12-week Treatment Research Articles

Clinician Perception of Antibiotics and Antibiotic Resistance in the Context of Managing Acne Vulgaris (AV), and Satisfaction With AV Treatment Outcomes Among Patients Administered Sarecycline in Clinical Practices Across the US: Results from PROSES Study

Objectives: To evaluate clinician perceptions about antibiotics and antibiotic resistance, and their satisfaction with AV treatment outcomes among AV patients administered sarecycline in community practices across the U.S. Methods: A single-arm, prospective cohort study (PROSES) was conducted with moderate-to-severe non-nodular AV patients >9 years who were prescribed sarecycline in real-world community practices in the US. At baseline, clinicians were asked about their concerns about antibiotic resistance, disruption of the microbiome with long-term antibiotic use, and the importance of narrow-spectrum antibiotics in supporting antibiotic stewardship; responses were on a 5-point likert scale of 0 (not at all) to 4 (extremely). Clinicians separately reported their level of satisfaction with sarecycline treatment outcomes at week-12. Results: A total of 253 AV patients (adults 60.08%; pediatric 39.92%) managed by 30 clinicians completed the study. Clinician concerns about antibiotic resistance to manage AV was - extreme:26.67%, moderate:40.00%, somewhat:20.00% and slightly/not-at-all:13.33%. Clinician concerns about disruption of microbiome associated with antibiotic use was - extreme:13.33%, moderate:50.00%, somewhat:20.00% and slightly/not-at-all:16.67%. Clinician reported importance of narrow-spectrum antibiotics in supporting antibiotic stewardship was - extreme:46.67%, moderate:43.33%, somewhat:10.00% and slightly/not-at-all:0%. Majority (88.14%) of clinicians reported very satisfied/satisfied with 12-week treatment outcomes associated with narrow-spectrum antibiotic sarecycline. Conclusion: Majority of clinicians expressed concerns about antibiotic resistance and associated disruption to microbiome and considered use of narrow-spectrum antibiotic as extremely/moderately important to antibiotic stewardship. Overwhelming majority of clinicians reported satisfaction with sarecycline treatment outcomes after 12 weeks of treatment with sarecycline, a narrow-spectrum, tetracycline-derived antibiotic.

A Multicenter, Open-Label, Single-Arm Trial of the Efficacy and Safety of Empagliflozin Treatment for Refractory Diabetes Mellitus with Insulin Resistance (EMPIRE-01).

Insulin resistance syndrome and lipoatrophic diabetes are characterized by severe insulin resistance and are often refractory to treatment. Trials assessing the efficacy of antidiabetes drugs for these rare conditions have been limited, however. Sodium-glucose cotransporter2 (SGLT2) inhibitors, which lower glycemia independently of insulin action, have shown efficacy for type2 diabetes with insulin resistance. We here investigated the efficacy and safety of the SGLT2 inhibitor empagliflozin for treatment of insulin resistance syndrome and lipoatrophic diabetes. The trial was conducted at five academic centers in Japan and included seven patients with insulin resistance syndrome and one patient with lipoatrophic diabetes. Participants received 10mg of empagliflozin daily. If the hemoglobinA1c (HbA1c) level was ≥ 7.0% (52mmol/mol) after 12weeks, the dose was adjusted to 25mg. The study duration was 24weeks, and the primary outcome was the change in HbA1c level by the end of the treatment period. Safety evaluations were performed for all participants. By the end of the 24-week treatment period, the mean HbA1c level for all eight patients had decreased by 0.99 percentage points (10.8mmol/mol) (95% confidence interval [CI], 0.59 to 1.38 percentage points, 6.6 to 14.9mmol/mol) and the mean fasting plasma glucose concentration had declined by 63.9mg/dL (3.55mmol/L) (95%CI 25.5 to 102.3mg/dL, 1.42 to 5.68mmol/L). Continuous glucose monitoring revealed a reduction in mean glucose levels from 164.3 ± 76.1 to 137.6 ± 46.6mg/dL (9.13 ± 4.23 to 7.65 ± 2.59mmol/L) as well as an increase in the time in range (70-180mg/dL) from 58.9 ± 36.1% to 70.8 ± 18.3%. Seventeen mild adverse events were recorded in five individuals throughout the study period. No severe events were reported. The mean body mass showed a slight decrease and the mean serum ketone body concentration showed a slight increase during treatment. Our results demonstrate that empagliflozin shows a certain level of efficacy and safety for treatment of insulin resistance syndrome and lipoatrophic diabetes. jRCTs2051190029 and NCT04018365.

Effect of Different Medium-Chain Triglycerides on Glucose Metabolism in High-Fat-Diet Induced Obese Rats.

