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The US Food and Drug Administration supports innovations to facilitate new indications for high-risk human papillomavirus testing. This report describes the retrospective testing of stored specimens and analysis of existing data to efficiently and cost-effectively support a new indication for the Onclarity human papillomavirus assay (Becton, Dickinson and Company, BD Life Sciences - Integrated Diagnostic Solutions, Sparks, MD). The performance of this index test was compared with that of a predicate test, the cobas human papillomavirus assay (Roche Diagnostics, Indianapolis, IN). Both human papillomavirus assays are based on real-time polymerase chain reaction platforms that detect the presence of 14 high-risk human papillomavirus genotypes. The predicate assay reports human papillomavirus types 16 and 18 as individual results and the other 12 human papillomavirus genotypes as 1 pooled result. The index assay reports 9 independent results (human papillomavirus types 16, 18, 31, 33/58, 35/39/68, 45, 51, 52, and 56/59/66). Both the index and predicate assays are approved by the Food and Drug Administration for cervical cancer screening, but at the time that this study was initiated, the index human papillomavirus assay was not approved for use with cervical specimens collected in PreservCyt (Hologic, Inc, San Diego, CA) liquid-based cytology media. The performance of the index human papillomavirus assay was compared with that of the predicate human papillomavirus assay for the detection of cervical intraepithelial neoplasia grades 2 or greater and 3 or greater (≥CIN2 or ≥CIN3) using PreservCyt liquid-based cytology specimens collected from women aged 21 to 65 years. In addition, the ability of the index test's extended genotyping to stratify ≥CIN2 and ≥CIN3 risks, using these specimens, was evaluated. The New Mexico HPV Pap Registry was used to select an age- and cytology-stratified random sample of 19,879 women undergoing opportunistic cervical screening and follow-up in routine clinical practice across New Mexico. A subset (n = 4820) of PreservCyt specimens was selected from 19,879 women for paired testing by the index and predicate human papillomavirus assays within age and cytology strata and included women with or without cervical biopsy follow-up. Point estimate differences and ratios were calculated for cervical disease detection and positivity rates, respectively, with 95% confidence intervals to determine statistical significance. The cumulative risk of ≥CIN2 or ≥CIN3, with up to 5-year follow-up, was estimated for the index assay using Kaplan-Meier methods. The 5-year cumulative ≥CIN3 detection rates were 5.6% for the index assay and 4.6% for the predicate assay (difference, 1.0%; 95% confidence interval, 0.5%–1.5%). The ≥CIN3 positivity rates within <1 year were 95.3% for the index assay and 94.5% for the predicate assay (ratio, 1.01; 95% confidence interval, 0.98–1.06). The ≥CIN3 cumulative positivity rates for the index and predicate assays were also similar at 5 years. Among cases of ≥CIN3, the positive agreement rates between the index and predicate assays for human papillomavirus types 16 and 18 were 100.0% (95% confidence interval, 95.0%–100.0%) and 90.9% (95% confidence interval, 62.3%–98.4%), respectively. Human papillomavirus type 16 carried the highest ≥CIN2 or ≥CIN3 risk, followed by human papillomavirus types 18/31/33/58/52/45 and human papillomavirus types 35/56/59/51/56/59/66. The index and predicate human papillomavirus assays demonstrated equivalent performance, and extended human papillomavirus genotyping, using the index assay, provided effective ≥CIN2 and ≥CIN3 risk stratification, supporting a new indication for use of the index assay with PreservCyt. [ABSTRACT FROM AUTHOR]

