Placebo-controlled Randomized Clinical Trial Research Articles

Effectiveness of Low-Level Laser Therapy in Orchialgia After Varicocelectomy Surgery.

Introduction: The management of chronic groin and scrotal content pain (orchialgia) is a complex condition after varicocelectomy that is encountered by most practicing clinicians. The aim of this study was to evaluate the effectiveness of low-level laser therapy (LLLT) in orchialgia after varicocelectomy surgery. Methods: This study was performed as a double-blind, placebo-controlled randomized clinical trial in which sixty patients with orchialgia after varicocelectomy were randomly divided into three groups of 20 as follows: (1) low-level laser group with red (650 nm, 50 mW), (2) low-level laser group with infrared (IR) (820 nm, 100 mW), and (3) laser placebo group. The treatment protocol consisted of 15 minutes, three times a week, for only 12 sessions. Then, the patients were evaluated for pain and sexual satisfaction during the 12-week follow-up. Results: The pain score in the two groups of low-level laser with red light and IR spectra showed a significant relief (P<0.05) 6 and 12 weeks after starting the treatment, In addition, a significant increase was observed in the level of sexual satisfaction in the red and infrared spectra LLLT groups (P<0.05). Conclusion: We concluded that the use of LLLT with red light (650 nm, 50 mW)/IR (820 nm, 100 mW) spectra with power of 6-25 J/cm2/day in 15 minutes, three times a week, for 12 sessions can significantly reduce pain and increase sexual satisfaction in these patients.

Efficacy of Omega-3 in Improving Sleep Quality of Healthcare Workers with Shiftwork Sleep Disorder: Phase III, Double-blind, Placebo-controlled Trial Study Protocol (SLEEP-O3 Trial)

Introduction: Healthcare workers are especially vulnerable to sleep disturbances, including shift work sleep disorder (SWSD). Even though omega-3 supplementation has been studied to enhance sleep quality in different populations, there is lack of evidence to support its effectiveness in SWSD. This trial aims to evaluate this compound potential benefits towards health care personnel suffering from SWSD. Methods: This study protocol consists of a phase III, single-center, double-blind, placebo-controlled randomized clinical trial. Participants will receive sleep hygiene orientation in addition to either omega-3 dietary supplementation or placebo for 8 weeks. The primary outcome will be sleep quality as measured by the Pittsburgh Sleep Quality Index and one of the secondary outcomes would be actigraphy as a reliable sleep assessment. The sample size will be 136 subjects. Discussion: The importance of improving sleep quality of health care workers relies on its impact on their wellness, and on patient safety. Sleep deprivation and disorders are responsible for multiple workplace errors and worse health outcomes alike. This trial can help determine if omega-3 supplementation can contribute to ameliorate sleep disturbances in health care professionals.

The effect of myo-inositol supplementation on AMPK/PI3K/AKT pathway and insulin resistance in patients with NAFLD.

Insulin resistance (IR) is the pivotal pathological hit in non-alcoholic fatty liver disease (NAFLD). There is specific attention to combination/conjugated therapies for NAFLD management. As myo-inositol (MI) has been shown to improve IR in animal and human trials, this study aimed to investigate the influence of MI supplementation on glycemic response and IR through AMPK/PI3K/AKT signaling pathway in obese patients with NAFLD. This double-blinded placebo-controlled randomized clinical trial was conducted on 48 obese (BMI = 30-40 kg/m2) patients with NAFLD who were randomly assigned to receiving either MI (4 g/day) or placebo (maltodextrin 4 g/day) group for 8 weeks. Before and after the trial, weight, height, serum glycemic parameters (inc. fasting glucose and insulin) as well as IR indices were assessed. Moreover, the mRNA expression levels of AMPK, AKT, and PDK-1 in peripheral blood mononuclear cells (PBMCs) were determined. MI supplementation resulted in significant increases in the fold changes of AMPK, AKT, and PDK-1 genes (p = .019, p = .049, and p = .029, respectively). Indeed, IR improved in terms of all IR indices in MI group (p < .05) after adjusting for the confounders, apart from quantitative insulin sensitivity check index (QUICKI). The results showed that MI supplementation not only upregulated AMPK, AKT, and PDK-1 mRNA in PBMCs but also improved IR in obese patients with NAFLD.

2023 Brazilian Society of Rheumatology guidelines for the treatment of systemic sclerosis

BackgroundSystemic sclerosis (SSc) is a rare chronic autoimmune disease with heterogeneous manifestations. In the last decade, several clinical trials have been conducted to evaluate new treatment options for SSc. The purpose of this work is to update the recommendations of the Brazilian Society of Rheumatology in light of the new evidence available for the pharmacological management of SSc.MethodsA systematic review including randomized clinical trials (RCTs) for predefined questions that were elaborated according to the Patient/Population, Intervention, Comparison, and Outcomes (PICO) strategy was conducted. The rating of the available evidence was performed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. To become a recommendation, at least 75% agreement of the voting panel was needed.ResultsSix recommendations were elaborated regarding the pharmacological treatment of Raynaud’s phenomenon, the treatment (healing) and prevention of digital ulcers, skin involvement, interstitial lung disease (ILD) and gastrointestinal involvement in SSc patients based on results available from RCTs. New drugs, such as rituximab, were included as therapeutic options for skin involvement, and rituximab, tocilizumab and nintedanib were included as therapeutic options for ILD. Recommendations for the pharmacological treatment of scleroderma renal crisis and musculoskeletal involvement were elaborated based on the expert opinion of the voting panel, as no placebo-controlled RCTs were found.ConclusionThese guidelines updated and incorporated new treatment options for the management of SSc based on evidence from the literature and expert opinion regarding SSc, providing support for decision-making in clinical practice.

