Thromboxane biosynthesis and future events in diabetes: the ASCEND trial.

BACKGROUND AND AIMS: Thromboxane (TX) A2, released by activated platelets, plays an important role in atherothrombosis. Urinary 11-dehydro-TXB2 (U-TXM), a stable metabolite reflecting the whole-body TXA2 biosynthesis, is reduced by ∼70% by daily low-dose aspirin. The U-TXM represents a non-invasive biomarker of in vivo platelet activation and is enhanced in patients with diabetes. This study assessed whether U-TXM is associated with the risk of future serious vascular events or revascularizations (SVE-R), major bleeding, or cancer in patients with diabetes. METHODS: The U-TXM was measured pre-randomization to aspirin or placebo in 5948 people with type 1 or 2 diabetes and no cardiovascular disease, in the ASCEND trial. Associations between log U-TXM and SVE-R (n = 618), major bleed (n = 206), and cancer (n = 700) during 6.6 years of follow-up were investigated by Cox regression; comparisons of these associations with the effects of randomization to aspirin were made. RESULTS: Higher U-TXM was associated with older age, female sex, current smoking, type 2 diabetes, higher body size, urinary albumin/creatinine ratio of ≥3 mg/mmol, and higher estimated glomerular filtration rate. After adjustment for these, U-TXM was marginally statistically significantly associated with SVE-R and major bleed but not cancer [hazard ratios per 1 SD higher log U-TXM (95% confidence interval): 1.09 (1.00-1.18), 1.16 (1.01-1.34), and 1.06 (0.98-1.14)]. The hazard ratio was similar to that implied by the clinical effects of randomization to aspirin for SVE-R but not for major bleed. CONCLUSIONS: The U-TXM was log-linearly independently associated with SVE-R in diabetes. This is consistent with the involvement of platelet TXA2 in diabetic atherothrombosis.

Immune-related microRNAs in breast milk and their relation to regulatory T cells in breastfed children.

BACKGROUND: The immunomodulatory capacity of breast milk may partially be mediated by microRNAs (miRNA), small RNA molecules that regulate gene expression on a post-transcriptional level and are hypothesized to be involved in modulation of immunological pathways. Here, we evaluate the expression of immune-related miRNAs in breast milk after pre- and postnatal supplementation with Limosilactobacillus reuteri and omega-3 (ω-3) polyunsaturated fatty acids (PUFAs), and the association to infant regulatory T cell (Treg) frequencies. METHODS: One-hundred and twenty women included in a double-blind, randomized, placebo-controlled allergy intervention trial received L. reuteri and/or ω-3 PUFAs daily from gestational week 20. Using Taqman qPCR, 24 miRNAs were analyzed from breast milk obtained at birth (colostrum) and after 3 months (mature milk) of lactation. The proportion of activated and resting Treg cells were analyzed in infant blood using flow cytometry at 6, 12, and 24 months. RESULTS: Relative expression changed significantly over the lactation period for most of the miRNAs; however, the expression was not significantly influenced by any of the supplements. Colostrum miR-181a-3p correlated with resting Treg cell frequencies at 6 months. Colostrum miR-148a-3p and let-7d-3p correlated with the frequencies of activated Treg cells at 24 months, as did mature milk miR-181a-3p and miR-181c-3p. CONCLUSION: Maternal supplementation with L. reuteri and ω-3 PUFAs did not significantly affect the relative miRNA expression in breast milk. Interestingly, some of the miRNAs correlate with Treg subpopulations in the breastfed children, supporting the hypothesis that breast milk miRNAs could be important in infant immune regulation. TRIAL REGISTRATION: ClinicalTrials.gov-ID: NCT01542970.

Feasibility and Safety of High-Definition Infraslow Pink Noise Stimulation for Treating Chronic Tinnitus-A Randomized Placebo-Controlled Trial.

