4-week Treatment Research Articles

Epigallocatechin gallate enhances sympathetic heart rate variability and decreases blood pressure in obese subjects: a randomized control trial

This study aimed to investigate effects of epigallocatechin gallate (EGCG) on blood pressure (BP) and autonomic nervous system, indicated by 5-min heart rate variability (HRV) measurement in obese subjects, and determine correlations of BP with metabolic factors. In a double-blind, randomized controlled trial, obese subjects (n = 30) were randomly allocated to receive 150 mg EGCG (n = 15) or placebo (n = 15) twice a day without dietary restrictions. After 8-week EGCG treatment, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) significantly decreased, while the low-frequency (LF) to high-frequency power (HF) ratio (LF/HF ratio) significantly increased (P < 0.05 all), indicating a shift toward sympathetic dominance, either directly or indirectly after BP lowering. SBP had positive correlations with obesity parameters, leptin, insulin, and insulin resistance but had a negative correlation with insulin sensitivity. DBP was positively correlated with age and HF in normalized unit, but negatively correlated with height and LF in ms2. High-density lipoprotein cholesterol (HDL-C) was negatively correlated with SBP, DBP, and MAP reflecting its protective effect against elevated BP. In conclusion, the 8-week EGCG treatment decreased BP and increased the LF/HF ratio, reflecting increased sympathetic activity, either a direct EGCG effect or an indirect compensatory response following BP reduction.

Abstract C025: A novel pan-RAS/β-catenin inhibitor, ADT-030, produces tumor regression in PDX models of pancreatic cancer

Abstract BACKGROUND: The absence of symptoms often leads to late diagnosis of pancreatic ductal adenocarcinoma (PDAC) limiting treatment options. Tumor cell proliferation and invasion/metastasis are usually driven by KRAS mutations and activation of Wnt/β-catenin pathway components. The recent approval of KRASG12C-specific inhibitors for lung cancer has validated RAS as a druggable target but has had limited application for PDAC given the rarity of this codon in PDAC. In addition, no Wnt/β-catenin inhibitors have been FDA approved. Thus, drugs which inhibit these important targets are urgently needed for PDAC and other cancers. Here, we describe treatment results with ADT-030, a novel dual pan-RAS/β-catenin inhibitor in murine models of PDAC and lung cancer. METHODS: In vitro assays of growth inhibition, colony formation, apoptosis, and cell cycle, along with western blotting for RAS signaling were performed to assess potency and selectivity of ADT-030. Murine 2838c3-Luc KRASG12D PDAC cells were implanted orthotopically into the pancreas of C57BL/6J mice and cells from two PDAC patient-derived xenograft (PDX) models harboring KRASG12D or KRASG12C mutations were implanted subcutaneously (SC) in NSG mice to evaluate the antitumor activity of ADT-030. ADT-030 was administered once daily by gavage 5x/week for 4 weeks. RESULTS: ADT-030 potently inhibited the growth of PDAC cells in vitro harboring the most prevalent KRASG12D mutation as well as those with KRASG12C. Annexin V assay revealed the capacity of ADT-030 to trigger apoptosis in KRAS mutant cells with minimal impact on BxPC3 RASWT cells. Cell cycle analysis using propidium iodide staining revealed that ADT-030 arrested cells in the G2/M phase. Other experiments showed that ADT-030 simultaneously suppressed both MAPK/AKT signaling and β-catenin transcriptional by inhibiting PDE10 and activating cGMP/PKG signaling. ADT-030 caused tumor regression in SC PDAC PDX mouse tumor models harboring either KRASG12D or KRASG12C mutations without discernable toxicity. Inhibition of orthotopic PDAC tumor growth by ADT-030 was dose-dependent, causing up to 80% reduction in tumor volume following a 4-week treatment period. In addition, ADT-030 significantly extended survival and yielded a high percentage of cures after stopping treatment in a murine model of KRAS- mutant lung cancer. CONCLUSION: ADT-030, novel dual pan-RAS/β-catenin inhibitor, showed strong and durable antitumor activity in clinically relevant and aggressive murine models of PDAC and lung cancer. ADT-030 is a promising development candidate for treatment of PDAC and other RAS-driven cancers, particularly given the complex KRAS mutation landscape of many cancers. Citation Format: Dhana Sekhar Reddy Bandi, Ganji P Nagaraju, Jeremy B Foote, Adam B Keeton, Xi Chen, Kristy L Berry, Yulia Y Maxuitenko, Upender Manne, Donald J Buchsbaum, Gary A Piazza, Bassel F El-Rayes. A novel pan-RAS/β-catenin inhibitor, ADT-030, produces tumor regression in PDX models of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C025.

