Treatment Groups Research Articles

DDDR-25. IBUDILAST AND ANTI-PD-L1 COMBINATION TREATMENT SIGNIFICANTLY IMPROVES SURVIVAL IN A SEX-DEPENDENT MANNER IN A MURINE MODEL OF GLIOBLASTOMA

Abstract INTRODUCTION Glioblastoma (GBM) is the most common primary malignant brain tumor, and there remains a significant need for new treatments. Previous trials studying immune checkpoint inhibitors (ICI) as single agents have been negative. Ibudilast is a brain penetrant inhibitor of the macrophage migration inhibitory factor (MIF)-CD74 interaction that sensitizes GBM to temozolomide in vitro and alters myeloid-derived suppressor cells in vitro and in vivo. The purpose of this study was to investigate whether ibudilast increases ICI efficacy in a murine model of GBM. METHODS 6-week-old male and female C57BL/6 mice were implanted with SB28 cells intracranially. One week after implantation, each group was randomized to receive intraperitoneal treatment with either: ibudilast (50 mg/kg), anti-PD-L1 (1mg/kg), combination, or vehicle control. Mice were euthanized at neurological endpoint. Survival was modeled with Cox proportional hazards regression. RESULTS Among females, there was a significant difference in survival among treatment groups (p=0.0002). Specifically, combination treatment led to significantly longer survival compared to ibudilast (p=0.004) and control (p=0.03), but not anti-PD-L1 (p=0.12). Among males, there was no significant difference in survival among groups (p=0.40). Males had significantly shorter median survival compared to females (overall: 18 versus 22 days, combination treatment: 20 days versus 32 days, anti-PD-L1: 14 versus 22 days, ibudilast: 17 versus 17 days, control: 18 versus 22 days, p=0.02). CONCLUSIONS Ibudilast with anti-PD-L1 is a promising combination treatment against GBM. Future research is needed to identify the mechanisms underlying this treatment regimen and its sex-dependent effect. These results may inform the development of a combination new clinical trial, as ibudilast is currently being evaluated in the newly-diagnosed and recurrent GBM setting with temozolomide.

Effects of L-arginine on gut microbiota and muscle metabolism in fattening pigs based on omics analysis

IntroductionL-arginine is an α-amino acid and a semi-essential nutrient of significant biological interest. It plays a role in influencing various aspects of animal meat traits, gut microbiota composition, and physiological metabolism.MethodsThis study aimed to investigate the combined effects of L-arginine supplementation on gut microbiota composition and the metabolism of the longissimus dorsi muscle in fattening pigs. Eighteen Yorkshire commercial pigs were divided into two groups: a control group that received no supplements and a treatment group that was given 1% L-arginine for 52 days. The diversity and composition of microorganisms in the feces of the control (NC) and L-arginine (Arg) groups were analyzed by sequencing the 16S rRNA V3 -V4 region of the bacterial genome.ResultsThe findings indicated that L-arginine supplementation increased both the abundance and diversity of gut microbiota, particularly affecting the Firmicutes and Bacteroidetes phyla. KEGG enrichment analysis revealed significant changes in several metabolism-related pathways, including amino acid, carbohydrate, and lipid metabolism. Metabolomic analysis identified 85 differential metabolites between the arginine and control groups, with phospholipids ranking among the top 20. Additionally, functional predictions indicated an increased abundance in the glycerophospholipid metabolism pathway. Correlation analysis linked changes in gut microbiota to phospholipid levels, which subsequently influenced post-slaughter meat color and drip loss.DiscussionThese results suggest that L-arginine supplementation positively impacts gut microbiota composition and the metabolic profile of the longissimus dorsi muscle in fattening pigs, with potential implications for meat quality.

Cecal Microbial Diversity and Metabolome Reveal a Reduction in Growth Due to Oxidative Stress Caused by a Low-Energy Diet in Donkeys

