Electroacupuncture Enhances the Functional Connectivity of Limbic System to Neocortex in the 5xFAD Mouse Model of Alzheimer's Disease.

Our previous study revealed that acupuncture may exhibit therapeutic effects on Alzheimer's disease (AD) through the activation of metabolism in memory-related brain regions. However, the underlying functional mechanism remains poorly understood and warrants further investigation. In this study, we used resting-state functional magnetic resonance imaging (rsfMRI) to explore the potential effect of electroacupuncture (EA) on the 5xFAD mouse model of AD. We found that the EA group exhibited significant improvements in the number of platforms crossed and the time spent in the target quadrant when compared with the Model group (p < 0.05). The functional connectivity (FC) of left hippocampus (Hip) was enhanced significantly among 12 regions of interest (ROIs) in the EA group (p < 0.05). Based on the left Hip as the seed point, the rsfMRI analysis of the entire brain revealed increased FC between the limbic system and the neocortex in the 5xFAD mice after EA treatment. Additionally, the expression of amyloid-ß(Aß) protein and deposition in the Hip showed a downward trend in the EA group compared to the Model group (p < 0.05). In conclusion, our findings indicate that EA treatment can improve the learning and memory abilities and inhibit the expression of Aß protein and deposition of 5xFAD mice. This improvement may be attributed to the enhancement of the resting-state functional activity and connectivity within the limbic-neocortical neural circuit, which are crucial for cognition, motor function, as well as spatial learning and memory abilities in AD mice.

Effectiveness of educational interventions in reducing the stigma of healthcare professionals and healthcare students towards mental illness: A systematic review and meta-analysis.

AIM: To examine the effectiveness of educational interventions in reducing stigma among healthcare professionals and students towards people with mental illness. DESIGN: A systematic review and meta-analysis of randomized controlled trials (RCTs) and cluster RCTs. DATA SOURCES: Articles published from database inception to October 2023 were systematically searched from seven databases (CINAHL, Embase, ProQuest Dissertations and Theses Global, PsycINFO, PubMed, Scopus, Web of Science), following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. METHODS: Random-effect meta-analyses were conducted. Heterogeneity was evaluated using the I2 statistics and Cochran's Q chi-squared test. A quality appraisal conducted at the study level used the Cochrane risk of bias tool and an outcome-level quality assessment utilized the Grades of Recommendation, Assessment, Development and Evaluation Approach. Publication bias was assessed using the funnel plot. RESULTS: Twenty-five articles were included in this review. Meta-analysis reported statistically significant medium and small effect sizes for attitudes towards mental illness and attitudes towards people with mental illness respectively, showing the association between educational interventions and improved attitudes among healthcare professionals and students. However, a statistically non-significant effect was reported for knowledge of mental illness. Subgroup analyses indicated that face-to-face and contact-based interventions were particularly effective at reducing stigma. Notably, single-session interventions were just as effective as multiple sessions, suggesting a potential for resource-efficient approaches. CONCLUSION: Educational interventions demonstrate promise in fostering more positive attitudes towards mental health issues. Future research should aim to determine the long-term effects of these interventions and include patient feedback on the stigmatizing behaviours of healthcare professionals and students, to holistically evaluate the effect of interventions. NO PATIENT OR PUBLIC CONTRIBUTION: This study is a secondary review and does not require relevant contributions from patients or the public. WHAT DOES THIS PAPER CONTRIBUTE TO THE WIDER GLOBAL CLINICAL COMMUNITY?: Face-to-face contact-based educational sessions have proven to be the most effective. Reinforcing learning may be achieved through a series of repeated single-session interventions.

Folic Acid Supplementation to Prevent Neural Tube Defects: US Preventive Services Task Force Reaffirmation Recommendation Statement.

Importance: Neural tube defects are among the most common congenital malformations in the US, with an estimated 3000 pregnancies affected each year. Many of these neural tube defects are caused by low folate levels in the body. Objective: The US Preventive Services Task Force (USPSTF) commissioned a reaffirmation evidence update on the benefits and harms of folic acid supplementation. Population: Persons who are planning to or could become pregnant. Evidence Assessment: The USPSTF concludes that, for persons who are planning to or could become pregnant, there is high certainty that folic acid supplementation has a substantial net benefit to prevent neural tube defects in their offspring. Recommendation: The USPSTF recommends that all persons planning to or who could become pregnant take a daily supplement containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid. (A recommendation).

