Incremental Doses Research Articles

Novel desensitization therapy of mesalamine intolerance in patients with ulcerative colitis.

Mesalamine is the first-line drug for treating mild-to-moderate ulcerative colitis (UC); however, some patients develop symptoms of intolerance. Although several desensitization methods have been reported, these desensitization regimens were rather complicated for physicians to prescribe in daily clinical practice; therefore, it has not yet become a major therapeutic option for intolerance patients. Thus, we developed an alternative desensitization protocol. We performed a single-center, retrospective study of patients with UC, who were intolerant to mesalamine and had undergone desensitization therapy. Desensitization starts with 50 mg of granule mesalamine, with an increase in the dose by 50 mg every week up to 200 mg, followed by incremental doses of 100 mg every week. After patients received dosages of more than 1000 mg, the dose was increased by 200 mg every week up to the target dose. Concomitant medications such as oral prednisolone or budesonide rectal foam were allowed during the protocol but were withdrawn before the end of desensitization. We evaluated the success rate of our mesalamine desensitization method and performed safety assessments during the protocol. Of 115 patients, 17 were intolerant to mesalamine. We excluded six patients who had severe disease or organ disorders. Overall, 11 patients received desensitization therapy without hospitalization. All 11 patients successfully underwent desensitization therapy and received the target dose of mesalamine (3000-4000 mg/day) at the end of the protocol. No serious adverse events were observed during this protocol. This retrospective study reports a successful and safe desensitization method for UC patients with mesalamine intolerance.

Safety, bactericidal activity, and pharmacokinetics of the antituberculosis drug candidate BTZ-043 in South Africa (PanACEA-BTZ-043-02): an open-label, dose-expansion, randomised, controlled, phase 1b/2a trial.