Telehealth-delivered recovery-orientated well-being plan group program for bipolar disorder: a pilot randomised feasibility and acceptability study.

Psychological interventions may assist in the management of bipolar disorder, but few studies have assessed the use of group therapy programs using telehealth. The present study aimed to assess the feasibility and acceptability of a well-being group program for people living with bipolar disorder designed to be delivered via telehealth (Zoom platform) using a randomised controlled pilot design. Participants were randomly assigned to either the 8-week well-being plan treatment condition or the wait-list control condition. They were administered a structured diagnostic instrument to confirm bipolar disorder diagnosis followed by a set of self-report questionnaires relating to mood, quality of life, personal recovery, and stigma. A total of 32 participants (16 treatment; 16 control) were randomised with 12 participants completing the intervention, and 13 the control condition. The program appeared acceptable and feasible (75% retention rate) with a mean attendance being reported of 7.25 sessions attended out of a possible 8 sessions. Participants reported high levels of satisfaction overall with the intervention, with a mean score of 9.18 out of 10. Preliminary evidence suggests that delivery of the group program online is feasible and acceptable for participants living with bipolar disorder. As the program was designed to prevent relapse over time, further research is needed to determine if the program may be helpful in improving symptom outcomes over a longer follow-up period.

Transdermal carbon dioxide may accelerate hoof growth in healthy, sound horses in a short-term, randomized, controlled clinical trial.

Slow hoof growth poses a clinical challenge when hoof wear exceeds natural growth. Many treatment options have been reported without controlled prospective trials. The objective of this study was to evaluate the effect of transdermal CO2 on the rate of growth in treated hooves. A prospective, randomized, blinded, crossover study of 14 Warmblood mares. Horses were randomly assigned a number and allocated for treatment of the front feet with room air or CO2 for 30 minutes 3 times per week, and groups were switched after 5 weeks. Hoof growth was measured on the dorsal midline and the quarters of each front foot. The distance from coronary band to lines made on the hoof wall was measured at the beginning, middle, and end of the study. The percentage of change in length at each location relative to baseline was evaluated at 5 weeks and 10 weeks using nonparametric analyses. All treatments were successfully administered. The left front medial (P = .028) and right front lateral (P = .03) sites of the CO2-treated hooves increased growth compared to the room air group at the 5-week point. The results of this study suggest that repeated, noninvasive transdermal application of CO2 may accelerate hoof growth in normal horses over a 5-week treatment period. This study suggests that transdermal CO2 may increase the rate of hoof growth in normal horses. The mechanism of action of this treatment is unclear, and further studies are required to fully elucidate the potential effects.

Efficacy on symptoms and mortality day vs. night administration of EGFR-TKIs for advanced non-small cell lung cancer.

This study has a purpose to investigate the side effects of three EGFR-TKIs targeted therapeutic agents (gefitinib, erlotinib, and afatinib) and all-cause mortality in patients with metastatic lung cancer. We performed a prospective cohort study. We selected all patients with newly diagnosed metastatic lung cancer between January and November 2019. Main exposure was daytime versus nighttime use of targeted EGFR TKIs. The study outcome was a symptom change using the mobile application, and all-cause mortality between January 2019 and March 2023. Among the 87 study participants, 35 (40%) took their medication at night. Among the 87 study participants, 35 (40%) took their medication at night. At 6weeks of treatment, acne (1.36; 95% confidence interval [CI] 1.09, 1.64; p for interaction = 0.04) and dry skin (1.35; 95% CI 1.09, 1.61, p for interaction = 0.01) in the day group showed a much increase from baseline compared to the night group. In contrast, the night group reported greater reductions in lung cancer-related symptoms from baseline compared to the day. During follow-up (median 43months), the night group had a lower risk of all-cause death than the day group, especially in younger patients (adjusted hazard ratio = 0.34; 95% CI 0.13, 0.87). The group taking EGFR-TKIs at night experienced fewer side effects and had longer overall survival compared to the day group. Clinicians should consider recommending that lung cancer patients take their once-daily oral anticancer drugs in the evening rather than the morning to improve treatment outcomes.

