Add-on Effect Research Articles

SGLT2i and GLP1-RA exert additive cardiorenal protection with a RAS blocker in uninephrectomized db/db mice.

Diabetic Kidney Disease (DKD) is the main cause of end-stage renal disease in the developed world. The current treatment of the DKD with renin-angiotensin system (RAS) blockade does not totally halt the progression to end stage kidney disease. Currently, several drugs have shown to delay DKD progression such as sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like-1 receptor agonists (GLP-1RA). We hypothesized that by combining several drugs that prevent DKD progression on top of RAS blockade a synergistic effect would be achieved in terms of cardiorenal protection. In the present study, we analysed if the combination of a RAS blocker (ramipril) with a SGLT2i (empagliflozin) and/or GLP-1RA (semaglutide) in a type 2 diabetic mouse model could have add-on effects in kidney and heart protection. Male and female uninephrectomized type 2 diabetic db/db mice were treated with empagliflozin and/or semaglutide on top of ramipril during 8weeks. During the study body weight, water and food intake were weekly monitored, glycaemia biweekly and albuminuria and glomerular filtration rate (GFR) before and after the treatment. At the end of the experiment, kidney and heart were isolated for histological and gene expression studies as well as for intrarenal RAS state assessment. Semaglutide combined with ramipril and/or empagliflozin significantly decreased albuminuria but only when combined with both compounds, semaglutide further decreased blood glucose, glomerular hyperfiltration in male mice and glomerular mesangial matrix expansion. In kidney, only the triple treatment with empagliflozin, semaglutide and ramipril reduced the expression of the proinflammatory and profibrotic genes ccl2 and TGFß1. In addition, the combination of empagliflozin and semaglutide on top of RAS blockade was superior in decreasing cardiomyocyte hypertrophy and heart fibrosis in db/db mice. Our results suggest that the combination of SGLT2i with GLP-1RA is superior in cardiorenal protection in DKD than the drugs administered alone on top of RAS blockade.

Effects of high-definition tDCS targeting individual motor hotspot with EMG-driven robotic hand training on upper extremity motor function: a pilot randomized controlled trial

BackgroundDelivering HD-tDCS on individual motor hotspot with optimal electric fields could overcome challenges of stroke heterogeneity, potentially facilitating neural activation and improving motor function for stroke survivors. However, the intervention effect of this personalized HD-tDCS has not been explored on post-stroke motor recovery. In this study, we aim to evaluate whether targeting individual motor hotspot with HD-tDCS followed by EMG-driven robotic hand training could further facilitate the upper extremity motor function for chronic stroke survivors.MethodsIn this pilot randomized controlled trial, eighteen chronic stroke survivors were randomly allocated into two groups. The HDtDCS-group (n = 8) received personalized HD-tDCS using task-based fMRI to guide the stimulation on individual motor hotspot. The Sham-group (n = 10) received only sham stimulation. Both groups underwent 20 sessions of training, each session began with 20 min of HD-tDCS and was then followed by 60 min of robotic hand training. Clinical scales (Fugl-meyer Upper Extremity scale, FMAUE; Modified Ashworth Scale, MAS), and neuroimaging modalities (fMRI and EEG-EMG) were conducted before, after intervention, and at 6-month follow-up. Two-way repeated measures analysis of variance was used to compare the training effect between HDtDCS- and Sham-group.ResultsHDtDCS-group demonstrated significantly better motor improvement than the Sham-group in terms of greater changes of FMAUE scores (F = 6.5, P = 0.004) and MASf (F = 3.6, P = 0.038) immediately and 6 months after the 20-session intervention. The task-based fMRI activation significantly shifted to the ipsilesional motor area in the HDtDCS-group, and this activation pattern increasingly concentrated on the motor hotspot being stimulated 6 months after training within the HDtDCS-group, whereas the increased activation is not sustainable in the Sham-group. The neuroimaging results indicate that neural plastic changes of the HDtDCS-group were guided specifically and sustained as an add-on effect of the stimulation.ConclusionsStimulating the individual motor hotspot before robotic hand training could further enhance brain activation in motor-related regions that promote better motor recovery for chronic stroke.Trial registrationThis study was retrospectively registered in ClinicalTrials.gov (ID NCT05638464).

Oral Chinese herbal medicine combined with donepezil for mild cognitive impairment: A systematic review and meta-analysis.