The broad use of bedaquiline and pretomanid as the mainstay of new regimens to combat tuberculosis is a risk due to increasing bedaquiline resistance. We aimed to assess the safety, bactericidal activity, and pharmacokinetics of BTZ-043, a first-in-class DprE1 inhibitor with strong bactericidal activity in murine models. This open-label, dose-expansion, randomised, controlled, phase 1b/2a trial was conducted in two specialised tuberculosis sites in Cape Town, South Africa. Adults aged 18-64years with newly diagnosed pulmonary tuberculosis sensitive to rifampicin and isoniazid, who weighed at least 40kg, had a positive sputum smear graded at least 1+, were HIV negative, and had no history of hypertension or other substantial comorbidities were admitted to hospital. In stage 1 (multiple-ascending dose phase 1b with an adaptive continual reassessment method), the starting dose of BTZ-043 was 250mg, with planned dose increments of 250mg up to 2000mg, and cohorts of three participants were enrolled sequentially. In stage 2 (phase 2a dose-expansion stage), participants were randomly assigned (3:3:3:2) to receive one of three doses of oral BTZ-043 (decided after stage 1) or standard of care (isoniazid, rifampicin, pyrazinamide, and ethambutol) using sealed opaque envelopes. The BTZ-043 groups also received oral dolutegravir (athird of participants) or a probe drug cocktail (caffeine [probe for CYP1A2], tolbutamide [CYP2C9], dextromethorphan [CYP2D6], midazolam [CYP3A4], and digoxin [P-glycoprotein]; two-thirds of participants). Study staff and participants were not masked, but laboratory staff were masked to treatment assignment. The primary outcome was to assess the safety and tolerability of BTZ-43 over 14days of dosing by evaluation of adverse events in the safety analysis population. Secondary outcomes were bactericidal activity, measured by time to positivity (TTP) and colony-forming unit (CFU) count; pharmacokinetics (stage 2; including the food effect on BTZ-043); and drug-drug interactions with CYP450 enzymes, P-glycoprotein, and dolutegravir. This study is registered with ClinicalTrials.gov, NCT04044001 (completed). In stage 1, 61patients were assessed for eligibility and 24were enrolled into seven dose cohorts between Nov13,2019, and Aug 13, 2020. Dose escalations were performed safely up to 1750mg of BTZ-043 with three participants per dose cohort (and two dose cohorts for the highest dose). In stage 2, 151patients were assessed for eligibility and 54were enrolled and randomly assigned between Feb 2, 2021, and Feb 9, 2022, to receive 250, 500, and 1000mg of BTZ-043 or standard of care. 66 (85%) of 78participants were male and 12 (15%) were female. The most frequently observed adverse events were nausea (12 [8%] of 154), headache (11 [7%]), dizziness (11[7%]), and vomiting (eight[5%]). Most participants had adverse events of mild (46 [60%] of 77participants) or moderate (22[29%]) severity. Transient increases in alanine aminotransferase were observed in both stages, which declined again despite continued dosing and were classified as signs of adaptation of hepatic metabolism rather than hepatotoxicity. The worsening of pre-existing anaemia and QTcF interval prolongation in one individual eachwere rated as possibly related to the study drug. One patient died before the first scheduled dose of BTZ-043 500mg due to a pulmonary embolism. In stage 1, bactericidal activity measured as CFU counts on solid media was highest at doses 750-1500mg; in stage 2, all doses of BTZ-043 showed 14-day bactericidal activity, highest at 1000mg on solid media (log10 CFU/mL per day -0·115 [95% CI -0·162to -0·069]) and TTP estimates were highest at 500mg in liquid media (log10 h per day 0·015 [0·010to 0·019]). BTZ-043 pharmacokinetics showed increased exposure with high-fat food versus fasting (area under thecurve [AUC]0-last geometric mean ratio 4·13[90% CI 1·65to 10·30] for BTZ-043; 2·99 [1·39to 6·41] for BTZ-043total [BTZ-043 plus metabolite 2]; and 1·25[0·66to 2·39] for metabolite 1). When taken with a standard breakfast, BTZ-043total AUC showed a dose-proportional increase up to 33 200ng/mL × h (range 12 500to 48 200) at 1000mg. The maximum concentration (Cmax) increased to 5060ng/mL (2450 to 8020); and median half-life was 3·72h (2·45to 6·60). Probe drug evaluations showed bioequivalence (ie,90% CI of the AUC0-infinity geometric mean ratio from administration to day14entirely within the range of 80 to 125%) for caffeine (100·0% [90% CI 86·3 to 115·9]), digoxin (113·4% [105·9 to 121·5]), and dolutegravir (106·1% [91·5 to 122·9]). Dextromethorphan (116·2% [104·6 to 129·1]), tolbutamide (252·7% [230·7 to 276·9]), and midazolam (77·0% [69·2 to 85·6]) did not meet the bioequivalence criterion. Based on a small sample size, BTZ-043 is a promising antituberculosis drug candidate with favourable safety and good bactericidal activity. Larger follow-up studies are needed to detect any less frequent safety signals, further explore drug-drug interactions, identify the best dose, and evaluate efficacy in combination with other drugs. EDCTP2 programme; German Ministry for Education and Research; German Center for Infection Research; InfectControl; Bavarian Ministry for Science and the Arts; Swiss State Secretariat for Education, Research, and Innovation; and Nederlandse Organisatie voor Wetenschappelijk Onderzoek.

Pharmacokinetics of ethambutol and weight banded dosing in South African adults newly diagnosed with tuberculosis and HIV.

Ethambutol is used to treat tuberculosis (TB) in individuals living with HIV. Low concentrations of ethambutol have been reported in patients dosed with the World Health Organization (WHO)-recommended first-line regimen. We analyzed the pharmacokinetics of ethambutol in 61 HIV-positive individuals diagnosed with drug-sensitive TB enrolled in the tuberculosis and highly active antiretroviral therapy (TB-HAART) study. Participants started on TB treatment and were randomized to early or later introduction of efavirenz-based antiretroviral treatment. We explored potential covariate effects and evaluated the current WHO dosing recommendations for ethambutol in drug-susceptible and multidrug-resistant (MDR)-TB. A two-compartment model with first-order elimination allometrically scaled by fat-free mass and transit compartment absorption best described the pharmacokinetics of ethambutol. Clearance was estimated to be 40.3 L/h for a typical individual with a fat-free mass (FFM) of 42 kg. The Antib-4 formulation had 26% higher bioavailability and slower mean transit time by 37% compared with Rifafour. Simulations showed that individuals in the lower weight bands (<55 kg) who were administered ethambutol at WHO-recommended doses had relatively low drug exposures. These individuals would need doses of 825 mg if their body weight is <37.9 kg and 1,100 mg if it is between 38 and 54.9 kg to achieve the reference maximum concentrations of 2-6 mg/L and an area under the concentration-time curve (0-24) of 16-29 mg·h/L. To achieve these targets in MDR-TB treatment, a dose increment of 400 mg (extra tablet) would be required for individuals in the lower weight band (<46 kg). Our dose adjustments are consistent with the literature and can be recommended for consideration by the WHO for first-line drug-susceptible and MDR-TB treatment.