Vitamin, Mineral, and Multivitamin Supplementation to Prevent Cardiovascular Disease and Cancer: US Preventive Services Task Force Recommendation Statement.

Importance: According to National Health and Nutrition Examination Survey data, 52% of surveyed US adults reported using at least 1 dietary supplement in the prior 30 days and 31% reported using a multivitamin-mineral supplement. The most commonly cited reason for using supplements is for overall health and wellness and to fill nutrient gaps in the diet. Cardiovascular disease and cancer are the 2 leading causes of death and combined account for approximately half of all deaths in the US annually. Inflammation and oxidative stress have been shown to have a role in both cardiovascular disease and cancer, and dietary supplements may have anti-inflammatory and antioxidative effects. Objective: To update its 2014 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a review of the evidence on the efficacy of supplementation with single nutrients, functionally related nutrient pairs, or multivitamins for reducing the risk of cardiovascular disease, cancer, and mortality in the general adult population, as well as the harms of supplementation. Population: Community-dwelling, nonpregnant adults. Evidence Assessment: The USPSTF concludes with moderate certainty that the harms of beta carotene supplementation outweigh the benefits for the prevention of cardiovascular disease or cancer. The USPSTF also concludes with moderate certainty that there is no net benefit of supplementation with vitamin E for the prevention of cardiovascular disease or cancer. The USPSTF concludes that the evidence is insufficient to determine the balance of benefits and harms of supplementation with multivitamins for the prevention of cardiovascular disease or cancer. Evidence is lacking and the balance of benefits and harms cannot be determined. The USPSTF concludes that the evidence is insufficient to determine the balance of benefits and harms of supplementation with single or paired nutrients (other than beta carotene and vitamin E) for the prevention of cardiovascular disease or cancer. Evidence is lacking and the balance of benefits and harms cannot be determined. Recommendation: The USPSTF recommends against the use of beta carotene or vitamin E supplements for the prevention of cardiovascular disease or cancer. (D recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the use of multivitamin supplements for the prevention of cardiovascular disease or cancer. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the use of single- or paired-nutrient supplements (other than beta carotene and vitamin E) for the prevention of cardiovascular disease or cancer. (I statement).

Acupuncture for neuropathic pain: A meta-analysis of randomized control trials.

Background: Neuropathic pain (NP) is expected to increase due to the high risk of global population aging. Acupuncture has a definite clinical effect on NP. Therefore, a systematic review and meta-analysis were conducted to evaluate the effect on pain intensity and safety of acupuncture in patients with NP. Methods: An encompassing search of specific authoritative databases in English, from their inception to 2022, was performed. The databases were as follows: Scopus, Ovid EMBASE, Ovid Cochrane Database of Systematic Reviews, Ovid Cochrane Central Register of Controlled Trials, Ovid MEDLINE(R) and Epub Ahead of Print, In-Process and Other Non-Indexed Citations, and Daily. All the randomized controlled trials regarding the acupuncture treatment of NP will be included. Methodological quality assessment of the included trials was assessed based on the risk of bias from the Cochrane handbook. A meta-analysis was performed for the main outcomes. In addition, sensitivity analysis, subgroup analysis, and funnel plot were also carried out. Results: A total of 16 studies with 1,021 patients with NP were evaluated in a systematic review. According to the results of the overall meta-analysis in eight RCTs with 338 participants, the acupuncture group was better than the control group in improving changes in pain intensity (SMD -0.59, 95% CI: -0.95 to -0.23, P = 0.001). In subgroup analysis, five trials indicated that acupuncture was more effective in improving changes in pain intensity than sham acupuncture (SMD -0.54, 95% CI: -0.95 to -0.13, P = 0.01), two trials evaluated the effect on changes in pain intensity in the comparison of acupuncture and conventional treatments, no significant difference existed (SMD -0.61, 95% CI: -1.83 to 0.61, P = 0.33), and one trial compared acupuncture with blank control evaluating the effect of changes in pain intensity with a significant difference. Eleven studies mentioned the safety conditions and acupuncture-induced AEs were mild and reversible. Both the sensitivity analysis and funnel plot analysis showed that the meta-analysis was stable and irreversible without publication bias. The GRADE was rated as "very low." Conclusion: The acupuncture group had higher effectiveness than sham intervention or blank control for changes in pain intensity, but there is no significant difference between acupuncture and conventional treatments in treating NP. The acupuncture-induced adverse events were mild and reversible. However, the interpretation of our results should be performed cautiously due to the low methodological quality of selected publications. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022306461.