A phase 2b double-blind placebo-controlled randomized clinical trial of SB-061, an aggrecan mimetic, in patients with symptomatic knee osteoarthritis

ObjectivesTo evaluate the efficacy and safety of intra-articular injections of a novel aggrecan mimetic, SB-061, in subjects with knee OA. MethodsThis was a randomized, placebo-controlled, double-blind phase II study comparing intra-articular injections of SB-061 with placebo (isotonic saline) for 52 weeks, administered at baseline, Wk 16, and Wk 32. Eligible subjects had a KL grade of 2 or 3 on X-ray of the target knee and a WOMAC pain score ≥20 out of 50 at screening and baseline visits. Subjects having any other knee condition were excluded. Use of analgesics was prohibited, except for rescue medication. The primary endpoint was change from baseline (CFB) in WOMAC pain at Week 8. Secondary endpoints were CFB in WOMAC function and total, ICOAP, PGA, and 20-meter walk test. Exploratory endpoints included structural CFB in MRI entities. Results288 subjects were randomized to SB-061 (n=145) or placebo (n=143), and 252 (87.5%) completed injections. The groups were comparable at baseline. The primary endpoint was not met, as no significant difference in the CFB of the WOMAC pain score at Week 8 between groups was observed, nor at any other time point during the study. Similarly, neither of the secondary or exploratory endpoints indicated any significant difference between groups. The frequency and type of adverse events was similar between groups. SB-061 was well-tolerated. ConclusionIntra-articular injections of SB-061 administered at baseline, Wk 16, and Wk 32, over one year in subjects with knee OA was safe but did not show any statistically significant effect on knee pain nor on other symptomatic or structural entities compared to placebo. Trial registration number EudraCT No2019-004515-31

Varenicline and Nicotine Replacement Therapy for Smokers Admitted to Hospitals

Varenicline is the most effective sole pharmacotherapy for smoking cessation. If used in combination with nicotine replacement therapy (NRT), cessation rates may be further improved, but the efficacy and safety of the combination need to be evaluated. To examine whether hospitalized smokers treated with varenicline and NRT lozenges achieve higher prolonged smoking abstinence rates compared with those treated with varenicline alone. A double-blind, placebo-controlled randomized clinical trial was conducted in adult medical or surgical inpatients of 5 Australian public hospitals with a history of smoking 10 cigarettes or more per day, interested in quitting, and available for 12-month follow-up between May 1, 2019, and May 1, 2021 (final 12-month data collection in May 2022). Data analysis was performed from June 1 to August 30, 2023. A 12-week varenicline regimen was initiated during hospitalization at standard doses in all participants. Participants were randomized to additionally use NRT (2 mg) or placebo lozenges if there was an urge to smoke. Behavioral support (Quitline) was offered to all participants. The primary outcome was biochemically verified sustained abstinence at 6 months. Secondary outcomes included self-reported prolonged abstinence, 7-day point prevalence abstinence (3, 6, and 12 months), and medicine-related adverse events. A total of 320 participants (mean [SD] age, 52.5 [12.1] years; 183 [57.2%] male) were randomized. The conduct of biochemical verification was affected by COVID-19 restrictions; consequently, the biochemically verified abstinence in the intervention vs control arms (18 [11.4%] vs 16 [10.1%]; odds ratio [OR], 1.14; 95% CI, 0.56-2.33) did not support the combination therapy. The secondary outcomes in the intervention vs control arms of 7-day point prevalence abstinence at 6 months (54 [34.2%] vs 37 [23.4%]; OR, 1.71; 95% CI, 1.04-2.80), prolonged abstinence at 12 months (47 [29.9%] vs 30 [19.1%]; OR, 1.77; 95% CI, 1.05-3.00), and 7-day point prevalence abstinence at 12-months (48 [30.6%] vs 31 [19.7%]; OR, 1.79; 95% CI, 1.07-2.99) significantly improved with the combination therapy. The self-reported 6-month prolonged abstinence (61 [38.6%] vs 47 [29.7%]; OR, 1.49; 95% CI, 0.93-2.39) favored the combination therapy but was not statistically significant. Medicine-related adverse events were similar in the 2 groups (102 [74.5%] in the intervention group vs 86 [68.3%] in the control group). In this randomized clinical trial of the combination of varenicline and NRT lozenges in hospitalized adult daily smokers, the combination treatment improved self-reported abstinence compared with varenicline alone, without compromising safety, but it did not improve biochemically validated abstinence. anzctr.org.au Identifier: ACTRN12618001792213.