INTRODUCTION: Tinnitus has been linked to activity and connectivity changes in the auditory cortex (AC), parahippocampus (PHC), and posterior cingulate cortex (PCC). Although previous studies have targeted these areas individually, no study has yet modulated them simultaneously. Furthermore, novel stimulation designs may be superior to traditional alternating or direct current stimulation. This pilot study investigated the feasibility and safety of a novel brain stimulation technique (high-definition transcranial infraslow pink noise stimulation [HD-tIPNS]) for treating chronic tinnitus targeting the AC, PHC, and PCC. MATERIALS AND METHODS: A pilot, double-blind, randomized two-arm placebo-controlled parallel trial was conducted, with clinical outcomes collected at baseline, three days, and ten days after treatment. Participants with chronic tinnitus (n = 20) received 12 sessions (three per week for four weeks) of either HD-tIPNS or acti-sham stimulation. Primary outcomes included feasibility, safety, and resting-state electroencephalography (rsEEG) measures, and secondary outcomes included tinnitus and quality of life questionnaires. Feasibility, safety, and secondary measures were assessed using descriptive statistics. rsEEG was analyzed using standard low-resolution electromagnetic brain tomography. RESULTS: No long-term adverse events were reported. Mild side effects included headache and dizziness, indicating the safety of this stimulation. Participants were rapidly recruited and adhered to the study protocol with minimal difficulty. Drop-out rate was 13%, and the treatment approach was acceptable to participants, supporting the feasibility of the protocol. Tinnitus measures were similar between HD-tIPNS and acti-sham stimulation. rsEEG analyses revealed decreased beta-1 activity in PCC ten days after treatment for acti-sham. The HD-tIPNS group showed decreased beta-1 activity in inferior parietal lobule three days after treatment. Increased functional connectivity in the beta-1 frequency between left and right PHC was found in the HD-tIPNS group compared with the acti-sham group, three days after treatment. CONCLUSIONS: In conclusion, the novel approach is safe and feasible and revealed EEG changes unsupported by clinical benefit. Further research is essential to evaluate the potential of this multifocal network stimulation approach. CLINICAL TRIAL REGISTRATION: This study was registered with the Australia New Zealand Clinical Trial Registry (Registry number: ACTRN12621000151831; Universal Trial Number: U1111-1261-6945).

High-Definition Transcranial Infraslow Pink-Noise Stimulation Can Influence Functional and Effective Cortical Connectivity in Individuals With Chronic Low Back Pain: A Pilot Randomized Placebo-Controlled Study.

INTRODUCTION: Pain can be regarded as an emergent property of multiple interacting, dynamically changing brain networks and thus needs a targeted treatment approach. A novel high-definition transcranial infraslow pink-noise stimulation (HD-tIPNS) technique was developed to modulate the key hubs of the three main nociceptive pathways simultaneously, ie, the pregenual anterior cingulate cortex (pgACC) (descending inhibitory pathway), the dorsal anterior cingulate cortex (dACC) (medial nociceptive pathway), and both somatosensory cortices (S1) (lateral nociceptive pathway). This study aimed to evaluate safety and verify whether a single session of HD-tIPNS may disrupt functional and effective connectivity between targeted cortical regions. MATERIALS AND METHODS: A pilot double-blind randomized two-arm placebo-controlled parallel trial was conducted. Participants (N = 30) with chronic low back pain were equally randomized to receive a single session of either sham stimulation or HD-tIPNS (targeting the pgACC, dACC, and bilateral S1). Primary outcomes included safety and electroencephalographic measures, and secondary outcomes included pain measures, collected after treatment. A Mann-Whitney U test was used to compare between-group differences in percentage changes with baseline for each outcome measures. A Wilcoxon signed-rank test was used to identify difference in effective connectivity measure before and after HD-tIPNS. RESULTS: No serious adverse events were reported. A significant decrease in instantaneous functional connectivity was noted between the pgACC and dACC (U = 47.0, Z = -2.72, p = 0.007) and the pgACC and left S1 (U = 41.0, Z = -2.97, p = 0.003) in the infraslow band after HD-tIPNS when compared with sham stimulation. A significant decrease in instantaneous effective connectivity was noted in the direction of the dACC to the pgACC (Z = -2.10, p = 0.035), in the infraslow band after HD-tIPNS when compared with baseline. No changes in clinical pain measures were detected. CONCLUSIONS: HD-tIPNS can safely modulate the functional and effective connectivity between targeted pain-related cortical hubs. Further studies are warranted to evaluate whether repeated exposures to HD-tIPNS can incur clinical benefits through inducing changes in functional and effective connectivity at targeted cortical regions. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is ACTRN12621001438842.

Acupuncture for Japanese Katakori (Chronic Neck Pain): A Randomized Placebo-Controlled Double-Blind Study.

