Maximum Effective Dose Research Articles

Anxiolytic Action of Dipeptide Mimetic of the BDNF Loop 2 in Adult Animals.

We studied the anti-anxiety effect of a low-molecular-weight mimetic of the BDNF loop 2, hexamethylenediamide bis-(-N-hexanoyl-L-seryl-L-lysine) (GTS-201) in adult animals. GTS-201 at a dose of 5 mg/kg after acute intraperitoneal administration to outbred male and female rats increased the time spent in the open arms and the number of entries into the open arms in the elevated plus maze (EPM). In "highly emotional" male BALB/c mice, GTS-201 exhibited a dose-dependent anxiolytic effect in the EPM in a dose range of 0.5-2.0 mg/kg with a maximum effective dose of 1 mg/kg. These data confirm the previously revealed anti-anxiety properties of GTS-201 in inbred male and female BALB/c mice and rats and indicate the dependence of the pharmacological activity of the BDNF mimetic on animal age.

Pharmacodynamic interaction between tamsulosin and finasteride treatment in mice induced benign prostate hyperplasia using the Chou-Talalay method

This study was conducted to evaluate the efficacy and interaction of tamsulosin with finasteride treatment on induced benign prostate hyperplasia (BPH) in mice. BPH was induced by subcutaneous injection of testosterone propionate (20 mg/kg) for 30 days. Eighty-five mice were divided into five groups. The first group (G1): twenty-five mice induced BPH treated with tamsulosin orally and divided into five equal subgroups with doses (0.017, 0.052, 0.087, 0. 123, and 0.158) mg/kg, the second group (G2): twenty-five mice induced BPH treated with finasteride orally and divided into five equal subgroups with doses (0.175, 0.527, 0.878, 1.23, and 1.580) mg/kg, the third group (G3): twenty-five mice induced BPH treated with a combination of tamsulosin with finasteride orally, and divided into five equal subgroups with doses (0.0085, 0.0875), (0.026, 0.2635), (0.0435, 0.439) , (0.0615, 0.615) and ( 0.079 , 0.790 ) mg/kg respectively. Fourth group (G4): five mice induced BPH and treated distilled water. Fifth group (G5): five mice were not inducing BPH and without any treatment. The results showed a gradual significant increase in prostate weight % and prostate index % inhibitions until reached saturation in the last two doses of tamsulosin, finasteride, and combination groups, the maximum effective doses of tamsulosin and finasteride were (0.156) and (1.495) mg/kg respectively. Moreover, the effective dose of the combination (tamsulosin and finasteride) was estimated (0.06876, 0.6876) mg/kg respectively as well as the type of interaction was synergism and the value of the combination index was 0.046. The combination of tamsulosin with finasteride showed a synergistic effect in BPH treatment by minimizing the side effect of each drug as a result of decreasing the dose of each one.

Cerebroprotective Effects of the TLR4-Binding DNA Aptamer ApTOLL in a Rat Model of Ischemic Stroke and Thrombectomy Recanalization.

ApTOLL, a TLR4 modulator aptamer, has demonstrated cerebroprotective effects in a permanent ischemic stroke mouse model, as well as safety and efficacy in early phase clinical trials. We carried out reverse translation research according to STAIR recommendations to further characterize the effects and mechanisms of ApTOLL after transient ischemic stroke in rats and to better inform the design of pivotal clinical trials. Adult male rats subjected to transient middle cerebral artery occlusion were treated either with ApTOLL or the vehicle intravenously at different doses and time-points. ApTOLL was compared with TAK-242 (a TLR4 inhibitor). Female rats were also studied. After neurofunctional evaluation, brains were removed for infarct/edema volume, hemorrhagic transformation, and histologic determinations. Peripheral leukocyte populations were assessed via flow cytometry. ApTOLL showed U-shaped dose-dependent cerebroprotective effects. The maximum effective dose (0.45 mg/kg) was cerebroprotective when given both before reperfusion and up to 12 h after reperfusion and reduced the hemorrhagic risk. Similar effects occurred in female rats. Both research and clinical ApTOLL batches induced slightly superior cerebroprotection when compared with TAK-242. Finally, ApTOLL modulated circulating leukocyte levels, reached the brain ischemic tissue to bind resident and infiltrated cell types, and reduced the neutrophil density. These results show the cerebroprotective effects of ApTOLL in ischemic stroke by reducing the infarct/edema volume, neurofunctional impairment, and hemorrhagic risk, as well as the peripheral and local immune response. They provide information about ApTOLL dose effects and its therapeutic time window and target population, as well as its mode of action, which should be considered in the design of pivotal clinical trials.

