Clinical Adverse Effects Research Articles

Comparison of Efficacy And Safety of Isotretinoin Versus Lymecycline Capsule For The Treatment of Acne Vulgaris

Background: Acne vulgaris is a very common condition which can cause significant physical and psychological morbidity. Oral retinoids and tetracyclines have a major role in acne treatment. Isotretinoin (13-cis-retinoic acid) is the only therapy that impacts on all of the major aetiological factors implicated in acne. Another agent is lymecycline, a tetracycline antibiotic have an antibacterial action against P. acnes and also an anti-inflammatory action and used for treatment of acne. Objectives: To determine the efficacy and safety of Isotretinoin capsules versus Lymecycline capsule in treatment of mild to moderate facial acne vulgaris. Materials & method: This open labelled, randomized study was conducted in Department of Dermatology and Venereology, Dr. Sirajul Islam Medical College & Hospital Ltd., Dhaka, from December 2021 to May 2022. Patients of mild to moderate facial acne vulgaris were enrolled for study. Clinical examination and relevant investigation were done meticulously. A total number of 50 patients was selected and randomization was done 1:1 parallel design into two groups (group-A and group-B), each of which included 25 patients. Group A patients received Isotretinoin and group B patients were given Lymecycline. Patients were followed up on 2nd, 4th, 8th and finally on 12th week to see clinical improvement and adverse effects. All information was recorded in data collection sheet. Result: The mean age was found 20.4±5.7 years in group A and 19.9±6.9 years in group B. The mean age difference was not statistically significant (p>0.05) between two groups. Male to female ratio was almost 1:3 in the whole study patients. Mean score for open comedone (0.28±0.22 vs. 2.2±1.13), closed comedone (1.92±0.19 vs. 2.08±0.25), papule (0.82±0.29 vs. 1.27±1.04) and pustule (0.85±0.33 vs. 1.19±0.39) was identical in group-A and B respectively and significantly better reduction of acne score (p=0.001) in the group A than the group B. It was evident that abdominal discomfort (4.0% vs. 32.0% in group A & B), diarrhea (0% vs. 16.0% in group A & B) and photosensitivity (4.0% vs. 16.0% in group A & B) was predominant in group B. The difference was statistically significant (p=0.029). Whereas, erythema and burning was predominant in group A. Mean burning was found 0.15±0.08 in group A and 0.11±0.05 in group B and mean scaling was found 1.27±0.98 in group A and 1.45±0.98 in group B which were statistically non significant (p>0.05) between two groups. At 4th follow up mean total safety score was found 3.05±0.92 in group A and 4.65±1.25 in group B. Conclusion: Isotretinoin was as effective as lymecycline for the treatment of moderately severe acne vulgaris. Both treatments were well tolerated & effective. J Dhaka Med Coll. 2023; 32(1) : 63-70

Investigating Associations between Subclinical Hypothyroidism and Pregnancy Outcomes and Effects of Levothyroxine Therapy on Improving Maternal and Infant Prognosis

Background: Current evidence shows subclinical hypothyroidism (SCH) is associated with increased risk of adverse pregnancy outcomes, though some controversies exist. However, little is known on the impacts and effectiveness of levothyroxine (LT4) therapy on pregnancy outcomes in women with SCH. Present study aims to investigate the associations between SCH and adverse pregnancy outcomes and clinical effects of levothyroxine (LT4) replacement therapy in patients with SCH. Methods: The clinical data of pregnant women (n = 635) with SCH who referred to Huai'an Maternal and Child Health Care Hospital, Huaian, China from June 2018 to December 2018 were retrospectively analyzed. Among them, 147 cases received standard thyroxine replacement therapy, 292 cases did not receive treatment and 150 cases who received irregular treatment or did not achieve the target or were lost to follow-up. 46 cases whose thyroid peroxidase antibody (TPOAb) was not checked during pregnancy were not included in the study. According to the TPOAb test results patients were divided into positive treatment (n = 14), negative treatment (n = 133), positive untreated (n = 19), or negative untreated (n = 273) subgroups. A total of 1876 pregnant women with normal thyroid function (TPOAb positive = 59; TPOAb negative = 1817) who delivered during the same period were selected as the control group. Pregnancy outcomes were assessed and compared between treated and control group, untreated and control group, TPOAb positive treatment subgroup and TPOAb positive and untreated subgroup, TPOAb negative treatment subgroup and TPOAb negative subgroup, and TPOAb positive and TPOAb negative subgroup. Results: Our data showed that the incidences of hypertensive disease, premature delivery, fetal growth restriction and fetal death during pregnancy in the untreated group were significantly higher than in the control group (p < 0.05). The incidence of preterm delivery in the treatment group was significantly lower compared to the untreated group and the control group (p < 0.05). Moreover, the incidence of premature birth in TPOAb positive treatment subgroup was significantly lower than their peers in TPOAb positive and untreated subgroup. The incidence of premature delivery in TPOAb negative treatment subgroup was significantly lower than TPOAb negative untreated subgroup and the difference was statistically significant (p < 0.05). There was no significant difference in the incidence of adverse pregnancy outcomes between TPOAb positive subgroup and TPOAb negative subgroup in the control group (p > 0.05). Conclusions: SCH during pregnancy is a risk factor for hypertensive disease during pregnancy, fetal growth restriction, premature delivery and fetal death. L-T4 replacement therapy improves maternal and infant outcomes in patients with SCH during pregnancy, regardless of whether or not TPOAb is positive.

