to 0.64) in the intervention group compared with the control group. The results of the metaregression revealed that only the variable "training period" (P< .001) had significant effects on symptoms, function, and lower limb muscle strength, and the 4 to 8 weeks of training subgroup showed greater effects than other subgroups (SMDbs =-0.70, -0.91 to -0.48; SMDbs = 0.76, 0.56 to 0.96). Compared with inactive treatments, RT is strongly recommended to improve symptoms, function, and muscle strength in individuals with KOA. Dose-response relationship analysis showed that 4 to 8 weeks of RT had more benefits.

Benefits of Virtual Reality Balance Training for Patients With Parkinson Disease: Systematic Review, Meta-analysis, and Meta-Regression of a Randomized Controlled Trial.

BackgroundVirtual reality (VR) balance training is increasingly being pursued in biomedical research, specifically with respect to investigating balance ability with VR. However, existing systematic reviews have found inconsistent conclusions about the efficacy of VR in improving balance in Parkinson disease (PD) patients.ObjectiveThe goal of the research was to evaluate the impact of VR balance training on the balance ability of patients with PD.MethodsAll major databases, including Web of Science, PubMed, Scopus, China National Knowledge Infrastructure, and Wanfang, were searched to identify all relevant studies published in English or Chinese since September 15, 2010. Two researchers independently conducted document retrieval, study selection, data extraction, and methodological quality evaluation.ResultsA total of 16 randomized controlled trials were analyzed (n=583 patients with PD), with the methodological quality evaluation score ranging from 5 to 8 points. A random effects model was selected to combine effect sizes. Meta-analysis showed that the balance ability of PD was significantly improved after VR training compared with the control group (standardized mean difference [SMD] 2.127, 95% CI 1.202 to 3.052, P<.001, I2=95.1, df=15). It is worth noting that the intervention platform may be the main reason for heterogeneity. Meta regression analysis showed that no training program could predict the impact of VR training (P=.57 to .94) on PD balance ability. Subgroup result showed that a single training time of 0 to 20 minutes (SMD 6.446), 4 to 6 times per week (SMD 4.067), training for 3 to 5 weeks (SMD 62.478), training course reached more than 30 times (SMD 4.405), and 201 to 300 minutes per week (SMD 4.059) maybe have more benefit.ConclusionsA systematic review and meta-analysis confirmed that VR balance training is a highly effective means to improve balance performance with large effects in PD. In addition, we preliminarily extracted dose-effect relationships for training volume, informing clinicians and practitioners to design effective VR balance training for balance ability. Further research is needed to reveal optimal dose-response relationships following VR balance training.

Preclinical Dose-Escalation Study of ZSJ-0228, a Polymeric Dexamethasone Prodrug, in the Treatment of Murine Lupus Nephritis.

Glucocorticoids (GCs) are widely used in the clinical management of lupus nephritis (LN). Their long-term use, however, is associated with the risk of significant systemic side effects. We have developed a poly(ethylene glycol) (PEG)-based dexamethasone (Dex) prodrug (i.e., ZSJ-0228) and in a previous study, demonstrated its potential therapeutic efficacy in mice with established LN, while avoiding systemic GC-associated toxicity. In the present study, we have employed a dose-escalation design to establish the optimal dose-response relationships for ZSJ-0228 in treating LN and further investigated the safety of ZSJ-0228 in lupus-prone NZB/W F1 mice with established nephritis. ZSJ-0228 was intravenously (i.v.) administered monthly at four levels: 0.5 (L1), 1.0 (L2), 3.0 (L3), and 8.0 (L4) mg/kg/day Dex equivalent. For controls, mice were treated with i.v. saline every 4 weeks. In addition, a group of mice received intraperitoneal injections (i.p.) of Dex every day or i.v. injections of Dex every four weeks. Treatment of mice with LN with ZSJ-0228 dosed at L1 resulted in the resolution of proteinuria in 14% of the mice. Mice treated with ZSJ-0228 dosed at L2 and L3 levels resulted in the resolution of proteinuria in ∼60% of the mice in both groups. Treatment with ZSJ-0228 dosed at L4 resulted in the resolution of proteinuria in 30% of the mice. The reduction and/or resolution of the proteinuria, improvement in renal histological scores, and survival data indicate that the most effective dose range for ZSJ-0228 in treating LN in NZB/W F1 mice is between 1.0 and 3.0 mg/kg/day Dex equivalent. Typical GC-associated side effects (e.g., osteopenia, adrenal glands atrophy, etc.) were not observed in any of the ZSJ-0228 treatment groups, confirming its excellent safety profile.