E075 Sacroiliitis potentially induced by isotretinoin: two case reports

Abstract Background/Aims Isotretinoin is a potent retinoid medication widely used to treat severe acne. Isotretinoin’s adverse effects range from well-documented dermatological side effects like dry skin to less common systemic manifestations. Sacroiliitis can arise from rheumatic and nonrheumatic causes. There has been limited attention in the literature to the rare occurrence of sacroiliitis as an adverse effect of isotretinoin. The precise mechanisms remain poorly understood, but the emergence of case reports suggests a potential link in immunomodulation through the alteration of cytokine balance and degradation of synovial membranes in joints. We present two patients with severe acne history who developed bilateral sacroiliitis within several weeks after starting isotretinoin Methods Case 1: A 19 year old male, started on 20 mg daily isotretinoin for acne vulgaris, experienced severe hip and lower back pain after one month, impacting his mobility. On examination, he displayed painful hip movements. Lumbar flexion was restricted and painful, with a 2 cm measurement on the Schober’s test. Medical investigation showed an elevation of erythrocyte sedimentation rate (ESR): 66mm/h, and C-reactive protein (CRP): 81 mg/l. HLA B27 was negative. X-ray radiography of the sacroiliac joint was normal, but the MRI examination showed the presence of bilateral sacroiliitis. Case 2: A 34 year old female received a six-months isotretinoin treatment for severe acne, with doses ranging from 20-40 mg daily. Then, in 2018, after a six-year gap, she received another isotretinoin course at 30 mg daily. Four months later, she began to experience gradual, intermittent lower back pain associated with 30 minutes of early morning stiffness. Her vital signs were stable, but she exhibited restricted and painful lumbar flexion. Her investigations revealed normal ESR and CRP. HLA B27 was negative. Her sacroiliac joint X-ray showed normal results, but her MRI indicated bilateral active sacroiliitis. Results Following the discontinuation of isotretinoin in both cases, NSAIDs were administered, which effectively relieved the pain. Our management of isotretinoin-induced sacroiliitis follows guidelines adapted from the ASAS-EULAR algorithm for axial spondyloarthritis. The algorithm entails an initial treatment with NSAIDs if no contraindications and to be titrated up to the maximum effective dose before considering biological/ targeted synthetic disease-modifying antirheumatic drugs. Conclusion The two cases highlight the rare but noteworthy association between isotretinoin therapy and sacroiliitis. In patients presenting with unexplained musculoskeletal symptoms during isotretinoin treatment at any point, clinicians should raise suspicions on the adverse effects of medication. Further research is needed to elucidate the immunomodulatory pathways involved in this association. Disclosure H. Almansoori: None. N. Alnuaimi: None. S. Alhosani: None. M. Alshehhi: None. S.A. Al Nokhatha: None.

Robustness of carbon-ion radiotherapy against DNA damage repair associated radiosensitivity variation based on a biophysical model.

Interpatient variation of tumor radiosensitivity is rarely considered during the treatment planning process despite its known significance for the therapeutic outcome. To apply our mechanistic biophysical model to investigate the biological robustness of carbon ion radiotherapy (CIRT) against DNA damage repair interference (DDRi) associated patient-to-patient variability in radiosensitivity and its potential clinical advantages against conventional radiotherapy approaches. The "UNIfied and VERSatile bio response Engine" (UNIVERSE) was extended by carbon ions and its predictions were compared to a panel of in vitro and in vivo data including various endpoints and DDRi settings within clinically relevant dose and linear energy transfer (LET) ranges. The implications of UNIVERSE predictions were then assessed in a clinical patient scenario considering DDRi variance. UNIVERSE tests well against the applied benchmarks. While in vitro survival curves were predicted with an R2>0.92, deviations from in vivo RBE data were less than 5.6% The conducted paradigmatic patient plan study implies a markedly reduced significance of DDRi based radiosensitivity variability in CIRT (13% change of in target) compared to conventional radiotherapy (62%) and that boosting the LET within the target further amplifies this robustness of CIRT (8%). In the case of heightened tumor radiosensitivity, a dose de-escalation strategy for photons allows a reduction of the maximum effective dose within the normal tissue (NT) from a of 2.65 to 1.64Gy, which lies below the level found for CIRT ( =2.41Gy) for the analyzed plan and parameters. However, even after de-escalation, the integral effective dose in the NT is found to be substantially higher for conventional radiotherapy in comparison to CIRT ( of 0.75, 0.46, and 0.24Gy for the conventional plan, its de-escalation and CIRT, respectively). The framework offers adequate predictions of in vitro and in vivo radiation effects of CIRT while allowing the consideration of DRRi based solely on parameters derived from photon data. The results of the patient planning study underline the potential of CIRT to minimize important sources of interpatient divergence in therapy outcome, especially when combined with techniques that allow to maximize the LET within the tumor. Despite the potential of de-escalation strategies for conventional radiotherapy to reduce the maximum effective dose in the NT, CIRT appears to remain a more favorable option due to its ability to reduce the integral effective dose within the NT.