Obesity can be associated with significant metabolic disorders. Our previous study found that medium-chain triglycerides (MCTs) improved lipid metabolism in obese rats. However, scant attention has been given to exploring the impact of MCTs on glucose metabolism in obese rats. This study is designed to examine the effects and mechanisms of three distinct MCTs on glucose metabolism in obese rats. To induce obesity, Sprague-Dawley (SD) rats were fed a high-fat diet, followed by a 12-week treatment with caprylic triglyceride (CYT), capric triglyceride (CT), and lauric triglyceride (LT). The results showed that three types of MCT intervention reduced the levels of lipids (TC, TG, LDL-c, and HDL-c), hyperglycemia, insulin resistance (insulin, OGTT, HOMA-IR, and ISI), and inflammatory markers (IL-4, IL-1β, and TNF-α) in obese rats (p < 0.01), The above parameters have been minimally improved in the high-fat restoring group (HR) group. MCTs can modulate the PI3K/AKT signaling pathways to alleviate insulin resistance and improve glucose metabolism in obese rats. Furthermore, MCTs can activate peroxisome proliferator-activated receptor (PPAR) γ and reduce the phosphorylation of PPARγser237 mediated by CDK5, which can improve insulin sensitivity without lipid deposition in obese rats. Among the MCT group, CT administration performed the best in the above pathways, with the lowest blood glucose level and insulin resistance. These findings contribute to a deeper understanding of the connection between health benefits and the specific type of MCT employed.

Exploratory study on the relationship between urinary sodium/potassium ratio, salt intake, and the antihypertensive effect of esaxerenone: the ENaK Study

Excessive salt intake is one of the causes of hypertension, and reducing salt intake is important for managing the risk of hypertension and subsequent cardiovascular events. Esaxerenone, a mineralocorticoid receptor blocker, has the potential to exert an antihypertensive effect in hypertensive patients with excessive salt intake, but evidence is still lacking, especially in clinical settings. We aimed to determine if baseline sodium/potassium ratio and baseline estimated 24-h urinary sodium excretion can predict the antihypertensive effect of esaxerenone in patients with essential hypertension inadequately controlled with an angiotensin receptor blocker (ARB) or a calcium channel blocker (CCB). This was an exploratory, open-label, interventional study with a 4-week observation period and a 12-week treatment period. Esaxerenone was orally administered once daily in accordance with the Japanese package insert. In total, 126 patients met the eligibility criteria and were enrolled (ARB subcohort, 67; CCB subcohort, 59); all were included in the full analysis set (FAS) and safety analysis. In the FAS, morning home systolic blood pressure (SBP)/diastolic blood pressure (DBP) significantly decreased from baseline to end of treatment (primary efficacy endpoint) (−11.9 ± 10.9/ − 6.4 ± 6.8 mmHg, both p < 0.001); a similar trend was observed in both subcohorts. Significant reductions were also shown in bedtime home and office SBP/DBP (all p < 0.001). Each BP change was consistent regardless of the urinary sodium/potassium ratio or estimated 24-h urinary sodium excretion at baseline. The urinary albumin-creatinine ratio (UACR) and N-terminal pro-brain natriuretic peptide (NT-proBNP) significantly decreased from baseline to Week 12 in the total population and both subcohorts. No new safety concerns were raised. Esaxerenone significantly decreased morning home, bedtime home, and office BP; UACR; and NT-proBNP in this patient population, regardless of concomitant ARB or CCB use. The antihypertensive effect of esaxerenone was independent of the urinary sodium/potassium ratio and estimated 24-h urinary sodium excretion at baseline.

Efficacy and safety of linaclotide in treating functional constipation in paediatric patients: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