When understanding fails: how diverging norms in medicine and research led to informed consent failures during the pandemic

During the COVID-19 pandemic, there were many vaccine trials which had significant purposes which participants needed to understand to validly consent. For example, participants needed to understand that the purpose...

ASSESSMENT OF TOXICITY AND ANTI-DIABETIC POTENTIAL OF CHAYA (Cnidoscolus chayamansa) ETHANOLIC LEAF EXTRACT ON ALLOXAN INDUCED DIABETIC RATS

The need to scientifically prove the claim of traditional uses of plant materials in treating diseases has led to investigations into the medicinal potency of various plants. Cnidoscolus chayamansa (Euphorbiaceae) leaves have been traditionally used to treat diabetes and other ailments such as obesity and kidney stones. Toxicity test was conducted by administering different doses of extract to six (6) groups of rats which has six rats each. The first group was given distilled water. However, the second group onward received incremental doses of extract (1000 – 5000 mg/kg). Anti-diabetic activities of Chaya extract was investigated using thirty (30) rats weighing between 120 g – 180 g. Animals were distributed into control and five treatment groups of five rats each. Group one received standard diet and water ad libitum, while treated groups (2 – 6) were given 200 mg/kg and 400 mg/kg of Chaya extract, 150 mg/kg of alkaloid fraction and 150 mg/kg of standard drug (Metformin) respectively. After observation for 24 hours, no death of animals was recorded. Therefore, LD50 of the extract was determined to be greater than 5000 mg/kg. Results of treatment procedure showed that diabetic rats treated with two different doses of extract, alkaloid fraction and standard drug decreased blood glucose at day 7, 14 and a further decrease at day 21, which was significantly (p ≤ 0.05) different from the control group. Therefore, Cnidoscolus chayamansa leaf can be safely consumed and possesses anti-diabetic properties.

Association between long-term exposure to air pollutants with breakthrough SARS-CoV-2 infections and antibody responses among COVID-19 vaccinated older adults in Northern Italy

AimsTo investigate the association between long-term exposure to PM2.5, PM10, NO2 and O3 with SARS-CoV-2 breakthrough infections and COVID-19 vaccine-induced antibody responses in a northern Italian population-based sample of older adults. MethodsWithin an ongoing prospective population-based study, we followed-up 1326 vaccinated individuals aged 65–83 years, with no prior SARS-CoV-2 infection, for their first positive SARS-CoV-2 swab until December 31st, 2022. We assessed spike IgG antibody levels in most participants (n = 1206). The 2019 annual mean levels of air pollutants derived from combined use of chemical-transport and random-Forest models (spatial resolution: 1Kmq) were individually assigned based on the latest residence address. We estimated multivariable-adjusted associations (per 1 interquartile range increase, IQR) of air pollutants with breakthrough infections using Cox models with time-dependent vaccine exposure; and with percent change in the IgG geometric mean using generalized additive models. ResultsThe mean (SD) age was 74.9 ± 4.1 years, and 50% were women. An IQR (1.2 μg/m3) increase in long-term PM2.5 exposure was associated with a 52% increase in breakthrough infection risk following a second vaccine and a 26% increase following a third vaccine. The effect vanished with the further increment of vaccination doses. Associations for NO2 were inconsistent. Ozone was negatively associated with breakthrough infection risk, but this association reversed in bi-pollutant models adjusting for PM2.5. PM2.5 was associated with a −7.3% (−13.9% to −0.2%) reduction in vaccine-induced IgG levels. The reduction became more pronounced as the time delay from vaccination increased, and with adjustment for NO2 co-exposure. ConclusionIn our population of vaccinated older adults, fine particulate matter exposure was independently associated with a higher risk of SARS-CoV-2 breakthrough infection and a lower antibody response, both effects being influenced by timely and repeated vaccination schedule.

Giant Photoluminescence Enhancement of Ga-Doped ZnO Microwires by X-Ray Irradiation.