Advance Care Planning in Older Adults with CKD: Patient, Care Partner, and Clinician Perspectives.

BACKGROUND: Older patients with advanced CKD are at high risk for serious complications and death, yet few discuss advance care planning (ACP) with their kidney clinicians. Examining barriers and facilitators to ACP among such patients might help identify patient-centered opportunities for improvement. METHODS: In semistructured interviews in March through August 2019 with purposively sampled patients (aged ≥70 years, CKD stages 4-5, nondialysis), care partners, and clinicians at clinics in across the United States, participants described discussions, factors contributing to ACP completion or avoidance, and perceived value of ACP. We used thematic analysis to analyze data. RESULTS: We conducted 68 semistructured interviews with 23 patients, 19 care partners, and 26 clinicians. Only seven of 26 (27%) clinicians routinely discussed ACP. About half of the patients had documented ACP, mostly outside the health care system. We found divergent ACP definitions and perspectives; kidney clinicians largely defined ACP as completion of formal documentation, whereas patients viewed it more holistically, wanting discussions about goals, prognosis, and disease trajectory. Clinicians avoided ACP with patients from minority groups, perceiving cultural or religious barriers. Four themes and subthemes informing variation in decisions to discuss ACP and approaches emerged: (1) role ambiguity and responsibility for ACP, (2) questioning the value of ACP, (3) confronting institutional barriers (time, training, reimbursement, and the electronic medical record, EMR), and (4) consequences of avoiding ACP (disparities in ACP access and overconfidence that patients' wishes are known). CONCLUSIONS: Patients, care partners, and clinicians hold discordant views about the responsibility for discussing ACP and the scope for it. This presents critical barriers to the process, leaving ACP insufficiently discussed with older adults with advanced CKD.

Using brain functional magnetic resonance imaging to evaluate the effectiveness of acupuncture combined with mirror therapy on upper limb function in patients with cerebral ischemic stroke: a study protocol for a randomized, controlled trial.

BACKGROUND: Upper limb and hand motor dysfunction is one of the challenges in rehabilitation after cerebral ischemic stroke (CIS), and the clinical efficacy of rehabilitation needs to be improved. This study aims to combine Jin's three-needle acupuncture (JTN) therapy with mirror therapy (MT) for hemiplegia after CIS, objectively evaluate the clinical effects and safety of JTN to treat upper limb dysfunction, and use functional magnetic resonance imaging (fMRI) of the brain to investigate the central mechanisms of the effects, which would provide a powerful evidence-based medical basis for further supporting the application of JTN combined with MT. METHODS/DESIGN: This trial will be a single-blind, randomized controlled study. Patients who meet the study criteria will be recruited and randomly assigned to either the combined treatment group (JTN+MT) or the JTN group. Both interventions will be conducted for 6 days per week and last for 4 weeks. The primary outcome will be the effective rate based on the Fugl-Meyer Assessment for Upper Extremity (FMA-UE). Other outcome measures will include scores on the motor assessment scale (MAS), action research arm test (ARAT), activities of daily living (ADL) scale, and fMRI analyses. For safety evaluation, adverse events will be observed and recorded. DISCUSSION: This study may help to identify the efficacy and safety of acupuncture combined with MT for upper limb dysfunction after CIS and explore the central mechanisms with brain fMRI. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-IOR-17012174 . Registered on 5 April 2017.

Interventions to Prevent Perinatal Depression: US Preventive Services Task Force Recommendation Statement.

