In-silico study of the impact of system design parameters on microcalcification detection in wide-angle digital breast tomosynthesis.

Purpose: Accurate detection of microcalcifications ( µ Calcs ) is crucial for the early detection of breast cancer. Some clinical studies have indicated that digital breast tomosynthesis (DBT) systems with a wide angular range have inferior µ Calc detectability compared with those with a narrow angular range. This study aims to (1) provide guidance for optimizing wide-angle (WA) DBT for improving µ Calcs detectability and (2) prioritize key optimization factors. Approach: An in-silico DBT pipeline was constructed to evaluate µ Calc detectability of a WA DBT system under various imaging conditions: focal spot motion (FSM), angular dose distribution (ADS), detector pixel pitch, and detector electronic noise (EN). Images were simulated using a digital anthropomorphic breast phantom inserted with 120 µ m µ Calc clusters. Evaluation metrics included the signal-to-noise ratio (SNR) of the filtered channel observer and the area under the receiver operator curve (AUC) of multiple-reader multiple-case analysis. Results: Results showed that FSM degraded µ Calcs sharpness and decreased the SNR and AUC by 5.2% and 1.8%, respectively. Non-uniform ADS increased the SNR by 62.8% and the AUC by 10.2% for filtered backprojection reconstruction with a typical clinical filter setting. When EN decreased from 2000 to 200 electrons, the SNR and AUC increased by 21.6% and 5.0%, respectively. Decreasing the detector pixel pitch from 85 to 50 µ m improved the SNR and AUC by 55.6% and 7.5%, respectively. The combined improvement of a 50 µ m pixel pitch and EN200 was 89.2% in the SNR and 12.8% in the AUC. Conclusions: Based on the magnitude of impact, the priority for enhancing µ Calc detectability in WA DBT is as follows: (1) utilizing detectors with a small pixel pitch and low EN level, (2) allocating a higher dose to central projections, and (3) reducing FSM. The results from this study can potentially provide guidance for DBT system optimization in the future.

Estimation of the absorbed dose in simultaneous digital breast tomosynthesis and mechanical imaging.

Purpose: Use of mechanical imaging (MI) as complementary to digital mammography (DM), or in simultaneous digital breast tomosynthesis (DBT) and MI - DBTMI, has demonstrated the potential to increase the specificity of breast cancer screening and reduce unnecessary biopsies compared with DM. The aim of this study is to investigate the increase in the radiation dose due to the presence of an MI sensor during simultaneous image acquisition when automatic exposure control is used. Approach: A radiation dose study was conducted on clinically available breast imaging systems with and without an MI sensor present. Our estimations were based on three approaches. In the first approach, exposure values were compared in paired clinical DBT and DBTMI acquisitions in 97 women. In the second approach polymethyl methacrylate (PMMA) phantoms of various thicknesses were used, and the average glandular dose (AGD) values were compared. Finally, a rectangular PMMA phantom with a 45 mm thickness was used, and the AGD values were estimated based on air kerma measurements with an electronic dosemeter. Results: The relative increase in exposure estimated from digital imaging and communications in medicine headers when using an MI sensor in clinical DBTMI was 11.9 % ± 10.4 . For the phantom measurements of various thicknesses of PMMA, the relative increases in the AGD for DM and DBT measurements were, on average, 10.7 % ± 3.1 and 11.4 % ± 3.0 , respectively. The relative increase in the AGD using the electronic dosemeter was 11.2 % ± < 0.001 in DM and 12.2 % ± < 0.001 in DBT. The average difference in dose between the methods was 11.5 % ± 3.3 . Conclusions: Our measurements suggest that the use of simultaneous breast radiography and MI increases the AGD by an average of 11.5 % ± 3.3 . The increase in dose is within the acceptable values for mammography screening recommended by European guidelines.

Correlation between dose-volume parameters and rectal bleeding after 12 fractions of carbon ion radiotherapy for prostate cancer.