This study aims to evaluate the add-on effects of oral Chinese herbal medicine (CHM) for mild cognitive impairment (MCI), when used in addition to donepezil compared to donepezil alone. Randomized controlled trials comparing these treatments across all types of MCI were identified from nine databases and three registers until August 2023. Outcome measures were Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and adverse events (AEs). Methodological quality was assessed using Cochrane risk-of-bias tool, and evidence certainty was evaluated using the GRADE method. Involving 1611 participants across 20 studies, meta-analysis results indicate that oral CHM combined with donepezil significantly improved cognitive function in MCI patients compared to donepezil alone, as evidenced by MMSE (1.88 [1.52, 2.24], I2 = 41%, 12 studies, 993 participants) and MoCA (MD: 2.01 [1.57, 2.44], I2 = 52%, 11 studies, 854 participants). Eleven studies reported details of AEs, identifying gastrointestinal symptoms and insomnia as the most common symptoms. No significant difference in AEs frequency was found between the groups (RR: 0.91 [0.59, 1.39], I2 = 4%, 11 studies, 808 participants). All 20 studies were evaluated as having "some concerns" regarding the overall risk of bias. The certainty of evidence for MMSE was "moderate" and "low" for MoCA. From frequently utilized herbs, two classical CHM formulae were identified: Kai xin san and Si wu decoction. The observed treatment effects of commonly used herbs may be exerted through multiple pharmacological mechanisms, including anti-inflammatory, anti-oxidative stress, anti-apoptotic actions, promotion of neuronal survival and modulation of the cholinergic system. The concurrent use of oral CHM and donepezil appears to be more effective than donepezil alone in improving the cognitive function of MCI, without leading to an increase in AEs. While recognizing concerns of overall methodological quality, this combined therapy should be considered as an alternative option for clinical practice.

Early Boost of Linguistic Skills? Individualized Non-Invasive Brain Stimulation in Early Postacute Aphasia.

Non-invasive brain stimulation, such as transcranial direct current stimulation (tDCS), has been shown to increase the outcome of speech and language therapy (SLT) in chronic aphasia. Only a few studies have investigated the effect of add-on tDCS on SLT in the early stage of aphasia; this may be due to methodological reasons, in particular the influence of spontaneous remission and the difficulty of establishing stimulation protocols in clinical routines. Thirty-seven participants with subacute aphasia (PwA) after stroke (23 men, 14 women; mean age 62 ± 12 years; mean duration 49 ± 28 days) were included in two consecutive periods of treatment lasting two weeks each. During the first period (P1) the participants received 10 sessions of SLT, during the second period (P2) the aphasia therapy was supplemented by anodal left hemispheric 2 mA tDCS over the left hemisphere. Severity-specific language tests (Aachen Aphasia Test (AAT), n = 27 and Bielefeld Aphasia Screening-Reha (BIAS-R), n = 10) were administered before P1, between P1 and P2, and after P2. Where information was available, the results were corrected for spontaneous remission (AAT sample), and the therapy outcomes of P1 and P2 were compared. Participants' overall language abilities improved significantly during P1 and P2. However, improvement-as measured by the AAT profile level or the BIAS-R mean percentage value-during P2 (with tDCS) was significantly higher than during P1 (p < 0.001; AAT sample and p = 0.005; BIAS-R sample). Thus, tDCS protocols can be implemented in early aphasia rehabilitation. Despite the limitations of the research design, which are also discussed from an implementation science perspective, this is preliminary evidence that an individually tailored anodal tDCS can have a significant add-on effect on the outcome of behavioral aphasia therapy in subacute aphasia.

Add-on effect of using 0.05% atropine in fast progressors of orthokeratology: A preliminary retrospective study