Probiotics and magnesium orotate for the treatment of major depressive disorder: a randomised double blind controlled trial

Following on from our pilot studies, this study aimed to test the efficacy of a combination of probiotics (Lactobacillus acidophilus, Bifidobacterium bifidum, Streptococcus thermophilus), magnesium orotate and coenzyme 10 for the treatment of major depressive disorder (MDD) through a double-blind placebo controlled clinical trial. The participants were 120 adults diagnosed with MDD randomised to daily oral administration, over 8 weeks, of either the intervention or placebo, with a 16-week follow-up period. Intent-to-treat analysis found a significantly lower frequency of the presence of a major depressive episode in the intervention group compared with placebo at the end of the 8-week treatment phase, with no difference between the two conditions at 8-week follow-up. Both the categorical and continuous measure of depressive symptoms showed a significant difference between the two conditions at 4 weeks, but not 8 and 16 weeks. The secondary end-point was demonstrated with an overall reduction in self-rated symptoms of anxiety and stress in the active treatment group compared with placebo. These findings suggest that the combination of probiotics, magnesium orotate and coenzyme 10 may be an effective treatment of MDD over an 8-week period.

Assessing Response Rates and Sleep Disorder Prevalence: Insights from a Propranolol Treatment Study for Infantile Haemangiomas.

Infantile haemangiomas (IHs) sometimes require treatment with propranolol. Sleep disturbances are the most frequently reported side effects. Monitoring adverse drug events necessitates repeated hospital visits, which can be challenging during a pandemic. To explore the effectiveness of a new electronic questionnaire in identifying sleep disturbances related to treatment with propranolol and potential confounding factors. To evaluate the response rate to the questionnaire. To report the proportion of patients on propranolol with sleep disturbances. In an observational, prospective cohort study, caregivers provided clinical information during ambulatory visits and via an electronic questionnaire after an 8-week treatment course with propranolol and at the time of treatment interruption. Adverse drug reaction reporting forms were assessed for causality. The questionnaire response rate was 91%, and the completion rate was 100%. A total of 59% of patients experienced sleep disturbances during propranolol treatment, which were considered adverse reactions. Sleep disorders were frequent during sleep regression phases and in subjects who fell asleep during physical contact with caregivers or bed-sharing with parents. The application of this questionnaire allows for identifying adverse sleep events associated with propranolol in IHs and potential confounders. Counselling on sleep hygiene is recommended before treatment onset.

A Digital Cognitive Behavioral Therapy Program for Adults With Alcohol Use Disorder

Cognitive behavioral therapy (CBT) is an evidence-based treatment for alcohol use, yet patient access is limited and may be enhanced through digital therapeutics. To evaluate the efficacy of a digital CBT program (Computer-Based Training for Cognitive Behavioral Therapy [CBT4CBT]) or clinician-delivered CBT compared with standard treatment for reducing alcohol use. A 3-arm randomized clinical trial was conducted at outpatient substance use treatment facilities in Connecticut between February 14, 2017, and December 31, 2021, that included an 8-week treatment period with a 6-month follow-up period. Treatment-seeking adults were included who met criteria for current alcohol use disorder and reported drinking at least 14 (men) or 7 (women) drinks per week in the past month and were sufficiently stable for outpatient treatment. Participants were randomly assigned to 1 of the following groups: (1) treatment as usual (TAU) consisting of weekly group or individual counseling, (2) CBT delivered weekly by trained and fidelity-monitored clinicians, or (3) web-based CBT plus brief weekly clinical monitoring. Rates of alcohol use were measured weekly during the treatment period and at 1-, 3-, and 6-month follow-up using the timeline follow-back method. The primary outcome was the percentage of days abstinent (PDA) from alcohol per month. Intention-to-treat analyses were conducted. Of the 99 randomized participants (mean [SD] age, 45.5 [12.7]), 66 were male (66.7%); 39 identified as Black/African American (39.8%), 19 (19.2%) as Hispanic, and 47 (48.0%) as White. Mean (SD) rates of PDA from baseline to 6-month follow-up were 49.3% (27.8%) to 69.6% (34.4%) for TAU; 53.7% (29.8%) to 70.2% (35.1%) for CBT; and 47.6% (31.8%) to 82.6% (25.3%) for digital CBT. Results of random-effects regression showed a significant increase in PDA during the study period, with those assigned to digital CBT increasing PDA at a faster rate than TAU (t733 = 2.55; P = .01) and CBT (t733 = 3.36; P < .001). However, there was no statistically significant difference between treatment groups during the 8-week treatment period. In this randomized clinical trial, while there was no significant difference between treatment groups during the 8-week treatment period, there was differential change between treatments during the 8-month study period that provides support for the efficacy of this digital CBT program. ClinicalTrials.gov Identifier: NCT02742246.