Background and Objectives: Although acupuncture is listed as a beneficial treatment for neck/shoulder stiffness, which has increased with the spread of information technology, to date, evidence of its efficacy under double-blind conditions has not been shown. This study aimed to assess whether acupuncture treatment with superficial skin piercing is superior to placebo treatment. Materials and Methods: A randomized, double-blind (practitioner-patient) placebo-controlled trial was performed at a single center with four arms (ISRCTN76896018). Four hundred patients with essential neck/shoulder stiffness were randomly assigned to penetrating needle treatment (acupuncture ritual and skin penetration), skin-touch needle treatment (acupuncture ritual and skin touch), no-touch needle treatment (acupuncture ritual alone), and no-treatment control. Each of the six acupuncturists applied a needle to each of the four acupoints in the neck/shoulder of 50 patients. Results: Each of the three treatments significantly (p = 0.01) improved neck/shoulder stiffness compared with the no-treatment control immediately and 24 h after treatment. There was a significant improvement in penetrating needle treatment over no-touch needle treatment 24 h later. However, there was no significant difference between the penetrating and skin-touch and skin-touch vs. no-touch. Conclusions: All treatments that received the ritual of acupuncture were better than the no-treatment control. Only genuine acupuncture involves the specific effects of needle insertion into the body. The acupuncture ritual had a significant impact on the subjective improvement of neck/shoulder stiffness; however, improvement with ritual alone versions of placebo acupuncture was not maintained as with superficial skin piercing. Our study provides important evidence of acupuncture efficacy and information regarding inert no-touch placebo control in acupuncture research.

Benefit of a flash dose of corticosteroids in digestive surgical oncology: a multicenter, randomized, double blind, placebo-controlled trial (CORTIFRENCH).

BACKGROUND: The modulation of perioperative inflammation seems crucial to improve postoperative morbidity and cancer-related outcomes in patients undergoing oncological surgery. Data from the literature suggest that perioperative corticosteroids decrease inflammatory markers and might be associated with fewer complications in esophageal, liver, pancreatic and colorectal surgery. Their benefit on cancer-related outcomes has not been assessed. METHODS: The CORTIFRENCH trial is a phase III multicenter randomized double-blind placebo-controlled trial to assess the impact of a flash dose of preoperative corticosteroids versus placebo on postoperative morbidity and cancer-related outcomes after elective curative-intent surgery for digestive cancer. The primary endpoint is the frequency of patients with postoperative major complications occurring within 30 days after surgery (defined as all complications with Clavien-Dindo grade > 2). The secondary endpoints are the overall survival at 3 years, the disease-free survival at 3 years, the frequency of patients with intraabdominal infections and postoperative infections within 30 days after surgery and the hospital length of stay. We hypothesize a reduced risk of major complications and a better disease-survival at 3 years in the experimental group. Allowing for 5% of drop-out, 1 200 patients (600 per arm) should be included. DISCUSSION: This will be the first trial focusing on the impact of perioperative corticosteroids on cancer related outcomes. If significant, it might be a strong improvement on oncological outcomes for patients undergoing surgery for digestive cancers. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03875690, Registered on March 15, 2019, URL: https://clinicaltrials.gov/ct2/show/NCT03875690 .

The Biota orientalis, oil extract Epiitalis®, is efficacious at reducing the symptoms of knee osteoarthritis: a pilot, multi-site, dose-ranging, randomized, blinded, placebo-controlled trial.

OBJECTIVE: To explore the safety, and efficacy of a proprietary hydrolyzed oil extract from seeds of Biota orientalis (hBO/Epiitalis®, Interpath Pty Ltd) in patients with knee pain due to osteoarthritis (OA). METHODS: Patients aged 40-65 with X-ray diagnosed knee OA and knee pain ≥ 60 on a 100-point VAS (visual analog scale) were enrolled and randomized into four groups to receive daily hBO for 56 days as high (hBO-HD, 640 mg), mid (hBO-MD, 320 mg) or low (hBO-LD, 160 mg) doses, or a matched placebo oil. The primary outcome was change in VAS knee pain from baseline to 56 days in the mITT (modified intention to treat) population. Exploratory outcomes were the mWOMAC (modified Western Ontario and McMaster Universities Arthritis Index), and the SF-36 QoL (quality of life) questionnaire. The OMERACT-OARSI (Outcome Measures in Arthritis Clinical Trials-Osteoarthritis Research Society International) responder index was also calculated. RESULTS: 223 patients were included in the mITT population. Reductions in VAS scores between baseline and day 56 [Least square mean (LS mean) and 95% confidence interval (CI) of LS mean] were 36.4 (31.7-41.0), 37.9 (33.2-42.7), 35.7 (31.2-40.1) and 9.8 (14.5-15.2) for the hBO-HD, hBO-MD, hBO-LD, and placebo groups respectively. The VAS changes in all hBO groups were significantly different (p < 0.0001) vs. changes in the placebo group. hBO treatment led to similar quantitative beneficial changes in mWOMAC, SF-36 and OMERACT-OARSI responder index. There were no SAEs and no adverse events ascribed to the intervention. CONCLUSION: In a 56-day trial, hBO was safe, and was efficacious at reducing symptoms in patients with knee OA. REGISTRATION: NCT04117490; Oct 7, 2019.