PurposeTo investigate the potential benefit of combining orthokeratology (OK) lenses with 0.05% atropine ophthalmic solution on the efficacy of myopia control in the fast progressors of OK. MethodsAverage axial length (AL) elongation of both eyes in 70 participants using OK lenses alone or OK lenses combined with 0.05 % atropine ophthalmic solution was retrospectively reviewed. During the observation period (phase 1), all participants exhibited an AL elongation that exceeded 0.15 mm over a 6-month period or 0.3 mm over a 12-month period. Subsequently, the participants were divided into two groups: one group received nightly 0.05 % atropine ophthalmic solution in addition to OK lenses for another 1 year (OKA), while the other group continued using OK lenses alone (phase 2). The changes in AL elongation over time and the differences in AL elongation between the two groups were then compared. ResultsThe baseline and phase 1 demographics and characteristics of the participants was similar between the two groups (all p > 0.05). when considering a one-year timeframe, the OKA group displayed a significantly less AL elongation compared to the OK group (0.14 ± 0.13 mm vs 0.27 ± 0.12 mm, p < 0.001). Within the OKA group, the AL elongation in the second half of the year was significantly faster than in the first half (0.12 ± 0.11 mm vs 0.02 ± 0.14 mm, p = 0.01). Conversely, there was no significant difference in AL elongation between the OK group in the first and second half of the year (0.12 ± 0.07 mm vs 0.15 ± 0.08 mm, p = 0.71). The combination of 0.05 % atropine ophthalmic solution had a significant effect on 1-year AL elongation (p < 0.001). ConclusionsThis study provided preliminary evidence that the combination of OK lenses and 0.05% atropine ophthalmic solution can significantly enhance the effectiveness of myopia control.

Cognitive Behavioral Psychotherapy as an Add-on in Comprehensive Outpatient Care of Non-affective Psychoses: A Multicenter Randomized-Controlled Effectiveness Trial in a Naturalistic Setting.

Non-affective psychoses (NAP) are associated with severe consequences with regard to social functioning, physical health, employment, and suicidality. Treatment guidelines recommend cognitive behavioral therapy for psychosis (CBTp) as an effective additional treatment strategy to psychopharmacology. We hypothesized that outpatient CBTp has an add-on effect in individuals with NAP who already receive comprehensive outpatient care (COC) in Germany. In a randomized-controlled effectiveness trial, 6 months of COC + CBTp were compared to COC. The primary outcomes were change of symptom severity as assessed by the Positive and Negative Symptom Scale (pre-/post-treatment and 6-month follow-up). Mixed linear models and effect sizes were used to compare changes across treatment groups. Additionally, the number of readmissions was compared. N = 130 individuals with chronic NAP were recruited (COC + CBTp: n = 64, COC: n = 66). COC + CBTp participants significantly improved more regarding positive symptom severity (estimated mean difference at follow-up: -2.33, 95% CI: -4.04 to -0.61, P = .0083, d = 0.32) and general psychopathology (estimated mean difference at follow-up: -4.55, 95% CI: -7.30 to -1.81, P = .0013, d = 0.44) than the COC group. In both groups, negative symptom severity did not change significantly over time nor did groups differ regarding readmissions. The results underline an add-on benefit of CBTp in chronically ill individuals with NAP. Superiority of CBTp was demonstrated in comparison with high-quality comprehensive care and may also be true in different comprehensive care settings. DRKS00015627.

The add-on effect of an intranasal antihistamine with an intranasal corticosteroid in Japanese cedar pollinosis

The add-on effect of an intranasal antihistamine with an intranasal corticosteroid in Japanese cedar pollinosis

Effectiveness of Extracorporeal Shock Wave Therapy after Botulinum Toxin Injection for Post-Stroke Upper Extremity Spasticity: A Randomized Controlled Study.

Post-stroke spasticity is a common complication that limits the functional performance of patients. Botulinum toxin (BTx) is an effective treatment for spasticity. Numerous researchers have applied extracorporeal shock wave therapy (ESWT) to address post-stroke spasticity, yielding positive clinical outcomes. We aimed to clarify the add-on effects of ESWT on BTx therapy for spasticity in patients with post-stroke. Sixteen eligible patients with upper extremity spasticity after stroke were recruited for this study. They were randomized to either a BTx with focused ESWT treatment group or a BTx alone group. Spasticity, measured using the modified Ashworth score (MAS) and modified Tardieu scale (MTS), showed statistically significant improvements in the elbow and wrist flexor muscles in both BTx + ESWT group and BTx alone groups. However, no significant differences were observed between the two groups with time flow. The BTx + ESWT group showed significantly decreased MAS of the finger flexors at follow-up and increased R1 (MTS) of the finger flexors at 3 weeks after treatment, which was not observed in the BTx alone group. This is the first study to identify the add-on effect of ESWT on BTx injections to improve post-stroke upper limb spasticity.