Diazoxide for Severe or Recurrent Neonatal Hypoglycemia

Neonatal hypoglycemia is an important preventable cause of neurodevelopmental impairment, but there is a paucity of evidence to guide treatment. To evaluate whether early, low-dose oral diazoxide for severe or recurrent neonatal hypoglycemia reduces time to resolution of hypoglycemia. This 2-arm, placebo-controlled randomized clinical trial was conducted from May 2020 to February 2023 in tertiary neonatal units at 2 New Zealand hospitals. Participants were neonates born at 35 or more weeks' gestation and less than 1 week of age with severe hypoglycemia (blood glucose concentration <22 mg/dL or <36 mg/dL despite 2 doses of dextrose gel) or recurrent hypoglycemia (≥3 episodes of a blood glucose concentration <47 mg/dL within 48 hours). Newborns were randomized 1:1 to receive diazoxide suspension (loading dose, 5 mg/kg; maintenance, 1.5 mg/kg every 12 hours) or placebo, titrated per protocol. The primary outcome was time to resolution of hypoglycemia, defined as enteral bolus feeding without intravenous fluids and normoglycemia (blood glucose concentration of 47-98 mg/dL) for at least 24 hours, compared between groups using adjusted Cox proportional hazards regression. Hazard ratios adjusted for stratification variables and gestation length are reported. Prespecified secondary outcomes, including number of blood glucose tests and episodes of hypoglycemia, duration of hypoglycemia, and time to enteral bolus feeding and weaning from intravenous fluids, were compared by generalized linear models. Newborns were followed up for at least 2 weeks. Of 154 newborns screened, 75 were randomized and 74 with evaluable data were included in the analysis (mean [SD] gestational age for the full cohort, 37.6 [1.6] weeks), 36 in the diazoxide group and 38 in the placebo group. Baseline characteristics were similar: in the diazoxide group, mean (SD) gestational age was 37.9 (1.6) weeks and 26 (72%) were male; in the placebo group, mean (SD) gestational age was 37.4 (1.5) weeks and 27 (71%) were male. There was no significant difference in time to resolution of hypoglycemia (adjusted hazard ratio [AHR], 1.39; 95% CI, 0.84-2.23), possibly due to increased episodes of elevated blood glucose concentration and longer time to normoglycemia in the diazoxide group. Resolution of hypoglycemia, when redefined post hoc as enteral bolus feeding without intravenous fluids for at least 24 hours with no further hypoglycemia, was reached by more newborns in the diazoxide group (AHR, 2.60; 95% CI, 1.53-4.46). Newborns in the diazoxide group had fewer blood glucose tests (adjusted count ratio [ACR], 0.63; 95% CI, 0.56-0.71) and episodes of hypoglycemia (ACR, 0.32; 95% CI, 0.17-0.63), reduced duration of hypoglycemia (adjusted ratio of geometric means [ARGM], 0.18; 95% CI, 0.06-0.53), and reduced time to enteral bolus feeding (ARGM, 0.74; 95% CI, 0.58-0.95) and weaning from intravenous fluids (ARGM, 0.72; 95% CI, 0.60-0.87). Only 2 newborns (6%) treated with diazoxide had hypoglycemia after the loading dose compared with 20 (53%) with placebo. In this randomized clinical trial, early treatment of severe or recurrent neonatal hypoglycemia with low-dose oral diazoxide did not reduce time to resolution of hypoglycemia but reduced time to enteral bolus feeding and weaning from intravenous fluids, duration of hypoglycemia, and frequency of blood glucose testing compared with placebo. ANZCTR.org.au Identifier: ACTRN12620000129987.

Jinlida for Diabetes Prevention in Impaired Glucose Tolerance and Multiple Metabolic Abnormalities