BACKGROUND: Carbon ion radiotherapy (CIRT) is currently used to treat prostate cancer. Rectal bleeding is a major cause of toxicity even with CIRT. However, to date, a correlation between the dose and volume parameters of the 12 fractions of CIRT for prostate cancer and rectal bleeding has not been shown. Similarly, the clinical risk factors for rectal bleeding were absent after 12 fractions of CIRT. AIM: To identify the risk factors for rectal bleeding in 12 fractions of CIRT for prostate cancer. METHODS: Among 259 patients who received 51.6 Gy [relative biological effectiveness (RBE)], in 12 fractions of CIRT, 15 had grade 1 (5.8%) and nine had grade 2 rectal bleeding (3.5%). The dose-volume parameters included the volume (cc) of the rectum irradiated with at least x Gy (RBE) (Vx) and the minimum dose in the most irradiated x cc normal rectal volume (Dx). RESULTS: The mean values of D6cc, D2cc, V10 Gy (RBE), V20 Gy (RBE), V30 Gy (RBE), and V40 Gy (RBE) were significantly higher in the patients with rectal bleeding than in those without. The cutoff values were D6cc = 34.34 Gy (RBE), D2cc = 46.46 Gy (RBE), V10 Gy (RBE) = 9.85 cc, V20 Gy (RBE) = 7.00 cc, V30 Gy (RBE) = 6.91 cc, and V40 Gy (RBE) = 4.26 cc. The D2cc, V10 Gy (RBE), and V20 Gy (RBE) cutoff values were significant predictors of grade 2 rectal bleeding. CONCLUSION: The above dose-volume parameters may serve as guidelines for preventing rectal bleeding after 12 fractions of CIRT for prostate cancer.

A preliminary report comparing the effect of Asafoetida with oral contraceptive on polycystic ovarian syndrome in a double-blind randomized trial.

Objective: Polycystic ovarian syndrome (PCOS) is the most common cause of infertility and endocrine disorders in women of childbearing age. In Persian medicine, Ferula assafoetida L. (Asafoetida) was recommended for treating PCOS. The present study was conducted to compare the effect of Asafoetida with oral contraceptive tablets on PCOS patients. Materials and Methods: Patients with PCOS (n=30) were enrolled in a double-blind randomized clinical trial. On Day 5 of the menstrual cycle, patients received two periods of 21-day treatment, with 7 days rest between the two treatments. On a daily basis, half of the patients (n=15) received Asafoetida (1 g), and the rest received low dose oral contraceptive (LD; one tablet). Menstrual status, anthropometric characteristics, hematology and biochemistry parameters, ovarian ultrasound examination and hirsutism were evaluated prior to the initiation of the experiment and 14 days after the end of treatment. The occurrence of menstrual cycles and pregnancy was assessed eight months after the end of treatment. Results: The incidence of pregnancy was greater in patients who received Asafoetida compared to those who received LD (p=0.019). The time intervals between menstrual cycles became shorter in both groups (p<0.05). The occurrence of regular menstrual cycles remained longer in the Asafoetida compared to the LD group (p=0.001). Concentrations of triglycerides, cholesterol, HDL and LDL were significantly increased after treating with LD (p<0.05). Conclusion: In PCOS patients, the occurrence of regular menstrual cycles and the incidence of pregnancy were improved following treatment with Asafoetida. This medicament could be considered a safe treatment for patients with PCOS.

Increased Cellular Dosage of Bone Marrow Aspiration Concentrate Does Not Translate to Increased Clinical Effectiveness in Knee Osteoarthritis: A Phase I Dose Escalation Study.

Introduction: Knee osteoarthritis (KOA), a chronic degenerative disease, significantly impairs quality of life due to pain and mobility limitations. Traditional treatments focus on symptom management without addressing the underlying disease progression, leading to a growing interest in regenerative medicine approaches. Bone marrow aspirate concentrate (BMAC), rich in mesenchymal stem cells and growth factors, has shown potential for cartilage repair and symptom relief in KOA. Despite promising outcomes, the optimal BMAC dosage for knee OA treatment remains undetermined. This study aims to evaluate the clinical efficacy and safety of varying BMAC dosages in knee OA treatment. Methods: This prospective controlled dose-escalation study involved 75 patients with early-stage knee OA, categorized into three groups based on BMAC dosage administered 10 × 106 cells (low-dose group), 50 × 106 cells (medium-dose group), or 100 × 106 cells (high-dose group). All the patients underwent a single intra-articular injection of BMAC and were monitored over a year. The primary outcomes include Visual Analog Scale (VAS) for pain and the Knee Injury and Osteoarthritis Outcome Score (KOOS) for joint function recorded at baseline, 1, 3, 6, and 12 months post-intervention. Adverse events were also documented. Results: Significant clinical improvements in VAS and KOOS scores were noted across all groups at all time points compared to the baseline. However, these improvements did not significantly differ between dosage groups throughout the follow-up period. Adverse effects were minimal and primarily consisted of transient post-injection pain and effusion, with no dose-dependent increase in complications. Conclusion: BMAC treatment for knee OA is safe and demonstrates potential for significant pain relief and functional improvement, irrespective of the dosage administered within the tested range. The lack of significant differences among varying dosages suggests a plateau in therapeutic efficacy beyond a certain threshold. Further research is necessary on the long-term outcomes to optimize the dosing strategy.

