Tag: nevin manimala

Anal Biochem. 2023 Jun 9:115211. doi: 10.1016/j.ab.2023.115211. Online ahead of print.

ABSTRACT

LC-MS based multi-attribute methods (MAM) have drawn substantial attention due to their capability of simultaneously monitoring a large number of quality attributes of a biopharmaceutical product. For successful implementation of MAM, it is usually considered a requirement that the method is capable of detecting any new or missing peaks in the sample when compared to a control. Comparing a sample to a control for rare differences is also commonly practiced in many fields for investigational purpose. Because MS signal variability differs greatly between signals of different intensities, this type of comparison is often challenging, especially when the comparison is made without enough replicates. In this report we describe a statistical method for detecting rare differences between two very similar samples without replicate analyses. The method assumes that an overwhelming majority of components have equivalent abundance between the two samples, and signals with similar intensities have similar relative variability. By analyzing several monoclonal antibody peptide mapping datasets, we demonstrated that the method is suitable for new-peak detection for MAM as well as for other applications when rare differences between two samples need to be detected. The method greatly reduced false positive rate without a significant increase of false negative rate.

PMID:37302778 | DOI:10.1016/j.ab.2023.115211

Eur J Pharm Sci. 2023 Jun 9:106492. doi: 10.1016/j.ejps.2023.106492. Online ahead of print.

ABSTRACT

While many novel therapies have been approved in recent years for treating patients with multiple myeloma, there is still no established curative regimen, especially for patients with high-risk disease. In this work, we use a mathematical modeling approach to determine combination therapy regimens that maximize healthy lifespan for patients with multiple myeloma. We start with a mathematical model for the underlying disease and immune dynamics, which was presented and analyzed previously. We add the effects of three therapies to the model: pomalidomide, dexamethasone, and elotuzumab. We consider multiple approaches to optimizing combinations of these therapies. We find that optimal control combined with approximation outperforms other methods, in that it can quickly produce a combination regimen that is clinically-feasible and near-optimal. Implications of this work can be used to optimize doses and advance the scheduling of drugs.

PMID:37302768 | DOI:10.1016/j.ejps.2023.106492

Ann Oncol. 2023 Jun 9:S0923-7534(23)00721-4. doi: 10.1016/j.annonc.2023.05.012. Online ahead of print.

ABSTRACT

PURPOSE: The HER2DX genomic test predicts pathological complete response (pCR) and survival outcome in early-stage HER2+ breast cancer. Here, we evaluated the association of HER2DX scores with 1) pCR according to hormone receptor status and various treatment regimens, and 2) survival outcome according to pCR status.

METHODS: Seven neoadjuvant cohorts with HER2DX and clinical individual patient data were evaluated (DAPHNe, GOM-HGUGM-2018-05, CALGB-40601, ISPY-2, BiOnHER, NEOHER and PAMELA). All patients were treated with neoadjuvant trastuzumab (n=765) in combination with pertuzumab (n=328), lapatinib (n=187) or without a second anti-HER2 drug (n=250). Event-free survival (EFS) and overall survival (OS) outcomes were available in a combined series of 268 patients (i.e., NEOHER and PAMELA) with a pCR (n=118) and without a pCR (n=150). Cox models were adjusted to evaluate whether HER2DX can identify patients with low- or high-risk beyond pCR status.

RESULTS: HER2DX pCR score was significantly associated with pCR in all patients (odds-ratio [OR] per 10-unit increase=1.59, 95% CI 1.43-1.77; AUC=0.75), with or without dual HER2 blockade. A statistically significant increase in pCR rate due to dual HER2 blockade over trastuzumab-only was observed in HER2DX pCR-high tumors treated with chemotherapy (OR=2.56, 1.29-5.20). A statistically significant increase in pCR rate due to multi-agent chemotherapy over a single taxane was observed in HER2DX pCR-medium tumors treated with dual HER2 blockade (OR=3.11, 1.54-6.49). The pCR rates in HER2DX pCR-low tumors were ≤30.0% regardless of treatment administered. After adjusting by pCR status, patients identified as HER2DX low-risk had better EFS (p<0.001) and OS (p=0.006) compared to patients with HER2DX high-risk.

CONCLUSION: HER2DX pCR-score and risk-score might help identify ideal candidates to receive neoadjuvant dual HER2 blockade in combination with a single taxane in early-stage HER2+ breast cancer.

PMID:37302750 | DOI:10.1016/j.annonc.2023.05.012

J Nutr. 2023 Jun 9:S0022-3166(23)72410-3. doi: 10.1016/j.tjnut.2023.05.031. Online ahead of print.

ABSTRACT

BACKGROUND: Vitamin B12 is involved in several physiological functions, and malabsorption is reported with medication use.