Previous studies have shown that Jinlida (JLD) granules, an approved treatment for type 2 diabetes in China, can reduce blood glucose level, reduce glycated hemoglobin (HbA1c), and improve insulin resistance in people with type 2 diabetes. To evaluate the effect of long-term administration of JLD vs placebo on the incidence of diabetes in participants with impaired glucose tolerance (IGT) and multiple metabolic abnormalities. This multicenter, double-blind, placebo-controlled randomized clinical trial (FOCUS) was conducted across 35 centers in 21 cities in China from June 2019 to February 2023. Individuals aged 18 to 70 years with IGT and multiple metabolic abnormalities were enrolled. Participants were randomly allocated 1:1 to receive JLD or placebo (9 g, 3 times per day, orally). They continued this regimen until they developed diabetes, withdrew from the study, were lost to follow-up, or died. The primary outcome was the occurrence of diabetes, which was determined by 2 consecutive oral glucose tolerance tests. Secondary outcomes included waist circumference; fasting and 2-hour postprandial plasma glucose levels; HbA1c; fasting insulin level; homeostatic model assessment for insulin resistance (HOMA-IR); total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels; ankle-brachial index; and carotid intima-media thickness. A total of 889 participants were randomized, of whom 885 were in the full analysis set (442 in the JLD group; 443 in the placebo group; mean [SD] age, 52.57 [10.33] years; 463 [52.32%] female). Following a median observation period of 2.20 years (IQR, 1.27-2.64 years), participants in the JLD group had a lower risk of developing diabetes compared with those in the placebo group (hazard ratio, 0.59; 95% CI, 0.46-0.74; P < .001). During the follow-up period, the JLD group had a between-group difference of 0.95 cm (95% CI, 0.36-1.55 cm) in waist circumference, 9.2 mg/dL (95% CI, 5.4-13.0 mg/dL) in 2-hour postprandial blood glucose level, 3.8 mg/dL (95% CI, 2.2-5.6 mg/dL) in fasting blood glucose level, 0.20% (95% CI, 0.13%-0.27%) in HbA1c, 6.6 mg/dL (95% CI, 1.9-11.2) in total cholesterol level, 4.3 mg/dL (95% CI, 0.8-7.7 mg/dL) in low-density lipoprotein cholesterol level, 25.7 mg/dL (95% CI, 15.9-35.4 mg/dL) in triglyceride levels, and 0.47 (95% CI, 0.12-0.83) in HOMA-IR compared with the placebo group. After 24 months of follow-up, the JLD group had a significant improvement in ankle-brachial index and waist circumference compared with the placebo group. The findings suggest that JLD can reduce the risk of diabetes in participants with IGT and multiple metabolic abnormalities. Chinese Clinical Trial Register: ChiCTR1900023241.

Menopausal hormone therapy and ovarian and endometrial cancers: Long-term follow-up of the Women’s Health Initiative randomized trials.

10506 Background: After decades of use,menopausal hormone therapy influence on ovarian and endometrial cancer remains unsettled. Therefore, we assessed the long-term influence of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) and CEE-alone use on ovarian and endometrial cancer incidence and mortality in long-term follow-up of the Women’s Health Initiative randomized, placebo-controlled clinical trials. Methods: Long-term follow-up of two placebo-controlled randomized clinical trials that recruited 27,347 postmenopausal women aged 50-79 years without prior breast cancer or invasive cancer within 10 years (and no baseline endometrial pathology in combined hormone trial participants) from 40 US centers from 1993-1998. In 16,608 women with a uterus, 8,506 were randomized to daily 0.625 mg/d of CEE plus 2.5 mg/d of MPA and 8,102, placebo. In 10,739 women with prior hysterectomy, 5,310 were randomized to daily 0.625 mg/d of CEE-alone and 5,429, placebo. Intervention was stopped for cause before the planned 8.5-year intervention after 5.6 years (CEE plus MPA) and after 7.2 years (CEE-alone). Cancers were verified by central pathology report review. Mortality findings were enhanced by serial National Death Index (NDI) queries. The primary study outcomes were ovarian cancer and endometrial cancer incidence and related mortality. Results: After 20-year follow-up, with mortality information for &gt; 98%; in the initial WHI report on CEE-alone influence on ovarian cancer, CEE-alone, versus placebo, significantly increased ovarian cancer incidence (35 cases [0.041% annualized rate] vs 17 [0.020%]; hazard ratio [HR], 2.04; 95% CI 1.14-3.65; P = 0.01) and ovarian cancer mortality (HR 2.79 95% CI 1.30-5.99, P = 0.006). KM-estimates and cumulative hazard ratios indicate a persistent CEE-alone adverse effect on ovarian cancer incidence that emerged after 12-years follow-up and did not diminish (P = 0.006). In contrast, use of CEE plus MPA, versus placebo, did not increase ovarian cancer incidence (75 cases [0.051%] vs 63 [0.045%]; HR, 1.14; 95% CI, 0.82-1.59; P = 0.44) or ovarian cancer mortality (HR 1.21 95% CI 0.84-1.74). CEE plus MPA did significantly lower endometrial cancer incidence (106 cases [0.073%] vs 140 [0.10%]; HR, 0.72; 95% CI, 0.56-0.92; P = 0.01), without statistically significant influence on endometrial mortality (HR 0.58 95% CI 0.29-1.16) Conclusions: In randomized, placebo-controlled, clinical trial settings, CEE-alone, in women with prior hysterectomy, significantly increased ovarian cancer incidence and increased ovarian cancer mortality while CEE plus MPA, in women with a uterus, in contrast to most observational studies, did not. However, CEE plus MPA reduced endometrial cancer incidence. These findings inform decisions regarding menopausal hormone therapy use. Clinical trial information: NCT00000611 .

Does metformin prolong pregnancy in preterm pre-eclampsia? A study protocol for a South African, hospital-based double-blind, randomised, placebo-controlled trial

IntroductionPreterm pre-eclampsia is a leading cause of maternal morbidity and mortality. The Pre-eclampsia Intervention 2 (PI 2) trial suggested that metformin sustained release (XR) may prolong gestation by a week...

