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.

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.

Cumulative radiation dose from medical imaging in paediatric congenital heart disease patients with epicardial cardiac implantable electronic devices.

Aims: To determine whether paediatric congenital heart disease (CHD) patients with epicardial cardiac implantable electronic devices (CIEDs) receive high cumulative effective doses (CEDs) of ionizing radiation from medical imaging tests. Methods and results: We compared 28 paediatric CHD patients with epicardial CIEDs (cases) against 40 patients with no CIED matched by age at operation, sex, surgical era, and CHD diagnosis (controls). We performed a retrospective review of radiation exposure from medical imaging exams between 2006 and 2022. Radiation dose from computed tomography (CT) and X-ray radiography was calculated using the National Cancer Institute Radiation Dosimetry Tool. We performed univariate analysis to compare the CED between the two groups. In the case subgroup, we convened experts' review to adjudicate the prevalence of CT exams that should have been performed with magnetic resonance imaging (MRI) in the absence of a CIED. Children (median age 2.5 years at implant) with CIEDs received significantly higher median CED compared with matched controls (6.90 vs. 1.72 mSv, P = 0.0018). In cases, expert adjudication showed that 80% of the CT exams would have been performed with MRI in the absence of a CIED. This resulted, on average, a five-fold increase in the effective dose (ED) from post-lead implant CTs. Conclusion: Paediatric CHD patients with CIED received four times higher CED than matched controls. Improved access to medical imaging tests without ionizing radiation, such as MRI, could potentially reduce the ED in CIED patients by up to five times.

The Use of Azelastine Hydrochloride/Fluticasone Propionate in the Management of Allergic Rhinitis in Asia: A Review.

The incidence of allergic rhinitis (AR) in Asia and the world is steadily rising. Patients experience incomplete symptom relief despite existing treatment options, which warrants the need for new therapeutic regimes. Azelastine hydrochloride/fluticasone propionate (MP-AzeFlu), a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate has been indicated in the treatment of AR. The current review discusses the effects of MP-AzeFlu versus conventional therapies in achieving superior clinical improvement with a very rapid onset of action (5 minutes). The superiority of MP-AzeFlu in offering complete symptom control with sustained relief in patients with AR compared to the existing therapeutic options is also discussed. MP-AzeFlu has been shown to improve the quality of life for patients with AR, thereby enhancing patient adherence to therapy and establishing its preference for the treatment of AR. Currently, the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines recommend the use of a combination of intranasal corticosteroids and intranasal antihistamines as first-line treatment in patients with persistent AR with visual analog scores ≥5 or when prior treatment with single agents has been ineffective. Widely published data on the efficacy and safety of its prolonged use in adults and children have validated that effective treatment of AR can be achieved with MP-AzeFlu.

Pyrazinamide Safety, Efficacy, and Dosing for Treating Drug-Susceptible Pulmonary Tuberculosis: A Phase 3, Randomized, Controlled Clinical Trial.

RATIONALE: Optimizing pyrazinamide dosing is critical to improve treatment efficacy while minimizing toxicity during tuberculosis treatment. Study 31/ACTG A5349 represents the largest Phase 3 randomized controlled therapeutic trial to date for such investigation. OBJECTIVES: We sought to report pyrazinamide pharmacokinetic parameters, risk factors for lower pyrazinamide exposure, and relationships between pyrazinamide exposure with efficacy and safety outcomes. We aimed to determine pyrazinamide dosing strategies that optimize risks and benefits. METHODS: We analyzed pyrazinamide steady-state pharmacokinetic data using population nonlinear mixed-effects models. We evaluated the contribution of pyrazinamide exposure to long-term efficacy using parametric time-to-event models and safety outcomes using logistic regression. We evaluated optimal dosing with therapeutic windows targeting ≥95% durable cure and safety within the observed proportion of the primary safety outcome. MEASUREMENTS AND MAIN RESULTS: Among 2255 participants with 6978 plasma samples, pyrazinamide displayed 7-fold exposure variability (151-1053 mg·h/L). Body weight was not a clinically relevant predictor of drug clearance and thus did not justify the need for weight-banded dosing. Both clinical and safety outcomes were associated with pyrazinamide exposure, resulting in a therapeutic window of 231-355 mg·h/L for the control and 226-349 mg·h/L for the rifapentine-moxifloxacin regimen. Flat dosing of pyrazinamide at 1000 mg would have permitted an additional 13.1% (n=96) participants allocated to the control and 9.2% (n=70) to the rifapentine-moxifloxacin regimen dosed within the therapeutic window, compared to the current weight-banded dosing. CONCLUSIONS: Flat dosing of pyrazinamide at 1000 mg daily would be readily implementable and could optimize treatment outcomes in drug-susceptible tuberculosis. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT02410772.