O74 EPOXYEICOSATRIENOIC ACIDS ANALOGUE (EET-A) FOR THE TREATMENT OF CHEMOTHERAPY-INDUCED HEART FAILURE WITH NEPHROTIC SYNDROME

Background and Objective: Doxorubicin (DOXO) is still commonly used anthracycline for the treatment of many types of cancers, but its application is burdened with a high risk of cardiotoxicity. The exact mechanisms of DOXO cardiotoxicity are still under investigation. Currently it is believed that the formation of topoisomerase II beta complex with DOXO, together with increased levels of reactive oxygen species (ROS) leads to cardiotoxicity. However, many additional mechanisms can weaken the heart and contribute to HFrEF development. Few years ago, new hypothesis emerged linking the DOXO-cardiotoxicity with the diminished expression of CYP2J2, an isoform of cytochrome P450, which is responsible for epoxyeicosatrienoic acids (EETs) formation. EETs were shown to exhibit vasodilation, decrease inflammation and to promote sodium excretion. Cardiac CYP2J2 overexpression decreased the cardiac injury in DOXO-treated mice. Hence, we decided to test the effectiveness of the EETs analogue (EET-A) in a model of DOXO-induced HFrEF with nephrotic syndrome. Methods: DOXO was administered to male Ren-2 transgenic rats (TGR) via five intravenous injections (cumulative dose 10 mg/kg of body weight). The long-term survival (20 weeks) of rats treated with EET-A (10 mg/kg of body weight administered in drinking water) was compared to ACE inhibitor (ACEi). Cardiac function was evaluated by echocardiography, urine and blood were collected for analysis. Results: The treatment with EET-A did not improve survival and cardiac function measured by echocardiography, however there was a clear renoprotective effect observed. Albuminuria was significantly lower in the EET-A treated group, when compared to ACEi. Plasma albumin did not change after 4-week treatment with EET-A, whereas in both placebo and ACEi a significant decrease was recorded. Conclusions: Despite the lack of improvement of survival, the beneficial effect of EET-A on the kidneys supports its potential for nephrotic syndrome treatment. Supported by MH CZ - DRO (“Institute for Clinical and Experimental Medicine - IKEM, IN 00023001”)

Promotion and Mechanism of Acupotomy on Chondrocyte Autophagy in Knee Osteoarthritis Rabbits.

To explore the effect of acupotomy intervention on autophagy of chondrocytes in rabbits with knee osteoarthritis (KOA), and to determine the possible mechanisms of acupotomy to alleviate cartilage degeneration. The modified Videman method was used to construct a KOA rabbit model. After modeling, 40 rabbits were randomly divided into 4 groups by a random number table: control; KOA (model); KOA + acupotomy (acupotomy), and KOA + sham acupotomy (sham), 10 in each group. After a 3-week treatment course, the knee joint activity was determined by the modified Lequesne MG index. Hematoxylin-eosin staining staining was used to examine the morphological changes of chondrocytes. Autophagy of chondrocytes was observed by transmission electron microscopy. The surface morphology of cartilage tissue was observed by scanning electron microscope. The mRNA and protein levels of AMP kinase/mammalian target of rapamycin/Unc-51 (AMPK/mTOR/ULK1) signal pathway key proteins, autophagy-related factor Beclin-1 and microtubule-associated protein 1A/1B light chain 3 (LC3) in rabbit knee cartilage were assessed by real-time fluorescence quantitative polymerase chain reaction and Western blot, respectively. The modified Lequesne MG score of acupotomy group was significantly lower than that of model group (P<0.05). Pathological results showed that chondrocyte autophagy decreased and cartilage surface was rough in the model group, which recovered after acupotomy treatment. The mRNA expressions of AMPK, ULK1, Beclin-1 and the protein levels of p-AMPK, p-ULK1, Beclin-1, and LC3 II/LC3 I were decreased in the model group, while the mRNA and protein expressions of mTOR were increased (P<0.01). However, acupotomy treatment reversed these abnormal changes (P<0.05). Acupotomy could effectively up-regulate the expressions of AMPK, ULK1 and Beclin1, reduce the expression of mTOR, promote autophagy, and alleviate joint degeneration. Acupotomy is a promising complementary and alternative therapy for KOA.