Development and Validation of a Novel Placental DNA Methylation Biomarker of Maternal Smoking during Pregnancy in the ECHO Program.

Maternal cigarette smoking during pregnancy (MSDP) is associated with numerous adverse health outcomes in infants and children with potential lifelong consequences. Negative effects of MSDP on placental DNA methylation (DNAm), placental structure, and function are well established. Our aim was to develop biomarkers of MSDP using DNAm measured in placentas (), collected as part of the Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function double-blind, placebo-controlled randomized clinical trial conducted between 2012 and 2016. We also aimed to develop a digital polymerase chain reaction (PCR) assay for the top ranking cytosine-guanine dinucleotide (CpG) so that large numbers of samples can be screened for exposure at low cost. We compared the ability of four machine learning methods [logistic least absolute shrinkage and selection operator (LASSO) regression, logistic elastic net regression, random forest, and gradient boosting machine] to classify MSDP based on placental DNAm signatures. We developed separate models using the complete EPIC array dataset and on the subset of probes also found on the 450K array so that models exist for both platforms. For comparison, we developed a model using CpGs previously associated with MSDP in placenta. For each final model, we used model coefficients and normalized beta values to calculate placental smoking index (PSI) scores for each sample. Final models were validated in two external datasets: the Extremely Low Gestational Age Newborn observational study, ; and the Rhode Island Children's Health Study, . Logistic LASSO regression demonstrated the highest performance in cross-validation testing with the lowest number of input CpGs. Accuracy was greatest in external datasets when using models developed for the same platform. PSI scores in smokers only () were moderately correlated with maternal plasma cotinine levels. One CpG (cg27402634), with the largest coefficient in two models, was measured accurately by digital PCR compared with measurement by EPIC array (). To our knowledge, we have developed the first placental DNAm-based biomarkers of MSDP with broad utility to studies of prenatal disease origins. https://doi.org/10.1289/EHP13838.

Differential Outcomes of Placebo Treatment Across 9 Psychiatric Disorders

Placebo is the only substance systematically evaluated across common psychiatric diagnoses, but comprehensive cross-diagnostic comparisons are lacking. To compare changes in placebo groups in recent high-quality randomized clinical trials (RCTs) across a broad spectrum of psychiatric disorders in adult patients. MEDLINE and the Cochrane Database of Systematic Reviews were systematically searched in March 2022 for the latest systematic reviews meeting predetermined high-quality criteria for 9 major psychiatric diagnoses. Using these reviews, the top 10 highest-quality (ie, lowest risk of bias, according to the Cochrane Risk of Bias tool) and most recent placebo-controlled RCTs per diagnosis (totaling 90 RCTs) were selected, adhering to predetermined inclusion and exclusion criteria. Following the Cochrane Handbook, 2 authors independently carried out the study search, selection, and data extraction. Cross-diagnosis comparisons were based on standardized pre-post effect sizes (mean change divided by its SD) for each placebo group. This study is reported following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. The primary outcome, pooled pre-post placebo effect sizes (dav) with 95% CIs per diagnosis, was determined using random-effects meta-analyses. A Q test assessed statistical significance of differences across diagnoses. Heterogeneity and small-study effects were evaluated as appropriate. A total of 90 RCTs with 9985 placebo-treated participants were included. Symptom severity improved with placebo in all diagnoses. Pooled pre-post placebo effect sizes differed across diagnoses (Q = 88.5; df = 8; P < .001), with major depressive disorder (dav = 1.40; 95% CI, 1.24-1.56) and generalized anxiety disorder (dav = 1.23; 95% CI, 1.06-1.41) exhibiting the largest dav. Panic disorder, attention-deficit/hyperactivity disorder, posttraumatic stress disorder, social phobia, and mania showed dav between 0.68 and 0.92, followed by OCD (dav = 0.65; 95% CI, 0.51-0.78) and schizophrenia (dav = 0.59; 95% CI, 0.41-0.76). This systematic review and meta-analysis found that symptom improvement with placebo treatment was substantial in all conditions but varied across the 9 included diagnoses. These findings may help in assessing the necessity and ethical justification of placebo controls, in evaluating treatment effects in uncontrolled studies, and in guiding patients in treatment decisions. These findings likely encompass the true placebo effect, natural disease course, and nonspecific effects.