Efficacy, effectiveness and immunogenicity of reduced HPV vaccination schedules: A review of available evidence.

Background: Current National Advisory Committee on Immunization (NACI) guidance recommends human papillomavirus (HPV) vaccines be administered as a two or three-dose schedule. Recently, several large clinical trials have reported the clinical benefit of a single HPV vaccine dose. As a result, the World Health Organization released updated guidance on HPV vaccines in 2022, recommending a two-dose schedule for individuals aged 9-20 years, and acknowledging the use of an alternative off-label single dose schedule. Objective: The objective of this overview is to provide a detailed account of the available evidence comparing HPV vaccination schedules, which was considered by NACI when updating recommendations on HPV vaccines. Methods: To identify relevant evidence, existing systematic reviews were leveraged where possible. Individual studies were critically appraised, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence. Results: Available evidence suggests that a one, two, or three-dose HPV vaccine schedule may provide similar protection from HPV infection. While antibody levels against HPV vaccine types were statistically significantly lower with a single dose schedule compared to two or three doses, titres were sustained for up to 16 years. The clinical significance of lower antibody titres is unknown, as there is no established immunologic correlate of protection. Conclusion: While the available evidence on single-dose HPV vaccination schedules shows a one-dose schedule is highly effective, continued follow-up of single-dose cohorts will be critical to understanding the relative duration of protection for reduced dose schedules and informing future NACI guidance on HPV vaccines.

Reduced frequency dosing of osimertinib in EGFR-mutant non-small cell lung carcinoma: real world data.

Introduction: Osimertinib is more efficacious and as safe as first-generation epidermal growth factor receptor (EGFR)-directed tyrosine kinase inhibitors. However, osimertinib is not affordable for most patients in developing nations. Moreover, the minimum biologically effective dose of osimertinib may be less than the approved dose. Materials and methods: This was a retrospective observational multicentric study aimed to describe the efficacy (objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS)) and toxicity of osimertinib 80 mg orally administered less frequently than daily (ranging from every other day to once-a-week) in patients with EGFR-mutated non-small cell lung cancer. Results: Between January 2021 and August 2023, we enrolled 22 patients. Six received osimertinib 80 mg once-a-week, nine received 80 mg once-in-3-days and seven received 80 mg on alternate days. Responses included 0 complete responses, 7 (31.8%) partial responses, 9 (40.9%) stable disease and 5 (22.7%) progressive disease. ORR was 31.8%, and DCR was 72.7%. Median PFS was 9.2 months (95% confidence interval (CI) 2.9-15.7), and median OS was 17.8 months (95% CI, 3.2-32.6). In patients who received reduced frequency osimertinib in the second line and beyond, the ORR was 29.4%, DCR was 70.5%, median PFS was 5.9 months (95% CI, 1.1-10.6) and median OS was 17.6 months (95% CI, 2.9-32.2). Grade 3 and higher toxicities were noted in 8 (36.3%) patients. Conclusion: Less frequent dosing of osimertinib may be a valid treatment option, especially in the second line and beyond setting in patients who cannot afford full dose daily osimertinib. This may provide an additional treatment option with a similar toxicity profile as that of standard dose osimertinib.