Importance: Perinatal depression, which is the occurrence of a depressive disorder during pregnancy or following childbirth, affects as many as 1 in 7 women and is one of the most common complications of pregnancy and the postpartum period. It is well established that perinatal depression can result in adverse short- and long-term effects on both the woman and child. Objective: To issue a new US Preventive Services Task Force (USPSTF) recommendation on interventions to prevent perinatal depression. Evidence Review: The USPSTF reviewed the evidence on the benefits and harms of preventive interventions for perinatal depression in pregnant or postpartum women or their children. The USPSTF reviewed contextual information on the accuracy of tools used to identify women at increased risk of perinatal depression and the most effective timing for preventive interventions. Interventions reviewed included counseling, health system interventions, physical activity, education, supportive interventions, and other behavioral interventions, such as infant sleep training and expressive writing. Pharmacological approaches included the use of nortriptyline, sertraline, and omega-3 fatty acids. Findings: The USPSTF found convincing evidence that counseling interventions, such as cognitive behavioral therapy and interpersonal therapy, are effective in preventing perinatal depression. Women with a history of depression, current depressive symptoms, or certain socioeconomic risk factors (eg, low income or young or single parenthood) would benefit from counseling interventions and could be considered at increased risk. The USPSTF found adequate evidence to bound the potential harms of counseling interventions as no greater than small, based on the nature of the intervention and the low likelihood of serious harms. The USPSTF found inadequate evidence to assess the benefits and harms of other noncounseling interventions. The USPSTF concludes with moderate certainty that providing or referring pregnant or postpartum women at increased risk to counseling interventions has a moderate net benefit in preventing perinatal depression. Conclusions and Recommendation: The USPSTF recommends that clinicians provide or refer pregnant and postpartum persons who are at increased risk of perinatal depression to counseling interventions. (B recommendation).

Cerebral Responses to Acupuncture at GV24 and Bilateral GB13 in Rat Models of Alzheimer's Disease.

Acupuncture has been widely used in China to treat neurological diseases including Alzheimer's disease (AD). However, its mechanism remains unclear. In the present study, eighty healthy Wistar rats were divided into a normal control group (n = 15) and premodel group (n = 65). Forty-five rats that met the criteria for the AD model were then randomly divided into the model group (MG), the nonacupoint group (NG), and the acupoint group (AG). All rats received positron emission tomography (PET) scanning, and the images were analyzed with Statistical Parametric Mapping 8.0. MG exhibited hypometabolism in the olfactory bulb, insular cortex, orbital cortex, prelimbic cortex, striatum, parietal association cortex, visual cortex, cingulate gyrus, and retrosplenial cortex. AG exhibited prominent and extensive hypermetabolism in the thalamus, hypothalamus, bed nucleus of the stria terminalis, cerebral peduncle, midbrain tegmentum, and pontine tegmentum compared to NG. These results demonstrated that acupuncturing at GV24 and bilateral GB13 acupoints may improve the learning and memory abilities of the AD rats, probably via altering cerebral glucose metabolism (CGM) in the hypothalamus, thalamus, and brain stem. The observed effects of acupuncture may be caused by regulating the distribution of certain kinds of neurotransmitters and enhancing synaptic plasticity.

Dexamethasone exacerbates cytotoxic chemotherapy induced lethargy and weight loss in female tumor free mice.

Cytotoxic chemotherapy can induce a systemic inflammatory response which has been proposed to be an underlying mechanism of cancer treatment related fatigue. Dexamethasone, a synthetic glucocorticoid that has potent anti-inflammatory effects, is incorporated into chemotherapy regimens to prevent chemotherapy-induced nausea and vomiting (CINV). The purpose of this study was to determine whether by suppressing cytotoxic chemotherapy-induced inflammation, dexamethasone could ameliorate chemotherapy induced fatigue/lethargy in tumor free mice. The effect of dexamethasone (DEX) on Cytoxan-Adriamycin (CA)-induced inflammation was assessed by measuring circulating levels of IL-1ß, TNF-α, IL-6, GCSF, KC, and MCP-1 twenty-four-hours post CA injection. Decline in voluntary wheel running activity (VWRA) from baseline (used as a proxy for fatigue/lethargy), body weight and composition, and food intake were monitored in mice administered four cycles of CA every two weeks with or without DEX. CA increased circulating levels of IL-6, GCSF, KC, and MCP-1 and caused a rapid decline in VWRA and body weight immediately following CA-injection. Although the acute CA-induced decline in VWRA and body weight was not evident in mice administered CA + DEX, DEX alone had a suppressive effect on VWRA, and body weight continued to decline in mice administered both CA and DEX while it returned to baseline in CA-treated mice. CA or DEX alone had no long term impact on VWRA but DEX exacerbated lethargy and weight loss in CA-treated mice. Despite dampening the systemic inflammatory response to chemotherapy, dexamethasone failed to ameliorate acute or long term chemotherapy related fatigue/lethargy. Our pre-clinical findings suggest that supportive therapies like dexamethasone used to acutely control nausea and vomiting in cancer patients may actually contribute to overall symptom burden in cancer patients.