Physiological and metabolic effects of short-term dopamine reduction in healthy horses using a tyrosine hydroxylase inhibitor (alpha-methyl-para-tyrosine)

Alpha-methyl-para-tyrosine (AMPT) is a reversible inhibitor of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis. This study aimed to determine whether AMPT could reduce dopamine concentrations in horses. Six healthy adult Standardbred geldings were administered AMPT (40 mg/kg BW, orally) or placebo in a randomised crossover study design. Clinical examination findings were recorded, and blood samples were collected for up to 6 h after administration of AMPT or placebo, for measurement of blood glucose, plasma ACTH and cortisol concentrations, and plasma metabolomic analysis. Plasma prolactin concentration was determined as a proxy index of central dopamine reduction. No adverse clinical effects were detected after oral administration of AMPT, with heart rate, mean arterial pressure and blood glucose concentration not differing between AMPT treatment or placebo. Plasma prolactin concentration peaked 1 h after AMPT administration before returning to baseline at 2 h (for five horses) or 6 h (for one horse). Metabolomic analysis demonstrated a reduction in plasma dopamine (0.72-fold change; P=0.016) 1 h after AMPT treatment. Plasma ACTH and cortisol concentrations were not different between AMPT and placebo over time. A few metabolites associated with ketogenesis were increased, and certain amino acids decreased, at 1 h compared with baseline, for both AMPT treatment and placebo. Therefore, AMPT was effective in reducing both central and circulating dopamine concentrations in healthy horses following a single oral dose. Further pharmacokinetic and pharmacodynamic studies are warranted to optimise the dose and duration of AMPT treatment to achieve longer-term dopamine reduction. Plasma metabolomic findings suggested an interruption to energy flux at the time of sample collection, which may be relevant to nutritional studies in horses and warrants further investigation.

Quantitative Tractography-Based Evaluations in Essential Tremor Patients after MRgFUS Thalamotomy.

Magnetic resonance-guided focused ultrasound (MRgFUS) targeting the thalamic ventral intermediate nucleus (VIM) is an innovative treatment for drug-refractory essential tremor (ET). The relationship between lesion characteristics, dentate-rubro-thalamic-tract (DRTT) involvement and clinical benefit remains unclear. To investigate whether clinical outcome is related to lesion volume and/or its overlap with the DRTT. To compare the reliability of probabilistic versus deterministic tractography in reconstructing the DRTT and improving VIM targeting. Forty ET patients who underwent MRgFUS thalamotomy between 2019 and 2022 were retrospectively analyzed. Clinical outcomes and adverse effects were recorded at 1/6/12 months after the procedure. The DRTT was generated using deterministic and probabilistic tractography on preoperative diffusion-tensor 3 T-images and location and volume of the lesion were calculated. Probabilistic tractography identified both decussating (d-DRTT) and non-decussating (nd-DRTT) components of the DRTT, whereas the deterministic approach only identified one component overlapping with the nd-DRTT. Despite the lesions predominantly intersecting the medial portion of the d-DRTT, with a significantly greater overlap in responder patients, we observed only a non-significant correlation between tremor improvement and increased d-DRTT-lesion overlap (r = 0.22, P = 0.20). The lesion volume demonstrated a significant positive correlation with clinical improvement at 1-day MRI (r = 0.42, P < 0.01). Variability in the reconstructed DRTT position relative to the lesion center of mass, even among good responders, suggests that this fiber bundle is unlikely to be considered the sole target for a successful MRgFUS thalamotomy in ET. Indirect individualized targeting allows for more precise and reproducible identification of actual treatment coordinates than the direct method.