High Dose Pantoprazole for Gastroesophageal Reflux Disease: Need, Evidence, Guidelines and Our Experience.

Gastroesophageal reflux disease (GERD) has a pooled prevalence of 15.2% in India with varying presentation in different subset of patients. The approach towards the management of GERD includes use of monotherapy or a combination of OTCs like antacids and/or prescription drugs like H2 receptor antagonists and proton pump inhibitors (PPI). Better efficacy and safety profile of PPIs have contributed to its wide spread use as compared with other drugs for the same indication. Among PPIs, most of the healthcare professionals prefer to prescribe pantoprazole in India. Standard dose of Pantoprazole (40 mg) is unable to meet the needs in case of extraesophageal symptoms, partial responders, patients with concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs), or severe presentation in cases of overweight/obese patients. Multiple guidelines recommend doubling the dose of PPI in such cases. Twice daily dosing of PPI may reduce compliance. Thus, there is a need for a higher dose of Pantoprazole (80 mg) to be prescribed once daily in these cases so that improved compliance leads to better outcomes. The use of dual release Pantoprazole 80 mg may help to improve compliance and also enhance the time for which acid suppression takes place. In this review, we discuss the use of higher dose PPI based on scientific evidence and experience of clinicians for the same. How to cite this article: Upadhyay R, Soni NK, Kotamkar AA, et al. High Dose Pantoprazole for Gastroesophageal Reflux Disease: Need, Evidence, Guidelines and Our Experience. Euroasian J Hepato-Gastroenterol 2024;14(1):86-91.

Opportunistic use of chest low-dose computed tomography (LDCT) imaging for low bone mineral density and osteoporosis screening: cutoff thresholds for the attenuation values of the lower thoracic and upper lumbar vertebrae.

Background: Osteoporosis remains substantially underdiagnosed and undertreated worldwide. Chest low-dose computed tomography (LDCT) may provide a valuable and popular opportunity for osteoporosis screening. This study sought to evaluate the feasibility of the screening of low bone mineral density (BMD) and osteoporosis with mean attenuation values of the lower thoracic compared to upper lumbar vertebrae. The cutoff thresholds of the mean attenuation values in Hounsfield units (HU) were derived to facilitate implementation of opportunistic screening using chest LDCT. Methods: The participants aged 30 years or older who underwent chest LDCT and quantitative computed tomography (QCT) examinations from August 2018 to October 2020 in our hospital were consecutively included in this retrospective study. A region of interest (ROI) was placed in the trabecular bone of each vertebral body to measure the HU values. The correlations of mean HU values of lower thoracic (T11-T12) and upper lumbar (L1-L2) vertebrae with age and lumbar BMD obtained with QCT were performed using the Pearson correlation coefficient, respectively. The area under the curve (AUC) of the receiver operator characteristic (ROC) curve was generated to determine the cutoff thresholds for distinguishing low BMD from normal and osteoporosis from non-osteoporosis. Results: A total of 1,112 participants were included in the final study cohort (743 men and 369 women, mean age 58.2±8.9 years; range, 32-88 years). The mean HU values of T11-T12 and L1-L2 were significantly different among 3 QCT-defined BMD categories of osteoporosis, osteopenia, and normal (P<0.001). The differences in HU values between T11-T12 and L1-L2 in each category of bone status were statistically significant (P<0.001). The mean HU values of T11-T12 (r=-0.453, P<0.001) and L1-L2 (r=-0.498, P<0.001) had negative correlations with age. Positive correlations were observed between the mean HU values of T11-T12 (r=0.872, P<0.001) and L1-L2 (r=0.899, P<0.001) with BMD. The optimal cutoff thresholds for distinguishing low BMD from normal were average T11-T12 ≤157 HU [AUC =0.941, 95% confidence interval (CI): 0.925-0.954, P<0.001] and L1-L2 ≤138 HU (AUC =0.950, 95% CI: 0.935-0.962, P<0.001), as well as distinguishing osteoporosis from non-osteoporosis were average T11-T12 ≤125 HU (AUC =0.960, 95% CI: 0.947-0.971, P<0.001) and L1-L2 ≤107 HU (AUC =0.961, 95% CI: 0.948-0.972, P<0.001). There was no significant difference between the AUC values of T11-T12 and L1-L2 for low BMD (P=0.07) and osteoporosis (P=0.92) screening. Conclusions: We have conducted a study on low BMD and osteoporosis screening using mean attenuation values of lower thoracic and upper lumbar vertebrae. Assessment of mean attenuation values of T11-T12 and L1-L2 can be used interchangeably for low BMD and osteoporosis screening using chest LDCT, and their cutoff thresholds were established.