Phase II Clinical Trial Evaluating the Standardization of CD3+ T-Cell Dose for Patients Receiving Allogeneic Peripheral Blood Stem Cell Transplants (PBSCT) from Matched Related Donors

<h3>Introduction</h3> Seminal studies of peripheral blood versus bone marrow grafts have elucidated the crucial role of CD3+ T-cells in mediating engraftment, immune reconstitution, disease control, and graft versus host disease (GVHD). An optimal dose-response relationship between the T-cell dose in the graft and outcomes is yet to be defined. Therefore, we performed a phase II clinical trial to evaluate whether T-cell dose standardization would adequately support engraftment and immune reconstitution while mitigating the risk of GVHD. <h3>Methods</h3> We conducted a clinical trial of dose standardization of T-cells between December 2014 and May 2018. Eligible adult patients (pts) with hematologic malignancies undergoing peripheral blood matched sibling allogeneic stem cell transplant were enrolled. Standardized T-cell dose was targeted 15-20 × 10e7. Tacrolimus and methotrexate were utilized for GVHD prophylaxis. The primary endpoint was to determine the incidence of grade II-IV acute GVHD. Secondary endpoints included overall survival (OS), progression-free survival (PFS), non-relapse mortality (NRM), and time to engraftment. Chronic GVHD was captured using conventional criteria. <h3>Results</h3> 17 pts were included in the study. Peripheral blood stem cell (PBSCT) graft from matched sibling donors was used in all pts. The mean age was 52 years (20-68 years). 53% pts were female and 82% were Caucasian. The median T-cell dose was 19.1 × 10e7 (range 9.1-21.8 × 10e7). Indications for PBSCT included AML/MDS (70.6%), ALL (17.6%), NHL and MPN (11.8 %). 35% pts received myeloablative and 65% received reduced-intensity conditioning. 59% had age-adjusted HCT-CI scores ≥3. 16 pts received tacrolimus and methotrexate for GVHD prophylaxis, with 1 patient receiving tacrolimus and mycophenolate. All pts successfully engrafted. The median time to engraftment was 15 days for neutrophils (range 10-20), and 12 days for platelets (range 9-22). The cumulative incidence of grade II-IV and grade III-IV acute GVHD at 1 year was 27% (95%-CI: 7-52) and 22.5 (95%-CI: 4.7-48.4) (no grade IV) and that of chronic GVHD was 47% (22-69) (N=8, all extensive by conventional criteria). 18% pts reactivated CMV (median - 40 days, range 33-50). 47% pts were alive in remission after a median follow-up of 18.1 months (3.3-52.2). The cumulative incidence of relapse at 1 year was 23.5% (95% CI: 7-46) (Figure 1). The 1 year PFS was 53% (95% CI: 28-73), and the OS was 65% (95% CI: 37-82). <h3>Conclusion</h3> Administration of a lower standardized T-cell dose is feasible, and when used in combination with standard immune suppression did not negatively affect outcomes. This study paves the way for a larger trial to evaluate the optimal T-cell dose and immune suppressive therapy to strike a favorable GVHD/GVL balance. Such a strategy could be used as a platform for additional interventions aimed towards improving the outcome of PBSCT for hematologic malignancies.