The Efficacy, Safety, and Persistence of Therapy after Non-Medical Switching from an Originator Adalimumab in Inflammatory Bowel Disease: Real-Life Experience from Two Tertiary Centres.

During the last two decades, an increased number of molecules with multiple mechanisms of action have been approved for the treatment of inflammatory bowel disease (IBD), with a substantial increase in the costs related to therapy, which has become a concern for payers, regulators, and healthcare professionals. Biosimilars are biologic medical products that are highly structurally similar to their reference products; have no clinically meaningful differences in terms of immunogenicity, safety, or effectiveness; and are available at a lower price. Materials and Methods: This was an observational prospective study conducted in two IBD centres in Bucharest and included 53 patients, 27 male (M) and 26 female (F), diagnosed with IBD according to standard clinical, endoscopic, radiological, and histological criteria, who were non-medically switched at the indication of the National Insurance House to a biosimilar of Adalimumab. Aims: The aim was to determine the rates of clinical remission, adverse effects, and treatment persistence at one year. Results: No significant differences were found in terms of the faecal calprotectin (FC) and C-reactive protein (CRP) levels 6 and 12 months after changing from the originator biologic treatment to a biosimilar. Only one patient required a change in their biological treatment following the clinical and biological loss of response. The main adverse effect reported by the patients was pain at the injection site. Of the 53 patients, only 2 reported pain at the injection site, and 1 patient reported experiencing abdominal pain and rectal bleeding immediately after the switch, but no recurrence was observed clinically or endoscopically. Conclusions: This observational study is the first to be carried out in Romania that shows that, after a non-medical switch, biosimilars of Adalimumab are as efficient and safe as the originator Adalimumab in the clinical treatment of patients with IBD.

Discospondylitis, osteomyelitis and sublumbar abscessation with a pathological vertebral fracture in a dog managed by ventral omentalisation and concurrent dorsal vertebral stabilisation

AbstractThis report describes a chronic case of discospondylitis and sublumbar abscessation managed with a combination of omentalisation and vertebral stabilisation. Although there are previous reports of omentalisation in patients presenting with sublumbar abscesses, there are no documented cases of these surgeries being combined with stabilisation of a vertebral body fracture secondary to discospondylitis. This case specifically discusses an initial conservative approach and subsequent surgical intervention. A 5‐year‐old, female, neutered, cocker spaniel presented with a 2‐month history of lethargy, non‐localised pain, reluctance to move and pyrexia. Diagnostic investigations revealed a fracture of the third lumbar vertebrae, associated discospondylitis and sublumbar abscessation due to suspected foreign material. Conservative management with rest and antimicrobial therapy was initiated; however, after worsening of clinical signs, surgery was subsequently carried out. We report post‐operative follow‐up of 4 years, which revealed an overall positive outcome, with no long‐term recurrence of clinical signs or adverse effects.

Clinical Outcomes and Adverse Effect Management of Sotorasib in a KRAS G12C Mutated NSCLC Patient

Clinical Outcomes and Adverse Effect Management of Sotorasib in a KRAS G12C Mutated NSCLC Patient

Clinical efficacy and adverse effects of LMWH combined with ASA in the treatment of RSA: A meta-analysis and systematic review.

The incidence of recurrent spontaneous abortion (RSA) in the clinic shows an increasing trend year by year, and the coagulation status of this group of patients is mostly relatively abnormal. Currently, commonly used drugs in clinical practice include Aspirin (ASA) and low molecular weight heparin (LMWH), but their optimal treatment remains controversial. We aimed to evaluate the clinical efficacy and adverse effects of LMWH combined with ASA in the treatment of RSA. Randomized controlled trials of LMWH combined with ASA for RSA were searched in the databases of PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, Wanfang, VIP, and Chinese Biomedical Literature Service System from the construction of the database to June 2024. Data were analyzed using Review Manager 5.3 and Stata software. Dichotomous variables were analyzed using relative risk (RR) and 95% confidence interval (CI) as their statistics. The included literature was assessed for bias and risk of bias of eligible studies using Cochrane risk of bias tool. The risk of bias was evaluated based on the evaluation criteria recommended by the Cochrane Guidance Manual for Systematic Evaluation. A total of 32 papers with a total of 3397 patients with RSA were finally included. LMWH combined with ASA treatment significantly improved the live birth rate (RR = 1.31, 95% CI: [1.19, 1.45], P < .00001), the rate of preterm stillbirths (RR = 0.23, 95% CI: [0.13, 0.40], P < .00001), rate of term delivery (RR = 1.55, 95% CI: [1.43, 1.67], P < .00001), rate of miscarriage (RR = 0.42, 95% CI: [0.36, 0.48], P < .00001), incidence of petechiae (RR = 0.44, 95% CI: [0.26, 0.72], P = .001), and incidence of thrombocytopenia (RR = 0.61, 95% CI: [0.39, 0.96], P = .03). In contrast, the incidence of preterm live births (RR = 1.07, 95% CI: [0.90, 1.28], P = .44), adverse reactions (RR = 0.77, 95% CI: [0.59, 1.00], P = .05), gingival bleeding (RR = 1.12, 95% CI: [0.65, 1.93], P = .69), and gastrointestinal reactions (RR = 0.87, 95% CI: [0.64, 1.17], P = .35) were not significant. LMWH combined with ASA treatment might improve pregnancy outcomes and reduces the incidence of adverse events in patients with RSA.