Bisoprolol in Patients With Chronic Obstructive Pulmonary Disease at High Risk of Exacerbation

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Observational studies report that β-blocker use may be associated with reduced risk of COPD exacerbations. However, a recent trial reported that metoprolol did not reduce COPD exacerbations and increased COPD exacerbations requiring hospital admission. To test whether bisoprolol decreased COPD exacerbations in people with COPD at high risk of exacerbations. The Bisoprolol in COPD Study (BICS) was a double-blind placebo-controlled randomized clinical trial conducted in 76 UK sites (45 primary care clinics and 31 secondary clinics). Patients with COPD who had at least moderate airflow obstruction on spirometry (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity <0.7; FEV1 <80% predicted) and at least 2 COPD exacerbations treated with oral corticosteroids, antibiotics, or both in the prior 12 months were enrolled from October 17, 2018, to May 31, 2022. Follow-up concluded on April 18, 2023. Patients were randomly assigned to bisoprolol (n = 261) or placebo (n = 258). Bisoprolol was started at 1.25 mg orally daily and was titrated as tolerated during 4 sessions to a maximum dose of 5 mg/d, using a standardized protocol. The primary clinical outcome was the number of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both during the 1-year treatment period. Safety outcomes included serious adverse events and adverse reactions. Although the trial planned to enroll 1574 patients, recruitment was suspended from March 16, 2020, to July 31, 2021, due to the COVID-19 pandemic. Two patients in each group were excluded postrandomization. Among the 515 patients (mean [SD] age, 68 [7.9] years; 274 men [53%]; mean FEV1, 50.1%), primary outcome data were available for 514 patients (99.8%) and 371 (72.0%) continued taking the study drug. The primary outcome of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both was 526 in the bisoprolol group, with a mean exacerbation rate of 2.03/y, vs 513 exacerbations in the placebo group, with a mean exacerbation rate of 2.01/y. The adjusted incidence rate ratio was 0.97 (95% CI, 0.84-1.13; P = .72). Serious adverse events occurred in 37 of 255 patients in the bisoprolol group (14.5%) vs 36 of 251 in the placebo group (14.3%; relative risk, 1.01; 95% CI, 0.62-1.66; P = .96). Among people with COPD at high risk of exacerbation, treatment with bisoprolol did not reduce the number of self-reported COPD exacerbations requiring treatment with oral corticosteroids, antibiotics, or both. isrctn.org Identifier: ISRCTN10497306.

Assessment of the Impact of RNase in Patients With Severe Fatigue Related to Post-Acute Sequelae of SARS-CoV-2 Infection: A Randomized Phase 2 Trial of RSLV-132.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and RNA debris persist in viral reservoirs for weeks to months following infection, potentially triggering interferon production and chronic inflammation. RSLV-132 is a biologic drug composed of catalytically active human RNase1 fused to human IgG1 Fc and is designed to remain in circulation and digest extracellular RNA. We hypothesized that removal of SARS-CoV-2 viral RNA from latent reservoirs may improve inflammation, neuroinflammation, and fatigue associated with post-acute sequelae of SARS-CoV-2 infection (PASC). This was a phase 2, double-blind, placebo-controlled randomized clinical trial in participants with a 24-week history of PASC and severe fatigue. The primary endpoint of the trial assessed the impact of 6 intravenous doses of RSLV-132 on the mean change from baseline at day 71 in the Patient-Reported Outcomes Measurement Information System Fatigue Short Form 7a (PROMIS Fatigue SF 7a). A statistically significant difference on day 71 was not observed with respect to the primary or secondary endpoints. This was likely due to a placebo response that increased during the trial. Statistically significant improvement in fatigue as measured by the PROMIS Fatigue SF 7a, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and Physicians Global Assessment (PGA) instruments were observed earlier in the trial, with women demonstrating greater responses to RSLV-132 than men. While fatigue was not statistically significantly improved at Day 71, earlier timepoints revealed statistically significant improvement in fatigue and physician global assessment. The data suggest eliminating latent viral RNA by increasing serum RNase activity may improve fatigue in PASC patients. Women may respond better to this approach than men. Future studies will aim to confirm these findings.

Cytisinicline for Vaping Cessation in Adults Using Nicotine E-Cigarettes

The prevalence of e-cigarette use among US adults, especially young adults, is rising. Many would like to quit vaping nicotine but are unable to do so. Cytisinicline, a plant-based alkaloid, targets nicotinic acetylcholine receptors, reduces nicotine dependence, and helps adults to stop smoking cigarettes. Cytisinicline may also help e-cigarette users to quit vaping. To determine the efficacy and safety of cytisinicline vs placebo to produce abstinence from e-cigarette use in adults seeking to quit vaping nicotine. This double-blind placebo-controlled randomized clinical trial compared 12 weeks of treatment with cytisinicline vs placebo, with follow-up to 16 weeks. It was conducted from July 2022 to February 2023 across 5 US clinical trial sites. A total of 160 adults who vaped nicotine daily, sought to quit, and did not currently smoke cigarettes were enrolled, and 131 (81.9%) completed the trial. Participants were randomized (2:1) to cytisinicline, 3 mg, taken 3 times daily (n = 107) or placebo (n = 53) for 12 weeks. All participants received weekly behavioral support. Biochemically verified continuous e-cigarette abstinence during the last 4 weeks of treatment (weeks 9-12; primary outcome) and through 4 weeks posttreatment (weeks 9-16; secondary outcome). Missing outcomes were counted as nonabstinence. Of 160 randomized participants (mean [SD] age, 33.6 [11.1] years; 83 [51.9%] female), 115 (71.9%) formerly smoked (≥100 lifetime cigarettes). Continuous e-cigarette abstinence in cytisinicline and placebo groups occurred in 34 of 107 participants (31.8%) vs 8 of 53 participants (15.1%) (odds ratio, 2.64; 95% CI, 1.06-7.10; P = .04) at end of treatment (weeks 9-12) and in 25 of 107 participants (23.4%) vs 7 of 53 participants (13.2%) during weeks 9 to 16 (odds ratio, 2.00; 95% CI, 0.82-5.32; P = .15). There was no evidence, based on nonsignificant interactions, that cytisinicline efficacy differed in subgroups defined by demographic characteristics, vaping pattern, e-cigarette dependence, or smoking history. Cytisinicline was well tolerated, with 4 participants (3.8%) discontinuing cytisinicline due to an adverse event. In this randomized clinical trial, cytisinicline for 12 weeks, with behavioral support, demonstrated efficacy for cessation of e-cigarette use at end of treatment and was well tolerated by adults, offering a potential pharmacotherapy option for treating nicotine e-cigarette use in adults who seek to quit vaping. These results need confirmation in a larger trial with longer follow-up. ClinicalTrials.gov Identifier: NCT05431387.