Rationale and Design of the COPERNIC Trial: A Study of On-treatment ctDNA Changes in Chemo-refractory Colorectal Cancer Patients

BackgroundEvidence suggests that ctDNA may be a reliable biomarker to monitor metastatic colorectal cancer (CRC) evolution. Nevertheless, evidence on the potential of liquid biopsy in this setting is still low quality, mostly consisting of retrospective studies. MethodsCOPERNIC is an international, multicenter clinical trial. The pilot study aims to confirm the predictive potential of early on-treatment ctDNA dynamics, and inform the design of a larger ctDNA-driven trial. Advanced CRC patients who are candidates for ≥3rd lines of systemic therapy undergo longitudinal blood sample collection during treatment (day 1, 15 and 29 for 2- or 4-weekly treatment regimens; day 1, 22 and 43 for 3-weekly treatment regimens) and at each imaging assessment. ctDNA analyses are carried out with the FoundationOne Liquid CDx and FoundationOneMonitor assays, and ctDNA changes during treatment are correlated with radiologic response (as assessed every 8-12 weeks by RECIST v1.1). The primary objective is to select the optimal timepoint and cut-off value for early ctDNA changes (at day 15/22) to predict progressive disease as best radiological response with a high positive predictive value. The cut-off value for ctDNA will be defined based on nonparametric ROC-curves with bootstrapping. Based on the expected rate of progressive disease and statistical assumptions, 109 patients are needed to be screened to have 87 assessable patients. COPERNIC is sponsored by the Institut Jules Bordet, and supported by Roche and Foundation Medicine. Recruitment is open in 13 centres across Belgium and France. The study is registered with clinicaltrials.gov (NCT05487248).

Acupuncture for overactive bladder in adults: Study protocol for a randomized controlled trial

BackgroundOveractive bladder (OAB) is a prevalent condition that substantially degrades patient quality of life. Acupuncture is recognized as an effective therapeutic approach for various urological diseases. However, there is limited evidence validating the effectiveness and safety of acupuncture for OABs. ObjectiveTo assess the therapeutic efficacy of acupuncture for OAB and to investigate the potential mechanisms by analyzing its effects on relevant urinary biomarkers. MethodsThis is a randomized, participants and outcome assessors blinded, sham acupuncture controlled trial. A total of 110 patients with OABs will be randomly divided in a 1:1 ratio between the acupuncture and sham acupuncture groups. Participants in the acupuncture group will undergo 30-min authentic acupuncture, while their counterparts in the sham acupuncture group will undergo sham acupuncture needling non-acupoints superficially three times weekly for a duration of 8 weeks. The two co-primary outcomes will be the change in the mean number of micturitions per 24 h from baseline to the end of the 8-week treatment and 20-week follow-up. The secondary outcomes will encompass the change in Overactive Bladder Symptom Score, Overactive Bladder Questionnaire Short Form, and average 24 h values of urgency, daytime micturition, nocturia, and mean volume voided per micturition from baseline to weeks 8 and 20. Urinary nerve growth factor, brain-derived neurotrophic factor, and monocyte chemoattractant protein-1 levels will be measured at baseline and week 8. Adverse events will also be documented. DiscussionThe results of this trial provide evidence for the effectiveness and safety of acupuncture in the management of OAB.

Abstract P377: Short-Chain Fatty Acids Improve Cardiac Function in a Hypertensive Rat Model of Heart Failure

Hypertension-induced ventricular remodeling contributes significantly to the progression of heart failure (HF). The global increase in HF prevalence results in heightened cardiovascular morbidity and mortality, yet treatment options remain limited. The gut microbiota ferments indigestible dietary fibers, producing essential metabolites such as short-chain fatty acids (SCFAs), amino acids metabolites. We hypothesize that direct oral administration of SCFAs modulates mucosal immune cells, thereby ameliorating the heart failure with preserved ejection fraction (HFpEF) phenotype in the double-transgenic rat (dTGR) model. Four-week-old male rats, double-transgenic for human renin and angiotensinogen (dTGRs), were utilized. These dTGR rats exhibit classical symptoms of HFpEF, including hypertension, inflammation, and fibrosis in the heart and kidneys. The rats were randomized into five experimental groups: healthy non-transgenic vehicle-treated controls (wild type), vehicle-treated dTGR, and dTGR treated with either acetate, propionate, or butyrate. Following a 3-week treatment period, comprehensive phenotyping was conducted, including echocardiography, Millar-tip catheterization, gene expression analysis, and histological examination. SCFA administration improves diastolic function, as evidenced by alterations in the end-diastolic pressure-volume relationship measured via Millar-tip catheter. Notably, butyrate treatment had the most pronounced effect on alleviating diastolic dysfunction and reducing blood pressure. Additionally, gene expressions such as atrial natriuretic peptide, connective tissue growth factor, and myosin heavy chain alpha and beta showed improvement in SCFA-treated dTGR HFpEF rats compared to vehicle-treated counterparts. Furthermore, SCFA treatment ameliorated cardiac inflammation. Our data suggest that SCFAs, particularly butyric acid, enhance hypertensive diastolic dysfunction and cardiac gene expression in dTGR rats, underscoring their therapeutic potential in HF.