Effect of Cellular Dosage of Bone Marrow Aspiration Concentrate on the Radiological Outcomes in Knee Osteoarthritis: A Phase I Dose-Escalation Study.

Introduction: Knee osteoarthritis(KOA), a chronic degenerative disease, significantly impairs quality of life due to pain and mobility limitations. Traditional treatments focus on symptom management without addressing the underlying disease progression, leading to a growing interest in regenerative medicine approaches. Bone marrow aspirate concentrate (BMAC), rich in mesenchymal stem cells and growth factors, has shown potential for cartilage repair and symptom relief in KOA. Despite promising outcomes, the optimal BMAC dosage for knee OA treatment remains undetermined. This study aims to evaluate the radiological outcomes of varying BMAC dosages in knee OA treatment. Methods: This prospective controlled dose-escalation study involved 75 patients with early-stage knee OA, categorized into three groups based on BMAC dosage administered 10x106 cells (low-dose group), 50 × 106 cells (medium-dose group), or 100x106 cells (high-dose group). All the patients underwent a single intra-articular injection of BMAC and were monitored over a year. The primary outcomes include magnetic resonance observation of cartilage repair tissue (MOCART 2.0) score to assess the cartilage. Results: We noted significant improvement in the overall MOCART score (p = 0.027) and subchondral change sub-score (p = 0.048) and defect filling sub-score (p = 0.025) in the medium- and high-dose cohorts compared to the low-dose cohort at 1 year follow-up. Although we noted positive correlation between the clinical and radiological outcome (r = 0.43), we did not find any significant different in the clinical outcome between the treatment groups. Conclusion: BMAC for OA knee resulted in significant improvement in the radiological scores compared to the baseline. Medium and high doses of BMAC result in significantly higher radiological scores compared to low-dose BMAC at 1 year. However, the radiological improvement did not translate into functional improvement, irrespective of the dosage administered at 1 year. Further research is necessary on the long-term outcomes to understand and optimize the dosing strategy based on clinico-radiological results.

Autologous Bone Marrow Aspiration Concentrate (BMAC) Therapy for Primary Knee Osteoarthritis-An Observational and Dose Escalation Study.

Introduction: Anti-inflammatory and anti-fibrotic properties maximize the therapeutic potential of bone marrow aspiration concentrate (BMAC) in osteoarthritis (OA) knee. There is a lack of studies to standardize the treatment procedure to make the studies done across various centers comparable to understand the lacunae better and develop further the deficiency in our understanding of BMAC for OA knee. We aimed to assess the degree of pain relief, functional outcome, and cartilage thickness with different doses of BMAC in primary OA knee. Materials and Methods: A single-centered prospective observational study was conducted with 80 patients of OA knee who were divided into 4 groups where group A (n = 20), group B (n = 20), group C (n = 20), and group D (n = 20) received intra-articular 1, 2, 5 million BMAC cells per kg body weight, and intra-articular saline, respectively. All patients were followed up with Visual Analog Scale (VAS), knee Injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and International Knee Documentation Committee (IKDC) scores both pre and post-procedurally at 1, 3, 6, and 12 months follow-up. Results: The study found no significant differences in demographics or co-morbidities across four participant groups (A, B, C, D). However, clinical outcomes varied markedly: Groups B and C showed significant improvements in pain perception (VAS scores), knee function, and quality of life (KOOS and WOMAC scores), while Group A showed marginal or non-significant changes, and Group D exhibited no significant improvements. These findings suggest that treatments in Groups B and C reached the Minimal Clinically Important Difference, significantly enhancing patient-reported outcomes. Conclusion: A dose of 2 million BMAC cells per kg body weight for knee OA serves as the better regenerative modality of choice in cartilage regeneration. With our dose-escalation study, we would be able to standardize the treatment procedure and enable global comparison of the treatment method across various regions of the world.

Improving 3D dose prediction for breast radiotherapy using novel glowing masks and gradient-weighted loss functions.