The existence of adrenal insufficiency in patients with COVID-19 pneumonia.

Introduction: Infection with SARS-CoV-2 virus may result in long COVID, a syndrome characterized by symptoms such as dyspnea, cardiac abnormalities, cognitive impairment, and fatigue. One potential explanation for these symptoms is hypocortisolism. Objective: To evaluate the prevalence of hypocortisolism in patients with a history of COVID-19 pneumonia. Methods: Cross-sectional study of patients who were aged ≥18 years and had a 3-month history of radiography-confirmed COVID-19 pneumonia. Exclusion criteria included current or previous treatment with glucocorticoids and use of an oral contraceptive. Adrenal function was evaluated using a low dose (1ug) corticotropin stimulation test (CST). Serum cortisol levels were measured at 0, 30, and 60 minutes, and baseline plasma ACTH was also measured. Results: Of the 41 patients enrolled, the median age was 62 years, 17 (42%) were female, and all 41 (100%) had severe pneumonia at baseline. Eleven patients (27%) had hypocortisolism, as evidenced by peak cortisol of less than 402.81 nmol/l after low dose (1 µg) CST. Of these 11 patients, 10 (91%) had secondary hypocortisolism (median ACTH 6.27 pmol/L, range 4.98-9.95 pmol/L) and one had primary hypocortisolism (mean ACTH 32.78 pmol/L). Six of the 11 patients with hypocortisolism (54.5%) reported symptoms of persistent fatigue and 5 (45.5%) required regular glucocorticoid replacement. Conclusions: Our results suggest that hypocortisolism, predominantly caused by pituitary disruption, may emerge after SARS-CoV-2 infection and should be considered in patients with a history of COVID-19 pneumonia with or without clinical hypocortisolism.

Transgenerational phenotypic responses to herbicide stress are more rapid than to shade and simulated herbivory in Arabidopsis.

Weeds in agricultural settings continually adapt to stresses from ecological and anthropogenic sources, in some cases leading to resistant populations. However, consequences of repeated sub-lethal exposure of these stressors on fitness and stress "memory" over generations remain poorly understood. We measured plant performance over a transgenerational experiment with Arabidopsis thaliana where plants were exposed to sub-lethal stress induced by the herbicides glyphosate or trifloxysulfuron, stresses from clipping or shading in either one (G1) or four successive generations (G1-G4), and control plants that never received stress. We found that fourth-generation (G4) plants that had been subjected to three generations of glyphosate or trifloxysulfuron stress produced higher post-stress biomass, seed weight, and rosette area as compared to that produced by plants that experienced stress only in the first generation (G1). By the same measure, clipping and shade were more influential on floral development time (shade) and seed weight (clipping) but did not show responsive phenotypes for vegetative metrics after multiple generations. Overall, we found that plants exhibited more rapid transgenerational vegetative "stress memory" to herbicides while reproductive plasticity was stressor dependent and similar between clipping/shade and anthropogenic stressors. Our study suggests that maternal plant stress memory aids next-generation plants to respond and survive better under the same stressors.

Prediction of dose distributions for non-small cell lung cancer patients using MHA-ResUNet.