Exercise and Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a complex endocrinopathy affecting both the metabolism and reproductive system of women of reproductive age. Prevalence ranges from 6.1-19.9% depending on the criteria used to give a diagnosis. PCOS accounts for approximately 80% of women with anovulatory infer-tility, and causes disruption at various stages of the reproductive axis. Evidence suggests lifestyle modification should be the first line of therapy for women with PCOS. Several studies have examined the impact of exercise interventions on reproductive function, with results indicating improvements in menstrual and/or ovulation frequency following exercise. Enhanced insulin sensitivity underpins the mechanisms of how exercise restores reproductive function. Women with PCOS typically have a cluster of metabolic abnormalities that are risk factors for CVD. There is irrefutable evidence that exercise mitigates CVD risk factors in women with PCOS. The mechanism by which exercise improves many CVD risk factors is again associated with improved insulin sensitivity and decreased hyperinsulinemia. In addition to cardiometabolic and reproductive complications, PCOS has been associated with an increased prevalence of mental health disorders. Exercise improves psychological well-being in women with PCOS, dependent on certain physiological factors. An optimal dose-response relationship to exercise in PCOS may not be feasible because of the highly individualised characteristics of the disorder. Guidelines for PCOS suggest at least 150 min of physical activity per week. Evidence confirms that this should form the basis of any clinician or healthcare professional prescription.

Equine-assisted interventions for veterans with service-related health conditions: a systematic mapping review

BackgroundEvidence-based treatments for service-related health conditions such as posttraumatic stress disorder (PTSD), depression, and traumatic brain injury (TBI) are not effective for all veterans. Equine-assisted interventions are emerging as an additional treatment modality, but little is known regarding the safe and effective delivery of these interventions. This study aimed to describe the following features of the body of literature concerning equine-assisted interventions among veterans: 1) veterans who have participated in equine-assisted interventions; 2) specific characteristics of equine-assisted interventions in veterans; and 3) the specific characteristics of research on equine-assisted interventions in veterans.MethodsWe conducted a systematic mapping review of peer-reviewed literature reporting on equine-assisted interventions among veterans between 1980 and 2017. Searches of nine databases yielded 3336 unique records, six of which met the inclusion criteria and were reviewed. Data relevant to the study aims were extracted and analyzed.ResultsEquine-assisted interventions among veterans disproportionately targeted psychosocial outcomes and yielded promising results. The detailed methods of EAI varied in the reported studies, ranging from communicating with the horse to mounted exercises. There was also great diversity in outcome measurement. The state of theoretical development regarding the mechanisms by which equine-assisted interventions benefit the veteran population is currently underdeveloped. Studies provided insufficient detail with respect to the description of the intervention, reasons for attrition, and the dose-response relationship.ConclusionsScientific development of equine-assisted interventions targeting psychosocial outcomes among veterans is warranted to establish their efficacy. Targeted outcomes should be expanded, including outcomes more closely aligned with the nature of polytraumatic injuries. Future research must also emphasize the theoretical development of equine-assisted interventions for veterans and thoroughly describe the participants, components of the intervention, factors contributing to attrition, and optimal dose-response relationships.