Improved Analysis of the Short-Term Station Blackout Accidents of the Peach Bottom Unit-2 Reactor with ASTEC Including Radiological Impact and Statistical Analysis with JRODOS

After the severe accident at Fukushima, the importance of BWR design and related structures and their contribution to the severe accident progression has increased. Fuel channel boxes, absorber crosses, water rods, and smaller primary containment design of the BWR have been considered in the ASTEC code to increase the knowledge of BWR design and associated models. The previously developed ASTEC model for Peach Bottom Unit-2 was updated to include modern GE14 10x10 fuel assemblies with realistic fission product inventories. The CASMO5 code predicted the fission product inventory and burnup for GE14 10x10 fuel assemblies based on real plant data obtained from the ENRESA samples. First, a Short-Term Station Blackout (ST-SBO) analysis was performed to compare the impact of the old and new fuel assembly designs on the accident progression and radiological consequences. Second, a short-term station blackout with a stuck open safety relief valve (ST-SBO SOSRV) was considered for modern fuel assemblies. The actuation of the safety valve resulted in a much lower corium ejection and a longer transient to basemat failure in the cavity. The scatter of corium ejection amounts between the considered scenarios showed the importance of the design of the bottom head and the penetration points in BWRs. In both cases, failure of the drywell head flange and release of radionuclides to the environment occurred. Higher burnup and radionuclide inventory in the 10x10 assemblies resulted in a larger release compared to the previous design. Radiological analysis using JRODOS was performed for both cases and the maximum total effective gamma dose rate was estimated to be 67.89 mSv/h and 119.46 mSv/h for ST-SBO and ST-SBO SOSRV, respectively. The statistical analysis and the number of records in the considered cities around the Peach Bottom Plant showed the distribution over the region and the risk factors of the populated cities. The collaborative use of three codes in this study allows users to identify the fission product inventory with CASMO5 and investigation of the severe accident scenario with ASTEC and identifying radiological impact of the released radioactive isotopes to the environment with JRODOS code.

Enhancing Resilience through Nuclear Emergency Preparedness at El Dabaa Site

The research utilized advanced PCTRAN and RASCAL software to evaluate the potential radiological impacts of hypothetical accidents, specifically loss-of-coolant accident (LOCA) and long-term station blackout (LTSBO), at the El Dabaa Nuclear Power Plant. Over a span of ten years, comprehensive meteorological data were meticulously analyzed to assess the dispersion of radioactive substances within a 40-kilometer radius across all four seasons. The outcomes revealed that only in the case of LTSBO did the radiological levels surpass the limits set by the Environmental Protection Agency (EPA). Notably, during spring, LTSBO exhibited a maximum total effective dose equivalent (TEDE) value of 13 millisieverts (mSv) at a distance of 3.2 kilometers, and the highest thyroid dose (TD) recorded was 63 mSv at 8 kilometers. These significant findings play a crucial role in shaping strategies related to the distribution of potassium iodide (KI) and further enhance the overall preparedness and evacuation planning protocols.