Preferences for attributes of oral antipsychotic treatments: results from a discrete-choice experiment in respondents with schizophrenia or bipolar I disorder

BackgroundAntipsychotic medications are effective treatments for schizophrenia (SZ) and bipolar I disorder (BD-I), but when presented with different treatment options, there are tradeoffs that individuals make between clinical improvement and adverse effects. As new options become available, understanding the attributes of antipsychotic medications that are valued and the tradeoffs that individuals consider when choosing among them is important.MethodsA discrete-choice experiment (DCE) was administered online to elicit preferences across 5 attributes of oral antipsychotics: treatment efficacy (i.e., improvement in symptom severity), weight gain over 6 months, sexual dysfunction, sedation, and akathisia. Eligible respondents were aged 18–64 years with a self-reported clinician diagnosis of SZ or BD-I.ResultsIn total, 144 respondents with SZ and 152 with BD-I completed the DCE. Of those with SZ, 50% identified themselves as female and 69.4% as White, with a mean (SD) age of 41.0 (10.1) years. Of those with BD-I, most identified themselves as female (69.7%) and as White (77.6%), with a mean (SD) age of 40.0 (10.7) years. In both cohorts, respondents preferred oral antipsychotics with better efficacy, less weight gain, no sexual dysfunction or akathisia, and lower risk of sedation. Treatment efficacy was the most important attribute, with a conditional relative importance (CRI) of 31.4% for respondents with SZ and 31.0% for those with BD-I. Weight gain (CRI = 21.3% and 23.1%, respectively) and sexual dysfunction (CRI = 23.4% and 19.2%, respectively) were adverse effects in this study that respondents most wanted to avoid. Respondents with SZ were willing to accept 9.8 lb of weight gain or > 25% risk of sedation for symptom improvement; those with BD-I were willing to accept 8.5 lb of weight gain or a > 25% risk of sedation.ConclusionsIn this DCE, treatment efficacy was the most important attribute of oral antipsychotic medications among respondents with SZ and BD-I. Weight gain and sexual dysfunction were the adverse effects respondents most wanted to avoid; however, both cohorts were willing to accept some weight gain or sedation to obtain better efficacy. These results highlight features that patients value in antipsychotic medications and how they balance benefits and risks when choosing among treatments.

Inflammatory biomarkers and clinical adverse effects associated with Isotretinoin treatment: A prospective study

Background Isotretinoin is considered now one of the most important drugs in the treatment of different dermatological diseases. However, different body systems can be affected during the treatment due to isotretinoin induced apoptosis. Objectives To evaluate the clinical adverse effects and laboratory changes associated with isotretinoin used in the treatment of different dermatological diseases. Methods 73 patients on isotretinoin treatment fulfilled a questionnaire about side effects associated with isotretinoin. Complete blood count (CBC), fasting lipid profile, liver enzymes, and the inflammatory markers Monocytes/HDL ratio (MHR), Neutrophil/lymphocyte (NLR), and Platelets/lymphocyte ratios (PLR) were assessed before treatment and monthly during the treatment period. Results The commonest adverse effects were related to dryness of skin and mucus membrane. 32.9% complained of myalgia and 12.3% arthralgia. Headache was reported in 13.7%, mood alteration in 11%, and insomnia in 12.3%. 24.5% of studied females reported menstrual irregularities. There were no statistically significant changes in CBC. TG, cholesterol, AST, ALT, and MHR significantly increased while HDL, NLR and PLR ratios significantly decreased after isotretinoin treatment. Conclusion: isotretinoin affects different body systems by side effects that are reversible in most instances; however, some of them are serious and need regular monitoring especially in high- risk patients.