Effects of Tai Chi versus Physical Therapy on Mindfulness in Knee Osteoarthritis.

Tai Chi mind-body exercise is widely believed to improve mindfulness through incorporating meditative states into physical movements. A growing number of studies indicate that Tai Chi may improve health in knee osteoarthritis (OA), a chronic pain disease and a primary cause of global disability. However, little is known about the contribution of mindfulness to treatment effect of Tai Chi practice. Therefore, our purpose was to investigate the effect of Tai Chi mind-body practice compared to physical therapy (PT) on mindfulness in knee OA. Adults with radiographic-confirmed, symptomatic knee OA were randomized to either 12 weeks (twice weekly) of Tai Chi or PT. Participants completed the Five Facet Mindfulness Questionnaire (FFMQ) before and after intervention along with commonly-used patient-reported outcomes for pain, physical function, and other health-related outcomes. Among 86 participants (74% female, 48% white, mean age 60 years, 85% at least college educated), mean total FFMQ was 142±17. Despite substantial improvements in pain, function, and other health-related outcomes, each treatment group's total FFMQ did not significantly change from baseline (Tai Chi= 0.76, 95% CI: -2.93, 4.45; PT= 1.80, 95% CI: -2.33, 5.93). The difference in total FFMQ between Tai Chi and PT was not significant (-1.04 points, 95% CI: -6.48, 4.39). Mindfulness did not change after Tai Chi or PT intervention in knee OA, which suggests that Tai Chi may not improve health in knee OA through cultivating mindfulness. Further study is needed to identify underlying mechanisms of effective mind-body interventions among people with knee OA.

Mindfulness Is Associated With Treatment Response From Nonpharmacologic Exercise Interventions in Knee Osteoarthritis.

OBJECTIVE: To examine the association between baseline mindfulness and response from exercise interventions in knee osteoarthritis (OA). DESIGN: Cohort study; responder analysis of a clinical trial subset. SETTING: Urban tertiary care academic hospital. PARTICIPANTS: Participants with symptomatic, radiographic knee OA (N=86; mean age, 60y; 74% female; 48% white). INTERVENTIONS: Twelve weeks (twice per week) of Tai Chi or physical therapy exercise. MAIN OUTCOME MEASURES: Treatment response was defined using Osteoarthritis Research Society International criteria indicating meaningful improvements in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, WOMAC function, or Patient Global Assessment scores. At baseline, participants completed the Five Facet Mindfulness Questionnaire (mean total score, 142±17) and were grouped into 3 categories of total mindfulness: higher, medium, or lower. Relative risk (RR) ratios were used to compare treatment response across groups. RESULTS: Participants with higher total mindfulness were 38% (95% confidence interval [CI], 1.05-1.83) more likely to meet responder criteria than those with lower mindfulness. We found no significant difference between medium and lower mindfulness groups (RR=1.0; 95% CI, 0.69-1.44). Among the 5 mindfulness facets, medium acting-with-awareness was 46% (95% CI, 1.09-1.96) more likely to respond than lower acting-with-awareness, and higher acting-with-awareness was 34% more likely to respond, but this did not reach significance (95% CI, 0.97-1.86). CONCLUSIONS: In this study, higher mindfulness, primarily driven by its acting-with-awareness facet, was significantly associated with a greater likelihood of response to nonpharmacologic exercise interventions in knee OA. This suggests that mindfulness-cultivating interventions may increase the likelihood of response from exercise.

Comparative Effectiveness of Tai Chi Versus Physical Therapy for Knee Osteoarthritis: A Randomized Trial.