To identify the status quo and key influencing factors of family resilience in cancer treatment. Eight electronic databases (PubMed, Cochrane Library, Embase, CINAHL, Web of Science, CNKI, Wan Fang Database, VIP Database) were searched from 2000 to 10 May 2023. Inclusion criteria were the following: (a) study subjects were cancer patients or their family caregivers, (b) family resilience was measured as a variable, (c) reported factors associated with family resilience, (d) employed either quantitative or mixed methods design, (e) written in English or Chinese, (f) published in peer-reviewed journals. All included studies were evaluated for quality using the Mixed Method Appraisal Tool. Thirty studies were included in the systematic review. According to our analysis, the family resilience of cancer patients could be influenced by various factors associated with six clusters: (a) demographic characteristics, (b) severe staging and treatment of cancer, (c) psychological and health statuses, (d) family, and (e) social environment. Meanwhile, several specific protective factors and risk factors of family resilience were also identified. Family resilience plays an important role in promoting positive adaptation in the face of adversity in families of cancer patients/caregivers. This study classifies related influencing factors by analyzing both protective factors and risk factors (and some controversial factors of family resilience). We found that longitudinal studies are needed to further verify the dynamic changes of family resilience, and future research should focus on understanding family resilience from the dual perspectives of cancer patients and their caregivers, to provide comprehensive information for health professionals, and facilitate the development of effective family resilience intervention programs. • Age and disease duration on family resilience remains somewhat controversial. • A certain interaction (dyadic effect) between cancer patients and their spouses. • Multi-angle investigations of cancer patients and their caregivers should be carried out to understand the family resilience of different cancer patients from a dual perspective. • This work focuses on the family resilience of cancer patients to provide references and new perspectives for cancer management. [ABSTRACT FROM AUTHOR]

• Platelet glycoprotein Ibα (GPIbα) dysfunction enhances radiation lethality in mice. • GPIbα dysfunction reduces platelet–leukocyte aggregation before/after irradiation. • GPIbα dysfunction increases monocyte activation and gut damage following radiation. • GPIbα dysfunction increases serum cytokine levels following radiation. Platelet membrane glycoprotein Ibα (GPIbα), the major ligand-binding subunit of the GPIb-IX–V complex, binds to a number of ligands contributing to hemostasis, thrombosis, and inflammation. Binding to von Willebrand factor (VWF) initiates the process of hemostasis/thrombosis, while binding to the leukocyte receptor Macrophage-1 antigen (Mac-1) has been implicated in modulating the inflammatory response. Thus as GPIbα resides at the nexus of thrombosis and inflammation, we investigated the impact of GPIbα on radiation injury outcomes as this injury triggers both the thrombotic and inflammatory pathways. We used wild-type (WT) C57BL/6J mice and a dysfunctional GPIbα mouse model, in which endogenous GPIbα is replaced with a non-functional α-subunit (hIL-4R/Ibα), to determine whether the impairment of platelet GPIbα alters radiation response. Following exposure to 8.5 Gy total body irradiation (TBI), a series of parameters including radiation lethality, platelet–neutrophil/monocyte interactions, neutrophil/monocyte activation, serum cytokine levels and intestinal injury, were compared between the strains. The lack of functional GPIbα resulted in higher radiation lethality, greater monocyte activation, increased levels of serum pro-inflammatory cytokines, heightened intestinal damage, and a reduction of intestinal neutrophil recovery. These data suggest that loss of platelet GPIbα enhances radiation toxicity and that GPIbα-mediated interactions may play a crucial role in limiting radiation damage. Thus, a mechanistic understanding of the biological impact of GPIbα following TBI could provide crucial insights for improving the safety of radiotherapy and minimizing the deleterious effects of accidental or occupational exposure to high-dose radiation. [ABSTRACT FROM AUTHOR]