BACKGROUND: The current level of automation in the production of radiotherapy plans for lung cancer patients is relatively low. With the development of artificial intelligence, it has become a reality to use neural networks to predict dose distributions and provide assistance for radiation therapy planning. However, due to the significant individual variability in the distribution of non-small cell lung cancer (NSCLC) planning target volume (PTV) and the complex spatial relationships between the PTV and organs at risk (OARs), there is still a lack of a high-precision dose prediction network tailored to the characteristics of NSCLC. PURPOSE: To assist in the development of volumetric modulated arc therapy (VMAT) plans for non-small cell lung cancer patients, a deep neural network is proposed to predict high-precision dose distribution. METHODS: This study has developed a network called MHA-ResUNet, which combines a large-kernel dilated convolution module and multi-head attention (MHA) modules. The network was trained based on 80 VMAT plans of NSCLC patients. CT images, PTV, and OARs were fed into the independent input channel. The dose distribution was taken as the output to train the model. The performance of this network was compared with that of several commonly used networks, and the networks' performance was evaluated based on the voxel-level mean absolute error (MAE) within the PTV and OARs, as well as the error in clinical dose-volume metrics. RESULTS: The MAE between the predicted dose distribution and the manually planned dose distribution within the PTV is 1.43 Gy, and the D95 error is less than 1 Gy. Compared with the other three commonly used networks, the dose error of the MHA-ResUNet is the smallest in PTV and OARs. CONCLUSIONS: The proposed MHA-ResUNet network improves the receptive field and filters the shallow features to learn the relative spatial relation between the PTV and the OARs, enabling accurate prediction of dose distributions in NSCLC patients undergoing VMAT radiotherapy.

Evaluating non-monotonic dose-response relationships in ecotoxicological risk assessment: A case study based on a systematic review of data on fluoxetine.

The environmental presence of pharmaceuticals, including the antidepressant fluoxetine, has become a subject of concern. Numerous studies have revealed effects of fluoxetine at environmental concentrations. Some of these studies have reported non-monotonic dose-response curves (NMDRs), leading to discussion because of the inconsistent detection of subtle effects and lack of mechanistic understanding. Nevertheless, investigating NMDRs in risk assessment is important, because neglecting them could underestimate potential risks of chemicals at low levels of exposure. Identification and quantification of NMDRs in risk assessment remains challenging, particularly given the prevalence of single outliers and the lack of sound statistical analyses. In response, the European Food Safety Authority (Beausoleil et al., 2016) presented a framework delineating six checkpoints for the evaluation of NMDR datasets, offering a systematic method for their assessment. The present study applies this framework to the case study of fluoxetine, aiming to assess the weight-of-evidence for the reported NMDR relationships. Through a systematic literature search, 53 datasets were selected for analysis against the six checkpoints. The results reveal that while a minority of these datasets meet all checkpoints, a significant proportion (27%) fulfilled at least five. Notably, many studies did not meet checkpoint 3, which requires NMDRs to be based on more than a single outlier. Overall, the current study points out a number of studies with considerable evidence supporting the presence of NMDRs for fluoxetine, while the majority of studies lacks strong evidence. The suggested framework proved useful for analysing NMDRs in ecotoxicological studies, but it is still imperative to develop further understanding of their biological plausibility.

Dose-dependent effects of polystyrene nanoplastics on growth, photosynthesis, and astaxanthin synthesis in Haematococcus pluvialis.