BACKGROUND: The quality of treatment plans for breast cancer can vary greatly. This variation could be reduced by using dose prediction to automate treatment planning. Our work investigates novel methods for training deep-learning models that are capable of producing high-quality dose predictions for breast cancer treatment planning. PURPOSE: The goal of this work was to compare the performance impact of two novel techniques for deep learning dose prediction models for tangent field treatments for breast cancer. The first technique, a "glowing" mask algorithm, encodes the distance from a contour into each voxel in a mask. The second, a gradient-weighted mean squared error (MSE) loss function, emphasizes the error in high-dose gradient regions in the predicted image. METHODS: Four 3D U-Net deep learning models were trained using the planning CT and contours of the heart, lung, and tumor bed as inputs. The dataset consisted of 305 treatment plans split into 213/46/46 training/validation/test sets using a 70/15/15% split. We compared the impact of novel "glowing" anatomical mask inputs and a novel gradient-weighted MSE loss function to their standard counterparts, binary anatomical masks, and MSE loss, using an ablation study methodology. To assess performance, we examined the mean error and mean absolute error (ME/MAE) in dose across all within-body voxels, the error in mean dose to heart, ipsilateral lung, and tumor bed, dice similarity coefficient (DSC) across isodose volumes defined by 0%-100% prescribed dose thresholds, and gamma analysis (3%/3 mm). RESULTS: The combination of novel glowing masks and gradient weighted loss function yielded the best-performing model in this study. This model resulted in a mean ME of 0.40%, MAE of 2.70%, an error in mean dose to heart and lung of -0.10 and 0.01 Gy, and an error in mean dose to the tumor bed of -0.01%. The median DSC at 50/95/100% isodose levels were 0.91/0.87/0.82. The mean 3D gamma pass rate (3%/3 mm) was 93%. CONCLUSIONS: This study found the combination of novel anatomical mask inputs and loss function for dose prediction resulted in superior performance to their standard counterparts. These results have important implications for the field of radiotherapy dose prediction, as the methods used here can be easily incorporated into many other dose prediction models for other treatment sites. Additionally, this dose prediction model for breast radiotherapy has sufficient performance to be used in an automated planning pipeline for tangent field radiotherapy and has the major benefit of not requiring a PTV for accurate dose prediction.

The use of community-oriented primary care (COPC) model to generate vaccine demand: The case of a remote fishing community in Cameroon.

BACKGROUND: Cameroon, a country in sub-Saharan Africa, ranks among the top 15 countries worldwide with the highest number of zero-dose (unvaccinated) children. Among other reasons, pockets of hard-to-reach communities that traditionally miss essential healthcare services, including childhood immunization, largely contribute to this sub-optimal vaccination coverage. This is the case of Manoka Health District (MHD), an archipelago district with a zero-dose proportion of 91.7%. High disease burdens such as malaria and water-borne diseases have forced the population to depend on herbalists and roadside drug vendors, eroding trust in the primary healthcare system and worsening vaccine hesitancy. This study, therefore, aims to describe how a project optimized vaccine demand generation in these hard-to-reach settlements using an integrated community health worker service delivery package developed using the Community-oriented primary healthcare (COPC) model. METHODOLOGY: This cross-sectional descriptive study was based on data collected from November 2021 to August 2022 in three project-implementing health areas (Kombo Moukoko, Kooh, and Toube) in the Manoka health district. Data was collected on the integrated health packages offered by Community Health Workers (CHWs). It comprised health education on malaria and water-borne diseases, screening for malaria using Rapid Diagnostic Test (RDT), treatment of under-5 for uncomplicated malaria and diarrhea, conduct of essential Antenatal Care (ANC) services, and vaccination counseling and referral in the three health areas. Microsoft Excel 2013 was used to analyze descriptive data and expressed results as percentages, with tables and column charts used for data visualization. All missing data were considered in the final analysis. RESULTS: Over 550 under-5 children and 187 pregnant women were identified to be in need of curative and preventive care services during the project period. About 81% of pregnant women received a minimum ANC package by CHWs, and 47% adhered to referrals to health facilities for continuous ANC and delivery. Half of the children under 5 with health issues were diagnosed and managed for uncomplicated malaria. Also, during home visits, 617 under-immunized and zero-dose children less than two years of age were identified, referred, and vaccinated either during an outreach program or at the nearest health post in a neighboring health area, representing about 64% (617/964) of under-2 children identified in these communities. There was a gradual increase from 0% vaccine acceptance post-referral in the first month to 47% after six months and 64% at one year of intervention. CONCLUSION: The use of the COPC model to co-develop integrated essential health service packages that meet the needs of communities showed value in building trust and increasing childhood immunization uptake in hard-to-reach communities.

A model study on the effect of human's height variability in particle deposition and retained dose in the respiratory tract.

The objective of the current study was to investigate the impact of human's height variability to the deposition percentage, the deposited and the retained dose of particulate matter in the respiratory tract. In addition, the dose to the oesophagus, blood and lymph nodes was evaluated after particle clearance. A methodology which correlates anatomical and physiological parameters with height was adopted into an existing particle dosimetry model (Exposure Dose Model 2, ExDoM2). Model results showed that deposition of particles with aerodynamic diameter (dae) ranging from 0.001 to 10 µm depends on the competition between anatomical/physiological parameters, with the maximum effect induced from height variability to be observed for particles in the size range of 0.30 µm

Analysis of hydrogen peroxide production in pure water: Ultrahigh versus conventional dose-rate irradiation and mechanistic insights.