260. LOW BLOOD LEVEL OF TUMOR SUPPRESSOR MIR-3619 AS A TARGET OF NUCLEIC ACID THERAPY TO PIM-1 IN ESOPHAGEAL CANCER

Abstract Background Numerous studies have attempted to understand the molecular mechanisms of tumorigenesis and identify clinical biomarkers and molecular targets for esophageal squamous cell carcinoma (ESCC). However, there are still only a few biomarkers and targets. We focused on tumor suppressor micro-RNA (miR)s in the plasma of ESCC patients, and we investigated the usefulness of these tumor suppressor miRs as biomarkers and therapeutic agents for ESCC. Methods: Plasma samples of 94 ESCC patients and 86 healthy volunteers were analyzed in this study. Among the group of 2600 miRs candidates registered in miRbase, we selected 25 miRs candidates which are low expressed in ESCC tissues, have tumor suppressive functions, and unreported as a body fluid biomarker. We selected 5 miRs (miR-564/ 637/ 1182/ 3178/ 3619), whose signals were detectable in the blood of healthy volunteers by microarray analysis. By test-scale analysis using TaqMan assay and validation analysis, we identified miR-3619, which showed the most significant difference in ESCC patients compared to healthy volunteers (p &amp;lt; 0.001). Results: 1) Prognostic analysis revealed that a low miR-3619 plasma level was significantly associated with advanced stage and recurrence rate, and was an independent factor predicting poor prognosis in ESCC patients (p = 0.028, HR = 2.09). 2) Overexpression of miR-3619 mimic inhibited the proliferation of ESCC cells, induced the accumulation of apoptosis or G1/S phase cells, and reduced the cell migration and invasion abilities compared with negative control mimic. 3) We tested PIM-1xas candidate putative target genes for miR-3619 using microRNA database. PIM-1 protein expression levels were decreased in miR-3619-5p transfectants compared with NC. 4) In vivo, subcutaneous injection of miR-3619 could significantly inhibit tumor growth in mice. Administration of miR-3619 did not cause any clinical adverse events or side effects in blood-based parameters reflecting organ disorders. Conclusion: These results suggest that depleted tumor-suppressor miR-3619 in plasma could be one of blood-based biomarkers for predicting malignant potential of ESCC.

Therapeutic Effects, Side Effects, and Adverse Effects of Neuropsychiatric Drugs in the Context of Treating Cancer-Related Anorexia With Olanzapine and Mirtazapine.

Drugs have actions that may be classified as therapeutic effects and side effects; side effects are actions that do not contribute to therapeutic benefit. Some side effects are neutral; others, experienced as undesirable or unpleasant, are recorded as adverse effects. Some drug actions are therapeutic for some disorders and adverse for others; or therapeutic during acute illness and adverse during maintenance treatment. As an example, anticholinergic action may be adverse when a tricyclic antidepressant is used to treat depression but therapeutic when the drug is used to treat irritable bowel syndrome with diarrhea. In clinical practice, side or adverse effects of a drug may be leveraged to manage troublesome symptoms. As an example, the sedative effect of a low dose of trazodone may be useful for some patients with insomnia. With this background, studies have examined whether the increase in appetite and weight associated with olanzapine and mirtazapine may be effective against anorexia and cachexia associated with cancer and cancer chemotherapy. The subject is important because cachexia may be present in 30%-50% of patients with cancer (with higher prevalence in patients with more advanced cancer) and because the presence of cachexia is associated with a higher risk of disease progression and mortality. Many randomized controlled trials (RCTs) have examined pharmacologic interventions such as progestins, corticosteroids, anamorelin, and medical cannabis for cancer related cachexia; most results have been disappointing. A recent RCT found that olanzapine (2.5 mg/d for 12 weeks) improved appetite, weight, other nutritional parameters, and quality of life in patients with locally advanced or metastatic cancer treated with chemotherapy. Another RCT, however, found that mirtazapine (30 mg/d for 8 weeks) brought no nutritional or anthropometric gain in patients with cancer and anorexia. It is concluded that olanzapine but not mirtazapine merits further investigation in patients with cancer who have anorexia and cachexia.

Evaluation of the use of tranexamic acid in the postoperative period in patients with scoliosis undergoing posterior fusion.