Effect of Daily Intake of Green Tea Catechins on Cognitive Function in Middle-Aged and Older Subjects: A Randomized, Placebo-Controlled Study.

Epidemiological studies in Japan, including the Nakajima study and the Tsurugaya study, have indicated that green tea consumption may improve cognitive impairment. Catechins, which are typical polyphenols contained in green tea, have been reported to have antioxidative, anti-inflammatory, and neuroprotective effects. However, their impact on human cognitive function remains unclear. Therefore, we performed a double-blind, randomized, controlled study to investigate the effect of 336.4 mg of decaffeinated green tea catechins (GTC) on cognitive function after a single dose and after 12 weeks of daily intake. This study included Japanese adults between the ages of 50 and 69 years with a Mini-Mental State Examination Japanese version score of >24 and self-assessed cognitive decline. The Cognitrax testing battery was used to evaluate cognitive function. The incorrect response rate on the Continuous Performance Test significantly decreased after a single dose of GTC. After 12 weeks of daily GTC intake, the response time for Part 4 of the 4-part Continuous Performance Test, which is a two-back test, was shortened. These results suggest that daily intake of GTC might have beneficial effects on working memory.

Study protocol: mycophenolate mofetil as maintenance therapy after rituximab treatment for childhood-onset, complicated, frequently-relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicenter double-blind, randomized, placebo-controlled trial (JSKDC07).

BACKGROUND: Idiopathic nephrotic syndrome (INS) is the most common chronic glomerular disease in children. Approximately 80-90% of patients with childhood INS have steroid-sensitive nephrotic syndrome (SSNS), and can obtain remission with steroid therapy, while the remainder have steroid-resistant nephrotic syndrome (SRNS). Furthermore, approximately 50% of children with SSNS develop frequently-relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). Children with FRNS/SDNS are usually treated with immunosuppressive agents such as cyclosporine, cyclophosphamide, or mizoribine in Japan. However, 10-20% of children receiving immunosuppressive agents still show frequent relapse and/or steroid dependence during or after treatment, which is defined as complicated FRNS/SDNS. Furthermore, 30% of SRNS patients who obtain remission after additional treatments such as cyclosporine also turn out to be complicated FRNS/SDNS. For such complicated FRNS/SDNS patients, rituximab (RTX) is currently used; however, recurrence after RTX treatment also remains an open issue. Because long-term use of existing immunosuppressive drugs has limitations, development of a novel treatment for maintenance therapy after RTX is desirable. Mycophenolate mofetil (MMF) is an immunosuppressive drug with fewer side effects than cyclosporine or cyclophosphamide. Importantly, recent studies have reported the efficacy of MMF in children with nephrotic syndrome. METHODS: We conduct a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of MMF after RTX therapy in children with complicated FRNS/SDNS. Patients are allocated to either RTX plus MMF treatment group, or RTX plus placebo treatment group. For the former group, MMF is administered at a dose of 1000-1200 mg/m2/day (maximum 2 g/day) twice daily for 17 months after RTX treatment. The primary endpoint is time-to-treatment failure (development of frequent relapses, steroid dependence or steroid resistance). DISCUSSION: The results will provide important data on the use of MMF as maintenance therapy after RTX to prevent complicated FRNS/SDNS patients from declining into treatment failure. In future, MMF in conjunction with RTX treatment may permit increased duration of remission in 'complicated' FRNS/SDNS cases. TRIAL REGISTRATION: This trial was prospectively registered to UMIN Clinical Trials Registry on June 23, 2014 (UMIN Trial ID: UMIN000014347 ).