Microalgae play an important role in aquatic ecosystems, but the widespread presence of micro- and nano-plastics (MNPs) poses significant threats to them. Haematococcus pluvialis is well-known for its ability to produce the antioxidant astaxanthin when it experiences stress from environmental conditions. Here we examined the effects of polystyrene nanoplastics (PS-NPs) at concentrations of 0.1, 1, and 10 mg/L on H. pluvialis over an 18-day period. Our results show that PS-NPs caused a significant, dose-dependent inhibition of H. pluvialis growth and a reduction in photosynthesis. Furthermore, PS-NPs severely damaged the morphology of H. pluvialis, leading to cell shrinkage, collapse, content release, and aggregation. Additionally, PS-NPs induced a dose-dependent increase in soluble protein content and a decrease in the production of extracellular polymeric substances. These findings indicate that PS-NPs has the potential to adversely affect both the physiology and morphology of H. pluvialis. An increase in reactive oxygen species and antioxidant enzyme activities was also observed, suggesting an oxidative stress response to PS-NPs exposure. Notably, the synthesis of astaxanthin, which is crucial for H. pluvialis's survival under stress, was significantly inhibited in a dose-dependent manner under strong light conditions, along with the down-regulation of genes involved in the astaxanthin biosynthesis pathway. This suggests that PS-NPs exposure reduces H. pluvialis's ability to survive under adverse conditions. This study enhances our understanding of the toxic effects of PS-NPs on microalgae and underscores the urgent need for measures to mitigate MNP pollution to protect aquatic ecosystems.

A phase 2, randomized, blinded, dose-finding, controlled clinical trial to evaluate the safety, tolerability, and immunogenicity of a 24-valent pneumococcal conjugate vaccine (VAX-24) in healthy adults 65 years and older.

Despite current polysaccharide and conjugate vaccine use, pneumococcal diseases remain prevalent in older adults. VAX-24 is a 24-valent pneumococcal conjugate vaccine (PCV) containing eCRM, a proprietary carrier protein with non-native amino acids (para-azidomethyl-L-phenylalanine) that undergo site-specific conjugation to pneumococcal polysaccharides that have been activated with a small-molecule linker (dibenzocyclooctyne). Site-specific conjugation utilizing click chemistry enables consistent exposure of T-cell epitopes, reduction in carrier protein to pneumococcal polysaccharide ratio, and enhances manufacturing process consistency to improve PCVs by increasing serotype coverage while minimizing carrier suppression. Healthy adults aged 65 or older were randomized in a 1:1:1:1 ratio to receive a single injection of VAX-24 at 1 of 3 dose levels (1.1, 2.2, or a mixed dose of 2.2 or 4.4 mcg) or Prevnar 20® (PCV20) in a phase 2, blinded study. Primary outcome measures were solicited local and systemic events within 7 days post-vaccination, unsolicited adverse events (AEs) within 1 month, and serious AEs, medically attended AEs, or new onset of chronic disease within 6 months of vaccination. Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) were measured pre-vaccination and at 1 month post-vaccination. Of 207 participants enrolled, 200 completed the trial. Safety profiles were comparable across the three VAX-24 doses and PCV20. Robust OPA and IgG immune responses were seen for all 24 serotypes. On average, immune responses to VAX-24 2.2 mcg dose were similar or higher compared to PCV20. In adults ≥ 65 years, VAX-24 had a safety profile similar to PCV20 through six months post-vaccination and induced robust OPA and IgG responses to all 24 serotypes, supporting prior data showing that site-specific conjugation allows for increased serotype coverage with similar or higher immune response vs other PCVs. The outcome of this phase 2 study further supports use of VAX-24 2.2 mcg dose in phase 3 trials. Clinicaltrials.gov: NCT05297578.

Association Between Single-Dose and Longer Term Clinical Response to Stimulants in Attention-Deficit/Hyperactivity Disorder: A Systematic Review of Randomized Controlled Trials.