Dietary energy level plays an important role in animal growth and development. The present study investigated the effect of dietary energy on the growth performance, antioxidative state, and nutrient digestion of meat donkeys. It simultaneously explored the probable reason for cecal microbiota and metabolome. Twelve meat donkeys (male) aged 1 year with a similar weight (150 ± 25 kg) were divided into two treatment groups: low-energy group (E1) and high-energy group (E2). The experiment was divided into a 10-day pre-trial period and a 135-day trial period. Donkeys in the trial periods were fed diets with digestible energy values (in dry matter) of 12.08 and 13.38 MJ/kg (pre-fattening, 1–45 d), 13.01 and 14.07 MJ/kg (mid-fattening, 46–90 d), and 13.54 and 14.93 MJ/kg (late-fattening, 91–135 d). The results show that E1 decreases body weight, average daily gain (ADG), and the digestibility of crude protein, ether extract, neutral detergent fiber, and acid detergent fiber (p < 0.05), but increases cecal acetate and butyrate concentrations, non-esterified fatty acids (NEFAs) in serum, and the ratio of dry matter intake to ADG(F/G). E1 diminished the activities of catalase and glutathione peroxidase, while it increased the content of interleukin, tumor necrosis factor-alpha, and reactive oxygen species (ROS) (p < 0.05). Cecal microbiome showed that the abundance of Firmicutes and Actinobacteria in E1 was significantly lower than in E2 (p = 0.029, p = 0.002), whereas Bacteroidetes was higher (p = 0.005). E1 increased the genera Ruminococcaceae-UCG-004, Acinetobacter, and Rikenellaceae_RC9_gut_group. Meanwhile, cecal metabolome showed that formyl-5-hydroxykynurenamine, chorismate, 3-sulfinoalanine, and 3-isopropylmalate were upregulated in E1, while brassinolide was downregulated. The altered metabolites were mainly enriched in metabolic pathways related to energy metabolism and metabolism to mitigate oxidative stress in the meat donkeys, such as tryptophan metabolism, brassinosteroid biosynthesis metabolism, etc. In conclusion, low-energy diets resulted in a negative energy balance in meat donkeys, resulting in more nutrients being oxidized to provide energy, inducing oxidative stress, and thereby leading to decreasing growth. The reduction in meat donkey growth from low-energy diets was related to changes in cecum microbiota and metabolites.

Length of hospital and intensive care unit stay in patients with invasive candidiasis and/or candidemia treated with rezafungin: a pooled analysis of two randomised controlled trials.

Invasive candidiasis/candidemia (IC/C) is associated with a substantial health economic burden driven primarily by prolonged hospital stay. The once-weekly IV echinocandin, rezafungin acetate, has demonstrated non-inferiority to caspofungin in the treatment of IC/C. This paper reports a post hoc pooled exploratory analysis of length of stay (LoS) for hospital and intensive care unit (ICU) stays in two previously published clinical trials (ReSTORE [NCT03667690] and STRIVE [NCT02734862], that compared rezafungin with daily IV caspofungin (stable patients in the caspofungin group who met relevant criteria could step down to fluconazole after 3days or more). LoS outcomes were analysed descriptively in the pooled modified intention to treat (mITT) population (all patients who had a documented Candida infection in line with trial requirements and received at least one dose of study drug). In addition, to adjust for an imbalance between treatment groups in the proportion receiving mechanical ventilation at baseline, a generalised linear model with mechanical ventilation as a binary covariate was applied. Responses to an exploratory question in the phase 3 trial on possible earlier discharge with weekly rezafungin are also reported. 294 patients were included (rezafungin 139, caspofungin 155), of whom 126 (43%) had ICU admission. Patients treated with rezafungin had a numerically shorter LoS than with caspofungin in all analyses. Mean total LoS was 25.2days, vs 28.3days with caspofungin, and mean ICU LoS was 16.1 vs 21.6days for rezafungin and caspofungin, respectively. After adjustment for mechanical ventilation status the difference in ICU LoS was 4.1days, a relative difference of 24% (95% CI -11%, 72%). Physicians would have considered earlier discharge for 16% of patients (30/187) with weekly rezafungin, an average of 5-6days earlier. Rezafungin may enable shorter hospital and ICU LoS in IC/C compared with daily IV caspofungin, with accompanying savings in resource use. Further research is needed to confirm this in the real-world setting. NCT03667690 (ReSTORE; September 12, 2018); NCT02734862 (STRIVE; April 12, 2016).

QOL-18. MANAGING CANCER AND LIVING MEANINGFULLY (CALM) IN PRIMARY AND SECONDARY MALIGNANT BRAIN TUMOR PATIENTS: INTERIM ANALYSIS OF A PHASE IIC RANDOMIZED CONTROL PILOT TRIAL