BACKGROUND: Ultrahigh dose-rate radiation (UHDR) produces less hydrogen peroxide (H2O2) in pure water, as suggested by some experimental studies, and is used as an argument for the validity of the theory that FLASH spares the normal tissue due to less reactive oxygen species (ROS) production. In contrast, most Monte Carlo simulation studies suggest the opposite. PURPOSE: We aim to unveil the effect of UHDR on H2O2 production in pure water and its underlying mechanism, to serve as a benchmark for Monte Carlo simulation. We hypothesized that the reaction of solvated electrons ( e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ ) removing hydroxyl radicals (•OH), the precursor of H2O2, is the reason why UHDR leads to a lower G-value (molecules/100 eV) for H2O2 (G[H2O2]), because: 1, the third-order reaction between e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ and •OH is more sensitive to increased instantaneous ROS concentration by UHDR than a two-order reaction of •OH self-reaction producing H2O2; 2, e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ has two times higher diffusion coefficient and higher reaction rate constant than that of •OH, which means e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ would dominate the competition for •OH and benefit more from the inter-track effect of UHDR. Meanwhile, we also experimentally verify the theory of long-lived radicals causing lower G(H2O2) in conventional irradiation, which is mentioned in some simulation studies. METHODS AND MATERIALS: H2O2 was measured by Amplex UltraRed assay. 430.1 MeV/u carbon ions (50 and 0.1 Gy/s), 9 MeV electrons (600 and 0.62 Gy/s), and 200 kV x-ray tube (10 and 0.1 Gy/s) were employed. For three kinds of water (real hypoxic: 1% O2; hypoxic: 1% O2 and 5% CO2; and normoxic: 21% O2), unbubbled and bubbled samples with N2O, the scavenger of e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ , were irradiated by carbon ions and electrons with conventional and UHDR at different absolute dose levels. Normoxic water dissolved with sodium nitrate (NaNO3), another scavenger of e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ , and bubbled with N2O was irradiated by x-ray to verify the results of low-LET electron beam. RESULTS: UHDR leads to a lower G(H2O2) than conventional irradiation. O2 and CO2 can both increase G(H2O2). N2O increases G(H2O2) of both UHDR and conventional irradiation and eliminates the difference between them for carbon ions. However, N2O decreases G(H2O2) in electron conventional irradiation but increases G(H2O2) in the case of UHDR, ending up with no dose-rate dependency of G(H2O2). Three-spilled carbon UHDR does not have a lower G(H2O2) than one-spilled UHDR. However, the electron beam shows a lower G(H2O2) for three-spilled UHDR than for one-spilled UHDR. Normoxic water with N2O or NaNO3 can both eliminate the dose rate dependency of H2O2 production for x-ray. CONCLUSIONS: UHDR has a lower G(H2O2) than the conventional irradiation for both high LET carbon and low LET electron and x-ray beams. Both scavengers for e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ , N2O and NaNO3, eliminate the dose-rate dependency of G(H2O2), which suggests e aq - ${\mathrm{e}}_{{\mathrm{aq}}}^ - $ is the reason for decreased G(H2O2) for UHDR. Three-spilled UHDR versus one-spilled UHDR indicates that the assumption of residual radicals reducing G(H2O2) of conventional irradiation may only be valid for low LET electron beam.

Radiological assessment of radon in groundwater of the northernmost Kashmir Basin, northwestern Himalaya.