Scoliosis is the most prevalent type of spinal deformity, with a 2-3% prevalence in the general population. Moreover, surgery for scoliotic deformity may result in severe blood loss and, consequently, the need for blood transfusions, thereby increasing surgical morbidity and the rate of complications. Several antifibrinolytic drugs, such as tranexamic acid, have been regarded as safe and effective options for reducing blood loss. Therefore, the present study aimed to analyse the effectiveness of this drug for controlling bleeding when used intraoperatively and in the first 48h after surgery. A prospective randomized study of a cohort of patients included in a mass event for scoliosis treatment using PSF was performed. Twenty-eight patients were analysed and divided into two groups: 14 patients were selected for intraoperative and postoperative use of tranexamic acid (TXA), and the other 14 were selected only during the intraoperative period. The drainage bleeding rate, length of hospital stay, number of transfused blood units, and rate of adverse clinical effects were compared. All the patients involved had similar numbers of fusion levels addressed and similar scoliosis profiles. The postoperative bleeding rate through the drain did not significantly differ between the two groups (p > 0.05). There was no significant difference in the number of transfused blood units between the groups (p = 0.473); however, in absolute numbers, patients in the control group received more transfusions. The length of hospital stay was fairly similar between the groups, with no statistically significant difference. Furthermore, the groups had similar adverse effects (p = 0.440), with the exception of nausea and vomiting, which were twice as common in the TXA group postoperatively than in the control group. No significant differences were found in the use of TXA during the first 48 postoperative hours or in postoperative outcomes.

A Comprehensive ddPCR Strategy for Sensitive and Reliable Monitoring of CAR-T Cell Kinetics in Clinical Applications.

In this study, we present the design, implementation, and successful use of digital droplet PCR (ddPCR) for the monitoring of chimeric antigen receptor T-cell (CAR-T) expansion in patients with B-cell malignancies treated with different CAR-T products at our clinical center. Initially, we designed a specific and highly sensitive ddPCR assay targeting the junction between the 4-1BB and CD3ζ domains of tisa-cel, normalized with RPP30, and validated it using blood samples from the first tisa-cel-treated patient in Switzerland. We further compared this assay with a published qPCR (quantitative real-time PCR) design. Both assays showed reliable quantification of CAR-T copies down to 20 copies/µg DNA. The reproducibility and precision were confirmed through extensive testing and inter-laboratory comparisons. With the introduction of other CAR-T products, we also developed a corresponding ddPCR assay targeting axi-cel and brexu-cel, demonstrating high specificity and sensitivity with a limit of detection of 20 copies/µg DNA. These assays are suitable for CAR-T copy number quantification across multiple sample types, including peripheral blood, bone marrow, and lymph node biopsy material, showing robust performance and indicating the presence of CAR-T cells not only in the blood but also in target tissues. Longitudinal monitoring of CAR-T cell kinetics in 141 patients treated with tisa-cel, axi-cel, or brexu-cel revealed significant expansion and long-term persistence. Peak expansion correlated with clinical outcomes and adverse effects, as is now well known. Additionally, we quantified the CAR-T mRNA expression, showing a high correlation with DNA copy numbers and confirming active transgene expression. Our results highlight the quality of ddPCR for CAR-T monitoring, providing a sensitive, precise, and reproducible method suitable for clinical applications. This approach can be adapted for future CAR-T products and will support the monitoring and the management of CAR-T cell therapies.

One-year Safety and Effectiveness of Ustekinumab in Patients With Crohn's Disease: The K-STAR Study.

This study investigated the safety and effectiveness of ustekinumab (UST) in Korean patients with Crohn's disease (CD). Adult patients with CD treated with UST were prospectively enrolled in the K-STAR (Post-MarKeting Surveillance for Crohn's Disease patients treated with STelARa) study between April 2018 and April 2022. Both the clinical effectiveness and adverse effects of UST therapy were analyzed. Missing data were handled using nonresponder imputation (ClinicalTrials.gov Identifier: NCT03942120). Of the 464 patients enrolled from 44 hospitals across Korea, 457 and 428 patients (Crohn's disease activity index ≥150) were included in the safety analysis and effectiveness analysis sets, respectively. At weeks 16 to 20 after initiating UST, clinical response, clinical remission, and corticosteroid-free remission rates were 75.0% (321 of 428), 64.0% (274 of 428), and 61.9% (265 of 428), respectively. At week 52 to 66, clinical response, clinical remission, and corticosteroid-free remission rates were 62.4% (267 of 428), 52.6% (225 of 428), and 50.0% (214 of 428), respectively. Combined effectiveness (clinical response + biochemical response) was achieved in 40.0% (171 of 428) and 41.6% (178 of 428) at week 16 to 20 and week 52 to 66, respectively. Biologic-naïve patients exhibited significantly higher rates of combined effectiveness than biologic-experienced patients (50.3% vs 30.7% at week 16-20, P < .001; 47.7% vs 36.0% at week 52-66, P = .014). No additional benefits were observed with the concomitant use of immunomodulators. Ileal location was independently associated with a higher probability of clinical remission compared with colonic or ileocolonic location at week 52 to 66. Adverse and serious adverse events were observed in 28.2% (129 of 457) and 12.7% (58 of 457), respectively, with no new safety signal associated with UST treatment. Ustekinumab was well-tolerated, effective, and safe as induction and maintenance therapy for CD in Korea.