Ga-doped zinc oxide (ZnO) microwires hold great promise for developing highly efficient light sources because of the wide bandgap with proper exciton binding energy. However, most microwires grown from one mainstream approach, i.e., chemical vapor deposition (CVD), are morphologically and crystallographically defective, exhibiting limited photoluminescence performances. Herein, a simple and effective X-ray irradiation strategy is demonstrated for enhancing the photoluminescence of Ga-doped ZnO microwire in ambient conditions. Under moderate doses (≤ 150Gy), the photoluminescence monotonically rockets up with X-ray dose increment and achieves nine-fold enhancement at a dose of ≈150Gy, recording high photoluminescence improvement of ZnO microwires to date. The elemental characteristics under different controlled irradiation atmospheres suggest the elimination of surface oxygen vacancy and the cross-section transmission electron microscope reveals prominent lattice relaxations after mild X-ray irradiation. In addition, the X-ray irradiated microwires further exhibit elevated electroluminescence by over three times. The enhanced photoluminescence and electroluminescence as well as long-term stability enable us to imagine the super-rapid applications of ZnO microwires in modern optoelectronic devices.

Abstract 4137449: Diagnostic Yield and Testing Characteristics of an Invasive Coronary Function Testing Program

Background: Angina, ischemia, or myocardial infarction in the absence of obstructive coronary artery disease (ANOCA, INOCA, or MINOCA) is common and underdiagnosed. Invasive coronary function testing (CFT) for microvascular disease through coronary thermodilution and for coronary vasospasm through coronary reactivity testing can provide definitive diagnoses and improve patient quality of life. Here, we describe a single site experience launching a CFT program and present the diagnostic yield and test characteristics of the first 66 patients. Methods: The first 66 patients who underwent invasive CFT at Mass General Hospital after the launch of the program in 2022 were included. Invasive CFT data and clinical characteristics before and after were entered into a registry. We used descriptive statistics to summarize patient characteristics, diagnostic yield and change in management with invasive CFT. We describe the dose-response and safety of incremental doses of acetylcholine. Results: Among 66 patients (mean age 61.73±11.02 years, 56% female), 17 patients underwent testing at the time of an index angiogram and 49 were scheduled after knowledge of coronary anatomy. Reasons for invasive coronary function testing were post-revascularization angina (n=30, 45.5%), ANOCA (n=21, 31.8%), INOCA (n=9, 13.6%), MINOCA (n=4, 6.1%), and heart transplant patients (n=2, 3%). 24 (36.3%) patients underwent coronary thermodilution only, 6 (9.1%) coronary reactivity testing only , and 36 (54.5%) both. CFT resulted in a definitive diagnosis in 45 (68.1%) of participants – 37.9% with coronary vasospasm only, 13.6% with microvascular dysfunction only, and 16.7% with both. There were 21 (31.8%) patients who remained negative after invasive CFT. Invasive CFT led to a change in management in 46 (70%) patients. For example, nitrate, calcium channel blocker and beta blocker prescriptions were modified in 47%, 50%, and 52.3% of patients, respectively. Among 42 patients who underwent coronary reactivity testing by provocation with intracoronary acetylcholine doses of 20, 100, and 200 mcg, there was a dose-response to angina (18.5%, 70.2%, and 95.2%), ischemic ECG changes (11.1%, 75.7%, and 95.2%), and vessel spasm of greater than 90% (3.7%, 27%, and 57.1%). There was only one safety event(PTCA to re-establish flow after spasm). Conclusions: We demonstrate the safe implementation of an invasive coronary function testing program with very high diagnostic yield and impact on management.

CTIM-22. MEDIAN AND 2 YEARS SURVIVAL OF NEWLY DIAGNOSED UNMETHYLATED MGMT GLIOBLASTOMA PATIENTS TREATED WITH TEMFERON IMMUNO-GENE THERAPY

Abstract TEM-GBM is an open-label, Phase 1/2a dose-escalation study aimed to evaluate the safety and efficacy of a myeloid cell-targeted therapy (Temferon) in up to 27 newly diagnosed GBM patients with unmethylated MGMT (uMGMT). Temferon, consists of autologous Hematopoietic Stem Progenitor Cells (HSPCs) genetically modified with a lentiviral vector to deliver IFN-α2 within the tumor microenvironment by Tie-2 expressing macrophages. As of 21st May 2024, 24 GBM patients in 8 cohorts received incremental doses of Temferon and 6 are still alive. For all patients, median overall survival (OS) and median progression free survival reach 17 months and 8.3 months from first surgery, respectively. The interim survival rate at 2 years in Temferon-treated patients is 30% (6 of 20 patients; 3 patients excluded as follow-up is below 1 year). The mOS and the % of patients surviving up to 2 years are currently higher than previously reported for uMGMT patients treated as per standard practice (12.7 months and 14,8%, respectively). Two out of the six patients did not receive any additional treatment lines up to two years after 1st surgery. The other four patients instead received a 2nd treatment line (bevacizumab, regorafenib, Gamma-Knife, metronomic Temozolomide, Lomustine) as per the PI judgment, on average after 443 days from 1st surgery (333 days from Temefron - range 223-1030 days from first surgery). Specifically, Bevacizumab administration started 12 months after 1st surgery for one patient and 19 months for the other 2 patients at 5 mg/kg. The data further confirms the initial evidence on safety and tolerability of Temferon and highlight the potential to prolong the survival of patients affected by uMGMT GBM.