Abstract BACKGROUND Patients with both primary and secondary brain tumors demonstrate substantial psychological distress but have been historically excluded from psychological research. Managing Cancer and Living Meaningfully (CALM), a supportive- expressive- psychotherapy, has proven to reduce depression and death-anxiety in advanced cancer patients but trials in neuro-oncology have been limited. Interim analyses (50% accrual) of the first randomized control pilot trial (RCT) of CALM in neuro-oncology are presented here. METHODS In this ongoing NIH ORBIT model Phase IIc pilot RCT, 60 adults with primary or secondary malignant brain tumors and heightened distress (PHQ/DADDS) are randomized (2:1) to a six-session CALM intervention or usual care. Data collection includes established feasibility and acceptability metrics, intervention satisfaction surveys and interviews, and clinically meaningful changes in distress severity scores across three timepoints (pre-, post-CALM, follow-up). RESULTS Of 64 patients screened, 36 were eligible and 32 enrolled (n=20 CALM, n=12 Control; 65% female; 90% White; Mage=46yrs). A multimodal recruitment model was used. Currently, assessment completion rates are: post-CALM (80%) and follow-up (67%). Reasons for withdrawal include disinterest in intervention topics (n=1) and lost to follow-up (n=1). Intervention retention is currently at 90%, with 8 participants still in active treatment. No adverse events have been documented. Perceived benefit appears high (4.1/5) and all participants report they would recommend CALM to others. Pre- to post-CALM, depression severity reductions appear equal across arms (CALM PHQ-9=30%; Control=33%) but death anxiety severity reductions appear more prevalent in the treatment group (CALM DADDS=70%; Control=50%). CONCLUSIONS Interim data suggests promising feasibility and acceptability results in this pilot RCT. Enrollment, retention, and assessment completion rates appear adequate. Participants are reporting high benefit and recommendation of CALM. Improvement in death anxiety appears greater in those treated with CALM compared to controls. These interim RCT findings are promising and suggest completion of the current phase.

Skeletal Anchorage as a Therapeutic Alternative for Mandibular Second Molar Impaction: A Prospective Case–Control Study

Background: The treatment of mandibular second molar (MM2) impaction presents a challenge for orthodontists and requires a surgical–orthodontic approach. This study aims to compare the effectiveness of two techniques for treating impacted MM2: a traditional technique using brass wire and a technique employing skeletal anchorage. Methods: Twelve MM2 with mesio-angular impaction, with an inclination angle between 25° and 40° and an impaction depth between 4 and 10 mm, were selected and randomly divided into two treatment groups. Patients in Group A were treated using the traditional brass wire technique, while those in Group B underwent treatment with a skeletal anchoring technique that utilized a miniscrew positioned in the retromolar region and an elastic sling chain. For both groups, treatment time and the influence of the disimpaction technique on oral health-related quality of life (OHRQoL) were evaluated using the short-form Oral Health Impact Profile (OHIP-14). Results: The results indicated an average treatment time of 168.67 ± 52.32 days for Group A and 76 ± 10.17 days for Group B, with a statistically significant difference (p-value = 0.0002). Regarding the impact on the patients’ OHRQoL, Student’s t-test did not reveal a statistically significant difference between the two groups at 3 and 7 days of follow-up. Conclusions: Both techniques are considered effective for the treatment of impacted MM2 (angulation 25–40°, depth 4–10 mm). The use of skeletal anchorage significantly reduces treatment times without negatively affecting OHRQoL. The results of this study should be confirmed by further studies with larger sample sizes.

NIMG-11. DISCOVERING POSTOPERATIVE APHASIA RECOVERY IN GLIOMA PATIENTS: THE ROLE OF THE RIGHT BROCA’S HOMOLOG AND VERIFICATION

Abstract OBJECTIVE This study aimed to elucidate the neurological mechanisms that support the recovery of postoperative aphasia by examining alterations in language and extended networks in patients with glioma. Additionally, we sought to determine the causal relationship between the right Broca’s homolog and language recovery using neuro-navigated repetitive transcranial magnetic stimulation (nrTMS). METHODS Sixty-two patients with left hemisphere gliomas were retrospectively analyzed and categorized into aphasia and non-aphasia groups based on Aphasia Quotient (AQ) scores. Resting-state functional MRI (rs-fMRI) data were collected and analyzed to investigate differences in functional connectivity (FC) and topological properties of language-related networks. Additionally, eight patients with surgery-induced aphasia were prospectively treated with nrTMS, targeting the node identified from the retrospective analysis. RESULTS Significant increases in FC between the left auditory cortex and the right inferior frontal gyrus in the Executive Control Network were observed in the non-aphasia group. Nodal properties, such as the nodal efficiency of the right Broca’s homolog, were independently associated with postoperative language function. The nrTMS treatment group demonstrated significant improvements in AQ scores, with correlations between increased nodal efficiency and positive language outcomes. CONCLUSION The right hemisphere, specifically the right inferior frontal gyrus, plays a compensatory role in maintaining language function after glioma resection. These findings suggest the therapeutic potential of nrTMS for enhancing postoperative language recovery, offering insights into individualized patient care and rehabilitation strategies for patients with glioma.