Towards an optimal dose-response relationship in gene electrotransfer protocols

In search of an optimal gene electrotransfer (GET) protocol, an electroporation-based (EP) tumor treatment with great potential as a non-viral gene-delivery system, the concept of the dose-response relationship is introduced. It is shown that a reliable dose parameter is the pulse dosage and reliable response parameters are the reversibly electroporated tissue area as well as the unwanted damaged tissue area and plasmid damage due to pH. The standard stationary EP model consists in computing the reversibly electroporated tissue area in the first pulse as the region of tissue subjected to an electric field distribution higher than an electric field threshold for EP, where the electric field threshold comes from an experimental measurement and the electric field distribution from the solution of the nonlinear stationary Laplace equation for the electrostatic potential. The extended standard EP model introduced here consists in replicating for n consecutive pulses the standard EP model, via the experimental measurement in time of the successive thresholds. Because experimental data of this threshold variation is lacking, an exponential time decay function is assumed based on experimental measurements. The damage induced by pH fronts is defined as the tissue area subjected to pH abrupt changes above a basic threshold or below an acid threshold, where these changes come from numerical solutions via the electrolytic ablation (EA) model for EP-based protocols and the basic and acid thresholds from experiments. An optimal dose-response relationship in a GET protocol, for the range of pulse intensities with fixed pulse length and frequency, tested here, is predicted as the critical pulse dosage yielding maximum reversibly electroporated tissue area with minimal tissue area damage induced by pH fronts. Moreover, since damage induced by pH changes is proportional to the Coulomb dosage, damage induced by pH fronts is negligible in typical EP-based tumor protocols such as in electrochemotherapy (ECT) and irreversible electroporation (IRE) but not in GET, due to the most often longer pulses applied/used, i.e. higher dosage applied.

Cold water immersion settings for reducing muscle tissue temperature: a linear dose-response relationship.

Although cold water immersion (CWI) is widely accepted and integrated as a recovery modality in sports practice, questions regarding its proposed working mechanisms remain. This study systematically reviews the existing literature on one the proposed mechanisms of CWI, its effect on muscle tissue temperature, and subsequently tries to identify a dose-response relationship in order to describe an optimal dose. A systematic literature search (PubMed and Sport Discus) was conducted in October 2017. Dose-response relationships were analyzed using linear regression while controlling for possible confounders (muscle measurement depth and immersion position). A total of 10 studies, with a total of 104 participants, were included utilizing 26 different CWI protocols. Muscle tissue temperatures were reduced significantly by 24 CWI protocols. A significant, relationship with a medium effect size (r=0.51) was identified between muscle tissue temperature and CWI. The most optimal dose-response relationship, with a large effect size, (r=0.87) was described for CWI protocols using full-body immersion at a measurement depth of 30 mm (y = 4.051 x + 0.535). CWI can decrease muscle tissue temperature significantly if a minimum CWI dose of 1.1 is applied, corresponding with an immersion of 11 minutes with a water temperature of 10 °C.

Optimal dose-response relationship in electrolytic ablation of tumors with a one-probe-two-electrode device

Electrolytic ablation (EA), a medical treatment used in solid tumor ablation due to its minimum side effects and low cost, consists in the passage of a low constant electric current through two or more electrodes inserted in the tissue thus inducing pH fronts that produce tumor necrosis. Combined with a recently introduced one-probe two electrode device (OPTED) this procedure results in a minimally invasive treatment. Despite its success, EA has drawbacks such as the difficulties in determining the optimum dose-response relationship between the applied current, treatment time and necrotized tumor volume (NTV) and choosing a reliable dose parameter. In this work, a theoretical model is introduced describing the EA/OPTED as an electrolytic process and the underlying electrochemical reactions through the Nernst-Planck equations for ion transport. Model results show that the coulomb dosage is a reliable dose parameter and predicts an optimal dose-response relationship for a given tumor size subjected to an EA/OPTED, considering the optimum as the minimum coulomb dosage necessary to achieve total tumor destruction while minimizing healthy tissue damage. Moreover, it predicts a nonlinear relationship between coulomb dosage and NTV, dosage and NTV scaling as Q1.4. Consequently, these results could have a significant impact on dose planning methodology aimed at improving the effectiveness of the electrolytic ablation.

Dose-Response Relationships of Resistance Training in Healthy Old Adults: A Systematic Review and Meta-Analysis.

Background Resistance training (RT) is an intervention frequently used to improve muscle strength and morphology in old age. However, evidence-based, dose–response relationships regarding specific RT variables (e.g., training period, frequency, intensity, volume) are unclear in healthy old adults.