A metabolic switch to the pentose-phosphate pathway induces radiation resistance in pancreatic cancer

PurposePancreatic ductal adenocarcinoma (PDAC) is remarkably resistant to standard modalities, including radiotherapy. We hypothesized that metabolic reprogramming may underlie PDAC radioresistance, and moreover, that it would be possible to exploit these metabolic changes for therapeutic intent. Methods and materialsWe established two matched models of radioresistant PDAC cells by exposing the AsPC-1 and MIAPaCa-2 human pancreatic cancer cells to incremental doses of radiation. The metabolic profile of parental and radioresistant cells was investigated using Nanostring technology, labeled-glucose tracing by liquid chromatography-mass spectrometry, Seahorse analysis and exposure to metabolic inhibitors. The synergistic effect of radiation combined with a pentose-phosphate pathway inhibitor, 6-aminonicotinamide (6-AN) was evaluated in a xenograft model established by subcutaneous injection of radioresistant-AsPC-1 cells into nude mice. ResultsThe radioresistant cells overexpressed pyruvate dehydrogenase kinase (PDK) and consistently, displayed increased glycolysis and downregulated the tricarboxylic acid (TCA) cycle and oxidative phosphorylation. Metabolic flux through the pentose-phosphate pathway (PPP) was increased, as were levels of reduced glutathione; pharmacological inhibition of the PPP dramatically potentiated radiation-induced cell death. Furthermore, the combined treatment of radiation with the PPP inhibitor 6-AN synergistically inhibited tumor growth in-vivo. ConclusionsWe provide a mechanistic understanding of the metabolic changes that underlie radioresistance in PDAC. Furthermore, we demonstrate that pancreatic cancer cells can be re-sensitized to radiation via metabolic manipulation, in particular, inhibition of the PPP. Exploitation of the metabolic vulnerabilities of radioresistant pancreatic cancer cells constitutes a new approach to pancreatic cancer, with a potential to improve clinical outcomes.

Vesicular Carriers for Improved Oral Anticoagulation Competence of Rivaroxaban: In Vitro and In Vivo Investigation

Rivaroxaban is an anticoagulant for avoidance and therapy of thromboembolic disorders. Unfortunately, oral bioavailability of rivaroxaban is compromised with dose increments. Accordingly, the aim was to test nano-vesicular lipid systems for improved oral anticoagulation activity of rivaroxaban. Rivaroxaban loaded niosomes, bilosomes and spanlastic formulations were prepared. The prepared systems were assessed in terms of particle size, zeta potential, transition electron microscopic features (TEM), entrapment efficiency, in-vitro drug release, and in-vivo anticoagulation performance in rats. The prepared vesicular systems exposed spherical negatively charged vesicles with mean particle size values between 136.6 nm to 387.9 nm depending on the composition. Rivaroxaban was efficiently entrapped in the vesicular systems with entrapment efficiency values ranging from 92.4% to 94.0%. Rivaroxaban underwent sustained release from the fabricated vesicular systems. The in vivo performance of the tested preparation revealed significant enhancement of the anticoagulation parameters. This was manifested from the prolonged clotting time, and prothrombin time. Moreover, the cut tails of the examined rats receiving the formulated nano-systems exposed a lengthy tail bleeding time compared to those receiving the un-processed rivaroxaban aqueous dispersion. In Conclusion, niosomes, bilosomes and spanlastic nano-dispersions have a potential to overwhelm the oral anticoagulation efficiency of rivaroxaban with spanlastic ranked as best.Graphical

AAAAI-EAACI PRACTALL: Standardizing oral food challenges-2024 Update.