Radiological Risk Assessment of Soil Using RESRAD-OFFSITE Code in Communities around Indorama Fertilizer Company Eleme, Port-Harcourt, Rivers State, Nigeria

Anthropogenic activities around a fertilizer company can cause elevation in the concentration of naturally-occurring radioactive materials (NORMs) within surrounding soils, as a result of effluent discharge or heaping of rocks used as raw materials. The aim of this study was to evaluate the human risk associated with exposure to NORMs in soils from communities around Indorama Fertilizer Company Eleme, Port-Harcourt, Rivers State, Nigeria. A sodium-iodide doped with thallium [NaI(TI)] detector was used to measure activity concentrations of these NORMs in 22 soil samples within the study area. The residual radioactivity (RESRAD) offsite modeling program(version 4.0) was then used to estimate the radiation doses and the cancer morbidity risk of uranium-238 (238U), thorium-232 (232Th) and potassium-40 (40K) for hypothetical resident farmer scenario. According to the RESRAD prediction, the maximum total effective dose equivalent (TEDE) during 100 years was found to be 2.82 x 10-5 mSvy-1 at year 12, while the maximum total excess cancer morbidity risk for all the pathways was 3.52E-08 at year 6. Therefore, results obtained from the RESRAD-OFFSITE code in this study has shown that the health risk from effluent discharge within the study area is within acceptable levels according to international standards.

Assessment of radiological environmental impact under various meteorological condition

The meteorological parameters, e.g., wind direction, wind speed and atmospheric stability, affect greatly the diffusion of pollution and radiological environmental impact assessment. Based on the hourly meteorological data obtained from an automatic monitoring station, the radiological impact indicated by the air concentration, individual dose and maximal individual effective dose were analyzed and compared between 2020 and 2021. The paper concluded that children are the main group to be the most easily infected, and the critical exposure path is internal exposure from inhalation. This paper offers a new window for timely decision-making for radiological safety under different climate conditions.

Simulation of excess lifetime cancer risk due to the presence of radon in groundwater in Wamba town of Wamba local government area, Nasarawa state, Nigeria

The measurements of Radon concentration in ten groundwater (4-wells and 6-boreholes) from Wamba town of Wamba Local Government Area of Nigeria had been carried out. The annual effective dose (AED) and the Excess Lifetime Cancer Risk (ELCR) due to ingestion of the groundwater was established to ascertain the risk outcome from the samples. Radon concentration was detected using RAD7. The minimum Radon concentration was 0.146 Bql-1 while the maximum was 0.474 Bql-1 with mean average of 0.3134 Bql-1 which are within the United States Environmental Protection Agencies (USEPA) 11.1 Bq/L recommendation. Moreso, the maximum and minimum Annual Effective Dose (AEDing) was 3.5×10^(-6) and 1.10×10^(-6) Sv/yr which are also within the 0.1 mSv/yr World Health Organization (WHO) recommendation, while the maximum and minimum Excess Lifetime Cancer Risk (ELCR) was 1.44×10^(-5) and 4.50×10^(-6) respectively. Cumulative probability simulation of the Excess Lifetime Cancer Risk (ELCR) was carried out using Oracle Crystal Ball software validated by 10 and 90% percentiles. Comparison of all the results with the European Union (EU)/World Health Organization (WHO) value of 500 Bq/L recommendation revealed that all the samples analyzed have Radon concentration below the recommended limit. The average mean Radon concentration in the ten locations from Wamba Town are within the recommended levels as confirmed by the simulation results. At 10% Probability, the highest risk was found in Event center (1.26×10^(-5)) while the lowest was found in the water sample collected from Angwan dalatu (1.05×10^(-6)) while at 90% probability the highest (1.62×10^(-5)) and lowest (1.37×10^(-6)) risk was found in the same Events center and Angwan dalatu. Though there is variation in the results based on locations which means that the concentration of Radon gas depends on the geological nature of the bedrock and generally increases with the uranium concentration in the local geology. The Excess Lifetime Cancer Risk (ELCR) dose results are far lower than the UNSCEAR (United Nations Scientific Committee on the Effects of Atomic Radiations) recommended maximum contamination level of 0.003875. Therefore, no indication of any likelihood of cancer incidence as a result of waterborne radon within the studied community that may demand urgent intervention from radiological point of view.