This study investigates the radon concentration in groundwater in Kupwara, the northernmost district of the Kashmir valley. It further assesses the annual effective dose experienced by the district's diverse population-infants, children, and adults-attributable to both inhalation of airborne radon released from drinking water and direct ingestion. In addition to this, the calculation of gamma dose rate is also carried out at each of the sampling site of radon. A portable radon-thoron monitor and a portable gamma radiation detector were respectively employed to estimate the activity concentration of radon in water samples and to measure the gamma dose rate. The radon concentration was found to exhibit variability from a minimum of 2.9 BqL-1 to a maximum of 197.2 BqL-1, with a mean of 26.3 BqL-1 and a standard deviation of 23.3 BqL-1. From a total of 85 samples, 10.6% of the samples had radon activity concentrations exceeding the permissible limits of 40 BqL-1 set by the United Nations Scientific Committee on Effects of Atomic Radiations as reported by UNSCEAR (Sources and effects of ionizing radiation, 2008) and only 1.2% of the samples have radon activity concentration exceeding the permissible limits of 100 BqL-1 set by the World Health Organization as reported by WHO (WHO guidelines for drinking-water quality, World Health Organization, Geneva, 2008). The mean of the annual effective dose due to inhalation for all age groups as well as the annual ingestion dose for infants and children, surpasses the World Health Organization's limit of 100 µSv y-1 as reported by WHO (WHO guidelines for drinking-water quality, World Health Organization, Geneva, 2008). The observed gamma radiation dose rate in the vicinity of groundwater radon sites ranged from a minimum of 138 nSv h-1 to a maximum of 250 nSv h-1. The data indicated no significant correlation between the dose rate of gamma radiation and the radon levels in the groundwater. Radon concentration of potable water in the study area presents a non-negligible exposure pathway for residents. Therefore, the judicious application of established radon mitigation techniques is pivotal to minimize public health vulnerabilities.

Negative association of steroids with immunotherapy efficacy in a multi-tumor cohort: time and dose-dependent.

Previous studies have suggested a negative impact of steroids on the efficacy of immune checkpoint inhibitors (ICI), but how this effect is modulated by the dosage and time of administration is yet to be clarified. We have performed a retrospective analysis of 475 patients with advanced solid tumors treated with ICI as monotherapy from 2015 to 2022. Data regarding immune-related adverse events (irAEs) and clinical outcomes were collected. For each patient, the daily steroid dose (in mg/kg of prednisone) was registered until disease progression or death. The impact of cumulative doses on response rates and survival outcomes was analyzed within different periods. The objective response rate (ORR) was significantly lower among patients exposed to steroids within 30 days before the first cycle of ICI (C1) (20.3% vs. 36.7%, p < 0.01) and within the first 90 days of treatment (25.7% vs. 37.7%, p = 0.01). This negative association was confirmed by multivariable analysis. Higher mean steroid doses were observed among non-responders, and cumulative doses were inversely correlated with the disease control rate (DCR) around ICI initiation. Remarkably, poorer outcomes were observed even in patients belonging to the lowest dose quartile compared to the steroid-naïve population. The exposure to steroids after 6 months of ICI was not associated with worse survival outcomes. Our results suggest that the potential impact of steroids on ICI efficacy may be time-dependent, prevailing around ICI initiation, and dose-dependent, with modulation of neutrophil-to-lymphocyte ratio as a possible underlying mechanism.

Tetracycline Three Times Daily Versus Four Times Daily in Bismuth-Containing Quadruple Therapy as the First-Line Treatment of Helicobacter pylori Infection: A Multicenter, Noninferiority, Randomized Controlled Trial.

BACKGROUND: Current guidelines recommend bismuth-containing quadruple therapy for patients newly diagnosed with Helicobacter pylori (H. pylori) infection. We aimed to compare the efficacy and safety of tetracycline administered three times daily versus four times daily in bismuth-containing quadruple therapy for first-line treatment of H. pylori infection. METHODS: This multicenter, noninferiority, randomized controlled study, conducted in China, recruited treatment-naïve adults with H. pylori infection, randomized 1:1 into two treatment groups to receive either of the following bismuth-containing quadruple therapies: esomeprazole 20 mg twice-daily; bismuth 220 mg twice-daily; amoxicillin 1000 mg twice-daily; and tetracycline 500 mg three times daily (TET-T) versus 500 mg four times daily (TET-F). At least 6 weeks post-treatment, a 13C-urea breath test was performed to evaluate H. pylori eradication. RESULTS: In total, 406 patients were randomly assigned to the two treatment groups. Intention-to-treat eradication rates were 91.63% (186/203; 95% confidence interval [CI] 87.82%-95.44%) versus 90.15% (183/203; 95% CI 86.05%-94.25%) (p = 0.0005) and per-protocol eradication rates were 95.34% (184/193; 95% CI 92.36%-98.31%) versus 95.72% (179/187; 95% CI 92.82%-98.62%) (p = 0.0002) for the TET-T and TET-F group, respectively. TET-T-treated patients had a lower incidence of adverse effects than TET-F-treated patients (21.61% vs. 31.63%, p = 0.024), with no significant differences in compliance to treatment between the groups. CONCLUSION: As a first-line therapy for H. pylori infection, the eradication rate of the TET-T therapy was noninferior to that of the TET-F therapy while significantly reducing the incidence of adverse reactions. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05431075.

PBPK model-based gender-specific risk assessment of N-nitrosodimethylamine (NDMA) using human biomonitoring data.