This common statement of the American Academy of Allergy, Asthma and Immunology (AAAAI) and The European Academy of Allergy and Clinical Immunology (EAACI) provides an update of the 2012 published guidelines on food challenges. The guidelines equally address food challenges in the research and the clinical settings. They first address the diagnostic tests which can guide the decision to conduct a challenge. Safety of food challenges is prime, and the various procedures and safety issues as well as medications potentially involved in challenges are extensively discussed. Challenges are suggested to be conducted with semi-logarithmic incremental doses based on the protein content, typically for IgE-mediated food allergy with intervals of 20-30 min between doses. Specific protocols for other types of reactions such atopic dermatitis or gastrointestinal food allergy are detailed separately. Proper stopping criteria are essential in order to reduce the risk of false-positive diagnoses, but also severe reactions. The guidelines recommend criteria based on "go on," "stop," or "observation." These revised guidelines will clearly provide much needed guidance for food challenges in the research and clinical settings. They will continue to evolve with new diagnostic tests or new needs in the field of food allergy.

Sex-differences in ANOCA patients undergoing invasive coronary function testing: preliminary results from the Dutch national NL-CFT registry

Abstract Background The majority of patients with angina and non-obstructive coronary arteries (ANOCA) are women. In most of these patients coronary vasomotor dysfunction, consisting of coronary vasospasm and coronary microvascular dysfunction (CMD), are identified through invasive coronary function testing (CFT). To acknowledge possible sex differences in clinical characteristics and in the entities of coronary vasomotor dysfunction more data are needed. Therefore, this study presents data from one centre participating in the Dutch national CFT (NL-CFT) registry in order to investigate sex differences in patients with a clinical indication for CFT. Methods This retrospective cohort study included 285 consecutive ANOCA patients undergoing clinically indicated CFT, using the Doppler wire or the bolus thermodilution method, from November 2016 till June 2023. CFT consisted of incremental doses of intracoronary acetylcholine (ACh) for the diagnosis of coronary vasospasm and intracoronary adenosine for the diagnosis of CMD defined as abnormal coronary flow reserve (CFR) and/or microvascular resistance (MR). Results In total, 285 patients of which 233 (82%) women and 52 (18%) men were included. Women were significantly younger (56 vs 59 yrs.; p=0.046), had less diabetes (6% vs 23% p&amp;lt;0.001), less prior PCI (12% vs 27%; p=0.019) and less statin use (39% vs 60%; p=0.006), and more often migraine at some point in their life (38% vs 9%; p&amp;lt;0.001). The prevalence of coronary vasomotor dysfunction (77% vs 65%, p=0.086), epicardial spasm (26% vs 31%, p=0.500), microvascular spasm (35% vs 23%, p=0.104), and CMD (35% vs 27%, p=0.304), was not significantly different between women and men. However, a trend was seen towards a higher prevalence of coronary vasomotor dysfunction, microvascular spasm and CMD in women. In total, 29% of women had an abnormal CFR compared to 16% of men (p=0.065) and an abnormal MR was seen in 11% of women and 12% of men (p=0.938). Cardiovascular risk factors were similar between women and men with epicardial spasm. In patients with microvascular spasm women had less prior PCI (p=0.025) and more migraine (p=0.005), in CMD patients women had less diabetes (p=0.002) and hypercholesterolemia (p=0.044) and more migraine (p=0.006). Conclusion In the NL-CFT registry study including ANOCA patients with a clinical indication for CFT women were younger, had less prior PCI and, diabetes and more often migraine. A trend towards a higher prevalence of coronary vasomotor dysfunction, microvascular spasm and CMD was found in women. Furthermore, our results suggest that men with CMD or microvascular spasm have a different cardiovascular risk profile compared to women, which might suggest different optimal tailored treatment for men compared to women. * Upon acceptance for presentation at the ESC Congress, all patients from the Dutch NL-CFT registry will be incorporated into this analysis, resulting in a study population of approximately 1200 individuals.

Relaxivity and In Vivo Human Performance of Brand Name Versus Generic Ferumoxytol.