Biological Mechanisms for the Cardioprotective Effects of Aerobic Exercise

Epidemiologic studies have consistently identified a strong inverse association between coronary heart disease (CHD) and regular, predominantly moderate-intensity physical activity and cardiorespiratory fitness. Supporting evidence of causative relationships has been provided by aerobic exercise training studies in both animals and humans. This research demonstrated multiple plausible cardioprotective biological mechanisms. These include direct antiatherosclerotic effects by improving artery endothelial function and reducing inflammation and indirectly via modification of other risk factor components of the metabolic syndrome, by reducing risk of a coronary thrombotic occlusion (antithrombotic effects), by decreasing myocardial oxygen demands and increasing its vascular supply (anti-ischemic effects), and by improving cardiomyocyte electrical stability and autonomic nervous system adaptations (antiarrhythmic effects). Although much additional research is needed to better define and establish optimal dose-response relationships, clearly these pleotropic effects strongly suggest that aerobic exercise can attenuate the risk of CHD at all stages of the underlying atherothrombotic process.

Diet, physical activity and energy balance and their impact on breast and prostate cancers

Obesity, physical activity status and circulating levels of sex steroid hormones and growth factor proteins are intrinsically linked to energy balance. Epidemiological studies have previously reported associations between these factors and the risk of hormone-related cancers such as prostate and breast cancer in men and postmenopausal women. An increasing number of intervention studies in 'at-risk' populations and cancer survivors are now investigating the effects of lifestyle interventions that promote negative energy balance on circulating levels of sex hormones and growth factor proteins as surrogate markers of cancer risk. Evidence from these studies suggests that lifestyle interventions can improve insulin sensitivity, alter the balance of circulating sex steroid hormones and insulin-like growth factor (IGF) axis proteins (including IGF-1 and the IGF binding proteins 1 and 3) and change the functioning of immune cells in peripheral blood. Such changes could influence the risk of developing hormone-related cancers, as well as having the potential to improve disease-free survival in patients recovering from cancer treatment. However, despite promising results, the methodological quality of most intervention studies has been limited due to small subject numbers, lack of adequate control groups or non-randomised designs and the absence of long-term follow-up measures. More intervention studies with randomised controlled designs, higher numbers of subjects and longer-term follow-up measures are needed to establish which combination of specific dietary and physical activity interventions work best for reducing risk in 'at-risk' populations and survivors, optimal dose-response relationships and the magnitude of change in surrogate markers of cancer risk that is required to induce a protective effect.

A randomised, double-blind, dose-ranging study to evaluate efficacy and safety of three doses of botulinum toxin type A (Botox) for the treatment of spastic foot

Botulinum toxin A (BTX) injections have been used successfully in the treatment of post-stroke foot spasticity, but the optimal dose-response relationship for selected muscles has yet to be established. The aim of this study was to outline beneficial and unwanted effects of three different doses of BTX in the treatment of spastic foot. In this randomised, double-blind, dose-ranging study, 45 spastic feet were randomly allocated to one of three groups, each of which was treated with a different dosage of BTX. The doses were decided on the basis of suggestions in the literature. Outcome measures (Modified Ashworth Scale, Medical Research Council Scale, gait assessment, presence of Achilles tendon clonus, Visual Analogue Scales for Gait Function and Pain, Adverse Effects scale) were applied at baseline, 4 weeks and 4 months after treatment. All the groups showed significant scales scores improvements after treatment with BTX. Group II (mean BTX total dose: 322 U) and Group III (mean BTX total dose: 540 U) showed a greater and more prolonged response than Group I (mean BTX total dose: 167 U). Group III showed the highest rate of adverse effects 4 weeks post-treatment. BTX injections constitute a useful and safe method of improving post-stroke foot spasticity, associated pain, gait speed and function. In particular, the medium BTX dosages (320 UI spread over 2-5 muscles) were found to be both safe and effective in producing long-lasting improvement of spastic foot dysfunction.