OBJECTIVE: Studies have reported an inverse association between use of metformin or acid lowering agents (ALAs) such as proton pump inhibitors (PPIs), histamine 2 receptor antagonists (H2RAs) and blood vitamin B12 concentration, due to malabsorption. The concomitant use of these medications is under reported. We sought to examine these associations in a cohort of Boston-area Puerto Rican adults.

METHODS: This analysis was conducted within the Boston Puerto Rican Health Study (BPRHS), an ongoing longitudinal cohort that enrolled 1499 Puerto Rican adults aged 45-75y at baseline. Our study comprised 1428, 1155 and 782 participants at baseline, wave2 (2.2y from baseline) and wave3 (6.2y from baseline), respectively. Covariate-adjusted linear and logistic regression were used to examine association between baseline medication use and vitamin B12 concentration or deficiency (vitamin B12 < 148 pmol/L or methylmalonic acid (MMA) > 271nmol/L), and long-term medication use (continuous use for ∼6.2y) and wave3 B12 concentration and deficiency. Sensitivity analyses were done to examine these associations in B12 supplement users.

RESULTS: At baseline, we observed an association between metformin use (β = -0.069, P = 0.03) and concomitant ALA and metformin use (β = -0.112, P = 0.02) and vitamin B12 concentration, but not deficiency. We did not observe associations between ALA, PPI, or H2RA, individually, with vitamin B12 concentration or deficiency.

CONCLUSIONS: These results suggest an inverse relationship between metformin and concomitant ALA and metformin use and serum vitamin B12 concentration.

PMID:37302714 | DOI:10.1016/j.tjnut.2023.05.031

World Neurosurg. 2023 Jun 9:S1878-8750(23)00766-0. doi: 10.1016/j.wneu.2023.05.120. Online ahead of print.

ABSTRACT

BACKGROUND: Asia has a marked shortage of neurosurgical care, with approximately 2.5 million critical cases left untreated. The Young Neurosurgeons Forum (YNF) of the World Federation of Neurosurgical Societies (WFNS) surveyed Asian neurosurgeons to identify the of research, education, and practice.

METHODS: A cross-sectional study using a pilot-tested e-survey was circulated to the Asian neurosurgical community from April to November 2018. Descriptive statistics were used to summarize variables pertaining to demographics and neurosurgical practices. Chi square test was utilized to explore the relation between World Bank income level and variables on neurosurgical practices.

RESULTS: A total of 242 responses were analyzed. Respondents were mostly from the low- and middle-income countries (70%). Most represented institutions were teaching hospitals (53%). >50% of the hospitals had between 25-50 neurosurgical beds. Access to an operating microscope (p=0.038) or image guidance system (p=0.001) appeared to increase in correlation to a higher World Bank income level. Limited opportunities for conducting research (56%) and hands-on operating opportunities (45%) were leading challenges in daily academic practice. The leading challenges were limited numbers of intensive care unit beds (51%), inadequate or absent insurance coverage (45%), and lack of organized peri-hospital care (43%). Inadequate insurance coverage decreased with increasing World Bank income levels (p<0.001). Organized peri-hospital care (p=0.001), regular MRI access (p=0.032), and equipment necessary for microsurgery (p=0.007) increased with higher World Bank income levels.

CONCLUSION: Improving neurosurgical care hinges on regional and international collaboration and national policies to ensure universal access to essential neurosurgical care.

PMID:37302707 | DOI:10.1016/j.wneu.2023.05.120

Ophthalmol Retina. 2023 Jun 9:S2468-6530(23)00254-3. doi: 10.1016/j.oret.2023.06.003. Online ahead of print.

ABSTRACT

PURPOSE: To compare accuracy, precision, and residual volume of commonly used syringes for intravitreal injections (IVI), and to assess the intraocular pressure (IOP) rise by variations in volumes delivered.

DESIGN: Experimental lab study.

SUBJECTS: No subjects were involved in this study.

METHODS: We tested 8 syringe models with 2 different needle setups, with 2 different solutions (distilled water or glycerin) and target volumes (50 and 70 μL). To obtain the delivered and residual volumes, we weighed the syringe-needle setups with scale before liquid withdrawal, with liquid, and after liquid release. We also created an experimental eye model to determine the transient rise in IOP following stepwise 10-μL increases in injection volumes.

MAIN OUTCOME MEASURES: Delivered and residual volumes, IOP rise.