Abstract 18: Persistent beneficial effects of angiotensinogen small interfering RNA (siRNA) and valsartan in spontaneously hypertensive rats after drug removal

Objective: Dual blockade of the renin-angiotensin system (RAS) with siRNA targeting hepatic angiotensinogen (AGT) plus the angiotensin receptor blocker valsartan synergistically lowers blood pressure and diminishes cardiac hypertrophy in spontaneously hypertensive rats (SHR). Since the effects of one siRNA injection may last for up to six months, here we evaluated whether the REVERSIR (reverse siRNA silencing, RVR) technology and/or stopping valsartan might acutely reverse the effects of dual RAS blockade in SHR. Methods: Ten-week old SHR were subjected to a 3-week treatment with vehicle or AGT-siRNA (10 mg/kg) + valsartan (4 mg/kg per day), followed by administration of vehicle or AGT-RVR at doses of 1, 10 and 20 mg/kg, both with and without continuation of valsartan, for 1 week. Mean arterial blood pressure (MAP) was monitored using radiotelemetry, and circulating AGT and renin were measured by enzyme-kinetic assay. Results: Baseline MAP was 143±2 mm Hg. Dual treatment lowered MAP by ≈70 mm Hg, cardiac hypertrophy (heart weight/tibia length) by ≈30%, and circulating AGT by &gt;99%, while renin increased &gt;100-fold versus vehicle. Discontinuing valsartan or applying AGT-RVR (1, 10 or 20 mg/kg) increased MAP similarly (by ≈20 mm Hg), while discontinuing valsartan + AGT-RVR (10 mg/kg) increased MAP by ≈40 mm Hg. Changes in cardiac hypertrophy mimicked those in MAP. Only valsartan discontinuation + AGT-RVR fully restored circulating AGT and renin to normal. When discontinuing valsartan only, AGT remained suppressed by &gt;95%, and renin was up 10-fold, while with AGT-RVR 1, 10 and 20 mg/kg only, AGT suppression was 25, 50 and 50%, while renin was up 25-, 15- and 15-fold, respectively. Conclusions: Discontinuing valsartan or applying AGT-RVR in SHR treated with valsartan + AGT siRNA partially restored MAP, AGT, and renin, likely reflecting the fact that this approach replaces dual RAS blockade by single RAS blockade. However, although discontinuing valsartan plus AGT-RVR fully restored RAS activity, MAP and cardiac hypertrophy remained suppressed under this condition. This agrees with observations that early RAS inhibition resets genetic pathways and networks, allowing persistent blood pressure normalization even when treatment has stopped.

Which kinesiotaping technique is effective? Comparision of two different techniques in patients with carpal tunnel syndrome

Background &amp; Objective: Although different kinesiotaping (KT) techniques can be applied in the treatment of carpal tunnel syndrome (CTS), to our knowledge, there is no study in the literature showing the superiority of these techniques over each other. The aim of this study is to compare the effectiveness of KT techniques applied to the dorsal surface and palmar surface of the forearm in patients with CTS. Methods: Forty six patients (70 wrists) diagnosed with CTS were randomized into 3 groups. Fabricated night splint was applied to the first group, KT was applied to the palmar surface of the wrist to the second group, and KT was applied to the dorsal surface of the wrist to the third group. Clinical, electrophysiological and ultrasonographic evaluations before treatment and at the end of 3-week treatment were compared. Results: In the comparison pre- and post-treatment, the changes in pain evaluated with Visual Analog Scale, and median motor nerve distal latency were significant in all groups, the change in median nerve sensory conduction velocity was significant in Groups 1 and 2, the change in median motor nerve conduction velocity was significant in only Group 2, the change in The Boston Carpal Tunnel Questionnaire (BCTQ)-Symptom Severity Status was significant in Group 1 and Group 3, the change in BCTQ-Functional Severity Scale and median nerve cross-sectional area was significant in only group 1. When the changes in treatment between the groups were compared, no statistically significant difference was found in any of the parameters. Conclusion: While splinting and different KT methods provided various benefits in CTS patients, they were not statistically superior to each other.