Despite several screening levels for NDMA reported in water, soil, air, and drugs, the human risk assessment using biomonitoring concentrations has not been performed. In this study, gender-specific exposure guidance values were determined in humans, then biomonitoring measurements in healthy Korean subjects (32 men and 40 women) were compared to the exposure guidance values to evaluate the current exposure level to NDMA. For the human risk assessment of NDMA, the gender-specific physiologically based pharmacokinetic (PBPK) model was developed in humans using proper physiological parameters, partition coefficients, and biochemical parameters. Using the PBPK model, a Monte Carlo simulation was performed to describe the magnitudes of inter-individual variability and uncertainty on the single model predictions. The PBPK modeling and Monte Carlo simulation allowed the estimation of the relationship between external dose and blood concentration for the risk assessment. The procedure for the human risk assessment was summarized as follows: (1) estimating a steady-state blood concentration (Cavg) corresponding to the daily no observed adverse effect level (NOAEL) administration in rats; (2) applying uncertainty factors (UFs) for deriving the human Cavg; (3) determining the exposure guidance values as screening criteria; (4) interpreting the human biomonitoring measurements by forward and reverse dosimetry approaches. Using the biomonitoring concentrations, current daily exposures to NDMA were estimated to be 3.95 µg/day/kg for men and 10.60 µg/day/kg for women, respectively. The result of the study could be used as a basis for implementing further risk management and regulatory decision-making for NDMA.

An inventory of patient-image based risk/dose, image quality and body habitus/size metrics for adult abdomino-pelvic CT protocol optimisation.

PURPOSE: Patient-specific protocol optimisation in abdomino-pelvic Computed Tomography (CT) requires measurement of body habitus/size (BH), sensitivity-specificity (surrogates image quality (IQ) metrics) and risk (surrogates often dose quantities) (RD). This work provides an updated inventory of metrics available for each of these three categories of optimisation variables derivable directly from patient measurements or images. We consider objective IQ metrics mostly in the spatial domain (i.e., those related directly to sharpness, contrast, noise quantity/texture and perceived detectability as these are used by radiologists to assess the acceptability or otherwise of patient images in practice). MATERIALS AND METHODS: The search engine used was PubMed with the search period being 2010-2024. The key words used were: 'comput* tomography', 'CT', 'abdom*', 'dose', 'risk', 'SSDE', 'image quality', 'water equivalent diameter', 'size', 'body composition', 'habit*', 'BMI', 'obes*', 'overweight'. Since BH is critical for patient specific optimisation, articles correlating RD vs BH, and IQ vs BH were reviewed. RESULTS: The inventory includes 11 BH, 12 IQ and 6 RD metrics. 25 RD vs BH correlation studies and 9 IQ vs BH correlation studies were identified. 7 articles in the latter group correlated metrics from all three categories concurrently. CONCLUSIONS: Protocol optimisation should be fine-tuned to the level of the individual patient and particular clinical query. This would require a judicious choice of metrics from each of the three categories. It is suggested that, for increased utility in clinical practice, more future optimisation studies be clinical task based and involve the three categories of metrics concurrently.

Unusual Presentation of Case of a Lung Carcinoid Tumor With Ectopic Adrenocorticotropic Secretion (EAS) Associated With Acute Weight Gain and Peripheral Edema.

Ectopic adrenocorticotropic secretion (EAS) is classically related to small-cell lung cancer but is caused by a wide variety of tumors. In approximately one-fifth of cases, the cause remains unidentified. Excess adrenocorticotropic hormone (ACTH) leads to Cushing's syndrome, and the presentation can be due to biochemical derangements such as hypokalemia and hyperglycemia. Alternatively, it may manifest with secondary symptoms such as weight gain, hypertension, skin thinning, abdominal striae, and/or psychotic manifestations. The diagnosis is established through dynamic testing after confirming excess cortisol and ACTH levels. Imaging is then used to identify the hormonally active lesion. Controlling hypercortisolism with steroidogenesis inhibitors is the initial step before proceeding to definitive treatment. Ideally, tumor resection, if possible, but bilateral adrenalectomies are considered in cases not amenable to curative surgery.

Calculated Drug Concentrations in Currently Available Intravitreal Therapies: Determination of Dilution Factor and Deviation From Recommended Doses.