• A classification method was established based on the functional parameters of powder; • w , a , k G , y 0 , k a , k b , b , k FES , k E3 are considered as key functional parameters; • The properties of each category of powder were analyzed in detail; • b is considered the most critical functional parameter affecting tablet quality; • In addition, w , k a , k G , and a related parameter affect the qualities of the tablet. Direct compaction (DC) is the ideal method for tablet production. However, DC requires the highest quality powder functional properties, such as good flowability, compressibility, compactibility, and appropriate elasticity. In the present study, 24 types of natural plant product (NPP) powders, prepared using three commonly used methods, and 18 types of fillers were evaluated for their fundamental and functional properties. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were used to classify the powders and analyze the characteristics of each category of powder, based on functional properties. Partial least squares (PLS) regression models were established to predict the tensile strength (TS), ejection force (EF), disintegration time (DT), and solid fraction (SF) based on the powder's functional properties. The results show that: (i) Except for the direct pulverization powder, the fundamental properties among the NPP powders were similar; however, the functional properties were quite different; (ii) The powders could be classified well based on their functional parameters (w , a , k G , y 0 , k a , k b , b , k FES , k E3). The order of powders suitable for DC is Group 4 > Group 5 > Group 2 > Group 3 > Group 1; (iii) The compressibility and compactibility of the powder are beneficial to the TS and EF of the tablet. The compressibility of the powders correlated negatively with DT; nevertheless, the compactibility correlated positively with DT and SF. The true density (ρ true), median particle size (D 0.5) of the powders correlated negatively with SF. Overall, this study systematically evaluated the properties of commonly used NPP powders and fillers and found the key properties that affect the quality of tablets. [ABSTRACT FROM AUTHOR]

Highlights • P75 regulated α-syn expression. • Dysregulation of siAH interacted with p75. • P75 controlled nuclear expression of p65. Abstract For Parkinson’s disease (PD), the regulatory mechanism of α-synuclein (α-syn) aggregation remains to be clarified. Ubiquitination modification is crucial for α-syn aggregation, with implications for Lewy body formation. Besides, ubiquitin ligase absentia homolog (siAH) is involved in the ubiquitination of α-syn. We investigated whether the p75 receptor can act as a potential regulator of α-syn accumulation through ubiquitination. Western blot, immunoprecipitation, gene transfection, and RNA interference technology were employed to detect the effect of p75 in in vivo and in vitro models. In a rotenone-based stereotactic (ST) infusion in vivo model of PD, p75 receptor and siAH expression was increased significantly compared with the control group. In cellular models of rotenone-mediated neurotoxicity, the interactions between p75 and siAH were revealed by immunoprecipitation; the colocalization of p75 with α-syn was observed in the cytoplasm; p75 promoted nuclear expression of NF-κB (p65), which might interact with the promoter of the siAH gene. Moreover, siRNA-mediated p75 depletion reduced the upregulation of α-syn and nuclear expression of p65 and protected against cell apoptosis induced by rotenone. Thus, aberrant expression of p75 may regulate the increased expression of α-syn, which is related to siAH-mediated ubiquitination and nuclear expression of p65. [ABSTRACT FROM AUTHOR]

Contamination of soil and water by waste from abandoned uranium mines has led to chronic exposures to metal mixtures in Native American communities. Our previous work demonstrated that community exposures to mine waste increase the likelihood of developing cardiovascular disease, as well as the likelihood of developing multiple chronic diseases including diabetes, hypertension and kidney disease. Exposure to various environmental metals is associated with elevated oxidative stress, which is considered a contributor to these and other chronic disease states. The purpose of the current research was to assess potential associations between exposure to uranium and arsenic and evidence for increased oxidative stress as measured by urinary F 2 -isoprostanes in pregnant women enrolled in the Navajo Birth Cohort Study. The current study also included an analysis of zinc as a potential mediator of oxidative stress in the study population. Urinary arsenic and uranium, serum zinc and urinary F 2 -isoprostanes were measured for each study participant at enrollment. Study participants were pregnant women with median age of 26.8; 18.9% were enrolled in the 1st trimester, 44.7% were enrolled in the 2nd trimester, and 36.4% were enrolled in the 3 rd trimester. Median urinary metal levels were 5.5 and 0.016 µg/g creatinine for arsenic and uranium, respectively. Multivariable regression analysis indicated a significant association between arsenic exposure and the lipid peroxidation product 8-iso-prostaglandin F 2α, controlling for zinc and trimester. No associations were detected with uranium despite evidence that levels were in the Navajo Birth Cohort samples were 2.3 times the median reported for women in the National Health and Nutrition Examination Survey (2011-12). Zinc was not found to have any causal mediation of the effects of the other metals on oxidative stress. The current work is consistent with other studies that have detected an association between arsenic and elevated oxidative stress. In contrast to arsenic, uranium did not appear to increase oxidative stress response in this study population. These findings are relevant to assessing the potential human impact of chronic exposure to mixed metal waste from abandoned uranium mines. [ABSTRACT FROM AUTHOR]