Intracoronary autologous bone marrow cell transfer after myocardial infarction: the BOOST-2 randomised placebo-controlled clinical trial.

AIMS: Intracoronary infusion of autologous nucleated bone marrow cells (BMCs) enhanced the recovery of left ventricular ejection fraction (LVEF) after ST-segment elevation myocardial infarction (STEMI) in the randomised-controlled, open-label BOOST trial. We reassessed the therapeutic potential of nucleated BMCs in the randomised placebo-controlled, double-blind BOOST-2 trial conducted in 10 centres in Germany and Norway. METHODS AND RESULTS: Using a multiple arm design, we investigated the dose-response relationship and explored whether γ-irradiation which eliminates the clonogenic potential of stem and progenitor cells has an impact on BMC efficacy. Between 9 March 2006 and 16 July 2013, 153 patients with large STEMI were randomly assigned to receive a single intracoronary infusion of placebo (control group), high-dose (hi)BMCs, low-dose (lo)BMCs, irradiated hiBMCs, or irradiated loBMCs 8.1 ± 2.6 days after percutaneous coronary intervention (PCI) in addition to guideline-recommended medical treatment. Change in LVEF from baseline (before cell infusion) to 6 months as determined by MRI was the primary endpoint. The trial is registered at Current Controlled Trials (ISRCTN17457407). Baseline LVEF was 45.0 ± 8.5% in the overall population. At 6 months, LVEF had increased by 3.3 percentage points in the control group and 4.3 percentage points in the hiBMC group. The estimated treatment effect was 1.0 percentage points (95% confidence interval, -2.6 to 4.7; P = 0.57). The treatment effect of loBMCs was 0.5 percentage points (-3.0 to 4.1; P = 0.76). Likewise, irradiated BMCs did not have significant treatment effects. BMC transfer was safe and not associated with adverse clinical events. CONCLUSION: The BOOST-2 trial does not support the use of nucleated BMCs in patients with STEMI and moderately reduced LVEF treated according to current standards of early PCI and drug therapy.

Home Use, Remotely Supervised, and Remotely Controlled Transcranial Direct Current Stimulation: A Systematic Review of the Available Evidence.

OBJECTIVES: Transcranial direct current stimulation (tDCS) is gaining growing importance in the treatment of neurological and psychiatric disorders and is currently investigated for home-based and remotely supervised applications. METHODS: Here, we systematically review the available evidence from a database search (PubMed, ICTRP, clinicaltrials.gov) from January 2000 to May 2017. RESULTS: We detected 22 original research papers, trial protocols or trial registrations dealing with tDCS as an add-on intervention to cognitive or physiotherapeutic intervention. Overall, study samples are small; many studies are single-blinded and focus on feasibility and safety. There are two guideline papers setting basic requirements for clinical trials. CONCLUSIONS: Further research needs to focus on home-based treatment from different viewpoints, that is, safety, technical monitoring, reproducibility of repeated applications, feasibility of combined interventions and systematic assessment of efficacy, and safety in large randomized controlled clinical trials (RCTs). However, remotely controlled and supervised tDCS for home use represents a promising approach for widespread use of noninvasive brain stimulation (NIBS) in clinical care.

Active and placebo transcranial magnetic stimulation effects on external and internal auditory hallucinations of schizophrenia.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) over the left temporo-parietal region has been proposed as a treatment for resistant auditory verbal hallucinations (AVH), but which patients are more likely to benefit from rTMS is still unclear. This study sought to assess the effects of rTMS on AVH, with a focus on hallucination phenomenology. METHOD: Twenty-seven patients with schizophrenia and medication-resistant AVH participated to a randomized, double-blind, placebo-controlled, add-on rTMS study. The stimulation targeted a language-perception area individually determined using functional magnetic resonance imaging and a language recognition task. AVH were assessed using the hallucination subscale of the Scale for the Assessment of Positive Symptoms (SAPS). The spatial location of AVH was assessed using the Psychotic Symptom Rating Scales. RESULTS: A significant improvement in SAPS hallucination subscale score was observed in both actively treated and placebo-treated groups with no difference between both modalities. Patients with external AVH were significantly more improved than patients with internal AVH, with both modalities. CONCLUSIONS: A marked placebo effect of rTMS was observed in patients with resistant AVH. Patients with prominent external AVH may be more likely to benefit from both active and placebo interventions. Cortical effects related to non-magnetic stimulation of the auditory cortex are suggested.