BACKGROUND: Few remedies effectively treat long-term pain and disability from knee osteoarthritis. Studies suggest that Tai Chi alleviates symptoms, but no trials have directly compared Tai Chi with standard therapies for osteoarthritis. OBJECTIVE: To compare Tai Chi with standard physical therapy for patients with knee osteoarthritis. DESIGN: Randomized, 52-week, single-blind comparative effectiveness trial. (ClinicalTrials.gov: NCT01258985). SETTING: An urban tertiary care academic hospital. PATIENTS: 204 participants with symptomatic knee osteoarthritis (mean age, 60 years; 70% women; 53% white). INTERVENTION: Tai Chi (2 times per week for 12 weeks) or standard physical therapy (2 times per week for 6 weeks, followed by 6 weeks of monitored home exercise). MEASUREMENTS: The primary outcome was Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at 12 weeks. Secondary outcomes included physical function, depression, medication use, and quality of life. RESULTS: At 12 weeks, the WOMAC score was substantially reduced in both groups (Tai Chi, 167 points [95% CI, 145 to 190 points]; physical therapy, 143 points [CI, 119 to 167 points]). The between-group difference was not significant (24 points [CI, -10 to 58 points]). Both groups also showed similar clinically significant improvement in most secondary outcomes, and the benefits were maintained up to 52 weeks. Of note, the Tai Chi group had significantly greater improvements in depression and the physical component of quality of life. The benefit of Tai Chi was consistent across instructors. No serious adverse events occurred. LIMITATION: Patients were aware of their treatment group assignment, and the generalizability of the findings to other settings remains undetermined. CONCLUSION: Tai Chi produced beneficial effects similar to those of a standard course of physical therapy in the treatment of knee osteoarthritis. PRIMARY FUNDING SOURCE: National Center for Complementary and Integrative Health of the National Institutes of Health.

Technology for Innovation in Radiation Oncology.

Radiation therapy is an effective, personalized cancer treatment that has benefited from technological advances associated with the growing ability to identify and target tumors with accuracy and precision. Given that these advances have played a central role in the success of radiation therapy as a major component of comprehensive cancer care, the American Society for Radiation Oncology (ASTRO), the American Association of Physicists in Medicine (AAPM), and the National Cancer Institute (NCI) sponsored a workshop entitled "Technology for Innovation in Radiation Oncology," which took place at the National Institutes of Health (NIH) in Bethesda, Maryland, on June 13 and 14, 2013. The purpose of this workshop was to discuss emerging technology for the field and to recognize areas for greater research investment. Expert clinicians and scientists discussed innovative technology in radiation oncology, in particular as to how these technologies are being developed and translated to clinical practice in the face of current and future challenges and opportunities. Technologies encompassed topics in functional imaging, treatment devices, nanotechnology, and information technology. The technical, quality, and safety performance of these technologies were also considered. A major theme of the workshop was the growing importance of innovation in the domain of process automation and oncology informatics. The technologically advanced nature of radiation therapy treatments predisposes radiation oncology research teams to take on informatics research initiatives. In addition, the discussion on technology development was balanced with a parallel conversation regarding the need for evidence of efficacy and effectiveness. The linkage between the need for evidence and the efforts in informatics research was clearly identified as synergistic.

Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis.

BACKGROUND: The relative efficacy of available treatments of knee osteoarthritis (OA) must be determined for rational treatment algorithms to be formulated. PURPOSE: To examine the efficacy of treatments of primary knee OA using a network meta-analysis design, which estimates relative effects of all treatments against each other. DATA SOURCES: MEDLINE, EMBASE, Web of Science, Google Scholar, Cochrane Central Register of Controlled Trials from inception through 15 August 2014, and unpublished data. STUDY SELECTION: Randomized trials of adults with knee OA comparing 2 or more of the following: acetaminophen, diclofenac, ibuprofen, naproxen, celecoxib, intra-articular (IA) corticosteroids, IA hyaluronic acid, oral placebo, and IA placebo. DATA EXTRACTION: Two reviewers independently abstracted study data and assessed study quality. Standardized mean differences were calculated for pain, function, and stiffness at 3-month follow-up. DATA SYNTHESIS: Network meta-analysis was performed using a Bayesian random-effects model; 137 studies comprising 33,243 participants were identified. For pain, all interventions significantly outperformed oral placebo, with effect sizes from 0.63 (95% credible interval [CrI], 0.39 to 0.88) for the most efficacious treatment (hyaluronic acid) to 0.18 (CrI, 0.04 to 0.33) for the least efficacious treatment (acetaminophen). For function, all interventions except IA corticosteroids were significantly superior to oral placebo. For stiffness, most of the treatments did not significantly differ from one another. LIMITATION: Lack of long-term data, inadequate reporting of safety data, possible publication bias, and few head-to-head comparisons. CONCLUSION: This method allowed comparison of common treatments of knee OA according to their relative efficacy. Intra-articular treatments were superior to nonsteroidal anti-inflammatory drugs, possibly because of the integrated IA placebo effect. Small but robust differences were observed between active treatments. All treatments except acetaminophen showed clinically significant improvement from baseline pain. This information, along with the safety profiles and relative costs of included treatments, will be helpful for individualized patient care decisions. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Assessing the comparative effectiveness of Tai Chi versus physical therapy for knee osteoarthritis: design and rationale for a randomized trial.