Ferumoxytol is a superparamagnetic iron-oxide product that is increasingly used off-label for contrast-enhanced magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). With the recent regulatory approval of generic ferumoxytol, there may be an opportunity to reduce cost, so long as generic ferumoxytol has similar imaging performance to brand name ferumoxytol. This study aims to compare the relaxation-concentration dependence and MRI performance of brand name ferumoxytol with generic ferumoxytol through phantom and in vivo experiments. The secondary purpose was to determine the optimal flip angle and optimal weight-based dosing. Phantom experiments were performed using both brand name (AMAG Pharmaceuticals) and generic (Sandoz Pharmaceuticals) ferumoxytol products. Each ferumoxytol product was diluted in saline, and separately in adult bovine whole blood, at 5 iron concentrations ranging from 0.3 to 2.1 mM. Vials were placed in an MR-compatible water bath at 37°C and imaged at both 1.5 T and 3.0 T. Longitudinal and transverse relaxation rate constants (R1, R2, R2*) were measured for each ferumoxytol concentration, and relaxation-concentration curves were estimated. An in vivo dose accumulation study with flip angle optimization was also implemented using a cross-over design, in healthy volunteers. Cumulative doses of 1, 3, 5, and 7 mg/kg diluted ferumoxytol were administered prior to MRA of the chest on a 3.0 T clinical MRI system. For each incremental dose, the flip angle was varied from 40° to 10° in -10° increments over 5 breath-holds followed by a repeated 40° flip angle acquisition. Regions of interest were drawn in the aortic arch, paraspinous muscles, and a noisy area outside of the patient, free from obvious artifact. Signal-to-noise ratio (SNR) was calculated as the quotient of the average signal in the aortic arch and the standard deviation of the noise, corrected for a Rician noise distribution. Contrast-to-noise ratio was calculated as the difference in SNR between the aorta and paraspinous muscles. Absolute SNR and contrast-to-noise ratio values were compared between products for different flip angles and doses. There were no statistically significant or clinically relevant differences in relaxation-concentration curves between AMAG and Sandoz products in phantom experiments. Six healthy volunteers (38.8 ± 11.5 years, 3 female, 3 male) were successfully recruited and completed both imaging visits. No clinically relevant differences in image quality were observed between ferumoxytol products. The optimal flip angle range and dose for both products was 20°-30° and 5 mg/kg, respectively. Brand name and generic ferumoxytol products can be used interchangeably for MRA.

Successful administration of cetuximab using dose escalation method: a case report

IntroductionCetuximab, used to treat head and neck squamous cell carcinoma and metastatic colorectal cancer, can cause severe infusion reactions.Case presentationWe report an 87-year-old East Asian woman with stage IV ileocecal signet ring cell carcinoma who experienced severe allergic reactions to cetuximab despite pre-treatment. A dose escalation method, involving weekly incremental doses with comprehensive pre-treatment and close monitoring, was employed, successfully reducing allergic reactions and allowing safe administration.ConclusionThis approach demonstrates a viable alternative for patients with hypersensitivity to cetuximab, warranting further research for personalized treatment optimization.

Oral corticosteroid dosage and taper duration at onset in myelin oligodendrocyte glycoprotein antibody-associated disease influences time to first relapse

BackgroundWe sought to identify an optimal oral corticosteroid regimen at the onset of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), which would delay time to first relapse while minimising cumulative corticosteroid...

The Effect of the Gonadotropin Dose Increment During Controlled Ovarian Hyperstimulation on Live Birth Rates of POSEIDON Group 3-4 Patients

This retrospective study seeks to explore whether modifying the gonadotropin dose in cases of poor ovarian response during controlled ovarian hyperstimulation contributes to improved live birth rates in Poseidon Group 3-4 patients. The study took place at a tertiary level university. The electronic database spanning 2012-2021 was scrutinized to identify patients with diminished ovarian reserve (DOR) who underwent intra-cytoplasmic sperm injection – embryo transfer (ICSI-ET). Diminished ovarian reserve was determined using the POSEIDON criteria. Patients were categorized into two groups based on whether dose adjustment was implemented during the initial ultrasound assessment in controlled ovarian hyperstimulation (COH). There were 188 patients in the dose adjustment (DA) group and 310 patients in the fixed-dose (FD) group. The demographic parameters were similar between the groups. The started gonadotropin dose was similar in both groups (300 IU). The median dose adjustment on the first control was +75 IU in the DA group. The follicle output rates, follicle to oocyte indexes, and the embryology parameters were comparable between the groups. The positive pregnancy rate was 19.7% (36/188) in the DA group vs. 19.1% (61/310) in the FD Group (p=0.4). The primary outcome of the study; live birth rates were 12% in the DA group vs. 9% in the FD group, and the results were statistically similar (p=0.3). Our research revealed that adjusting the gonadotropin dose in cases of inadequate ovarian response during COH results in comparable live birth rates to those observed in the fixed-dose group. For patients exhibiting an inadequate response, dose adjustment may be deemed necessary.