Objectives: Stimulants, such as methylphenidate (MPH) and amphetamines, represent the first-line pharmacological option for attention-deficit/hyperactivity disorder (ADHD). Randomized controlled trials (RCTs) have demonstrated beneficial effects at a group level but could not identify characteristics consistently associated with varying individual response. Thus, more individualized approaches are needed. Experimental studies have suggested that the neurobiological response to a single dose is indicative of longer term response. It is unclear whether this also applies to clinical measures. Methods: We carried out a systematic review of RCTs testing the association between the clinical response to a single dose of stimulants and longer term improvement. Potentially suitable single-dose RCTs were identified from the MED-ADHD data set, the European ADHD Guidelines Group RCT Data set (https://med-adhd.org/), as updated on February 1, 2024. Quality assessment was carried out using the Cochrane Risk of Bias (RoB) 2.0 tool. Results: A total of 63 single-dose RCTs (94% testing MPH, 85% in children) were identified. Among these, only a secondary analysis of an RCT tested the association between acute and longer term clinical response. This showed that the clinical improvement after a single dose of MPH was significantly associated with symptom improvement after a 4-week MPH treatment in 46 children (89% males) with ADHD. The risk of bias was rated as moderate. A further RCT used near-infrared spectroscopy, thus did not meet the inclusion criteria, and reported an association between brain changes under a single-dose and longer term clinical response in 22 children (82% males) with ADHD. The remaining RCTs only reported single-dose effects on neuropsychological, neuroimaging, or neurophysiological measures. Conclusion: This systematic review highlighted an important gap in the current knowledge. Investigating how acute and long-term response may be related can foster our understanding of stimulant mechanism of action and help develop stratification approaches for more tailored treatment strategies. Future studies need to investigate potential age- and sex-related differences.

Optimal dose and type of non-pharmacological treatments to improve cognitive function in people with Alzheimer's disease: a systematic review and network meta-analysis.

OBJECTIVES: To evaluate and rank the effectiveness of specific non-pharmacological treatments (NPTs) in improving the global cognitive function in individuals with Alzheimer's disease (AD) and to examine the dose-response relationship. METHOD: We conducted a systematic search in PubMed, MEDLINE, Embase, PsycINFO, CENTRAL, WOS, and CNKI from their inception to 15 February 2023. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcomes using random effects models. RESULTS: We included 68 studies involving 5053 participants in this meta-analysis. The treatments with the highest cumulative probabilities for improving global cognitive function were transcranial direct current stimulation (tDCS), followed by physical exercise (PE), and repetitive transcranial magnetic stimulation (rTMS). Additionally, cognitive stimulation (CS), cognitive training CT), multidisciplinary program (MD), and reminiscence treatment (RT) also significantly improve the global cognitive function of people with AD. A non-linear dose-response association was observed for tDCS, PE, rTMS, CS, and CT with global cognitive improvement. Notably, no minimal threshold was identified for the beneficial effects of PE on cognition. The estimated minimal doses for clinically relevant changes in cognition were 33 min per week for tDCS, 330 MET-min per week for PE, and 8000 pulses per week for rTMS. CONCLUSION: tDCS, PE, and rTMS are the better effective NPTs for enhancing global cognitive function in individuals with AD. Properly dosing these treatments can yield significant clinical benefits. Our findings support the clinical utility of low-dose exercise in improving cognition in people with AD.

Leveraging pharmacokinetic parameters as covariate in Bayesian logistic regression model to optimize dose selection in early phase oncology trial.

Dose selection and optimization in early phase of oncology drug development serves as the foundation for the success of late phases drug development. Bivariate Bayesian logistic regression model (BLRM) is a widely utilized model-based algorithm that has been shown to improve the accuracy for identifying recommended phase 2 dose (RP2D) based on dose-limiting-toxicity (DLT) over traditional method such as 3 + 3. However, it remains a challenge to optimize dose selection that strikes a proper balance between safety and efficacy in escalation and expansion phase of phase I trials. In this paper, we first use a phase I clinical trial to demonstrate how the variability of drug exposure related to pharmacokinetic (PK) parameters among trial participants may add to the difficulties of identifying optimal dose. We use simulation to show that concurrently or retrospectively fitting BLRM model for dose/toxicity data from escalation phase with dose-independent PK parameters as covariate lead to improved accuracy of identifying dose level at which DLT rate is within a prespecified toxicity interval. Furthermore, we proposed both model- and rule-based methods to modify dose at patient level in expansion cohorts based on their PK/exposure parameters. Simulation studies show this approach leads to higher likelihood for a dose level with a manageable toxicity and desirable efficacy margin to be advanced to late phase pipeline after being screened at expansion phase of phase I trial.