Linaclotide, a guanylate cyclase C agonist, has been approved in the USA for the treatment of chronic idiopathic constipation and irritable bowel syndrome with predominant constipation in adults. We aimed to assess the efficacy and safety of linaclotide in paediatric patients aged 6-17 years with functional constipation. This randomised, double-blind, placebo-controlled, multicentre, phase 3 study was done at 64 clinic or hospital sites in seven countries (USA, Canada, Israel, Italy, the Netherlands, Ukraine, and Estonia). Patients aged 6-17 years who met modified Rome III criteria for functional constipation were randomly assigned (1:1), with a block size of four and stratified by age (6-11 years and 12-17 years), to receive either oral linaclotide 72 μg or placebo once daily for 12 weeks. Participants, investigators, and data assessors were masked to assignment. The primary efficacy endpoint was change from baseline (CFB) in the 12-week frequency rate of spontaneous bowel movements (SBMs; occurring in the absence of rescue medication on the calendar day of or before the bowel movement) per week and the secondary efficacy endpoint was CFB in stool consistency over the 12-week treatment period; efficacy and safety were analysed in all patients in the randomised population who received at least one dose of study intervention (modified intention-to-treat population and safety population, respectively). The study is registered with ClinicalTrials.gov, NCT04026113, and the functional constipation part of the study is complete. Between Oct 1, 2019, and March 21, 2022, 330 patients were enrolled and randomly assigned to linaclotide (n=166) or placebo (n=164). Two patients in the linaclotide group did not receive any treatment; thus, efficacy and safety endpoints were assessed in 328 patients (164 patients in each group). 293 (89%) patients completed the 12-week treatment period (148 in the linaclotide group and 145 in the placebo group). 181 (55%) of 328 patients were female and 147 (45%) were male. At baseline, the mean frequency rate for SBMs was 1·28 SBMs per week (SD 0·87) for placebo and 1·16 SBMs per week (0·83) for linaclotide, increasing to 2·29 SBMs per week (1·99) for placebo and 3·41 SBMs per week (2·76) for linaclotide during intervention. Compared with placebo (least-squares mean [LSM] CFB 1·05 SBMs per week [SE 0·19]), patients treated with linaclotide showed significant improvement in SBM frequency (LSM CFB 2·22 SBMs per week [0·19]; LSM CFB difference 1·17 SBMs per week [95% CI 0·65-1·69]; p<0·0001). Linaclotide also significantly improved stool consistency over placebo (LSM CFB 1·11 [SE 0·08] vs 0·69 [0·08]; LSM CFB difference 0·42 [95% CI 0·21-0·64]; p=0·0001). The most reported treatment-emergent adverse event (TEAE) by patients treated with linaclotide was diarrhoea (seven [4%] of 164 vs three [2%] of 164 patients in the placebo group) and by patients treated with placebo was COVID-19 (five [3%] vs four [2%] in the linaclotide group). The most frequent treatment-related TEAE was diarrhoea (linaclotide: six [4%] patients; placebo: two [1%] patients). One serious adverse event of special interest (treatment-related severe diarrhoea resulting in dehydration and hospitalisation) occurred in a female patient aged 17 years in the linaclotide group; this case resolved without sequelae after administration of intravenous fluids. No deaths occurred during the study. Linaclotide is an efficacious and well tolerated treatment for functional constipation in paediatric patients and has subsequently been approved by the US Food and Drug Administration for this indication. AbbVie and Ironwood Pharmaceuticals.

Comparative effectiveness of pelvic floor muscle training, mirabegron, and trospium among older women with urgency urinary incontinence and high fall risk: a feasibility randomized clinical study

BackgroundUntreated, urgency urinary incontinence (UUI) and overactive bladder (OAB) can precipitate a vicious cycle of decreasing physical activity, social isolation, fear of falling, and falls. Structured behavioral interventions and medications are common initial treatment options, but they elicit their effects through very different mechanisms of action that may influence fall-related outcomes differently. This study will determine the feasibility of conducting a comparative effectiveness, three-arm, mixed methods, randomized clinical trial of a behaviorally based pelvic floor muscle training (PFMT) intervention versus two recent drug options in older women with UUI or OAB who are also at increased risk of falling.MethodsForty-eight women 60 years and older with UUI or OAB who screen positive for increased fall risk will be recruited through the urogynacology and pelvic health clinics of our university health system. Participants will be randomly assigned to one of three 12-week treatment arms: (1) a course of behavioral and pelvic floor muscle training (PFMT) provided by physical therapists; (2) the beta-3 agonist, mirabegron; and (3) the antimuscarinic, trospium chloride. Study feasibility will be established through objective metrics of evaluability, adherence to the interventions, and attrition. We will also assess relevant measures of OAB symptom severity, quality of life, physical activity, incident falls, and concern about falling.DiscussionThe proposed research seeks to ultimately determine if linkages between reduction in UI symptoms through treatment also reduce the risk of falling in this patient population.Trial registrationNCT05880862. Registered on 30 May 2023.

Buspirone for the treatment of anxiety in Williams syndrome: a retrospective chart review study

ABSTRACT Background Williams syndrome (WS) is a rare genetic disorder associated with a high prevalence of anxiety disorders. Evidence-based pharmacologic treatments for anxiety in WS are lacking. The purpose of this study is to provide naturalistic data on the use of buspirone for the treatment of anxiety in WS. Research design and methods Medical records of 24 individuals with Williams syndrome (ages 7–47 years) and anxiety who received treatment with buspirone were reviewed. Treatment response to buspirone was rated by assigning a retrospective Clinical Global Impression Improvement subscale (CGI-I) score. Results Twenty-three of 24 (96%) patients completed at least a 16-week treatment course with buspirone. Sixteen patients (67%; 95% CI 47%, 82%) were treatment responders (CGI-I ≤ 2). Only 1 (4%) patient discontinued buspirone due to a treatment-emergent side effect (nausea and vomiting). The most common side effect was nausea (13%). Twenty (84%) patients remained on buspirone at the time of their most recent follow-up visit. Conclusions In this retrospective study, the majority of patients responded to a 16-week course of buspirone. Prospective studies are warranted to further assess the efficacy and tolerability of buspirone for anxiety in WS.