Digital foam index for evaluating fly ash air entrainer interactions

Real-time evaluation of fly ash and air-entrainer (AEA) interaction was performed by acquiring and analyzing videos of the evolving foam layer in cement-fly ash-water mixtures using the foam index test. This modified foam index test or digital foam index, defines two fundamental parameters linked to foam generation and stability, and thus can be used to improve concrete air-entrainment for freeze-thaw durability. The AEA dosage required to produce a metastable foam is defined as foam stability dosage, whereas the incremental AEA dosage beyond the foam stability dosage to achieve a foam layer covering the entire container surface is termed foam efficiency dosage, and the summation of these dosages is the traditional foam index. The foam stability and efficiency dosages are independent parameters as a vinsol resin-based AEA had a higher foam efficiency dosage but a lower foam stability dosage than a sulfonate–based AEA.

Switching from a 2-dose to a 1-dose program of gender-neutral routine vaccination against human papillomavirus in Canada: a mathematical modelling analysis.

Worldwide, countries are examining whether to implement 1-dose human papillomavirus (HPV) vaccination instead of using 2 doses. To inform policy, we sought to project the population-level impact and efficiency of switching from 2-dose to 1-dose gender-neutral routine HPV vaccination in Canada. We used HPV-ADVISE, an individual-based transmission-dynamic model of HPV infections and diseases, to mathematically model vaccination programs in 2 provinces, Quebec, a province with high HPV vaccination coverage (around 85%), and Ontario, which has lower coverage (around 65%). We examined non-inferior and pessimistic scenarios of the efficacy (vaccine efficacy of 98% or 90%) and average vaccine duration (lifelong, 30 yr, or 25 yr) of 1 dose compared with 2 doses (98% vaccine efficacy, lifelong vaccine duration). Our main outcomes were the relative reduction in HPV-16 (by sex) and cervical cancers, and the number of doses needed to prevent 1 cervical cancer. Our model projected that 1-dose HPV vaccination would avert a similar number of cervical cancers as 2 doses in Canada, under various scenarios. Under the most pessimistic scenario (25-yr vaccine duration), 1-dose vaccination would avert fewer cervical cancers than 2 doses, by about 3 percentage points over 100 years. All 1-dose scenarios were projected to lead to elimination of cervical cancer (< 4 cervical cancers/100 000 female-years) and to be a substantially more efficient use of vaccine doses than a 2-dose scenario (1-dose v. no vaccination = 800-1000 doses needed to prevent 1 cervical cancer; incremental doses for 2-dose v. 1-dose vaccination > 10 000 doses needed to prevent 1 additional cervical cancer). If the average duration of 1-dose protection is longer than 25 years, a 1-dose HPV vaccination program would protect those vaccinated during their peak ages of sexual activity and prevent a similar number of HPV-related cancers as a 2-dose program, while being a more efficient use of vaccine doses.

Determination of the optimal dose and dosing strategy for effective L-menthol oral rinsing during exercise in hot environments.

This multi-study programme investigated the optimal concentration of L-menthol delivered as an oral mouth rinse to modulate thermo-behaviour during exercise in a hot environment (35°C). In study 1, 38 participants completed a survey to establish an effective and tolerable range of L-menthol concentration. 31 participants completed an RPE-protocol examining 1. the dose-response effect of L-menthol mouth rinse on exercise performance (n = 16) and 2. the temporal effectiveness of administering L-menthol in an incremental and decremental dosing pattern (n = 15). Power output, heart rate, body core temperature and thermal sensation were reported throughout. The optimal menthol concentration for peak power was between 0.01 and 0.1% (~ 6% increase, P < 0.05) and 0.5% (~ 9% increase, P < 0.05) with respect to control. Work completed was increased at 0.01% (~ 5%, P < 0.05), at 0.1% (~ 3%, P < 0.05) and had a detrimental effect at 0.5% (- 10% decrease, P < 0.05). There were no differences between an ascending dose protocol (0.01 to 0.5%), descending dose protocol (0.5-0.01%) or a constant 0.01% dose protocol. There were no reported differences in body core temperature or heart rate across trials (P > 0.05). The optimal dose of L-menthol when delivered via oral rinsing is between 0.01 and 0.1%. At lower concentrations, L-menthol appears to be less effective and at higher concentrations (> 0.5%) L-menthol appears to elicit greater irritation and may not positively modulate thermo-behaviour during exercise in a hot environment.