Chitin-mediated blockade of chitinase-like proteins reduces tumor immunosuppression, inhibits lymphatic metastasis and enhances anti-PD-1 efficacy in complementary TNBC models

BackgroundChitinase-like proteins (CLPs) play a key role in immunosuppression under inflammatory conditions such as cancer. CLPs are enzymatically inactive and become neutralized upon binding of their natural ligand chitin, potentially reducing CLP-driven immunosuppression. We investigated the efficacy of chitin treatment in the context of triple-negative breast cancer (TNBC) using complementary mouse models. We also evaluated the immunomodulatory influence of chitin on immune checkpoint blockade (ICB) and compared its efficacy as general CLP blocker with blockade of a single CLP, i.e. chitinase 3-like 1 (CHI3L1).MethodsFemale BALB/c mice were intraductally injected with luciferase-expressing 4T1 or 66cl4 cells and systemically treated with chitin in combination with or without anti-programmed death (PD)-1 ICB. For single CLP blockade, tumor-bearing mice were treated with anti-CHI3L1 antibodies. Metastatic progression was monitored through bioluminescence imaging. Immune cell changes in primary tumors and lymphoid organs (i.e. axillary lymph nodes and spleen) were investigated through flow cytometry, immunohistochemistry, cytokine profiling and RNA-sequencing. CHI3L1-stimulated RAW264.7 macrophages were subjected to 2D lymphatic endothelial cell adhesion and 3D lymphatic integration in vitro assays for studying macrophage-mediated lymphatic remodeling.ResultsChitin significantly reduced primary tumor progression in the 4T1-based model by decreasing the high production of CLPs that originate from tumor-associated neutrophils (TANs) and Stat3 signaling, prominently affecting the CHI3L1 and CHI3L3 primary tumor levels. It reduced immunosuppressive cell types and increased anti-tumorigenic T-cells in primary tumors as well as axillary lymph nodes. Chitin also significantly reduced CHI3L3 primary tumor levels and immunosuppression in the 66cl4-based model. Compared to anti-CHI3L1, chitin enhanced primary tumor growth reduction and anti-tumorigenicity. Both treatments equally inhibited lymphatic adhesion and integration of macrophages, thereby hampering lymphatic tumor cell spreading. Upon ICB combination therapy, chitin alleviated anti-PD-1 resistance in both TNBC models, providing a significant add-on reduction in primary tumor and lung metastatic growth compared to chitin monotherapy. These add-on effects occurred through additional increase in CD8α+ T-cell infiltration and activation in primary tumor and lymphoid organs.ConclusionsChitin, as a general CLP blocker, reduces CLP production, enhances anti-tumor immunity as well as ICB responses, supporting its potential clinical relevance in immunosuppressed TNBC patients.

Point prevalence of metabolic syndrome in HIV positive patients.

Human immunodeficiency virus (HIV)-related morbidity and mortality have declined over time, but this increased longevity may lead to the development of other diseases, which may further manifest as the metabolic syndrome (MS). To find out the point prevalence of MS in HIV positive patients, a cross-sectional prospective observational study was conducted on 200 patients who approached ART plus Centre of Government Medical College and Hospital Jammu, including 50 symptomatic patients HIV negative as controls. The mean age group in MS was 37.85 ± 6.61. Males consisted of 55% (110) and females consisted of 45% (90). The overall prevalence of MS was 13.5%, with prevalence in males being 16.3% and in females 10%. Patients receiving first line highly active antiretroviral therapy (HAART) showed a 24% prevalence, while that of second line HAART showed a 14% prevalence. Central obesity (47.3%) was the most common component of MS followed by hyperglycemia (43.3%), hypertriglyceridemia (38.6%), and low high density cholesterol (HDL-C) level (38.6%). Out of 84 males with MS, 94% (79) males were having hypertriglyceridemia, 88% (74) were hypertensive, and 72% (60) were having FBS >=100. Out of 66 females with MS, 100% (66) females had central obesity and 88% (58) had hypertriglyceridemia and low HDL-C levels. The metabolic complications as a result of treatment with HAART leave HIV patients at a risk of developing cardiovascular disease and diabetes in spite of improvements in morbidity and mortality. Risk factors like central obesity, hypertension, hyperglycemia, and hypertriglyceridemia should be taken into consideration well before to prevent the add-on effect of developing MS.

Limitation on C=N → B–O complex formation for isoindigo derivatives and its neglectable electron-withdrawing add-on effect

Attempts to merge three isoindigo derivatives, namely diazaisoindigo (DAII), thiazoloisoindigo (TzII) and hydroxyisoindigo (OHII), with CN → B–O complex for stronger acceptors show that only OHII can form stable CN → B–O complexation, however, no obvious electron-withdrawing capability enhancement was observed.