Exercise-promoted adiponectin secretion activates autolysosomes to protect the liver of ApoE-/- mice from a high-fat diet.

Fat is a "double-edged sword": while it is a necessary substance for the body, the long-term intake of excessive fat will cause obesity, with the liver subjected to lipotoxicity as it accumulates. It will then continue to deteriorate, eventually leading to liver failure, which is a negative impact of high-fat food intake. Research has shown that exercise can reverse the side effects of a chronic high-fat diet and help the body to mitigate the harmful effects of lipotoxicity. In our study, it was found that moderate-intensity cardio-training (MICT) and high-intensity interval exercise (HIIT) effectively protected the livers of high-fat diet (HFD) ApoE-/- mice against lipotoxicity. Previous results demonstrated that 12 weeks of HFD resulted in a significant elevation of CD36 in the livers of C57BL/6J mice, while knockdown of CD36 did not reduce the accumulation of fat in the liver. Therefore, we used ApoE-/- mice as experimental subjects. Although HFD caused the development of hyperlipidemia and atherosclerosis, it is interesting to note that, due to the knockdown of ApoE, the livers of ApoE-/- mice in the non-exercise group did not show significant lipid deposition; however, after 12 weeks of MICT and HIIT, the livers of ApoE-/- mice showed significant lipid deposition. After we analyzed the lipid metabolism in their livers, we found that this was caused by the promotion of transport of peripheral fat into the liver due to exercise. Moreover, 12 weeks of exercise effectively reduced atherosclerosis, and the livers of ApoE-/- mice in the exercise group were not damaged by lipotoxicity. The results showed that a 12-week exercise treatment activated AMPK in the livers of HFD ApoE-/- mice through the APN-AdipoR1 signaling pathway, improved hepatic lipid metabolism disorders, and promoted the nuclear translocation of TFEB to enhance autophagic-lysosomal lipid scavenging. After the peripheral lipid is input into the liver due to exercise, the energy generated through gluconeogenesis can be used to replenish the energy consumed by exercise and maintain the normal operation of various functions in the liver, based on which the high autophagic flux in the liver can be maintained and the lipid clearance rate can be enhanced to protect the liver from lipotoxicity.

Development of a Multimodal, Personalized Intervention of Virtual Reality Integrated Within Physiotherapy for Patients With Complex Chronic Low-Back Pain.

Chronic low-back pain (CLBP) is the leading cause of years lived with disability. Physiotherapy is the most common treatment option for CLBP, but effects are often unsatisfactory. Virtual reality (VR) offers possibilities to enhance the effectiveness of physiotherapy treatment. Primary aim was to develop and test a personalized VR intervention integrated within a physiotherapy treatment for patients with CLBP. This study describes an intervention development process using mixed methods design that followed the Medical Research Council (MRC) framework. This involved a cocreation process with patients, physiotherapists, and researchers. A draft intervention was constructed based on a literature review and focus groups, and subsequently tested in a feasibility study and evaluated in focus groups. Focus group data were analyzed using thematic analysis. This intervention development process resulted in a final intervention. Focus group data showed that VR and physiotherapy can strengthen each other when they are well integrated, and that VR needs to be administered under the right conditions including flawless technology, physiotherapists with sufficient affinity and training, and the right expectations from patients. The draft intervention was considered feasible after evaluation by four patients and three physiotherapists and was further complemented by expanding the training for physiotherapists and improving the protocols for physiotherapists and patients. The final intervention consisted of a 12-week physiotherapy treatment with three integrated VR modules: pain education, physical exercise, and relaxation. Using the MRC framework in cocreation with the end users, a personalized VR intervention integrated within a physiotherapy treatment for patients with CLBP was developed. This intervention was found to be feasible and will subsequently be evaluated for (cost-)effectiveness in a cluster randomized controlled trial.

Plasma metabolome analysis for predicting antiviral treatment efficacy in chronic hepatitis B: diagnostic biomarkers and therapeutic insights.