Carry-Over Effect of Deep Cerebellar Stimulation-Mediated Motor Recovery in a Rodent Model of Traumatic Brain Injury.

We previously demonstrated that deep brain stimulation (DBS) of lateral cerebellar nucleus (LCN) can enhance motor recovery and functional reorganization of perilesional cortex in rodent models of stroke or TBI. Considering the treatment-related neuroplasticity observed at the perilesional cortex, we hypothesize that chronic LCN DBS-enhanced motor recovery observed will carry-over even after DBS has been deactivated. Here, we directly tested the enduring effects of LCN DBS in male Long Evans rats that underwent controlled cortical impact (CCI) injury targeting sensorimotor cortex opposite their dominant forepaw followed by unilateral implantation of a macroelectrode into the LCN opposite the lesion. Animals were randomized to DBS or sham treatment for 4 weeks during which the motor performance were characterize by behavioral metrics. After 4 weeks, stimulation was turned off, with assessments continuing for an additional 2 weeks. Afterward, all animals were euthanized, and tissue was harvested for further analyses. Treated animals showed significantly greater motor improvement across all behavioral metrics relative to untreated animals during the 4-week treatment, with functional gains persisting across 2-week post-treatment. This motor recovery was associated with the increase in CaMKIIα and BDNF positive cell density across perilesional cortex in treated animals. LCN DBS enhanced post-TBI motor recovery, the effect of which was persisted up to 2 weeks beyond stimulation offset. Such evidence should be considered in relation to future translational efforts as, unlike typical DBS applications, treatment may only need to be provided until such time as a new function plateau is achieved.

Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle.

Nemaline myopathy (NM) is a genetic muscle disease, primarily caused by mutations in the NEB gene (NEB-NM) and with muscle myosin dysfunction as a major molecular pathogenic mechanism. Recently, we have observed that the myosin biochemical super-relaxed state was significantly impaired in NEB-NM, inducing an aberrant increase in ATP consumption and remodelling of the energy proteome in diseased muscle fibres. Because the small-molecule Mavacamten is known to promote the myosin super-relaxed state and reduce the ATP demand, we tested its potency in the context of NEB-NM. We first conducted in vitro experiments in isolated single myofibres from patients and found that Mavacamten successfully reversed the myosin ATP overconsumption. Following this, we assessed its short-term in vivo effects using the conditional nebulin knockout (cNeb KO) mouse model and subsequently performing global proteomics profiling in dissected soleus myofibres. After a 4week treatment period, we observed a remodelling of a large number of proteins in both cNeb KO mice and their wild-type siblings. Nevertheless, these changes were not related to the energy proteome, indicating that short-term Mavacamten treatment is not sufficient to properly counterbalance the metabolically dysregulated proteome of cNeb KO mice. Taken together, our findings emphasize Mavacamten potency in vitro but challenge its short-term efficacy in vivo. KEY POINTS: No cure exists for nemaline myopathy, a type of genetic skeletal muscle disease mainly derived from mutations in genes encoding myofilament proteins. Applying Mavacamten, a small molecule directly targeting the myofilaments, to isolated membrane-permeabilized muscle fibres from human patients restored myosin energetic disturbances. Treating a mouse model of nemaline myopathy in vivo with Mavacamten for 4weeks, remodelled the skeletal muscle fibre proteome without any noticeable effects on energetic proteins. Short-term Mavacamten treatment may not be sufficient to reverse the muscle phenotype in nemaline myopathy.

IFNL4 genotype and other personal characteristics to predict response to 8-week sofosbuvir-based treatment for chronic hepatitis C

Shorter duration therapy for hepatitis C virus (HCV) infection might reduce treatment costs and increase the number of patients treated and cured. We determined factors associated with treatment response after an 8-week sofosbuvir-based therapy and developed a simple model to predict an individual's likelihood of treatment success. Among 2907 patients who received ledipasvir/sofosbuvir for 8 weeks, we determined failure rates by demographic and clinical characteristics, and IFNL4-∆G/TT genotype. We estimated the average IFNL4 genotype-related treatment failure rate in major ancestry groups by applying our IFNL4 genotype results to genotype distributions from reference populations. We created a treatment response model based on three personal characteristics. Overall, 4.4% of the patients failed treatment. We observed significantly lower failure rates for persons <50 years (1.6%), females (2.6%), those carrying the IFNL4-TT/TT genotype (1.8%), those with HCV RNA <5.8log10 copies/mL (2.0%) or HCV genotype-1B infection (2.6%). In a model based on ancestry, age and sex, the predicted probability of treatment failure ranged from 0.5% among females of East Asian ancestry <50 years of age to 8.5% among males of African ancestry age ≥65 years. Applying this algorithm at the point-of-care might facilitate HCV elimination, especially in low- and middle-income countries.