EXTH-59. ESTABLISHING GAUSSIA LUCIFERASE REPORTER AS A BIOMARKER FOR ESTIMATING THERAPEUTIC RESPONSE AND PROGRESSION-FREE SURVIVAL IN PATIENT-DERIVED XENOGRAFT MODELS OF GLIOBLASTOMA

Abstract Serial monitoring of tumor burden in patient-derived xenograft (PDX) models used for testing new cancer drugs via MRI and other imaging techniques can be costly. We theorized that transducing the Gaussia luciferase (GLuc) reporter gene into glioma PDX models (GliomaPDOX) allows for GLuc to be used as a biomarker for tumor burden. This current study investigates whether changes in the rate of GLuc secretion over time (i.e., “growth rate” changes) can predict survival in GliomaPDOX. Optimal cutoff values to define disease progression via GLuc measurements were established resulting in a strong association between progression-free survival (PFS) and overall survival (OS). The pLenti-CMV-sGluc-T2A-EGFP plasmid was packaged into a second-generation lentiviral system via HEK293FT cells, and the resulting virus transduced into directly-isolated glioma patient cells to establish the MGMT-Unmethylated and MGMT-Methylated GliomaPDOX. MGMT-Unmethylated GliomaPDOX were treated with placebo or Temozolomide (TMZ) until endpoint. MGMT-Methylated GliomaPDOX were treated with placebo or TMZ for three weeks or TMZ for six weeks until endpoint. Treatment response was monitored through GLuc measurements obtained via tail blood collection. The optimal cutoff for time to progression was a 30% increase in GLuc, which yielded a significant positive association between PFS and OS across all models and treatments (R2 = 0.8177, p<0.0001). Compared to the MGMT-Methylated placebo and MGMT-Unmethylated groups, the MGMT-Methylated treatment groups exhibited substantial changes in GLuc growth rates and significantly longer PFS and OS (p<0.0001). More specifically, the six-week MGMT-Methylated TMZ-treated group demonstrated a significant difference in GLuc growth rates and a considerable PFS (p<0.0038) and OS increase (p<0.0049) when compared to the three-week MGMT-Methylated TMZ-treated group. Therefore, GLuc measurement is a valuable biomarker for PDX tumor burden and can be used to estimate treatment response and PFS.

DDDR-14. IMPROVED ANTI-GLIOBLASTOMA EFFICACY BY BRG399, A NOVEL ORAL MICROTUBULE BINDING AGENT

Abstract Glioblastoma (GBM) is a highly malignant form of brain tumor with a poor prognosis despite advances in treatments. Therapeutic resistance/relapse remains a significant challenge necessitating the development of novel approaches. BRG399 is a brain permeant, non P-gp substrate, microtubule-targeting agent that displays anti-cancer activity in vitro and in vivo. BRG399 was well tolerated in rat and dog toxicology studies. Anti-cancer activity (IC50) of BRG399 in in vitro models of GBM was assessed to have potency ranging from 42nm to 89nM in the 3 cell lines tested. Here, in vivo tumor activity of BRG399 was assessed in Sprague Dawley rats implanted with 3x105 C6 rat glioma cells into the right entorhinal cortex/subiculum region. 14 days post successful implantation tumors were assessed by MRI, rats were randomized to receive vehicle (2% Labrasol) or BRG399 (5, 10, 20 mg/kg groups) twice daily by oral gavage for 16 days, and MRIs were performed on survivors on days 31 and 45 post implantation. BRG399 administration resulted in a marked improvement in survival (from 7.7 ± 2.6 days to 25.5 ± 15.6 days, log-rank test, p:0.007) compared to controls. Six animals receiving BRG399 remained alive beyond day 60 of post-treatment initiation. To assess biodistribution of BRG399 in the brain, rats were implanted with C6 cells and tumor establishment assessed 12 days later by MRI. Animals were treated with vehicle or BRG399 (10, 20, 25 mg/kg) and plasma and brains were collected for bioanalytical assessment. Tissue single cell biodistribution was performed using TIMSTOF FLEX spatial OMICS. These results demonstrate a therapeutic effect of BRG399 on intracranial glioma-bearing rats with survival of the BRG399 treatment groups of strong statistical significance over the control group. Analysis of drug levels in plasma and brain will serve as guidance for dose and scheduling decisions for further therapeutic development.

Enhanced Vasoconstriction in Sickle Cell Disease is Dependent on ETA Receptor Activation.