Abstract 5310: KK2269, an epithelial cell adhesion molecule-targeted CD40 agonist, demonstrates antitumor effects in combination with standard therapies for NSCLC

Abstract CD40 is a key molecule expressed on antigen presenting cells (APCs), whose signaling activates APCs and generates antitumor immune responses. Although CD40 agonists have been investigated in clinical trials, systemic toxicities have limited their full potential in providing adequate antitumor effects. To overcome this limitation, we developed KK2269, a bispecific antibody, using REGULGENT™ technology. KK2269 binds to CD40 and tumor-expressed epithelial cell adhesion molecule (EpCAM) to allow activation of CD40+ APCs only at EpCAM+ tumor sites, thus avoiding systemic toxicity. EpCAM is overexpressed in many types of epithelial cancers, including non-small cell lung cancer (NSCLC). KK2269 exerts synergistic antitumor activity and tumor-specific immune responses in combination with docetaxel, a common chemotherapy for NSCLC, in an EpCAM-expressing tumor mouse model. Hence, we aimed to evaluate KK2269 for the treatment of NSCLC. Docetaxel is used as a combination therapy with ramucirumab, an anti-VEGF receptor 2 (VEGFR2) antibody, for previously treated advanced NSCLC. In addition, many clinical studies are evaluating the add-on effects of PD-1/PD-L1 blockade combined with standard chemotherapies (including docetaxel) in NSCLC, which may become the standard of care for advanced NSCLC in the future. Therefore, we investigated the antitumor effect of KK2269 in combination with docetaxel + anti-mouse VEGFR2 (study 1) and with docetaxel + anti-mouse PD-1 (study 2) using a mouse EpCAM-expressing B16F10 tumor-bearing human CD40 transgenic mouse model. The prolongation of TTP5X (the day on which the tumor volume is observed to be ≥5-fold of that observed on day 0) was evaluated. In study 1, the median TTP5X (95% confidence interval [CI]) with the control, docetaxel + anti-VEGFR2, and triple combination (KK2269, docetaxel, anti-VEGFR2) was 10.0 days (7.0, 10.0), 26.0 days (17.0, 28.0), and 52.0 days (42.0, not calculable), respectively. The TTP5X was significantly prolonged with the triple combination compared with the control (p=0.000007, log-rank test) and docetaxel + anti-VEGFR2 (p=0.000004, log-rank test). In study 2, the median TTP5X (95% CI) was 7.0 days (not calculable), 9.0 days (6.0, 11.0), 16.0 days (7.0, 18.0), and 26.5 days (7.0, 32.0) with the control, KK2269, docetaxel + anti-PD-1, and triple combination (KK2269, docetaxel, anti-PD-1), respectively. TTP5X was significantly prolonged with the triple combination compared with the control, KK2269, and docetaxel + anti-PD-1 (p&amp;lt;0.0001, p=0.0003, and p=0.0023, respectively, log-rank test). Thus, a significant antitumor effect was demonstrated when KK2269 was added to the standard treatment of NSCLC (docetaxel + anti-VEGFR2 antibody) and to docetaxel + anti-PD-1 antibody. Our findings strongly suggest that KK2269 provides improved treatment options for patients with NSCLC. Citation Format: Yuta Tezuka, Kyoko Kawasaki, Yoshiki Sumitomo, Masato Saito, Akari Yao, Munetoshi Ando. KK2269, an epithelial cell adhesion molecule-targeted CD40 agonist, demonstrates antitumor effects in combination with standard therapies for NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5310.

Effect of branched-chain amino acid supplementation and exercise on quadriceps muscle quantity and quality in patients with cirrhosis as assessed by ultrasonography: A randomized controlled trial