Evaluation of markers of apoptotic processes and peroxide oxidation of lipids of the mitochondrial fraction of the liver of animals carrying Lewis epidermoid carcinoma at different stages of the development of the tumor process with the introduction of organotin compounds with a tread fragment

Objective: to evaluate changes in markers of apoptotic processes and lipid peroxidation (POL) by accumulation of malondialdehyde (MDA) in the mitochondrial fraction of the liver of animals carrying Lewis epidermoid carcinoma at different stages of the tumor process with the introduction of bis-(3,5-di-tert-butyl-4-hydroxyphenyl)dimethylolol thiolate (Me-3) and (3,5-di-tert-butyl-4-hydroxyphenyl)triphenylololate (Me-5). Materials and methods: the work was performed using laboratory animals - female mice of the C57Bl line/6. 48 hours after the Lewis epidermoid carcinoma strain was transplanted, substances Me-3 and Me-5 were administered once a day for 5 days intraperitoneally at the maximum effective dose of 375 mg/kg and 250 mg/kg, respectively. Animals of the control group were injected with a carrier in similar modes and volumes. Results: when Me-3 was administered at the maximum effective dose on days 7 and 21, a decrease in the level of all the studied indicators was noted, which indicates a high actioxidant activity of a hybrid organotin compound containing one tin-containing [-Sn(CH3)2] and two protective antioxidant fragments (3,5-di-tert-butyl-4-hydroxyphenyl). The compound Me-5 has a more pronounced prooxidant potential, as evidenced by high levels of damage to mitochondrial DNA (8–hydroxy–2'–deoxyguanosine) and malonic dialdehyde. Conclusion: the introduction of bis-(3,5-di-tert-butyl-4-hydroxyphenyl)dimethylolol (Me-3) and (3,5-di-tert-butyl-4-hydroxyphenyl)triphenylolol (Me-5) compounds revealed a change in the pro/antioxidant state and the launch of apoptotic processes in liver cells.

The Effects of Giving Coconut Milk on Aortic Wall Thickness of Rats (Rattus norvegicus strain Wistar) Fed with High Fat Diet (HFD)

Atherosclerosis is a chronic disease due to fat accumulation in the blood vessel walls. Atherosclerosis is the leading cause of cardiovascular disease. Indonesian people’s habit of consuming coconut milk is suspected of causing dyslipidemia, a risk factor for atherosclerosis, by increasing low-density lipoprotein (LDL). However, other studies suggest that coconut milk can increase high-density lipoprotein (HDL), an antioxidant that prevents atherosclerosis. Because of the different findings, this study aims to determine the effects of coconut milk administration on the aortic wall thickness of rats (Rattus norvegicus strain Wistar) fed a high-fat diet (HFD). This true experimental study used samples of 28 male Wistar rats divided into seven groups. These groups consisted of the normal group (N), the negative control group (Kn), and five treatment groups that received coconut milk at various doses, including 2, 5, 3.75, 5, 7. 5, and 10 ml/kgBW/day. The results obtained were then analyzed using SPSS. The statistical tests used are the independent t-test, one-way ANOVA, LSD post hoc, Pearson correlation test, and regression test. Based on this study, the results showed that giving HFD for 45 days could cause the aortic wall to thicken. Meanwhile, giving an HFD accompanied by coconut milk for 45 days can prevent the thickening of the aortic wall, with the maximum effective dose that can be given being 9.75 ml/kg BW/day.

Real-World Evidence of Avatrombopag for the Treatment of Immune Thrombocytopenia Intolerant or Ineffective to Eltrombopag/Hetrombopag