Evaluating the Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR) for Clinical Trials of Antibiotics in Pediatric Pneumonia.

Objective outcomes for pediatric community-acquired pneumonia (CAP) are lacking. The desirability of outcome ranking (DOOR) and response adjusted for duration of antibiotic risk (RADAR) outcome encompass clinical benefit and adverse effects, while also accounting for antibiotic exposure. We evaluated DOOR/RADAR through simulations and compared sample size considerations to non-inferiority designs in a hypothetical trial comparing antibiotics to no antibiotics (i.e., placebo) for children with mild CAP. We also evaluated a trial comparing different durations of antibiotics. Three scenarios were considered - one with no difference in DOOR between the two groups, one in which placebo is more efficacious, and another in which amoxicillin is more efficacious than placebo. Power to detect a difference between arms was greater using DOOR/RADAR compared to DOOR. Assuming a sample size of 200, DOOR had 2.5%, 50%, and 65% power to detect a statistical difference between arms for Scenarios 1-3, respectively, significantly less than DOOR/RADAR. Importantly, DOOR/RADAR incorrectly identified placebo as superior in Scenario 3 where amoxicillin was truly efficacious. Sample size requirements for non-inferiority designs were larger to achieve similar levels of power as DOOR and DOOR/RADAR. DOOR/RADAR has the potential to lead to an incorrect conclusion declaring placebo superior when amoxicillin is efficacious.

Safety of Gonadal Tissue-Derived Mesenchymal Stem Cell Therapy in Geriatric Dogs with Chronic Disease.

Ensuring the safety of mesenchymal stem cell (MSC) therapy is a fundamental requirement in clinical practice. This study aimed to assess the safety of using gonadal tissue-derived MSCs (n = 10) compared to the commonly utilized adipose tissue-derived MSCs (n = 9) in geriatric dogs with chronic diseases. All participants received allogeneic MSC therapy, and no allergic reactions due to allogeneic cell immunogenicity were noted. Both groups showed no adverse changes in physical exams or hematological parameters before and after therapy. Importantly, there were no instances of tumor formation or growth post-treatment in either group. The findings demonstrated that dogs treated with gonadal tissue-derived MSCs experienced no clinical adverse effects. However, clinical adverse effects were reported in one case of adipose tissue-derived MSC therapy. Despite limitations in monitoring beyond one year and constraints due to a small and diverse patient group, this pioneering study validates the safe use of gonadal tissue-derived MSCs in aged companion animals. It underscores the potential of utilizing tissues from neutering procedures to advance regenerative medicine and expand cell banks and therapy options for companion animals.

Clinical benefits of transarterial chemoembolization combined with tyrosine kinase and immune checkpoint inhibitors for unresectable hepatocellular carcinoma.

Combination therapy has emerged as the focus of research for unresectable hepatocellular carcinoma (HCC). In recent years, several studies have explored the clinical efficacy and safety of the combination therapies of transarterial chemoembolization (TACE) with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). To conduct an updated meta-analysis verifying the clinical benefits and adverse effects of the triple combination therapy for unresectable HCC. All eligible cohort, non-randomized controlled, and randomized controlled trial studies from the PubMed, Web of Science, Embase, Cochrane Library, and MedLine databases up to March 20, 2024 were screened for the present meta-analysis. The study endpoints included complete response (CR), objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs). Stata 16/18 software was used for this meta-analysis, and a P value of <0.05 was considered statistically significant. A total of 29 studies with 1754 patients were included. Among the patients who received the TACE therapy with TKIs and ICIs, the tumor response results revealed a pooled CR, ORR, and DCR of 14% [95%CI (0.11-0.18)], 61% [95%CI (0.55-0.66)], and 85% [95%CI (0.83-0.87)], respectively. In terms of the survival outcomes, the pooled median PFS and OS were 10.25 months [95%CI (9.31-11.18)] and 20.47 months [95%CI (18.98-21.97)], respectively. The pooled prevalence of all-grade AEs during the triple treatment was 90% [95%CI (0.84-0.94)] and that of grade ≥ 3 AEs was 32% [95%CI (0.24-0.42)]. The combination therapy of TACE, TKIs, and ICIs exhibits great clinical benefits for unresectable HCC in terms of tumor responses and survival outcomes without increasing the risk of severe AEs.