Sickle Cell Disease (SCD) carries a significant risk for poor vascular health and vascular dysfunction. High levels of vascular reactive oxygen species (ROS) as well as elevated plasma endothelin-1 (ET-1), a potent vasoconstrictor with actions via the ETA receptor, are both common phenotypes in SCD. Alpha-1 adrenergic receptor activation is a major mediator of stress-induced vasoconstriction. However, the mechanism of the SCD enhanced vasoconstrictive response is unknown. We hypothesized that SCD induces enhanced alpha-1 adrenergic mediated vasoconstriction through the ET-1/ETA receptor pathway in arterial tissues. Utilizing humanized SCD (HbSS) and genetic control (HbAA) mice, alpha-1a, but not alpha-1b or alpha-1d, receptor expression was significantly greater in aortic tissue from HbSS mice compared to HbAA mice. Significantly enhanced vasoconstriction in aortic and carotid arterial segments were observed from HbSS mice compared to HbAA mice. Treatment with ambrisentan, a selective ETA receptor antagonist, and a ROS scavenger normalized the aortic vasoconstrictive response in HbSS mice. In a randomized translational study, patients with SCD were treated with placebo or ambrisentan for 3 months, with the treatment group showing an increase in the percent brachial arterial diameter. Taken together, these data suggest that the ETA receptor pathway interaction with the adrenergic receptor pathway contributes to enhanced aortic vasoconstriction in SCD. Findings indicate the potential of ETA antagonism as a therapeutic avenue for improving vascular health in SCD.

A Dynamic, D-dimer-based Thromboprophylaxis Strategy in Patients with COVID-19

Background COVID-19 pandemics increases venous thromboembolism (VTE) risk during hospitalization, despite prophylactic anticoagulation. Limited radiological diagnosis in pandemic requires a guided protocol for anticoagulant adjustment. Methods This retrospective cohort study was conducted at a single center as part of a quality improvement program evaluating the efficacy and safety of anticoagulation protocols. The study focused on implementing a guideline for anticoagulant dosing protocol based on dynamic changes in D-dimer levels in COVID-19 hospitalized patients. The dosing guideline allowed for dose escalation from standard prophylactic levels to escalated prophylactic or therapeutic levels, depending on the patient's risk profile for VTE. The primary endpoints included in-hospital survival comparing between fix and dynamic adjustment treatment groups. Secondary endpoints encompassed major and clinically relevant non-major bleeding (CRNMB) events, incidence of breakthrough thrombosis, length of hospitalization and ICU stay, days of mechanical ventilator use, and survival duration. Findings Among the 260 COVID-19-infected patients hospitalized between March 15th and June 15th, 2020. The patients received fixed anticoagulant dosage in 188, 72.3%) patients, while 72 (27.7%) were up-titrated according to the protocol. In-hospital survival at 30 days demonstrated superiority among patients whose anticoagulation was up-titrated to either escalated prophylactic or therapeutic (80.2%) compared to receiving fixed anticoagulant dosage (51.3%) (p=0.01). Bleeding events were significantly higher in up-titrate group (12.5%) compared to fixed anticoagulant dosage group (2.13%). Most of them are CRNMB. Conclusion A dynamic, D-dimer-based dose escalation of anticoagulation for hospitalized patients with COVID-19 holds promise in improving in-hospital mortality rates without a significant increase in fatal bleeding events.

TMOD-04. SAFETY AND EFFICACY DATA FROM A CLINICAL TRIAL OF SONODYNAMIC THERAPY WITH 5-ALA HCL ORAL SOLUTION AND CV-01 DELIVERED WHOLE HEMISPHERIC LOW-INTENSITY NON-ABLATIVE ULTRASOUND IN PET FRENCH BULLDOGS WITHDE NOVO NATURALLY OCCURRING HIGH-GRADE GLIOMA