Abstract Objectives: Thrombopoietin receptor agonists (TPO-RA) have dramatically changed the treatment landscape for immune thrombocytopenia (ITP). Although avatrombopag has been confirmed to achieve platelet response for chronic ITP in clinical trials, and it has no hepatotoxicity unlike eltrombopag or hetrombopag, there is still a lack of real-world research on the application of avatrombopag in Chinese ITP patients. Here, we aimed to evaluate the effect and safety of avatrombopag in ITP treatment in a real-world clinical practice. Methods: In this retrospective analysis, we enrolled consecutive cohorts of 50 adult ITP patients who received avatrombopag in two centers from January 2021 to March 2023. The median duration of follow-up of these patients was 16.5 months (range from 3.8 to 25.4 months). Results: The median age of patients was 44 years when they received the treatment of avatrombopag, and 42% of them were males. Most patients (n=45) had a persistent (3-12 months) or chronic course (more than 12 months) of ITP. The patients in our study were heavily treated, who received a median of 4 kinds of ITP treatment prior to avatrombopag. The baseline TPO levels was 88.1 (110.2±84.5) pg/ml. Based on the reasons for choosing avatrombopag, these patients were divided into eltrombopag/hetrombopag intolerance group (IG, n=14) and eltrombopag/hetrombopag unresponsive group (UG, n=36). The reasons for choosing avatrombopag in IG included active hepatitis B (n=4), hepatic insufficiency before using TPO-RA (n= 6), autoimmune hepatitis (n=1), hepatic lesion after using eltrombopag (n=2), and myelofibrosis after using eltrombopag (n=1). Compared with UG, more patients had a history of liver disease (active Hepatitis B and autoimmune liver diseases, P=0.003). The median platelet count before avatrombopag was 9 × 10 9/L. The median duration of avatrombopag treatment was 12 weeks and the median weekly dose of avatrombopag was 140 mg. Among the total cohort, platelet response (platelet count ≥30 × 10 9 /L) was achieved in 44/50 (88%) and complete platelet response (platelet count ≥100 × 10 9 /L) was seen in 35/50 patients (70%) after using avatrombopag. The median time of platelets rising above 30 × 10 9 /L was 7 days, while it was 8 days when platelet count exceeded 50 × 10 9 /L. Nearly half patients (47%) were able to discontinue more than 1 concomitant ITP medication after avatrombopag treatment. Besides, most patients (74%) in our study tapered off or withdrew steroids. There were no significant differences in baseline platelet count, 30-day response rate, the maximum effective dose of avatrombopag and duration of avatrombopag between IG and UG. So far, 19 patients achieved platelet response were still taking avatrombopag, and 58% of them maintained platelet count above 100× 10 9 /L. Meanwhile, 31 patients discontinued avatrombopag.The reasons for withdrawal of drug included adverse events (n=2), sustained remission in ITP (n=8), no/lose response to avatrombopag (n=10), and unablity to afford the cost consistently (n=11). Avatrombopag was well tolerated in most patients, even those suffered from hepatic insufficiency and/or myelofibrosis after other TPO-RA. However, two cases had thrombosis and two patients reported mild fatigue. Conclusion: In the ITP population, avatrombopag was effective and safe, especially for those intolerant or ineffective to eltrombopag/hetrombopag. However, most patients with ITP were not able to afford the long-term usage of avatrombopag in China.

Consequence assessment of hypothetical urban radiological dispersal device incident in Korea

Radiological Dispersal Devices (RDDs) are designed to disperse radioactive material over a wide area, leading to significant consequences to the environment and public health. This paper discusses the radiological effects of a potential RDD detonation containing 137Cs and 241Am in the commercial area of Busan, South Korea. The assessment, conducted with HotSpot Health Physics and RESRAD-RDD codes, found that summer had the most significant impact, with a maximum total effective dose equivalent (TEDE) of 280 mSv at 100 m and this decreased to 1 mSv at 4.5 km from the detonation point within the time interval of 35 min.

THE EFFECT OF NEEM GUM ON THE REDUCTION IN RAT BLOOD GLUCOSE LEVELS INDUCED BY STREPTOZOTOCIN

Pharmacological therapy for diabetes, which is primarily made up of chemicals, still causes a lot of side effects. The numerous side effects of pharmacological therapy for diabetes have generated innovations in alternative diabetes therapies using ingredients derived from nature. One of the natural ingredients with an anti-hyperglycemia effect is neem gum (NG), or the sap of the neem plant (Azadirachta indica). The aim of this study was to determine the effect of NG on the reduction of blood glucose levels. Moreover, this study had six groups, including a normal control group and groups with doses of 0, 3.75, 7.5, 15, and 30 grams/kgBW. The results showed that NG reduced blood glucose levels in diabetic rats. The paired t-test showed a significant reduction in blood glucose in all groups administered NG except for the dose 3.75 group (P<0.05). The minimum and maximum effective doses of NG were calculated using the quadratic regression test with the equation y = 1.059x2–46.576x+408. With a target blood glucose level of between 80 and 126 mg/dL, the minimum and maximum effective doses of NG were obtained in the range of 12–15 mg/dL. This study concluded that administering NG to diabetic rats can reduce blood glucose levels. Phytochemical studies and research are needed with serial examinations using the effective dose range of neem gum.