BACKGROUND: Knee osteoarthritis (OA) causes pain and long-term disability with annual healthcare costs exceeding $185 billion in the United States. Few medical remedies effectively influence the course of the disease. Finding effective treatments to maintain function and quality of life in patients with knee OA is one of the national priorities identified by the Institute of Medicine. We are currently conducting the first comparative effectiveness and cost-effectiveness randomized trial of Tai Chi versus a physical-therapy regimen in a sample of patients with symptomatic and radiographically confirmed knee OA. This article describes the design and conduct of this trial. METHODS/DESIGN: A single-center, 52-week, comparative effectiveness randomized controlled trial of Tai Chi versus a standardized physical-therapy regimen is being conducted at an urban tertiary medical center in Boston, Massachusetts. The study population consists of adults ≥ 40 years of age with symptomatic and radiographic knee OA (American College of Rheumatology criteria). Participants are randomly allocated to either 12 weeks of Tai Chi (2x/week) or Physical Therapy (2x/week for 6 weeks, followed by 6 weeks of rigorously monitored home exercise). The primary outcome measure is pain (Western Ontario and McMaster Universities WOMAC) subscale at 12 weeks. Secondary outcomes include WOMAC stkiffness and function domain scores, lower extremity strength and power, functional balance, physical performance tests, psychological and psychosocial functioning, durability effects, health related quality of life, and healthcare utilization at 12, 24 and 52 weeks. DISCUSSION: This study will be the first randomized comparative-effectiveness and cost-effectiveness trial of Tai Chi versus Physical Therapy in a large symptomatic knee OA population with long-term follow up. We present here a robust and well-designed randomized comparative-effectiveness trial that also explores multiple outcomes to elucidate the potential mechanisms of mind-body effect for a major disabling disease with substantial health burdens and economic costs. Results of this study are expected to have important public health implications for the large and growing population with knee OA. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01258985.

Unresectable hepatocellular carcinoma: randomized controlled trial of transarterial ethanol ablation versus transcatheter arterial chemoembolization.

PURPOSE: To compare effectiveness of transarterial ethanol ablation (TEA) and transcatheter arterial chemoembolization (TACE) for unresectable hepatocellular carcinoma and determine whether TEA leads to better overall survival and tumor response than TACE. MATERIALS AND METHODS: In this institutional review board-approved preregistered randomized controlled trial (n = 200), informed consent was obtained. Primary outcome was overall survival; secondary outcomes were time to progression (TTP), progression-free survival (PFS), tumor response at computed tomography, and treatment-related toxicity. Eligible patients were randomized at a 1:1 ratio. Treatment included transcatheter delivery of ethiodized oil-ethanol mixture (2:1 ratio by volume up to 60 mL) for TEA and cisplatin-ethiodized oil emulsion (0.5 mg cisplatin per milliliter up to 30 mg), followed by 1-mm gelatin-sponge pellets, for TACE. Study was terminated after interim analysis (n = 98); 90 patients were available for analysis. Overall survival, TTP, and PFS were analyzed with Kaplan-Meier method; differences were compared with log-rank test. RESULTS: Study was terminated prematurely after interim analysis, which showed no difference in overall survival; this was unlikely to change with further patient accrual. Median overall survival in TEA and TACE was 24.3 months (95% confidence interval [CI]: 12.8, 32.7) and 20.1 months (95% CI: 9.3, 31.2), respectively (P = .358). Median TTP and PFS for intralesional progression were longer with TEA than TACE (TTP, 34.6 months [95% CI: 28.2, 41] vs 26.05 months [95% CI: 18.7, 33.3]; PFS, 14.8 months [95% CI: 10.2, 19.5] vs 9.3 months [95% CI: 7.1, 11.5]) (P = .028 and 0.029, respectively). Complete response rate on a tumor basis was persistently and significantly higher with TEA at 3 months (62 of 88 [70%] vs 39 of 76 [51%], P = .012), 6 months (64 of 88 [73%] vs 41 of 76 [54%], P = .012), and 12 months (66 of 88 [75%] vs 45 of 76 [59%], P = .031). CONCLUSION: Although there was no significant difference in overall survival, TEA demonstrated better complete tumor response, longer time to intralesional progression, and longer PFS.