High-Dose Opioid Prescribing in Individuals with Acute Pain: Assessing the Effects of US State Opioid Policies.

BACKGROUND: How state opioid policy environments with multiple concurrent policies affect opioid prescribing to individuals with acute pain is unknown. OBJECTIVE: To examine how prescription drug monitoring programs (PDMPs), pain management clinic regulations, initial prescription duration limits, and mandatory continued medical education affected total and high-dose prescribing. DESIGN: A county-level multiple-policy difference-in-difference event study framework. SUBJECTS: A total of 2,425,643 individuals in a large national commercial insurance deidentified claims database (aged 12-64 years) with acute pain diagnoses and opioid prescriptions from 2007 to 2019. MAIN MEASURES: The total number of acute pain opioid treatment episodes and number of episodes containing high-dose (> 90 morphine equivalent daily dosage (MEDD)) prescriptions. KEY RESULTS: Approximately 7.5% of acute pain episodes were categorized as high-dose episodes. Prescription duration limits were associated with increases in the number of total episodes; no other policy was found to have a significant impact. Beginning five quarters after implementation, counties in states with pain management clinic regulations experienced a sustained 50% relative decline in the number of episodes containing > 90 MEDD prescriptions (95 CIs: (Q5: - 0.506, - 0.144; Q12: - 1.000, - 0.290)). Mandated continuing medical education regarding the treatment of pain was associated with a 50-75% relative increase in number of high-dose episodes following the first year-and-a-half of enactment (95 CIs: (Q7: 0.351, 0.869; Q12: 0.413, 1.107)). Initial prescription duration limits were associated with an initial relative reduction of 25% in high-dose prescribing, with the effect increasing over time (95 CI: (Q12: - 0.967, - 0.335). There was no evidence that PDMPs affected high-dose opioids dispensed to individuals with acute pain. Other high-risk prescribing indicators were explored as well; no consistent policy impacts were found. CONCLUSIONS: State opioid policies may have differential effects on high-dose opioid dispensing in individuals with acute pain. Policymakers should consider effectiveness of individual policies in the presence of other opioid policies to address the ongoing opioid crisis.

Validation of Acuros for total body irradiation at extended distance.

PURPOSE: Standardized and accurately reported doses are essential in conventional total body irradiation (TBI), especially lung doses. This study evaluates the accuracy of the Acuros algorithm in predicting doses for extended-distance TBI. METHODS: Measurements and calculations were done with both 6 and 18 MV. Tissue Maximum Ratio (TMR), output and off axis ratios (OAR) were measured at 200 and 500 cm source to detector distance and compared to Acuros calculated values. Two end-to-end tests were carried out, one with an in-house phantom (solid water and Styrofoam) with inserted ion chambers and the other was with the Imaging and Radiation Oncology Core (IROC) TBI anthropomorphic phantom equipped with TLDs. The end-to-end test was done for 6 and 18 MV both with and without lung blocks. The source to midplane distance for both phantoms were at 518 and 508 cm respectively. Lung blocks were placed at the phantom surface and a beam spoiler was positioned 30 cm from the surface of the phantoms as per our clinical set up. RESULTS: The agreement between measured and calculated TMR, output and off axis ratios for both 6 and 18 MV were within 2%. Ion chamber measurements in both the Styrofoam and solid water for both energies carried out with and without lung blocks were within 2% of calculated values. TLD measured doses for both 6 and 18 MV in the IROC phantom were within 5% of calculated doses which is within the uncertainty of the TLD measurement. CONCLUSIONS: The results indicate that the clinical beam model for Acuros 16.1 commissioned at standard clinical distances is capable of calculating doses accurately at extended distances up to 500 cm.