The early and accurate identification of predictive biomarkers for antiviral treatment efficacy remains a significant clinical challenge, particularly in the management of chronic hepatitis B (CHB). This study aimed to assess whether the plasma metabolome could reliably predict the success of antiviral therapy in CHB patients. We conducted a retrospective analysis on 56 treatment-naive CHB patients at the First Affiliated Hospital of Zhejiang University from December 2013 to March 2016. Patients who underwent a 48-week treatment regimen of entecavir (ETV) and interferon-alpha (IFN-α) were randomly assigned to either a discovery cohort (n=29) or a validation cohort (n=27). Based on the outcome of the treatment, patients were classified as HBeAg seroconversion group (High responders, Hrp) or the non-remission group (Low responder, Lrp). Our methodology involved an untargeted analysis of the amine/phenol and carboxylic acid submetabolomes in the CHB patients under treatment, utilizing chemical isotope labeling (CIL) techniques with liquid chromatography-mass spectrometry (LC-MS). Several metabolites were identified as having significant diagnostic potential for distinguishing Hrp from Lrp, with areas under the receiver operating characteristic curve (AUC) exceeding those typical clinical indicators. Notably, four metabolites, namely 2-methyl-3-ketovaleric acid, 2-ketohexanoic acid, 6-oxo-1,4,5,6-tetrahydronicotinic acid, and α-ketoisovaleric acid, demonstrated exceptionally high sensitivity and specificity in both cohorts, nearing 100%. In contrast, the clinical indicators, including HBcAb, log(HBsAg), and HBeAb, demonstrated lower and inconsistent sensitivity and specificity between the discovery and validation cohorts. Using HBcAb as a marker, the sensitivity was 87.5% with 76.9% specificity in the discovery cohort; however, the sensitivity dropped to 46.7% with 91.7% specificity in the validation cohort. Using log(HBsAg), the sensitivity was 84.6% with 69.2% specificity in the discovery cohort, compared to 85.7% sensitivity and 83.3% specificity in the validation cohort. For HBeAb, the separation of Hrp and Lrp had a sensitivity of 87.5% with 69.2% specificity in the discovery cohort, while the validation cohort showed 86.7% sensitivity and 91.7% specificity.

IMPAHCT: A randomized phase 2b/3 study of inhaled imatinib for pulmonary arterial hypertension.

AV-101 (imatinib) powder for inhalation, an investigational dry powder inhaled formulation of imatinib designed to target the underlying pathobiology of pulmonary arterial hypertension, was generally well tolerated in healthy adults in a phase 1 single and multiple ascending dose study. Inhaled Imatinib Pulmonary Arterial Hypertension Clinical Trial (IMPAHCT; NCT05036135) is a phase 2b/3, randomized, double-blind, placebo-controlled, dose-ranging, and confirmatory study. IMPAHCT is designed to identify an optimal AV-101 dose (phase 2b primary endpoint: pulmonary vascular resistance) and assess the efficacy (phase 3 primary endpoint: 6-min walk distance), safety, and tolerability of AV-101 dose levels in subjects with pulmonary arterial hypertension using background therapies. The study has an operationally seamless, adaptive design allowing for continuous recruitment. It includes three parts; subjects enrolled in Part 1 (phase 2b dose-response portion) or Part 2 (phase 3 intermediate portion) will be randomized 1:1:1:1 to 10, 35, 70 mg AV-101, or placebo (twice daily), respectively. Subjects enrolled in Part 3 (phase 3 optimal dose portion) will be randomized 1:1 to the optimal dose of AV-101 and placebo (twice daily), respectively. All study parts include a screening period, a 24-week treatment period, and a 30-day safety follow-up period; the total duration is ∼32 weeks. Participation is possible in only one study part. IMPAHCT has the potential to advance therapies for patients with pulmonary arterial hypertension by assessing the efficacy and safety of a novel investigational drug-device combination (AV-101) using an improved study design that has the potential to save 6-12 months of development time. ClinicalTrials.gov Identifier: NCT05036135.

The efficacy of Topical Clascoterone versus systematic spironolactone for treatment of acne vulgaris: A systematic review and network meta-analysis.

This study aimed to evaluate the effectiveness of topical clascoterone (TC) compared to oral spironolactone for acne vulgaris treatment. A computerized search through PubMed/MEDLINE, SCOPUS, and the Cochrane Library was conducted to find relevant papers. We used the "netmeta" and "meta" packages for network meta-analysis (NMA) in RStudio 1.2.5019 (2009-2019 RStudio, Inc.) to conduct all of our statistical tests. Seven articles (n = 2,006 patients) were included. The fixed-effect size showed that TC 1% bis in die (BID) showed potential effectiveness in reducing the inflammatory and non-inflammatory lesion count compared to placebo (Standardized mean difference, SMD = -0.27, 95% CI: -0.36 to -0.17) and (SMD = -0.31, 95% CI: -0.41 to -0.22), respectively. The random-effect size showed that TC 1% BID was significantly associated with a 12-week treatment success compared to placebo (Odds ratio, OR = 2.44, 95% CI: 1.12 to 5.30). Spironolactone 200 mg was associated with a significant reduction in total lesion count (SMD = -4.46, 95% CI: -5.60 to -3.32). TC appears to reduce both inflammatory and non-inflammatory lesion count and may lead to treatment success. Spironolactone at 200 mg showed potential effectiveness in terms of total lesion count reduction. These results suggest that both TC and Spironolactone could be beneficial in treating patients with acne vulgaris.