Background/aimSarcopenia and myosteatosis are common in patients with cirrhosis. The study aimed to evaluate efficacy of ultrasound to monitor muscle status during branched-chain amino acid (BCAA) supplementation and/or muscle exercise interventional approaches. Patients & MethodsA randomized controlled study, included 220 liver cirrhosis patients with Child- Pugh B & C, randomized into a control group (55 patients) received only the standard care, and interventional groups (165 patients) equally distributed into three subgroups, in addition to standard care, they received BCAA, programmed exercise, or BCAA and programmed exercise. At baseline and after 28 days, all participants were subjected to ultrasound-measured quadriceps muscle thickness and echo-intensity, muscle strength using handgrip, performance using short physical performance battery (SPPB), MELD score and nutritional assessment using 7- subjective global assessment score (SGA) and laboratory assessment. ResultsAll interventional groups showed a significant improvement in the ultrasound detected quadriceps muscle thickness (p = 0.001) & echo intensity, in addition to muscle strength, muscle performance, and SGA. Hematological parameters (hemoglobin & platelet count), biochemical parameters (ALT, AST, bilirubin, creatinine, urea and INR) & MELD score were also improved in the interventional groups. In Child-Pugh B patients BCAA combined with exercise showed an add-on effect. ConclusionBCAA supplements, programed muscle exercise and both are useful interventional methods in improving muscle quality and quantity in cirrhosis patients, which can be monitored by ultrasound. The best results can be achieved by combined intervention in Child-Pugh B, while in Child-Pugh C single intervention may lead to an acceptable improvement. The trial was registered retrospectively in the Clinical Trials RegistryRegistration number NCT06088550).

Pharmacopuncture Therapy as an Adjunctive Treatment for Patients with Lumbar Spinal Stenosis: A Pragmatic Randomized Controlled Pilot Trial.

Pharmacopuncture therapy (PPT) combines medicinal extracts with acupuncture and is widely used as an adjunct in clinical practice. This study assessed the safety and feasibility of PPT in addition to conventional Korean Medicine treatment (CKMT), including electroacupuncture, cupping and infra-red, for lumbar spinal stenosis (LSS). Forty patients diagnosed with LSS were randomly assigned to undergo PPT with CKMT (experimental group) or CKMT alone (control group) at a 1:1 ratio, receiving 10 sessions of each intervention over five weeks. The primary clinical outcome was measured using the 100-mm Visual Analog Scale (VAS) for buttock and leg pain five weeks post-treatment. Secondary outcomes included clinically important difference (CID), Zurich Claudication Questionnaire, self-reported walking capacity, Modified-Modified Schober test, EuroQol 5-dimension 5-level questionnaire, and the patient's global impression of change. The adverse events were assessed at each visit. The analysis of covariance was conducted to compare between two groups. Intervention completion rates were 95% and 100% in the experimental and control groups, respectively. No statistically significant differences were found between groups regarding the primary outcome (adjusted mean difference: 8.0; 95% confidence interval: -1.4-17.4). The mean difference in the 100-mm VAS for low back pain at week 5 (adjusted mean difference: 12.9; 95% confidence interval: 2.4-23.4) and the proportion of patients who reached the minimum CID was higher in the experimental group than in the control group. However, no significant differences were observed with other secondary outcomes. One patient in the experimental group experienced a systemic skin rash that resolved the same day, whereas the adverse events in the other group were mild and transient. This trial demonstrated the feasibility of add-on effects and the safety of pharmacopuncture in patients with LSS. Further studies are warranted to evaluate the add-on effects of PPT in treating LSS. Clinical Research Information Service (CRIS), KCT0007229; registered on April 26, 2022.

Comparison of the long-term effects of atropine in combination with Orthokeratology and defocus incorporated multiple segment lenses for myopia control in Chinese children and adolescents.

The aim of this study was to evaluate the efficacy of Orthokeratology (Ortho-K), defocus incorporated multiple segment (DIMS) lens, combined Ortho-K/atropine, and combined DIMS/atropine for myopia control in children. A retrospective study included 167 myopic children aged 6-14 years with a spherical equivalent refraction (SER) of -0.75 to -4.00 diopter treated with Ortho-K (OK, n = 41), combined Ortho-K/atropine (OKA, n = 43), DIMS (n = 41), or combined DIMS/atropine (DIMSA, n = 42). Axial length (AL) was measured at baseline and at 3, 6, 9 and 12 months. Axial elongation over time and between groups were analysed. After 12 months, the AL change was 0.20 ± 0.12 mm, 0.12 ± 0.14 mm, 0.22 ± 0.14 mm, and 0.15 ± 0.15 mm in the OK, OKA, DIMS, and DIMSA, respectively. There was no significant difference in AL change between OK and DIMS. OKA and DIMSA significantly slowed axial elongation compared to OK and DIMS monotherapy. After stratification by age, in the subgroup aged 6-10 years, there was significant difference in AL change between OKA and DIMS (p = 0.013), and no difference between other groups, while in the subgroup aged 10-14 years, the difference between OKA and DIMS became insignificant (p = 0.237), and the difference between OK and OKA, OK and DIMSA, DIMS and DIMSA became significant. Ortho-K and DIMS lenses show similar reductions in myopia progression among children with low initial myopia. Atropine can significantly improve the efficacy of myopia control of both Ortho-K and DIMS lenses, and this add-on effect is better in older children.