Abstract To date, no animal model has been able to accurately test emerging therapeutics for high-grade glioma. Pet dogs’ high-grade gliomas closely mimic human tumors histopathologically and radiologically as well as with poor clinical survival. Dogs with these tumors have notably shorter survival than humans, with French Bulldogs showing the shortest survival of all breeds affected, aiding swift therapeutic evaluations. We report the first use of the novel CV-01 device delivering non-ablative low-intensity diffuse ultrasound (LIDU) with oral 5-ALA as a recurrent high-grade glioma treatment in a veterinary safety and efficacy trial. This Phase 1 study focused on safety, with secondary outcomes assessing histopathological efficacy markers (CC3, Iba1) and overall survival. After one SDT treatment pre-resection, treatments every 3-4 weeks were administered to eight French Bulldogs, totaling 60 administrations (average of 7.5 total treatments/patient). The control group matched breed, age, and histopathologic diagnosis. Average age was 6.35 years (range: 4.8 – 7.8 years), slightly older than controls (5.9 years, range: 3.0 - 9.9 years). No complications or toxicities were noted, and MRI scans showed no damage to the normal brain. Histopathologic analysis from four canine tumor samples revealed increased apoptosis and immune activation markers post-SDT (e.g. cleaved caspase 3 [CC3] and ionized calcium-binding adaptor molecule 1 [Iba1]), indicating selective tumor cell death. Median overall survival in the treatment group reached 205.5 days (6.8 months) compared to 55 days (1.8 months) in controls, with the longest survival at 587 days (versus 213 in controls). Although preliminary, these results affirm the safety of 5-ALA-mediated SDT in canine glioma patients. A multi-center, First-In-Human trial in recurrent high-grade glioma recently completed enrollment, aiming to further validate canine trials for emerging high-grade glioma therapeutics.

Repetitive Transcranial Magnetic Stimulation for Auditory Verbal Hallucinations in Schizophrenia: A Randomized Clinical Trial.

Auditory verbal hallucinations (AVH) are a common symptom of schizophrenia, increasing the patient's risks of suicide and violence. Repetitive transcranial magnetic stimulation (rTMS) is a potential treatment for AVH. To investigate the effect of imaging-navigated rTMS on AVH in patients with schizophrenia. This 6-week, double-blind, sham-controlled, randomized clinical trial was performed at the Anhui Mental Health Center, Hefei, China, from September 1, 2016, to August 31, 2021. Participants included 66 patients with AVH and schizophrenia. Data were analyzed from May 1, 2022, to March 31, 2023. Participants were randomly assigned 1:1 to either imaging-navigated active or sham rTMS over the left temporoparietal junction for 2 weeks. The primary outcome measured improvements in AVH from baseline to week 2 and week 6 using the Auditory Hallucination Rating Scale (AHRS) scores. In addition, the TMS-induced electric field strength was used to estimate improvements in AVH as a secondary outcome. A total of 62 participants (33 women [53%]; mean [SD] age, 27.4 [9.2] years) completed the 2-week treatments. Of these, 32 were randomized to the active rTMS group (18 women [56%]; mean [SD] age, 26.9 [9.2] years) and 30 to the sham treatment group (15 women [50%]; mean [SD] age, 27.8 [9.4] years). In the intention-to-treat analyses, patients receiving active rTMS showed a significantly greater reduction in AHRS scores compared with those receiving sham treatment at week 2 (difference, 5.96 [95% CI, 3.42-8.50]; t = 4.61; P < .001; Cohen d, 1.17 [95% CI, 0.62-1.71]). These clinical effects were sustained at week 6. Additionally, a stronger TMS-induced electric field within a predefined AVH brain network was associated with greater reductions in AHRS scores (B = 3.12; t = 3.58; P = .002). No serious adverse event was observed. The findings of this randomized clinical trial suggest that imaging-navigated rTMS may effectively and safely alleviate AVH in patients with schizophrenia. Findings also suggest that the electric field strength in the individualized AVH network is a vital parameter for optimizing the efficacy of the rTMS protocol. ClinicalTrials.gov Identifier: NCT02863094.

Comparing anti-drug antibody signal-to-noise ratios to assess immunogenicity and interchangeability in adalimumab biosimilar studies

ABSTRACT Background To support an interchangeability designation for Sandoz adalimumab biosimilar (GP2017), antidrug antibody (ADA) signal-to-noise (S/N) ratios were assessed in the GP2017 ADACCESS trial to directly assess potential changes in immunogenicity. Research design and methods ADACCESS was a 51-week trial in patients with moderate-to-severe plaque psoriasis that included patients treated continuously with reference adalimumab (cH), and patients who experienced four switches between reference adalimumab and GP2017 (H2H). ADAs were measured every 6 weeks during the switching phase using an electrochemiluminescence assay. A non-parametric analysis was performed to estimate the 90% confidence interval (CI) of the median of difference in ADA S/N ratios between the cH and H2H treatment groups at week 41. If the 90% CI was within the margin of –0.16 to 0.16 (representing assay noise), this was considered a non-clinically meaningful difference in immunogenicity. Results The 90% CIs of the median of difference in ADA S/N ratios between the two treatment groups were within the defined margin of –0.16 to 0.16 at week 41, and at all other time points. Efficacy and safety data were also similar between the treatment groups. Conclusion Analysis of ADA S/N ratios showed no increase in immunogenicity following up to four switches between reference adalimumab and GP2017. Trial registration NCT02016105