Ivermectin therapy for young children with scabies infection: a multicentre phase 2 non-randomized trial

Ivermectin, an effective treatment for scabies, is not licensed for children weighing <15kg. Pharmacokinetic modelling has shown a 3mg dose in young children (2-4 years, weighing 10-14kg) achieves comparable drug exposure to a 200μg/kg dose in children aged ≥5 years. This trial evaluated a 3mg dose in young children. Multicentre, phase 2 trial in five health centres in Lao PDR. Children aged 2-4 years, weighing 10-14kg with scabies received 3mg ivermectin and had two plasma concentrations determined (Clinicaltrials.gov ID NCT05500326). On day 14, clinical outcomes and adverse effects were assessed, and a second dose given to complete treatment. The primary outcome was the mean plasma ivermectin exposure (AUC0-∞) after the first dose (compared to a historical control of Indigenous Australian children aged ≥5 years weighing ≥15kg receiving 200μg/kg). Secondary outcomes were clinical improvement and adverse effects. Overall, 100 children with a median age of 3.0 years (IQR 2.6-3.9) and weight of 11.9kg (IQR 11.0-13.1) were enrolled. The mean observed ivermectin AUC0-∞ was comparable to the historical control group aged 5-11 years (815μgh/L vs 953μgh/L, p=0.256). Complete resolution of scabies occurred in 90/99 children by day 14. Adverse effects were mild, occurring in 7/99. A 3mg ivermectin dose in children aged 2-4 years and weighing 10-14kg achieved a mean plasma AUC0-∞ comparable to older children, was highly effective in treating scabies and well tolerated. This study supports extending ivermectin treatment to younger children improving global efforts to control this neglected disease. Project funding provided by a Thrasher Foundation Early Career Research Award.

Detection and characterisation of a sixth Candida auris clade in Singapore: a genomic and phenotypic study

The emerging fungal pathogen Candida auris poses a serious threat to global public health due to its worldwide distribution, multidrug resistance, high transmissibility, propensity to cause outbreaks, and high mortality. We aimed to characterise three unusual Cauris isolates detected in Singapore, and to determine whether they constitute a novel clade distinct from all previously known Cauris clades (I-V). In this genotypic and phenotypic study, we characterised three Cauris clinical isolates, which were cultured from epidemiologically unlinked inpatients at a large tertiary hospital in Singapore. The index isolate was detected in April, 2023. We performed whole-genome sequencing (WGS) and obtained hybrid assemblies of these Cauris isolates. The complete genomes were compared with representative genomes of all known Cauris clades. To provide a global context, 3651international WGS data from the National Center for Biotechnology Information (NCBI) database were included in a high-resolution single nucleotide polymorphism (SNP) analysis. Antifungal susceptibility testing was done and antifungal resistance genes, mating-type locus, and chromosomal rearrangements were characterised from the WGS data of the three investigated isolates. We further implemented Bayesian logistic regression models to classify isolates into known clades and simulate the automatic detection of isolates belonging to novel clades as their WGS data became available. The three investigated isolates were separated by at least 37 000SNPs (range 37 000-236 900) from all existing Cauris clades. These isolates had opposite mating-type allele and different chromosomal rearrangements when compared with their closest clade IV relatives. The isolates were susceptible to all tested antifungals. Therefore, we propose that these isolates represent a new clade of Cauris, clade VI. Furthermore, an independent WGS dataset from Bangladesh, accessed via the NCBI Sequence Read Archive, was found to belong to this new clade. As a proof-of-concept, our Bayesian logistic regression model was able to flag these outlier genomes as a potential new clade. The discovery of a new Cauris clade in Singapore and Bangladesh in the Indomalayan zone, showing a close relationship to cladeIV members most commonly found in South America, highlights the unknown genetic diversity and origin of Cauris, particularly in under-resourced regions. Active surveillance in clinical settings, along with effective sequencing strategies and downstream analysis, will be essential in the identification of novel strains, tracking of transmission, and containment of adverse clinical effects of Cauris infections. Duke-NUS Academic Medical Center Nurturing Clinician Researcher Scheme, and the Genedant-GIS Innovation Program.