Effects of probiotic supplementation on testosterone levels in healthy ageing men: A 12-week double-blind, placebo-controlled randomized clinical trial

Levels of the male sex hormone testosterone are generally stable in the age interval 20–70 years, but several studies indicate an earlier, age-dependent decline. Testosterone deficiency is often underdiagnosed and under-treated, but replacement therapy has nonetheless increased during the last couple of years. Owing to possible negative side effects, alternative treatments have been investigated, including different supplementation protocols. The aim of this study was to investigate the effect of probiotic supplementation on the testosterone level in healthy men aged between 55 and 65. Hence, 12 weeks randomized, double-blinded, placebo-controlled trial was conducted to investigate the effect on testosterone levels following supplementation of the recognized probiotic Limosilactobacillus reuteri ATCC PTA 6475 on testosterone levels, using high-, low- or placebo treatment. Venous blood samples were collected at baseline, 6 and 12 weeks, for analysis of bloodwork, lipid profile, hormones, and electrolytes. Subjects were also asked to complete a questionnaire. The supplementation had no effect on testosterone levels, neither using high- or low dose, nor placebo. However, a significant decrease of triglyceride levels was observed in the high-dose group. No other parameters showed any significant change. The present study does not support the hypothesis that a probiotic supplementation can increase testosterone levels in ageing men.

Effects of a diverse prebiotic fibre supplement on HbA1c, insulin sensitivity and inflammatory biomarkers in pre-diabetes: a pilot placebo-controlled randomised clinical trial.

Prebiotic fibre represents a promising and efficacious treatment to manage pre-diabetes, acting via complementary pathways involving the gut microbiome and viscosity-related properties. In this study, we evaluated the effect of using a diverse prebiotic fibre supplement on glycaemic, lipid and inflammatory biomarkers in patients with pre-diabetes. Sixty-six patients diagnosed with pre-diabetes (yet not receiving glucose-lowering medications) were randomised into treatment (thirty-three) and placebo (thirty-three) interventions. Participants in the treatment arm consumed 20 g/d of a diverse prebiotic fibre supplement, and participants in the placebo arm consumed 2 g/d of cellulose for 24 weeks. A total of fifty-one and forty-eight participants completed the week 16 and week 24 visits, respectively. The intervention was well tolerated, with a high average adherence rate across groups. Our results extend upon previous work, showing a significant change in glycated haemoglobin (HbA1c) in the treatment group but only in participants with lower baseline HbA1c levels (< 6 % HbA1c) (P = 0·05; treatment -0·17 ± 0·27 v. placebo 0·07 ± 0·29, mean ± sd). Within the whole cohort, we showed significant improvements in insulin sensitivity (P = 0·03; treatment 1·62 ± 5·79 v. placebo -0·77 ± 2·11) and C-reactive protein (P FWE = 0·03; treatment -2·02 ± 6·42 v. placebo 0·94 ± 2·28) in the treatment group compared with the placebo. Together, our results support the use of a diverse prebiotic fibre supplement for physiologically relevant biomarkers in pre-diabetes.

Effectiveness of Laser Acupuncture for Reducing Pain and Increasing Mouth Opening Range in Individuals with Temporomandibular Disorder: A Systematic Review and Network Meta-Analysis.