In ophthalmology, intravitreal therapies are currently not personalized/customized and are not adjusted to the individual vitreous volume. With reference to the recently published calculation formula for a more accurate estimation of the vitreous body, we determined the dose of intravitreal medication for different vitreous volumes and compared them with the average volume. Using the axial length of the eye, the formula for the vitreous volume exact (VIVEX) can provide a more accurate indication of the vitreous volume in individual cases than an assumed standard volume of 4 mL. The concentration of active substances in small eyes may be twice as high as that in normal-sized emmetropic eyes. In contrast, large eyes may show less than half of the recommended drug concentration. The calculated concentrations of the investigated intravitreal drugs in small and large eyeballs showed impressive differences with large deviations from the recommended doses. Further systematic studies should follow to find out whether this has any impact on the effectiveness or side effects of the injected drugs.

Comparison of sensitivity between blood parameters and a genotoxic biomarker at low blood Pb levels: A population-based study.

BACKGROUND: Previous studies reported that lead (Pb) exposure induced adverse health effects at high exposure concentrations, however, there have been limited data on sensitivity comparisons among different health outcomes at low blood Pb levels. OBJECTIVES: To compare sensitivity between blood parameters and a genotoxic biomarker among workers exposed to low blood Pb levels (< 20 µg/dl), and to estimate a benchmark dose (BMD). METHODS: Pb-exposed workers were recruited from a lead-acid storage battery plant. Their blood lead levels (BLLs) were measured. Blood parameters and micronuclei (MN) frequencies were determined. Multivariate linear or Poisson regression was used to analyze relationships between blood parameters or MN frequencies with BLLs. Two BMD software were used to calculate BMD and its 95 % lower confidence limit (BMDL) for BLLs. RESULTS: The median BLL for 611 workers was 10.44 µg/dl with the 25th and 75th percentile being 7.37 and 14.62 µg/dl among all participants. There were significantly negative correlations between blood parameters and BLLs. However, MN frequencies correlated positively with BLLs (all P<0.05). Results from the two BMD software revealed that the dichotomous model was superior to the continuous model, and the BMDL for BLL derived from red blood cell (RBC) was 15.11 µg/dl, from hemoglobin (HGB) was 8.50 µg/dl, from mean corpuscular hemoglobin (MCH) was 7.87 µg/dl, from mean corpuscular hemoglobin concentration (MCHC) was 3.98 µg/dl, from mean corpuscular volume (MCV) was 11.44 µg/dl, and from hematocrit (HCT) was 6.65 µg/dl. The conservative BMDL obtained from the MN data was 7.52 µg/dl. CONCLUSION: Our study shows that low dose Pb exposure caused decrease of blood parameters and increase of MN frequencies. The genotoxic biomarker was more sensitive than most blood parameters. BMDLs for BLL derived from MN frequencies and the red blood cell indicators should be considered as new occupational exposure limits. Our results suggest that MN assay can be considered as a part of occupational health examination items.

Improvements in Therapy Experience with Evoked Compound Action Potential Controlled, Closed-Loop Spinal Cord Stimulation - Primary Outcome of the ECHO-MAC Randomized Clinical Trial.

Spinal cord stimulation (SCS) is a well-established treatment for chronic neuropathic pain. However, over- or under-delivery of the SCS may occur because the spacing between the stimulating electrodes and the spinal cord is not fixed; spacing changes with motion and postural shifts may result in variable delivery of the SCS dose, and in turn a sub-optimal therapy experience for the patient. The evoked compound action potential (ECAP)-a measure of neural activation - may be used as a control signal to adapt SCS parameters in real-time to compensate for this variability. In this prospective, multicenter, randomized, single-blind, crossover trial, reduction in overstimulation intensity was used as a perceptual measure to evaluate a novel ECAP-controlled, closed-loop (CL) SCS algorithm relative to traditional open-loop (OL) SCS. The primary outcome used a Likert scale to assess sensation during activities of daily living with CL versus OL SCS. Of the 42 subjects in the Intent-to-Treat Analysis set, 97.6% had a reduction in sensation with CL versus OL SCS. The primary objective was met as the lower confidence limit (87.4%) exceeded the performance goal of 50% (p < 0.001). A total of 88.1% (37/42) of subjects preferred CL and 11.9% (5/42) preferred OL SCS. SCS dose consistency during CL SCS was demonstrated by the reduced variability in ECAP amplitude with CL SCS (SD: 8.72 µV) relative to OL SCS (SD: 19.95 µV). Together, these results demonstrate that the ECAP-controlled, CL algorithm reduces or eliminates unwanted sensation, and thereby provides a more preferred and consistent SCS experience. PERSPECTIVE: Patients with chronic pain need durable and dependable options for pain relief. SCS is an important therapy option, and new technology advancements could improve long-term therapy use. Closed-loop SCS offers a preferred and more consistent therapy experience for patients that could lead to increased therapy utilization and reliable therapy outcomes.