Benefit of Topical Combination Therapy for Acne: Analyzing Effect Size Using Number Needed to Treat.

Topical acne trials often are confounded by high vehicle response rates and differing outcome measures, making it difficult to compare treatments. Number needed to treat (NNT) can be a simple, clinically meaningful way to indirectly compare treatment options without head-to-head data. NNT is the number of patients who need to be treated with an intervention to observe one additional patient successfully achieving a desired outcome versus vehicle/placebo. While treatment attributes such as adverse events may not be captured, lower NNT is a good indicator of a more effective treatment. Following a search of combination topical treatments for acne vulgaris, all treatments that reported pivotal trial efficacy data consistent with the 2018 FDA definition of success were included in NNT analyses.&nbsp; Results: Of 13 treatments, 7 reported 12-week treatment success rates in 11 phase 3 trials, with similar baseline demographics/disease severity. Treatment success ranged from 26.8% with tretinoin 0.1%/benzoyl peroxide (BPO) 3% cream to 50% with triple-combination clindamycin phosphate 1.2%/adapalene 0.15%/BPO 3.1% gel. NNTs for the triple-combination gel were 4 and 5 (from 2 pivotal trials). Adapalene 0.3%/BPO 2.5% gel had an NNT of 5. Tretinoin/BPO had the largest range between trials, with NNTs of 4 and 9. The other 4 treatments had NNTs ranging from 6 to 8. A comparison of combination topical acne treatment trial data, using the same treatment outcome and similar patient populations, resulted in triple-combination clindamycin phosphate/adapalene/BPO gel and adapalene/BPO gel having the most favorable NNTs.J Drugs Dermatol. 2024;23(2):42-49.&nbsp; doi:10.36849/JDD.7927.

Acupuncture for early Parkinson's disease with mild to moderate depression: a randomized controlled trial protocol with functional MRI.

Depression is a common non-motor symptom of Parkinson's disease (PD), which seriously affects the quality of life of patients with PD. The main clinical treatment method for depression in Parkinson's disease is medication treatment. However, the medication treatment has a long cycle and many adverse reactions. Acupuncture as a non-pharmacological intervention method, has been widely used in the treatment of patients with Parkinson's disease and depressive disorders in China. Therefore, the study of acupuncture in the treatment of early Parkinson's disease with mild to moderate depression has important practical significance. In this randomized, single-blinded, and placebo-controlled study, a total of 88 patients with depression in Parkinson's disease (DPD) will be randomly allocated to either an acupuncture group or a control group in parallel in a 1:1 allocation ratio. Each group will receive 30 min acupuncture treatments or sham acupuncture treatments, 3 times a week, for 12 weeks, followed by a 36-week follow-up period. The primary outcome is the response rate of the Hamilton Depression Rating Scale-17 at 12 weeks. Data will be collected at baseline, at the end of the 12-week treatment period, and during the 12-week and 36-week follow-up. This study hypothesized that acupuncture may treat DPD by restoring pathological alterations in brain neural activity. The findings will provide scientific evidence for acupuncture in the treatment of early PD with mild to moderate depression. This clinical trial has been approved by the Medical Ethics Committee of the Beijing Hospital of Traditional Chinese Medicine (Approval No. 2023BL02-013-01). This trial has been registered with the Chinese Clinical Trials Registry (Registration No. ChiCTR2300069310). The results will be published in a peer-reviewed academic journal. https://www.chictr.org.cn/, identifier ChiCTR2300069310.

A phase 4 multicentre, 2×2 factorial randomised, double-blind, placebo-controlled trial to investigate the efficacy and safety of tobramycin inhalation solution for Pseudomonas aeruginosa eradication in bronchiectasis: ERASE.