[Pharmacoeconomic analysis of using mirabegron to treat overactive bladder in the setting of the Russian Federation health care].

RELEVANCE: The present paper presents, for the first time in Russia, a comparative pharmacoeconomic analysis of using mirabegron (Betmiga) to treat overactive bladder (OAB). MATERIALS AND METHODS: Three medical technologies were evaluated: treatment of OAB with mirabegron 50 mg/day, solifenacin 5 mg/day and solifenacin 10 mg/day. In addition, the strategies of mirabegron and botulinum toxin type A were analyzed as a result of simulating the second-line treatment. RESULTS: When modeling for 1-year horizon, the lowest cost was found in mirabegron strategy, which was 16% lower than with solifenacin. When comparing the second line strategies using mirabegron and botulinum toxin type A, costs of mirabegron group were 61% lower. According to the selected performance criteria, mirabegron was more effective in comparison with other strategies. The findings of the budget impact analysis revealed that using mirabegron was preferable compared with solifenacin as the first line treatment, and compared with botulinum toxin type A as the second-line treatment. The analysis of cost-effectiveness and availability of technology showed growth when using mirabegron strategy; there was an increase in the efficiency of mirabegron strategy relative to solifenacin strategy, accompanied by cost reduction and, as a consequence, reducing the burden on the budget. CONCLUSIONS: Thus, using mirabegron to treat OAB both as the first and the second line treatment is absolutely cost-effective and profitable medical technology.

Coenzyme Q10 supplementation ameliorates inflammatory markers in patients with multiple sclerosis: a double blind, placebo, controlled randomized clinical trial.

OBJECTIVES: Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of central nervous system and recent studies show that inflammatory processes are highly associated with neurodegeneration in the brain. The purpose of this study was to investigate the effect of coenzyme Q10 supplementation on inflammatory and anti-inflammatory markers in patients with MS. METHODS: This randomized, double-blind, placebo-controlled clinical study was performed among 48 patients with relapsing-remitting MS. Subjects were randomly assigned to a placebo group (n = 24) or coenzyme Q10 (CoQ10)-supplemented group (500 mg/day, n = 24). The intervention was administered for 12 weeks. Peripheral blood samples were collected at baseline and after 12-week intervention, to measure inflammatory (tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and matrix metalloproteinase (MMP)-9) and anti-inflammatory (IL-4 and TGF-ß) markers. RESULTS: Forty-five patients completed the study. After 12 weeks of intervention, the TNF-α levels (P = 0.003) decreased significantly in the CoQ10 group. Subjects in the CoQ10 group had significantly lower IL-6 levels (P = 0.037), compared to the placebo group. CoQ10 supplementation also resulted in decreased serum levels of MMP-9 as compared to the placebo group (P = 0.011). However, CoQ10 supplementation did not alter the IL-4 and TGF-ß levels (P = 0.16 and P = 0.81, respectively). DISCUSSION: CoQ10 supplementation at a dosage of 500 mg appears to decrease the inflammatory markers (TNF-α, IL-6, and MMP-9) in patients with MS.

Reduction in radiation-induced lymphocytopenia by famotidine in patients undergoing radiotherapy for prostate cancer.

BACKGROUND: Ionizing radiation causes a series of hematological alterations especially profound lymphocytopenia during and after the radiotherapy course. To investigate whether famotidine can reduce hematologic toxicity in patients treated with radiotherapy for prostate cancer. METHODS: A total of 36 patients undergoing radiotherapy for prostate cancer were randomized to receive either placebo or famotidine tablets. Participants were pretreated with 40 mg of oral famotidine or placebo tablets twice daily, 4 and 3 hr before each radiotherapy fraction. The patients received external-beam radiotherapy up to 70 Gy. Complete blood counts with differential, platelet counts, and hemoglobin levels were obtained at baseline, biweekly during the treatment and once 4 weeks after the end of radiotherapy course. Magnitude of changes from baseline in the hematological parameters was determined and compared using Repeated Measures ANOVA. RESULTS: Famotidine was well tolerated. A total of 112 blood samples were evaluated. A significant reduction in radiation-induced lymphocytopenia was noted in patients receiving famotidine than in patients receiving placebo (P = 0.006). No significant difference was observed between two groups for the decline in platelets, erythrocytes and leucocytes. For both groups, neutrophil, monocyte, eosinophil, and hemoglobin levels did not change significantly during the treatment. CONCLUSIONS: Our results indicate that famotidine could result in a significant reduction in radiation-induced lymphocytopenia and may consequently increase radiotherapy efficacy as well as survival times. This radioprotective effect may be chiefly associated with its antioxidant and radical scavenging properties. Further studies are required to confirm these encouraging results.