A rank-based approach to improve the efficiency of inferential seamless phase 2/3 clinical trials with dose optimization

To accelerate clinical development, seamless 2/3 adaptive design is an attractive strategy to combine phase 2 dose selection with phase 3 confirmatory objectives. As the regulatory requirement for dose optimization in oncology drugs shifted from maximum tolerated dose to maximum effective dose, it's important to gather more data on multiple candidate doses to inform dose selection. A phase 3 dose may be selected based on phase 2 results and carried forward in phase 3 study. Data obtained from both phases will be combined in the final analysis. In many disease settings biomarker endpoints are utilized for dose selection as they are correlated with the clinical efficacy endpoints. As discussed in Li et al. (2015), the combined analysis may cause type I error inflation due to the correlation and dose selection. Sidák adjustment has been proposed to control the overall type I error by adjusting p-values in phase 2 when performing the combined p-value test. However, this adjustment could be overly conservative as it does not consider the underlying correlations among doses/endpoints. We propose an alternative approach utilizing biomarker rank-based ordered test statistics which takes the rank order of the selected dose and the correlation into consideration. If the correlation is unknown, we propose a rank-based Dunnett adjustment, which includes the traditional Dunnett adjustment as a special case. We show that the proposed method controls the overall type I error, and leads to a uniformly higher power than Sidák adjustment and the traditional Dunnett adjustment under all potential correlation scenarios discussed.

An Evaluation of Radon in Drinking Water Supplies in Major Cities of the Province of Chimborazo, Central Andes of Ecuador

The activity concentrations of 222Rn were measured in 53 public water supplies of underground (50) and surface (3) origin, and the relation of such with five geological units where these supplies are located, in the central Ecuadorian Andes, was also explored. These units supply drinking water to 10 cities, located between the 1500 and 3120 m.a.s.l. The experimental setup consisted of the RAD7 radon detector and the RAD H2O degassing system. The 222Rn levels measured in groundwater ranged from 0.53 to 14.78 Bq/L while surface waters did not indicate detectable radon levels. The radon concentrations were below the parametric value of 100 Bq/L for water intended for human consumption, recommended by the European Atomic Energy Community (EURATOM) in its Directive 2013/51, and the alternative maximum contamination level (AMCL) of 150 Bq/L, proposed by the Environmental Protection Agency (EPA). The Pisayambo Volcanic unit, mapped as intermediate volcaniclastic to felsic deposits, presented a mean radon concentration higher than the other geological units and lithologies (9.58 ± 3.04 Bq/L). The Cunupogyo well (11.36 ± 0.48 Bq/L) presented a radon concentration more than 70% higher than the neighboring springs, which may be explained by its proximity to the Pallatanga geological fault. The maximum annual effective doses, by cities, due to the ingestion and inhalation of radon, ranged from 0.010 to 0.108 mSv and from 0.008 to 0.091 mSv, respectively; therefore, these waters do not represent a risk to the health of the population. In addition, a correlation was observed between the activity concentration of 222Rn and the activity concentration of the parent 226Ra in samples collected from some springs.

ПОВТОРНОЕ КРАНИОСПИНАЛЬНОЕ ОБЛУЧЕНИЕ У ПАЦИЕНТОВ ДЕТСКОГО ВОЗРАСТА С РЕЦИДИВОМ МЕДУЛЛОБЛАСТОМЫ: ОПЫТ ПРИМЕНЕНИЯ ПРОТОННОЙ ТЕРАПИИ В КЛИНИКЕ МИБС

Repeated craniospinal irradiation (CSR) is one of the options in the treatment of multifocal recurrences of medulloblastomas (MB), however, it is prescribed to a limited extent due to its toxicity. The use of proton therapy can reduce the toxicity of treatment. Materials and methods used: a single-center retrospective cohort study was conducted in 25 patients (18 (72%) boys/7 (28%) girls) aged 7 to 18 y/o (median 13 (10-14) y/o) in 2019-2023. Repeated CSR was performed for leptomeningeal MB recurrence using a proton beam at the Treatment and Diagnostic Center of the International Institute of Biological Systems named after Sergey Berezin (Saint Petersburg, Russia). The median dose of primary CSR was 35.2 Gy (24-35.2). The median dose of repeated CSR was 30.6 Gy (24-35.2). 23 patients after CSR were given a local boost on the area of metastatic lesions and local recurrence (if any). 7 had previously received courses of repeated radiation therapy for recurrent MB. Results: during the course of the treatment thrombocytopenia was noted with a statistically significant decrease by the 3rd week of treatment (M=97x109/l, p<0.001). The median follow-up was 12.5 months (8-19.5). In 8 patients, progression of the disease was observed, which resulted in the death of 7 of them. In one patient, the appearance of radiation necrosis in the local boost area (left cerebellar peduncle) was noted 5 months after the completion of the repeated irradiation course. The median progression period was 17 months (95% CI 10.8-23.1). Conclusions: proton therapy makes it possible to deliver therapeutic doses for CSR with an acceptable level of hematological toxicity. The obtained data on relapse-free and overall survival indicate the need for further study of the role of repeated CSR and the development of a methodology for calculating the permissible maximum effective dose during the repeated exposure.