Functional interrogation of adult hypothalamic neurogenesis with focal radiological inhibition.

The functional characterization of adult-born neurons remains a significant challenge. Approaches to inhibit adult neurogenesis via invasive viral delivery or transgenic animals have potential confounds that make interpretation of results from these studies difficult. New radiological tools are emerging, however, that allow one to noninvasively investigate the function of select groups of adult-born neurons through accurate and precise anatomical targeting in small animals. Focal ionizing radiation inhibits the birth and differentiation of new neurons, and allows targeting of specific neural progenitor regions. In order to illuminate the potential functional role that adult hypothalamic neurogenesis plays in the regulation of physiological processes, we developed a noninvasive focal irradiation technique to selectively inhibit the birth of adult-born neurons in the hypothalamic median eminence. We describe a method for Computer tomography-guided focal irradiation (CFIR) delivery to enable precise and accurate anatomical targeting in small animals. CFIR uses three-dimensional volumetric image guidance for localization and targeting of the radiation dose, minimizes radiation exposure to nontargeted brain regions, and allows for conformal dose distribution with sharp beam boundaries. This protocol allows one to ask questions regarding the function of adult-born neurons, but also opens areas to questions in areas of radiobiology, tumor biology, and immunology. These radiological tools will facilitate the translation of discoveries at the bench to the bedside.

Concurrent versus sequential sorafenib therapy in combination with radiation for hepatocellular carcinoma.

Sorafenib (SOR) is the only systemic agent known to improve survival for hepatocellular carcinoma (HCC). However, SOR prolongs survival by less than 3 months and does not alter symptomatic progression. To improve outcomes, several phase I-II trials are currently examining SOR with radiation (RT) for HCC utilizing heterogeneous concurrent and sequential treatment regimens. Our study provides preclinical data characterizing the effects of concurrent versus sequential RT-SOR on HCC cells both in vitro and in vivo. Concurrent and sequential RT-SOR regimens were tested for efficacy among 4 HCC cell lines in vitro by assessment of clonogenic survival, apoptosis, cell cycle distribution, and γ-H2AX foci formation. Results were confirmed in vivo by evaluating tumor growth delay and performing immunofluorescence staining in a hind-flank xenograft model. In vitro, concurrent RT-SOR produced radioprotection in 3 of 4 cell lines, whereas sequential RT-SOR produced decreased colony formation among all 4. Sequential RT-SOR increased apoptosis compared to RT alone, while concurrent RT-SOR did not. Sorafenib induced reassortment into less radiosensitive phases of the cell cycle through G1-S delay and cell cycle slowing. More double-strand breaks (DSBs) persisted 24 h post-irradiation for RT alone versus concurrent RT-SOR. In vivo, sequential RT-SOR produced the greatest tumor growth delay, while concurrent RT-SOR was similar to RT alone. More persistent DSBs were observed in xenografts treated with sequential RT-SOR or RT alone versus concurrent RT-SOR. Sequential RT-SOR additionally produced a greater reduction in xenograft tumor vascularity and mitotic index than either concurrent RT-SOR or RT alone. In conclusion, sequential RT-SOR demonstrates greater efficacy against HCC than concurrent RT-SOR both in vitro and in vivo. These results may have implications for clinical decision-making and prospective trial design.