Effect of Shi-Style Steaming and Bathing Decoction in Patients with Knee Osteoarthritis: Study Protocol for a Randomized Placebo-Controlled Trial.

Purpose: To prove more accurately that Chinese herbal bath therapy may be a safe, effective, simple alternative treatment modality for knee OA, we designed a randomized, double-blind, placebo-controlled trial to explore the effectiveness of SSBD for the relief of pain, daily activities, and quality of life in patients with knee OA. Patients and Methods: A single-center, 52-week, randomized controlled trial of SSBD versus placebo is being performed. A total of 200 patients with symptomatic knee OA will be randomly allocated to the SSBD treatment or placebo intervention group for 4 weeks. The two groups of patients are allowed to steam and bathe their knees once every other day, using one packet of SSBD each time, for 30 minutes, 3 times a week, for a total of 4 weeks. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale at 4 weeks is the primary outcome measure, and the secondary outcomes include WOMAC stiffness and function scores, the Lysholm knee scale score, quality of life, the Brief Pain Inventory score, the Patient's Global Impressions of Improvement Scale score and the Clinical Global Impressions of Severity scale score. The safety of the herbal medications will also be evaluated. Conclusion: We will discuss whether SSBD has greater advantages in terms of efficacy, safety, and patient overall perception than does placebo control in middle-aged and elderly patients with knee OA. The findings may provide new and valuable information about the efficacy and safety of Chinese herbal bath therapy in the treatment of knee osteoarthritis.

Effects of serial radon spa therapy on pain and peripheral immune status in patients suffering from musculoskeletal disorders- results from a prospective, randomized, placebo-controlled trial.

In this randomized, placebo-controlled cross-over trial we aimed to investigate if radon spa therapy exerts more pain relief than exposure to warm water alone. In addition, immunological parameters were assessed in both treatment groups. In the RAD-ON02 trial, 116 patients suffering from musculoskeletal disorders (MSDs) received either serial radon spa or solely warm water baths. Pain intensity was assessed by determination of different pain parameters on a visual analogue scale and by pressure point dolorimetry at baseline and at weeks 4, 12 and 24. The longitudinal immune status of the patients was analyzed by a flow cytometry-based assay from peripheral blood at the time points of pain assessments. There were no side effects attributable to radon exposure observed. However, radon spa was superior to warm water applications at week 4 in terms of pain reduction. Pain and morning stiffness at the time of assessment were significantly reduced after radon spa (p<0.001, p<0.01) but not after warm water baths. The dolorimetry resulted in a significantly higher exerted pressure strength in patients after radon spa (p<0.001), but not after warm water applications. During the long-term follow-up, both treatment modalities reduced pain to a similar degree and pain modulation was not distorted by the participants' intake of analgesics. No significant changes in the immune status attributable specifically to radon were found, even though the increase in regulatory T cell counts occurs earlier after radon baths than after sole warm water baths and a higher level of significance is reached after radon spa at week 24. Serial radon spa has additive pain-relieving effects. The immunological parameters assessed in our study appear not to be directly linked to the pain reduction caused by radon exposure, at least in MSD patients with predominantly degenerative diseases. Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search/search?query=rad-on02, identifier 2016-002085-31; https://drks.de/search/de/trial, identifier DRKS00016019.

A controlled trial of intravenous immunoglobulin in multifocal motor neuropathy.