Chronic Pseudomonas aeruginosa (PA) infection significantly contributes to morbidity and mortality in bronchiectasis patients. Initiating antibiotics early may lead to the eradication of PA. Here we outline the design of a trial (ERASE; NCT06093191) assessing the efficacy and safety of inhaled tobramycin, alone or with oral ciprofloxacin, in bronchiectasis patients with a new isolation of PA. This multicentre, 2×2 factorial randomised, double-blind, placebo-controlled, parallel-group trial includes a 2-week screening period, a 12-week treatment phase (with a combination of ciprofloxacin or a placebo at initial 2 weeks) and a 24-week follow-up. 364 adults with bronchiectasis and a new PA isolation will be randomly assigned to one of four groups: placebo (inhaled saline and ciprofloxacin placebo twice daily), ciprofloxacin alone (750 mg ciprofloxacin and inhaled saline twice daily), inhaled tobramycin alone (inhaled 300 mg tobramycin and ciprofloxacin placebo twice daily) or a combination of both drugs (inhaled 300 mg tobramycin and 750 mg ciprofloxacin twice daily). The primary objective of this study is to assess the proportion of patients successfully eradicating PA in each group by the end of the study. Efficacy will be evaluated based on the eradication rate of PA at other time points (12, 24 and 36 weeks), the occurrence of exacerbations and hospitalisations, time to first pulmonary exacerbations, patient-reported outcomes, symptom measures, pulmonary function tests and the cost of hospitalisations. To date no randomised trial has evaluated the benefit of different PA eradication strategies in bronchiectasis patients. The ERASE trial will therefore generate crucial data to inform future clinical guidelines.

Adalimumab vs placebo as add-on to Standard Therapy for autoimmune Uveitis: Tolerability, Effectiveness and cost-effectiveness—a protocol for a randomised controlled trial (ASTUTE trial)

IntroductionAdalimumab is an effective treatment for autoimmune non-infectious uveitis (ANIU), but it is currently only funded for a minority of patients with ANIU in the UK as it is restricted...

Evaluation of Effectiveness of 9- and 6-Month Treatment Regimens in Patients with Multiple Drug Resistant or Rifampicin-Resistant Tuberculosis in the Republic of Belarus

The objective: to evaluate the effectiveness of 39- and 24-week treatment regimens in patients with multiple drug resistant or rifampicin-resistant tuberculosis (MDR/RR-TB).Subjects and Methods. We evaluated the effectiveness of 39- and 24-week treatment regimens containing bedaquiline, levofloxacin, linezolid, clofazimine, and cycloserine or delamanid (modified short-course regimens - mSCR) and bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM), in cohorts of patients with MDR/RR-TB. Results. Of the 550 and 139 patients were included in the mSCR and SMARRTT Studies (BPaLM regimen) from December 2019 to October 2021 and from March 2022 to August 2022, 90.7% (487/537) and 94.2% (131/139) achieved a successful treatment outcome, respectively, 13 patients were excluded from the mSCR Study and continued treatment according to an individual regimen. Median (ME) and quartiles [Q1-Q3] of sputum culture conversion time in patients treated with mSCR and BPaLM made 30.0 (25.0-56.0) and 27.0 (25.0-29.8) days (p&lt;0.01) respectively. The prognostic factor for an unfavorable outcome for the BPaLM and mSCR regimens was a positive sputum microscopy result before treatment (OR – 7.92, 95% CI 1.5 – 41.0, p = 0.014; OR – 1.97, 95% CI 1.1–3.5, p=0.02, respectively), and for the mSCR regime, the time of sputum culture conversion &gt;90 days was an additional prognostic factor (OR – 3.35, 95% CI 1.2–9.5, p=0.03) .Conclusions. The effectiveness of the mSCR and BPaLM regimens in patients with MDR/RR-TB is high (90.7% and 94.2%, respectively). Patients with positive sputum microscopy and late sputum culture conversion have a lower chance of cure.

Implementation of the advanced HIV disease care package with point-of-care CD4 testing during tuberculosis case finding: A mixed-methods evaluation.

During TB-case finding, we assessed the feasibility of implementing the advanced HIV disease (AHD) care package, including VISITECT CD4 Advanced Disease (VISITECT), a semiquantitative test to identify a CD4≤200cells/μl. Adult participants with tuberculosis symptoms, recruited near-facility in Lesotho and South-Africa between 2021-2022, were offered HIV testing (capillary blood), Xpert MTB/RIF and Ultra, and MGIT culture (sputum). People living with HIV (PLHIV) were offered VISITECT (venous blood) and Alere tuberculosis-lipoarabinomannan (AlereLAM, urine) testing. AHD was defined as a CD4≤200cells/μl on VISITECT or a positive tuberculosis test. A CD4≤200cells/μl on VISITECT triggered Immy cryptococcal antigen (Immy CrAg, plasma) testing. Participants were referred with test results. To evaluate feasibility, we assessed i) acceptability and ii) intervention delivery of point-of-care diagnostics among study staff using questionnaires and group discussions, iii) process compliance, and iv) early effectiveness (12-week survival and treatment status) in PLHIV. Predictors for 12-week survival were assessed with logistic regression. Thematic content analysis and triangulation were performed. Among PLHIV (N = 676, 48.6% of 1392 participants), 7.8% were newly diagnosed, 81.8% on ART, and 10.4% knew their HIV status but were not on ART. Among 676 PLHIV, 41.7% had AHD, 29.9% a CD4≤200cells/μl and 20.6% a tuberculosis diagnosis. Among 200 PLHIV tested with Immy CrAg, 4.0% were positive. The procedures were acceptable for study staff, despite intervention delivery challenges related to supply and the long procedural duration (median: 73 minutes). At 12 weeks, among 276 PLHIV with AHD and 328 without, 3.3% and 0.9% had died, 84.8% and 92.1% were alive and 12.0% and 7.0% had an unknown status, respectively. Neither AHD nor tuberculosis status were associated with survival. Implementing AHD care package diagnostics was feasible during tuberculosis-case finding. AHD was prevalent, and not associated with survival, which is likely explained by the low specificity of VISITECT. Challenges with CD4 testing and preventive treatment uptake require addressing.