Longer-term safety and efficacy of baricitinib for atopic dermatitis in pediatric patients 2 to

Background Baricitinib, an oral selective Janus kinase inhibitor, improved clinical signs and symptoms of moderate-to-severe atopic dermatitis (AD) at week 16 in the phase 3 pediatric study BREEZE-AD-PEDS. Objective To assess longer-term efficacy and safety of baricitinib in pediatric patients aged 2 to <18 years. Methods In BREEZE-AD-PEDS long-term extension, responders and partial responders (validated Investigator Global Assessment-Atopic Dermatitis [vIGA-AD®] 0/1/2) at Week 16 remained on double-blind treatment to which they were randomized (placebo, baricitinib [1-mg equivalent, 2-mg equivalent, or 4-mg equivalent); non-responders (vIGA-AD 3 or 4) at Week 16 transitioned to open-label baricitinib 4-mg equivalent. Safety was summarized for all randomized patients who received ≥1 dose of study treatment. Results In total 467 patients received baricitinib for 750.7 patient-years. Proportion of responders/partial responders (at Week 16) who achieved vIGA-AD 0/1 at Week 52 was greater for baricitinib 4-mg equivalent (56.8%) versus all other treatment groups (42.2%, 47.7%, and 39.7% for 2-mg equivalent, 1-mg equivalent, and placebo, respectively). Most treatment-emergent adverse events were mild/moderate in severity. No deaths, pulmonary emboli, deep vein thromboses or arterial thrombotic events, major adverse cardiovascular events, malignancies, tuberculosis events, or gastrointestinal perforations were reported. Conclusions Baricitinib demonstrated sustained long-term efficacy. No new safety signals were identified. Trial Registration ClinicalTrials.gov Identifier: NCT03952559

Effect of Supplementation of Spirulina (Spirulina platensis) on Growth Performance of Broiler in Konkan Region, India

The experimental trial of six weeks was conducted on 200 broiler chicks. They were randomly distributed into five experimental treatment groups. Each treatment group was replicated into four with 10 birds per replication. The control (T1) group was fed standard ration and T2, T3, T4 and T5 group were provided same standard ration supplemented with 1.00 g, 2.00 g, 3.00 g and 4.00 g spirulina powder, respectively. The result of experimental trial showed that supplementation of spirulina powder was significantly highest live body weight in treatment T5 (1944.50 g/bird) as well as average live body weight gain (277.79 g/bird). It is concluded that, 4.00 g of spirulina powder significantly improved growth performance of broiler chicks than other treatments groups.

An evaluation of 30 years’ experience in the use of botulinum toxin injections in the management of sixth nerve palsies

ABSTRACT Intrroduction Sixth nerve palsy is the most common type of extraocular muscle palsy. The therapy options in sixth nerve palsies include monitoring with or without conservative treatment, botulinum toxin injections or strabismus surgery. The aim of this retrospective study was to compare botulinum toxin (BT) injections into the medial rectus to conservative treatment in sixth nerve palsies. The rate of patients improved after intervention and treatment outcomes for the two treatment options were be evaluated at a German tertiary referral center. Methods A service evaluation was conducted on adult patients with sixth nerve palsy. Patient files were reviewed and data including abduction deficit and size of deviation were collected retrospectively. Patients which presented between January 1987 and April 2022 were considered. Patients were allocated into two treatment groups: BT injected into medial rectus or conservative treatment, which included observation, providing occlusion and Fresnel prisms. Inclusion criteria were attendance of two visits with orthoptic assessment. Exclusion criteria included presence of further oculomotor palsies, strabismus, strabismus surgery and suppression. Non-parametric statistical analysis was conducted using IBM® SPSS Statistics. Results A total of 606 adult patients with unilateral or bilateral sixth nerve palsy attended during the named period. A total of 137 adult patients met the inclusion criteria. Of which, 36 had a bilateral palsy, 101 had a unilateral palsy. 45.26% (n = 62) were treated with BT injections and 54.75% (n = 75) were treated conservatively. The median initial abduction deficit was greater in the BT group, (−4 to −5 after Scott and Kraft) than in the conservative treatment group (−1). The initial angle of deviation at distance was significantly larger in the BT group than in the conservative treatment group (p = <0.001). The rate of improvement in the BT group was 24.19% (n = 15) and 20% (n = 15) in the conservative treatment group. When excluding longstanding palsies rates of improvement in both groups increased to 28.85%. The improvement of the angle of deviation at distance in all patients was greater in the BT group (p = <.001). The improvement of abduction in bilateral palsies were greater in the BT group (p = .016), but in unilateral palsies, there was no significant difference in abduction improvement in the two treatment groups (OD p = .3, OS p = .406). Conclusion This service evaluation found that BT injection into medial rectus in unilateral and bilateral sixth nerve palsies did not increase the rate of improvement compared to conservative treatment. But BT injections reduced the angle of deviation to a greater extent than conservative treatment. Additionally, BT was able to improve abduction in bilateral palsies to a greater extent than conservative treatment. It is recommended a BT injection is considered in symptomatic bilateral sixth nerve palsies to enable fixation and improved ocular motility. More research is needed to verify reliable clinical guidelines for the use of BT in sixth nerve palsies.