RESULTS: We tested a total of 600 syringe-needle setups. BD Ultra-Fine (0.34 ± 0.28 μL), Zero Residual (1.53 ± 1.15 μL) and Zero Residual Silicone Oil-free (1.40 ± 1.16 μL) syringes showed the lowest residual volume (p<0.001) in comparison to the others (range: 24.86 ± 1.78 μL for Injekt-F to 51.97 ± 3.37 μL for Omnifix-F). The most accurate setups were (percentage deviation from target volume): Zero Residual Silicone Oil-free (+0.70%), Zero Residual 0.3 mL (+4.49%), BD Ultra-Fine (+7.83%), Injekt-F (9.42%), Norm-Ject (+15.88%), Omnifix-F (+16.96%), BD Plastipak Brazil (+17.96%), and BD Plastipak Spain syringes (+19.41%). There was a statistically significant difference between the Zero Residual Silicone Oil-free syringe and all other syringes (p<0.0001), except for the Zero Residual 0.3 mL syringe (p=0.029). The coefficient of variation was low for all syringes. The modeled IOP rise ranged from 32.3 (SD 1.4) mmHg for 20-μL injection volume to 76.5 (SD 1.0) mmHg for 80-μL injection volume. For the standard 50-μL injection volume, the peak pressure was 50.7 (SD 0.1) mmHg, and the pressure rise duration was 28 (SD 2) minutes.

CONCLUSIONS: There were significant differences in accuracy and residual volume between syringes, whereas they showed a high precision. Volume excess results in a considerable increase in IOP rise following injection. These findings may provide a relevant overview to clinicians and to both device and drug manufacturers regarding pharmacoeconomic, safety and efficacy issues.

PMID:37302655 | DOI:10.1016/j.oret.2023.06.003

J Acad Nutr Diet. 2023 Jun 9:S2212-2672(23)00301-5. doi: 10.1016/j.jand.2023.06.003. Online ahead of print.

ABSTRACT

BACKGROUND: The Child and Adult Care Food Program (CACFP) is the primary national program that enables child care settings to provide healthy meals for children. Associations between CACFP participation and child health and development and health care utilization are understudied.

OBJECTIVE: To assess associations between children’s health, development, health care utilization and food security by meal source (child care-provided versus parent-provided) among children from low-income families with a child care subsidy attending child care in settings likely eligible to participate in CACFP.

DESIGN: The study used repeat cross-sectional surveys (new sample at successive time-points) conducted year-round.

PARTICIPANTS: /Setting: Primary caregivers of 3,084 young children accessing emergency departments (EDs) or primary care in Baltimore, Boston, Little Rock, Minneapolis, and Philadelphia were interviewed between 2010-2020. The sample was limited to children aged 13-48 months, receiving a child care subsidy and attending child care centers or family child care homes >20 hours per week.

MAIN OUTCOME MEASURES: Outcomes included household and child food security; child health, growth, and developmental risk; and admission to the hospital on the day of the ED visit.

STATISTICAL ANALYSES: Meal source and participant characteristics were analyzed using chi-square; associations of outcomes with parent-provided meals were analyzed with adjusted logistic regression.

RESULTS: The majority of children had child care-provided meals (87.2% child care-provided vs. 12.8% parent-provided). Compared to children with parent-provided meals, children with child care-provided meals had lower adjusted odds of living in a food-insecure household (AOR 0.70, [95%CI 0.55, 0.88]), being in fair or poor health (AOR 0.61, [95%CI 0.46, 0.81]), or hospital admission from the ED (AOR 0.59, [95%CI 0.41, 0.83]), with no differences in growth or developmental risk.

CONCLUSIONS: Compared to meals provided from home, child care provided meals likely supported by the Child and Adult Care Food Program (CACFP) is related to food security, early childhood health, and reduced hospital admissions from the ED among low-income families with young children.

PMID:37302653 | DOI:10.1016/j.jand.2023.06.003

Sci Total Environ. 2023 Jun 9:164804. doi: 10.1016/j.scitotenv.2023.164804. Online ahead of print.

ABSTRACT

Exposure to chemical contaminants found in foods has been associated with various adverse health effects. Burden of disease studies are increasingly used to estimate the public health impact of such exposures. The aims of this study were to estimate the burden of disease due to dietary exposure to four chemicals in France in 2019 (lead (Pb), cadmium (Cd), methylmercury (MeHg), and inorganic arsenic (i-As)), and to develop harmonized methods that can be applied for other chemicals and countries. We used national food consumption data from the third French national food consumption survey, chemical food monitoring data from the Second French Total Diet Study (TDS), dose-response data and disability weights from scientific literature, and disease incidence and demographics from national statistics. We adopted a risk assessment approach to estimate disease burden, incidence, mortality, and Disability-Adjusted Life Years (DALYs) attributable to dietary exposure to the chemicals. In all models, we harmonized food classification and exposure assessment. We propagated uncertainty through the calculations using Monte Carlo simulation. We estimated that, among these chemicals, i-As and Pb were responsible for the highest disease burden. i-As was estimated to cause 820 DALYs, or approximately 1.25 DALYs per 100,000 inhabitants. The estimated burden of Pb was 1834 to 5936 DALYs, or 2.7 (lower bound) to 8.96 (upper bound) DALYs/100,000. The burden of MeHg (192 DALYs), and Cd (0 DALY) was substantially lower. The foods contributing most to disease burden was drinks (30 %), “other foods” (mostly composite dishes) (19 %), and fish and seafood (7 %). Interpretation of estimates needs to consider all underlying uncertainties, linked with data and knowledge gaps. The harmonized models are the first to make use of data from TDS, which are available in several other countries. Thus, they can be applied to estimate the burden and to rank food-associated chemicals at national level.