Adding Chinese herbal medicine bath therapy to conventional therapies for psoriasis vulgaris: A systematic review with meta-analysis of randomised controlled trials

BackgroundChinese herbal medicine (CHM) bath is commonly used in China as an adjuvant therapy for managing psoriasis vulgaris. Previous systematic reviews showed that CHM bath therapy was effective and safe for psoriasis vulgaris, however, without exploration of the specifics of CHM bath therapy such as the optimal temperature, duration of each session, and the total treatment duration. PurposeTo evaluate the add-on effects of CHM bath therapy to conventional therapies for adult psoriasis vulgaris. MethodsWe conducted a comprehensive search in nine medical databases from inception to September 2022 to identify relevant randomised controlled trials (RCTs) published in Chinese or English. The included studies compared the combination of CHM bath therapy and conventional therapies to conventional therapies alone for adult psoriasis vulgaris. Methodological quality assessment of the included RCTs was performed using the Cochrane risk-of-bias tool 2 (RoB 2). Statistical analysis was carried out using RevMan 5.4, R 4.2.3 and Stata 12.0 software. The certainty of evidence of outcome measures was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation Working Group (GRADE) system. ResultsA total of 23 RCTs involving 2,183 participants were included in this systematic review. Findings suggested that the combination of CHM bath therapy and conventional therapies was more effective in reducing Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI) and itch visual analogue scale, compared to using conventional therapies alone. These enhanced effects were notably observed when the CHM bath was set above 38 °C and had a duration of 20 and 30 min, as assessed by DLQI. Moreover, an eight-week treatment duration resulted in better effects for PASI compared to shorter durations. Additionally, the top ten frequently used herbs in the included studies were identified. Despite the findings, the certainty of evidence was rated as ‘low’ or ‘moderate’ based on the GRADE assessment, and significant heterogeneity was detected in subgroup and sensitivity analyses. ConclusionThe CHM bath therapy combined with conventional therapies is more effective and safer than conventional therapies alone for adult psoriasis vulgaris. The results suggest a potential correlation between treatment effects and factors such as extended treatment duration, increased bath temperature, and longer bath sessions. However, the certainty of evidence was downgraded due to methodological limitations of the included studies. To confirm the findings of this systematic review, a double-blinded, placebo-controlled RCT is needed in the future.

Add-on effects of oral tocopherol supplementation to surgical varicocelectomy on the outcome of assisted reproductive technology: a single-center pilot study report.

Varicocelectomy is well known to improve the pregnancy outcome of patients with clinical varicoceles in assisted reproductive technologies as well as spontaneous conception. Therefore, this study aimed to evaluate the additional effects of oral antioxidant therapy after varicocelectomy on the pregnancy outcome in the assisted reproductive technology setting. This study was a retrospective cohort study. The subjects were couples among whom the male partner had undergone varicocelectomy and was scheduled for subsequent assisted reproductive technology. Pregnancy outcomes were followed retrospectively in 62 couples with male partners who received tocopherol (antioxidant group) and 37 couples who did not (control group). The tocopherol and control groups were assigned dependent on the decision of the physician in charge and the patient's request. The clinical pregnancy rates per couple and embryo transfer, time to pregnancy, and the number of cycles during transfer to pregnancy were evaluated. No significant differences were observed in the pregnancy rate per couple (antioxidant group 70.9% vs. control group 64.9%, P = 0.55) and per embryo transfer (50.4% vs. 39.6%, P = 0.22). Regarding the time to event analyzed by adjusted restricted mean survival time, the mean time to pregnancy was significantly shorter in the antioxidant (tocopherol) group (14.2 vs. 17.4 months, P = 0.025). No significant difference was observed in the embryo transfer cycle to pregnancy (mean embryo transfer cycles: 2.6 vs. 3.0, P = 0.238). Additional oral tocopherol nicotinate as antioxidant therapy after varicocelectomy was shown to shorten the time to pregnancy. It is recommended that add-on effects be tested in more well-designed randomized controlled trials to examine whether it improves assisted reproductive outcomes.