Serum metabolomics characteristics and fatty-acid-related mechanism of cirrhosis with histological response in chronic hepatitis B.

Background and aims: The serum metabolites changes in patients with hepatitis B virus (HBV)-related cirrhosis as progression. Peroxisome proliferator-activated receptor gamma (PPARγ) is closely related to lipid metabolism in cirrhotic liver. However, the relationship between fatty acids and the expression of hepatic PPARγ during cirrhosis regression remains unknown. In this study, we explored the serum metabolic characteristics and expression of PPARγ in patients with histological response to treatment with entecavir. Methods: Sixty patients with HBV-related cirrhosis were selected as the training cohort with thirty patients each in the regression (R) group and non-regression (NR) group based on their pathological changes after 48-week treatment with entecavir. Another 72 patients with HBV-related cirrhosis and treated with entecavir were collected as the validation cohort. All of the serum samples were tested using ultra-performance liquid chromatography coupled to tandem mass spectrometry. Data were processed through principal component analysis and orthogonal partial least square discriminant analysis. Hepatic PPARγ expression was observed using immunohistochemistry. The relationship between serum fatty acids and PPARγ was calculated using Pearson's or Spearman's correlation analysis. Results: A total of 189 metabolites were identified and 13 differential metabolites were screened. Compared to the non-regression group, the serum level of fatty acids was higher in the R group. At baseline, the expression of PPARγ in hepatic stellate cells was positively correlated with adrenic acid (r 2 = 0.451, p = 0.046). The expression of PPARγ in both groups increased after treatment, and the expression of PPARγ in the R group was restored in HSCs much more than that in the NR group (p = 0.042). The adrenic acid and arachidonic acid (AA) in the R group also upgraded more than the NR group after treatment (p = 0.037 and 0.014). Conclusion: Baseline serum differential metabolites, especially fatty acids, were identified in patients with HBV-related cirrhosis patients who achieved cirrhosis regression. Upregulation of adrenic acid and arachidonic acid in serum and re-expression of PPARγ in HSCs may play a crucial role in liver fibrosis improvement.

Serum thrombospondin-2 level changes with liver stiffness improvement in patients with type 2 diabetes.

Baseline circulating thrombospondin-2 (TSP2) level was identified as a potential novel hepatic fibrosis biomarker that associates with development and progression of hepatic fibrosis in patients with nonalcoholic fatty liver disease and type 2 diabetes. Here, we investigated whether circulating TSP2 levels changed with improvement in liver stiffness (LS), which reflects liver fibrosis on transient elastography. Serum TSP2 levels were measured in participants from a randomized, open-label intervention study, at baseline and after 24-weeks treatment of either dapagliflozin 10 mg (N = 30) or sitagliptin 100 mg daily (N = 30). Vibration-controlled transient elastography was performed to evaluate the severity of hepatic fibrosis and steatosis using LS and controlled attenuation parameter (CAP), respectively. Among all 60 participants with similar clinical characteristics at baseline (mean HbA1c 8.9%, CAP 289 dB/m and LS 5.8 kPa), despite similar HbA1c lowering, treatment with dapagliflozin, but not sitagliptin, led to significant improvements in body weight (BW) (p = .012), CAP (p = .015) and LS (p = .011) after 24 weeks. Serum TSP2 level decreased significantly from baseline in dapagliflozin-treated participants (p = .035), whereas no significant change was observed with sitagliptin. In correlation analysis, change in serum TSP2 levels only positively correlated with change in LS (r = .487, p = .006), but not with changes in BW, CAP or HbA1c after dapagliflozin treatment. Serum TSP2 level decreased with LS after dapagliflozin treatment, and was independent of improvements in BW, glycemic control and hepatic steatosis, further supporting the potential of serum TSP2 level as a novel hepatic fibrosis biomarker in type 2 diabetes.