Laser acupuncture (LA) demonstrates promising results in the treatment of musculoskeletal disorders. However, its effects on temporomandibular disorder (TMD) are not yet fully understood. Thus, the aim of this systematic review and network meta-analysis was to assess the effectiveness of LA on pain intensity and maximum mouth opening range (MMO) related to TMD. A search was carried out in 11 electronic databases and references of included studies to locate randomized clinical trials (RCTs) that evaluated LA as a primary treatment for TMD. The risk of bias was assessed using the RoB 2 tool. Network meta-analysis was conducted on the MetaInsight platform, considering the pain intensity and counseling (C) as the outcome of reference. The GRADE system was used to assess the certainty of the evidence. Five studies evaluated pain intensity, four with a high risk of bias and one with a low risk. Two studies evaluated pain intensity on palpation (one with high and one with low risk of bias), and one study with high risk of bias evaluated MMO. Laser parameters were: 690-810nm, 40-150 mW, and 7.5-112.5J/cm2. Occlusal splint (OS) [- 2.47; CI 95% - 3.64, - 1.30] and Physiotherapy (PT) [-2.64; CI 95% - 3.94, - 1.34] reduced pain intensity compared to C. The ranking of treatments in order of effectiveness was PT > OS > LA > C > CR (craniopuncture). The certainty of the evidence was very low or low. The data do not support the indication of LA for the treatment of TMDs and new placebo-controlled RCTs must be conducted to demonstrate its effectiveness more precisely.

Effect of theophylline on stent-related symptoms in patients undergoing Double-J ureteral stent insertion: a randomized controlled trial.

To investigate the effect of oral theophylline on stent-related syndrome (SRS) after Double-J insertion. Double-J stent is widely using in many urological procedures. Infection, hematuria, and discomfort are some of common complication after stenting. Theophylline is a dimethylated xanthine that inhibits phosphodiesterase and blocks adenosine receptors. To relaxing effect of theophylline on smooth muscles and its effects on the urinary system, it seems it could reduce complications after inserting Double-J stent especially ureteral stent syndrome. In this double-blind placebo-controlled randomized clinical trial, 67 patients were enrolled. Mean (SD) age of control and theophylline group was 51.8 (12.5) and 43.9 (10.4) years old, respectively. Patients were randomized into two groups of control and theophylline. All patients were stenting with silicon Double J. Theophylline group received 100mg of theophylline, twice daily for 30days, while control group received placebo. Stent symptoms were assessed by questionnaire and urine culture was performed before stent removal at removal day. Statistical analysis was performed using Chi-squared test and t test with P < 0.05 considered significant. Logistic regression models were fitted, crudely and adjusted for age and sex. Of 67 eligible patients, 60 completed the study. Theophylline significantly decreased percentages of gross hematuria (P < 0.001), dysuria (P < 0.001), and urinary frequency (P < 0.001). Microscopic hematuria (P = 0.042) and chills (P = 0.042) also decreased after theophylline. Theophylline could be an effective and safe choice for reducing SRS among patients undergoing Double-J stent insertion.

Oral Minoxidil vs Topical Minoxidil for Male Androgenetic Alopecia

There has been increased interest in low-dose oral minoxidil for androgenetic alopecia (AGA) treatment. However, the efficacy of oral minoxidil for male AGA is yet to be evaluated in comparative therapeutic trials. To compare the efficacy, safety, and tolerability of daily oral minoxidil, 5 mg, vs twice-daily topical minoxidil, 5%, for 24 weeks in the treatment of male AGA. This double-blind, placebo-controlled randomized clinical trial was conducted at a single specialized clinic in Brazil. Eligible men with AGA aged 18 to 55 years classified using the Norwood-Hamilton scale as 3V, 4V, or 5V were included and randomized. Data were collected from January to December 2021, and data were analyzed from September 2022 to February 2023. Participants were randomized 1:1 into 2 groups: oral minoxidil, 5 mg, daily and topical placebo solution; or 1 mL of topical minoxidil, 5%, twice daily and oral placebo for 24 weeks. The primary outcome was change in terminal hair density on the frontal and vertex regions of the scalp. The secondary outcomes were change in total hair density and photographic evaluation. Among 90 enrolled participants, 68 completed the study; of these, the mean (SD) age was 36.6 (7.8) years. A total of 33 participants were enrolled in the oral minoxidil group and 35 in the topical treatment group. Both groups were homogenous in terms of demographic data and AGA severity. For the frontal area, the mean change from baseline to week 24 between groups was 3.1 hairs per cm2 (95% CI, -18.2 to 21.5; P = .27) for terminal hair density and 2.6 hairs per cm2 (95% CI, -10.3 to 15.8; P = .32) for total hair density. For the vertex area, the mean change from baseline to week 24 was 23.4 hairs per cm2 (95% CI, -0.3 to 43.0; P = .09) for terminal density and 5.5 hairs per cm2 (95% CI, -12.5 to 23.5; P = .32) for total hair density. According to the photographic analysis, oral minoxidil was superior to topical minoxidil on the vertex (24%; 95% CI, 0 to 48; P = .04) but not on the frontal scalp (12%; 95% CI, -12 to 36; P = .24). The most common adverse effects in the oral minoxidil group were hypertrichosis (22 of 45 [49%]) and headache (6 of 45 [14%]). In this study, oral minoxidil, 5 mg, once per day for 24 weeks did not demonstrate superiority over topical minoxidil, 5%, twice per day in men with AGA. Brazilian Registry of Clinical Trials Identifier: RBR-252w9r.