Usefulness of deep sedation with intravenous dexmedetomidine and midazolam in cardiac catheterization procedures for pediatric patients.

Dexmedetomidine (DEX) is a highly selective alpha 2 receptor agonist that has the advantage of causing less respiratory depression than other sedative agents. We evaluated the add-on effects of DEX on sedation among pediatric patients who received midazolam and pentazocine during cardiac catheterization. 120 cardiac catheterization procedures in 110 patients under deep sedation at Department of Pediatrics, Kanazawa University Hospital from January 2013 to August 2018: 63 procedures without DEX (i.e., non-DEX group) and 57 procedures with DEX (i.e., DEX group). Intravenous midazolam and pentazocine were used in both groups, and DEX without an initial loading dose (0.6 μg/kg/h) was used in the DEX group. We retrospectively investigated complications during catheterization, doses of sedative agents, and changes in vital signs. Hypoxemia requiring oxygen administration during catheterization tended to be higher in the non-DEX group than in the DEX group (4.8% vs. 0%). Additional dose of midazolam was significantly lower in the DEX group (median [IQR]: 0.05 mg/kg [0-0.11]) than in the non-DEX group [0.09 mg/kg (0-0.23), p = 0.0288]. The additional dose of midazolam in the non-DEX group with hypoxemia was significantly higher than the dose used in the non-DEX group without hypoxemia. No case of bradycardia below the criteria for bradycardia occurred and no serious complications occurred in the DEX group. The use of intravenous DEX in combination with midazolam and pentazocine in pediatric cardiac catheterization may reduce the need for an additional dose of midazolam and may contribute to the prevention of airway complications associated with respiratory depression caused by sedative agents.

Efficacy of Adding Locoregional Therapy in Non-Complete Remission Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab: A Preliminary Study.

Atezolizumab plus bevacizumab (Atez/Bev) therapy is extremely effective and has a high response rate in hepatocellular carcinoma (HCC) treatment. This study investigated the efficacy of adding locoregional therapy with Atez/Bev for non-complete response (CR) HCC cases. Twenty-eight HCC patients without CR during Atez/Bev therapy received locoregional therapy, and treatment efficacy was evaluated based on the modified RECIST criteria. The study included 23 male and five female participants with a mean age of 73.5 years. In the Atez/Bev and locoregional combination therapy effective group, both transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) were combined in all patients. A significant reduction in neutrophil-to-lymphocyte ratio (NLR) was observed after adding locoregional therapy (p=0.039). Moreover, a combination of TACE and RFA was performed in all patients of the CR group. When assessing the add-on effect of the combination of TACE and RFA in the progressive disease (PD) group, seven patients were found to achieve non-PD. For patients who did not achieve PD, a significant NLR reduction was noted after the addition of locoregional therapy. Adding locoregional therapy such as TACE/RFA was found to exert an effect even in non-CR patients who had received Atez/Bev therapy. A reduction in NLR after locoregional therapy was noted. Even when a response is not obtained during Atez/Bev therapy, it is important to avail the option to add locoregional therapy, as it may contribute to improved prognosis via immune modulation with tolerable adverse reactions.

Radiotherapy with or without chemotherapy for locally advanced head and neck cancer in elderly patients: analysis of the Head and Neck Cancer Registry of Japan.

Whether concurrent chemotherapy with radiotherapy (CRT) is effective for elderly patients with head and neck cancer is a controversial topic. This study aimed to analyze the effectiveness of CRT vs. radiation therapy (RT) among elderly patients in Japan. Data from the Head and Neck Cancer Registry of Japan were extracted and analyzed. Patients with locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, or larynx who received definitive CRT or RT between 2011 and 2014 were included. CRT was administered to 78% of the 1057 patients aged ≥ 70years and 67% of the 555 patients aged ≥ 75years. For the patients aged ≥ 75years, the overall survival (OS) rate was significantly better in the CRT group than in the RT group (P < 0.05), while the progression-free survival (PFS) rate was not significantly different (P > 0.05). The add-on effect of CRT was significantly poor in elderly patients (P < 0.05), and it was not a significant factor in the multivariate analysis for patients aged ≥ 75years. After propensity score matching, there were no significant differences in the OS and PFS rates between the patients aged ≥ 70years and those aged ≥ 75years (all, P > 0.05). Although aggressive CRT is administered to elderly patients in Japan, its effectiveness is uncertain. Further prospective randomized trials are needed to verify whether CRT is superior to RT alone for elderly patients.