ПОВТОРНОЕ КРАНИОСПИНАЛЬНОЕ ОБЛУЧЕНИЕ У ПАЦИЕНТОВ ДЕТСКОГО ВОЗРАСТА С РЕЦИДИВОМ МЕДУЛЛОБЛАСТОМЫ: ОПЫТ ПРИМЕНЕНИЯ ПРОТОННОЙ ТЕРАПИИ В КЛИНИКЕ МИБС

Repeated craniospinal irradiation (CSR) is one of the options in the treatment of multifocal recurrences of medulloblastomas (MB), however, it is prescribed to a limited extent due to its toxicity. The use of proton therapy can reduce the toxicity of treatment. Materials and methods used: a single-center retrospective cohort study was conducted in 25 patients (18 (72%) boys/7 (28%) girls) aged 7 to 18 y/o (median 13 (10-14) y/o) in 2019-2023. Repeated CSR was performed for leptomeningeal MB recurrence using a proton beam at the Treatment and Diagnostic Center of the International Institute of Biological Systems named after Sergey Berezin (Saint Petersburg, Russia). The median dose of primary CSR was 35.2 Gy (24-35.2). The median dose of repeated CSR was 30.6 Gy (24-35.2). 23 patients after CSR were given a local boost on the area of metastatic lesions and local recurrence (if any). 7 had previously received courses of repeated radiation therapy for recurrent MB. Results: during the course of the treatment thrombocytopenia was noted with a statistically significant decrease by the 3rd week of treatment (M=97x109/l, p<0.001). The median follow-up was 12.5 months (8-19.5). In 8 patients, progression of the disease was observed, which resulted in the death of 7 of them. In one patient, the appearance of radiation necrosis in the local boost area (left cerebellar peduncle) was noted 5 months after the completion of the repeated irradiation course. The median progression period was 17 months (95% CI 10.8-23.1). Conclusions: proton therapy makes it possible to deliver therapeutic doses for CSR with an acceptable level of hematological toxicity. The obtained data on relapse-free and overall survival indicate the need for further study of the role of repeated CSR and the development of a methodology for calculating the permissible maximum effective dose during the repeated exposure.

DIAGNOSTIC PERFORMANCE OF CONE-BEAM COMPUTED TOMOGRAPHY TO DIAGNOSE IN VIVO/IN VITRO ROOT RESORPTION: A SYSTEMATIC REVIEW AND META-ANALYSIS

This review analyses the diagnostic performance of cone-beam computed tomography (CBCT) for the in vivo/in vitro detection of external root resorption (ERR) and critically analyses current and past methods of measuring or classifying ERR in vivo/in vitro in terms of radiation doses and cumulative radiation risks. A diagnostic test accuracy (DTA) protocol was used for a systematic review of diagnostic methods following PRISMA guidelines. The protocol was registered with PROSPERO (ID: CRD42019120513). A thorough and exhaustive electronic search of 6 core electronic databases was performed, applying the ISSG Search Filter Resource. The eligibility criteria were designed [problem-intervention-comparison-outcomes (PICO) statement: Population, Index test, Comparator, Outcome] and methodological quality was assessed by QUADAS-2. Seventeen papers were selected from a total of 7841 articles. Six in vivo studies were assessed as having a low risk of bias. The overall sensitivity and specificity of CBCT for diagnosis of ERR was 78.12% and 79.25%, respectively. The highest and lowest sensitivity and specificity of CBCT for diagnosis of external root resorption are 42%-98% and 49.3%-96.3%. Most of the selected studies reported quantitative diagnoses with single linear measurements of ERR even though multislice radiographs were available. The cumulative radiation dose (μS) to radiation-sensitive structures, such as the bone marrow, brain and thyroid, was observed to increase using the 3-dimensional (3D) radiography methods reported. The highest and lowest sensitivity and specificity of CBCT for diagnosis of external root resorption are 42%-98% and 49.3%-96.3%. The minimum and maximum effective doses of dental CBCT for external root resorption diagnosis are 34 μSv and 1073 μSv.