A new parameter named Strain/Stress Max was found to be highly relevant to tablet friability. A design space was developed to achieve <1% tablet friability at various combinations of Strain/Stress Max and tensile strength. [Display omitted] • The tablet quality attributes and texture performances of five excipients were studied systematically. • A new parameter highly relevant to tablet friability, named Strain/Stress Max, was discovered. • Strain/Stress Max was directly obtained from the diametrical breaking test. • Tablet friability values of binary mixtures were satisfactorily predicted through the constructed correlation model. • A design space of <1% tablet friability was constructed based on Strain/Stress Max and tensile strength. In this paper, a new parameter highly relevant to tablet friability is proposed based on a systematical study of the tablet quality attributes and texture performances of five different direct compression excipients, including microcrystalline cellulose, starch, lactose, mannitol, and dicalcium phosphate anhydrous. The new parameter, named Strain/Stress Max, could indicate the tablet's ability against external force to maintain integrity. It was directly obtained from the diametrical breaking test which is extensively used to assess tablet mechanical strength, and thus no extra work is required. The values varied significantly among the tablets formed by materials with different mechanical properties under the same compression pressure. A design space was developed to achieve <1% tablet friability at various combinations of Strain/Stress Max and tensile strength. Additionally, data from binary mixture tablets validated the availability of the constructed design space. And the upper limit of Strain/Stress Max value was advisable for 1.5 MPa−1 for pharmaceutical tablets. In conclusion, the new parameter and design space are available for fast identification of the tablets with acceptable friability to facilitate the development of tablet formulation using as few active pharmaceutic ingredients as possible. [ABSTRACT FROM AUTHOR]

[Display omitted] • A high-dose, high-hydrophobicity API was used for HSWG. • Failure Modes and Effect Analysis was used to evaluate CPPs and CQAs in detail. • Evaluated the influence of process variables on granule and tablet properties. • Combination of QbD and MVA provides a paradigm for HSWG–based product development. High shear wet granulation (HSWG), as a widely used granulation technology, has been studied extensively. However, for the HSWG of formulations containing hydrophobic components, the influence of process variables on the properties of granules and tablets has not been reported. In the present study, based on a combination of quality by design and multivariate analysis (MVA) approaches, quercetin with high-dose and high-hydrophobicity was used to study the relationship between process variables, granule properties, and tablet properties in HSWG systematically. Control and response variables were determined using risk assessment. The optimal fitting empirical models established by Box-Behnken design showed that the liquid to solid ratio and impeller speed were the most important factors, which affected all product properties except Carr's index and yield pressure. Instead, the influence of wet massing time was relatively small (only the effects on yield, granule size, granule hardness, and compression ratio were significant). Then, the process design space was obtained by limiting the related critical quality attributes, which was verified effectively. Scanning electron microscope images showed that smooth granules were produced using higher process parameters, whereas rough and porous granules resulted at lower process parameters. Furthermore, the MVA results demonstrated that increasing the granule hardness led to an increase in the compression ratio and a decrease in tensile strength of the tablets. Tablet fragility and disintegration time were mainly affected by granule density and bulk density, respectively, and both were negatively correlated. The established research paradigm is not only conducive to the successful development of quercetin products, but also provides valuable guidance for improving HSWG–based product development with such formulation characteristics. [ABSTRACT FROM AUTHOR]