Inhibition of Orthodontic Relapse by Local Application of Simvastatin-Loaded Gelatin Hydrogel in a Rabbit Model.

This study aims to determine the effect of gelatin-simvastatin hydrogel application on bone remodelling during relapse. Twenty-four rabbits (Oryctolagus cuniculus) were divided into a control group (n = 12) and a treatment group (n = 12). The lower incisors were subjected to orthodontic force and moved distally by an open coil spring. The force (50 cN) was extended for 1 week and retained in a new position for 2 weeks (stabilisation period). The treatment group received a local gelatin-simvastatin hydrogel administration during stabilisation, and the control group received only gelatin hydrogel. The springs were debonded after the stabilisation phase from both groups to facilitate a relapse. The percentage of relapse was measured in a model study using digital callipers. Levels of OPG and RANKL were analysed using ELISA. The local application of gelatin-simvastatin hydrogel in the treatment group significantly decreases the relapse percentage and RANKL level. Additionally, the gelatin-simvastatin hydrogel significantly increases the level of OPG and ratio of OPG/RANKL. Applying gelatin-simvastatin hydrogel in the retention period can induce bone formation, inhibit orthodontic relapse and increase tooth stability (in vivo).

Comparing Intraoperative and In-Office Steroid Injections for Management of Subglottic Stenosis.

Intralesional corticosteroid injection for management of subglottic stenosis (SGS) is thought to improve patients' surgery free interval (SFI). The objective of this study was to determine the difference in SFI between idiopathic SGS (iSGS) patients treated with endoscopic dilation alone, dilation with a single intraoperative intralesional corticosteroid injection, or dilation with intraoperative steroid injection followed by serial in-office serial intralesional steroid injection (SILSI) procedures. Retrospective review of patients with iSGS from 1/1/2012 to 12/1/2023. The SFI was calculated as the time between surgical interventions and independent samples median test was used to compare the difference in SFIs between treatment groups. This study identified 305 procedures, involving 104 patients. Fifty-five procedures involved endoscopic dilation alone (median SFI = 658, IQR: 595 days), 102 involved one injection of steroids intraoperatively (median SFI = 395, IQR: 296 days), 27 involved endoscopic dilation (ED) followed by a single postoperative ILSI (median SFI = 533, IQR: 351), and 15 involved postoperative SILSI (median SFI = 585, IQR: 338 days). Comparing SFI between groups found mean SFI was significantly longer among patients managed with only ED compared with a single intraoperative steroid injection (p = 0.001). Patients who were initially managed with ED and an intraoperative steroid injection has a statistically significant decrease in SFI (p = 0.032) when transitioned to management with ED and intraoperative steroid injection followed by a single ILSI postoperatively. Patients who received a single intraoperative steroid injection experienced shorter SFI when compared with those managed with dilation alone. SILSI did not result in a significant increase of SFI within this population. 3 Laryngoscope, 2024.

The Use of Real-World Data for Estimating Relative Treatment Effects in NICE Health Technology Assessment Submissions: A Review.

This paper investigates the current use of real-world data (RWD) for estimating relative treatment effects in National Institute for Health and Care Excellence (NICE) health technology assessment (HTA) submissions. This review included 64 HTA submissions, which accounted for approximately 11% of the total NICE HTA submissions between January 2016 and December 2023. The main sources of RWD considered in the submissions were disease registries and electronic health records. RWD were primarily used to provide an external control arm to enable comparisons within single-arm trials and to inform long-term treatment effects when extrapolating survival data beyond the trial follow-up. Adjustments for potential systematic differences between treatment groups have improved over time; however, approximately one-third of the submissions still relied on unadjusted treatment comparisons. We found that approximately 10% of NICE HTA submissions used RWD to directly inform treatment effects estimation. Over one-third of the submissions relied on naïve and/or unadjusted treatment comparisons, which may have introduced biases. To ensure that RWD provide sound evidence for HTA, submissions should follow published guidelines, including the NICE real-world evidence (RWE)framework.