Intravenous immunoglobulin (IVIG) has become the standard treatment for multifocal motor neuropathy (MMN) based on limited data. To critically assess the efficacy, safety, and tolerability of 10% liquid IVIG (IVIG), 44 adults with MMN were randomized 1 : 1 to either double-blind treatment of IVIG followed by placebo for 12 weeks each or the reverse. Open-label IVIG was administered for 12 weeks at the beginning and end of the study for clinical stabilization, and between double-blinded periods to prevent a carry-over effect. To avoid potential worsening, switching to open-label IVIG was permitted if deterioration occurred during blinded treatment. Mean maximal grip strength of the more affected hand declined 31.38% during placebo and increased 3.75% during IVIG (p = 0.005). In 35.7% of participants, Guy's Neurological Disability scores for upper limbs worsened during placebo and not during IVIG, whereas the converse was true in 11.9% (p = 0.021). Sixty-nine percent (69.0%) switched prematurely from placebo to open-label IVIG and 2.4% switched from blinded to open-label IVIG (p < 0.001). One serious adverse reaction (pulmonary embolism) and 100 non-serious reactions (69 mild, 20 moderate, and 11 severe) to IVIG occurred. IVIG was effective in improving disability and muscle strength, and was safe and well tolerated in adults with MMN.

Results of a double-blind, placebo-controlled pharmacotherapy trial in alcoholism conducted in Germany and comparison with the US COMBINE study.

The results of placebo-controlled trials (RCTs) with acamprosate or naltrexone vary substantially. Those differences have been attributed to differing patient characteristics, recruitment strategies, treatment settings and remuneration systems. We tested these assumptions by comparing a new double-blind, placebo-controlled randomized trial conducted in Germany (called PREDICT Study) with data from the US COMBINE Study. PREDICT was designed according to the protocol of the COMBINE Study. A total of 426 alcohol-dependent patients were compared to 459 COMBINE Study patients corresponding to the treatment cells in PREDICT. All patients received acamprosate, naltrexone or placebo for 3 months (PREDICT) or 4 months (COMBINE). Biweekly manualized 'medical management' to enhance compliance was delivered in both studies. Time until the first occurrence of heavy drinking was the main outcome measure. PREDICT found neither acamprosate nor naltrexone to supply any additional benefit compared with placebo, which is at variance with a positive naltrexone effect being reported in the COMBINE Study. A secondary comparison between both studies showed better overall treatment outcomes in PREDICT, although these patients had been more severely affected than their COMBINE counterparts. The divergence in results may be attributable to basic differences in the treatment environments (such as in-patient pre-treatment versus primary outpatient care). We suggest that identically designed RCTs conducted in different parts of the world may help improve the external validity of RCTs. This approach could be called 'comparative efficacy research'.

Effect of Biologic Therapies on Airway Hyperresponsiveness and Allergic Response: A Systematic Literature Review.

Background: Airway hyperresponsiveness (AHR) is a key feature of asthma. Biologic therapies used to treat asthma target specific components of the inflammatory pathway, and their effects on AHR can provide valuable information about the underlying disease pathophysiology. This review summarizes the available evidence regarding the effects of biologics on allergen-specific and non-allergen-specific airway responses in patients with asthma. Methods: We conducted a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, including risk-of-bias assessment. PubMed and Ovid were searched for studies published between January 1997 and December 2021. Eligible studies were randomized, placebo-controlled trials that assessed the effects of biologics on AHR, early allergic response (EAR) and/or late allergic response (LAR) in patients with asthma. Results: Thirty studies were identified for inclusion. Bronchoprovocation testing was allergen-specific in 18 studies and non-allergen-specific in 12 studies. Omalizumab reduced AHR to methacholine, acetylcholine or adenosine monophosphate (3/9 studies), and reduced EAR (4/5 studies) and LAR (2/3 studies). Mepolizumab had no effect on AHR (3/3 studies), EAR or LAR (1/1 study). Tezepelumab reduced AHR to methacholine or mannitol (3/3 studies), and reduced EAR and LAR (1/1 study). Pitrakinra reduced LAR, with no effect on AHR (1/1 study). Etanercept reduced AHR to methacholine (1/2 studies). No effects were observed for lebrikizumab, tocilizumab, efalizumab, IMA-638 and anti-OX40 ligand on AHR, EAR or LAR; benralizumab on LAR; tralokinumab on AHR; and Ro-24-7472 on AHR or LAR (all 1/1 study each). No dupilumab or reslizumab studies were identified. Conclusion: Omalizumab and tezepelumab reduced EAR and LAR to allergens. Tezepelumab consistently reduced AHR to methacholine or mannitol. These findings provide insights into AHR mechanisms and the precise effects of asthma biologics. Furthermore, findings suggest that tezepelumab broadly targets allergen-specific and non-allergic forms of AHR, and the underlying cells and mediators involved in asthma.