PMID:37302596 | DOI:10.1016/j.scitotenv.2023.164804

Sci Total Environ. 2023 Jun 9:164700. doi: 10.1016/j.scitotenv.2023.164700. Online ahead of print.

ABSTRACT

Geographic location and meteorological factors can affect the content of bioaerosol concentrations. This study was conducted to determine the natural background concentrations of culturable fungal spores and dust particles in three different geographical areas. Focus was given to the dominant airborne genera Cladosporium, Penicillium, Aspergillus and the species Aspergillus fumigatus. The influence of weather conditions on the microorganism concentrations in urban, rural and mountain regions were examined. Possible correlations between particle counts and culturable fungal spore concentrations were investigated. 125 measurements of the air were conducted using the air sampler MAS-100NT® and the particle counter Alphasense OPC-N3. The analyses of the collected samples were based on culture methods using different media. The highest median of fungal spore concentrations was detected in the urban region and was of 2.0 × 10³ CFU/m³ for xerophilic fungi and 1.7 × 10³ CFU/m³ for the genus Cladosporium. The concentrations of fine and coarse particles in rural and urban regions were the highest of 1.9 × 10⁷ pa/m³ and 1.3 × 10⁷ pa/m³, respectively. Little cloud cover and slight wind had a positive influence on the concentration of fungal spores. Furthermore, correlations were observed between air temperature and the concentrations of xerophilic fungi as well as the genera Cladosporium. In contrast, relative humidity correlated negatively with total fungi and Cladosporium and no correlation was found with the other fungi. For the region of Styria in summer and early autumn, the natural background concentration for xerophilic fungi ranged between 3.5 × 10² and 4.7 × 10³ CFU/m³ air. No significant differences were detected between the fungal spore concentrations in urban, rural and mountainous regions. The data of this study could be used as a reference to compare the natural background concentrations of airborne culturable fungi in further studies concerning air quality assessment.

PMID:37302594 | DOI:10.1016/j.scitotenv.2023.164700

J Hepatol. 2023 Jun 9:S0168-8278(23)00399-9. doi: 10.1016/j.jhep.2023.05.027. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Machine perfusion is increasingly tested in clinical transplantation. Despite this success, the number of large prospective clinical trials remains limited. The aim of this study is therefore to compare the impact of machine perfusion on outcomes after liver transplantation versus static cold storage (SCS).

METHODS: A systematic search of MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials (CENTRAL) was conducted to identify randomized controlled trials (RCTs) reporting “posttransplant” outcomes of machine perfused livers compared to SCS. Data were pooled using random effect models. Risk ratios (RR) were calculated for relevant outcomes. The quality of evidence was rated using the GRADE-framework. PROSPERO-registration: CRD42022355252.

RESULTS: Seven RCTs were identified with hypothermic oxygenated (HOPE, n=4) and normothermic machine perfusion (NMP, n=3), including a total number of 1017 patients. Both techniques were associated with significantly lower rates of early allograft dysfunction (NMP: n=41/282; SCS: n=74/253; RR:0.50, 95%CI:0.30-0.86, p=0.01, I²:39%; HOPE: n=45/241; SCS: n=97/241, RR:0.48, 95%CI:0.35-0.65, p<0.00001, I²:5%). The HOPE-approach led to a significant reduction of major complications (Clavien Grade ≥IIIb; HOPE: n=90/241; SCS: n=117/241, RR: 0.76, 95%CI: 0.63-0.93, p=0.006, I²:0%), “retransplantation” (HOPE: n=1/163; SCS: n=11/163; RR:0.21, 95%CI: 0.04-0.96, p=0.04; I²:0%) and graft loss (HOPE: n=7/163; SCS: n=19/163; RR:0.40, 95%CI: 0.17-0.95, p=0.04; I²:0%). Both perfusion techniques were found to likely reduce overall biliary complications and non-anastomotic strictures.

CONCLUSIONS: Although this study provides the highest current evidence on the role of machine perfusion, outcomes remain limited to a one-year follow-up after liver transplantation. Comparative RCTs and large real world cohort studies with longer follow-up are required to enhance the robustness of the data further, thereby supporting the introduction of perfusion technologies in routine clinical practice.

PMID:37302578 | DOI:10.1016/j.jhep.2023.05.027