Virtual reality improves sleep quality and associated symptoms in patients with chronic insomnia

PurposeThe present study aimed to explore the effectiveness of virtual reality (VR) therapy on sleep quality and associated symptoms, such as depression and anxiety, cognitive decline and autonomic nervous dysfunction, in chronic insomnia patients. MethodsSixty-three chronic insomnia patients were randomly divided into VR group (n = 32) and control group (n = 20) based on a standard drug therapy. Patients were instructed to use VR at home once a day at evening for 6-week treatment. All participants received evaluations of subjective sleep quality measured with the Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI), and the Epworth Sleepiness Scale (ESS), depression and anxiety symptoms measured with the Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA), cognitive function, and objective sleep structure and autonomic nerve function examination measured with the sleep respiration monitoring device at baseline and after 6-week treatment. The main objective of this study was sleep quality assessment as the primary outcome. ResultsAfter 6-week treatment, the decreases in PSQI score (−5.60 ± 2.37 vs −4.10 ± 1.80, P = 0.020) and ISI score (−8.81 ± 4.52 vs −6.35 ± 2.89, P = 0.038) of the VR group were significantly greater compared with the control group. The VR group showed more reduction in HAMD score (−9.96 ± 4.41 vs −7.50 ± 2.89, P = 0.035) and HAMA score (−8.96 ± 3.80 vs −6.80 ± 3.22, P = 0.046), and more increase in processing speed (0.54 ± 0.60 vs 0.00 ± 0.79, P = 0.011) than the control group. Moreover, the low-frequency coupling (−10.00 ± 17.40 vs. 8.25 ± 20.03, P = 0.001) was lowered and the high-frequency coupling (9.99 ± 17.40 vs. −8.24 ± 20.03, P = 0.001) was elevated in the VR group relative to the control group. ConclusionOur findings offered preliminary evidence that VR therapy enhanced sleep quality and also lessened depressive and anxious symptoms, and improved cognitive and autonomic functioning in patients with chronic insomnia.

The Injected Plasma of Myasthenia Gravis Patient with A Low T-reg Level Caused Clinical Myasthenic Syndromes in Swiss-Webster Mice

BACKGROUND: Myasthenia gravis (MG) is a rare autoimmune disease affecting neuromuscular junction involvement. The finding that T-reg level in MG patients was lower than that in normal persons leads to the idea that the primary pathology of the disease is T-reg dependent. The T-reg level of MG patients seems to be decreasing compared to that of normal persons. The study was conducted to observe the contribution of T-reg level in plasma injected into Swiss-Webster mice to develop clinically and pathologically myasthenic syndromes.METHODS: Swiss-Webster mice were grouped into three groups: the groups received plasma with normal, low, and high T-reg levels, respectively. The T-reg levels of the mice were measured with flow cytometry analysis and a human regulatory T-cell cocktail for T-cell surface cell marker. The motor function, interleukin (IL)-2, interferon (IFN)-γ, and thymus weight of mice were measured after the injection. Histopathological examination was performed to analyze mice’s muscles and thymus.RESULTS: The result identified that the motor function (2-week treatment group: p=0.021 and 3-week treatment group: p=0.032) and muscle width (p=0.014, p=0.032 and p≤0.001) were significantly lower in the low T-reg level plasma group compared to control and high T-reg level plasma groups. The thymus showed an increase in weight without an increase in the cortex-medulla ratio of the thymus, indicating hyperplasia. Both IL-2 and IFN-γ levels were lower in the low and high T-reg level groups compared with the control group, indicating the autoimmune process.CONCLUSION: Low T-reg level was associated with lower motor function, muscle width, increased thymus weight, as well as lower IL-2 and IFN-γ levels. T-reg level contributed to clinical myasthenic syndromes but not pathological findings. This research method is expected to be a basis for the development of animal models with Swiss-Webster mice.KEYWORDS: animal model, Myasthenia gravis, Swiss-Webster mice