ABSTRACT
Despite widespread interest and substantial investment in the adoption of sensor-based digital health technologies (sDHTs) for remote data capture in drug development trials, no drug has been approved based on an sDHT-derived primary endpoint in the United States (US). One reason for this lack of advancement is the complexity of obtaining regulatory endorsement for those endpoints within current US regulatory pathways. The goal of our review is to describe the two choices currently available to pharmaceutical study Sponsors: (i) they may navigate the traditional route of compiling the evidence to support the sDHT-derived endpoint in their investigational new drug (IND) application, requiring specific expertise and substantial resources; or (ii) they may navigate the drug development tool (DDT) pathway with the goal of qualifying their sDHT-derived endpoint as a biomarker or clinical outcome assessment applicable to a broader context of use (COU), either alone or as part of a partnership or consortium. We describe the nuances of each pathway; the evidentiary requirements for supporting an sDHT-derived endpoint and the technology used to capture it; and the impact that an sDHT's regulatory status may have on a Sponsor's decision to use it for data capture. By systematically comparing the IND and DDT pathways, our over-arching goals are to support the increasing deployment of sDHTs within the clinical research setting and help advance regulatory science in the field of digital medicine.
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RATIONALE: The precision of the doubly labeled water (DLW) method is determined by the precision and accuracy of the isotopic measurements. Quality control (QC) procedures to mitigate sample variability require additional measurements if sample duplicates differ more than a factor of instrument precision. We explored the effect of widening QC ranges on total daily energy expenditure (TDEE) determined using the two-point sampling method. METHODS: We screened DLW data from 121 individuals for instances where samples were analyzed more than twice using our existing QC criteria (±2.0 per mil [δ] for 2H and ±0.5 δ for 18O). We then applied wider QC ranges for accepting duplicate measures and recalculated TDEE. RESULTS: Widening the 2H QC range to ±10.0 δ in samples collected on the first day (most enriched) and to ±5.0 δ in samples collected on the final day (less enriched) produced almost identical mean TDEE compared to the originally calculated TDEE (2684 ± 508 vs. 2687 ± 512 kcal/day, p = 0.40). There was a strong correlation with the originally calculated TDEE (r2 = 0.97, p < 0.001). CONCLUSIONS: Expanding the 2H QC range to ±10.0 δ for samples collected on the first day and ±5.0 δ for samples collected on the final day provides similar mean TDEE results. These findings may help DLW labs optimize QC criteria and reduce analytical costs.
ABSTRACT
The detection of magnetic nanoparticles in a liquid medium and the quantification of their concentration have the potential to improve the efficiency of several relevant applications in different fields, including medicine, environmental remediation, and mechanical engineering. To this end, sensors based on the magneto-impedance effect have attracted much attention due to their high sensitivity to the stray magnetic field generated by magnetic nanoparticles, their simple fabrication process, and their relatively low cost. To improve the sensitivity of these sensors, a multidisciplinary approach is required to study a wide range of soft magnetic materials as sensing elements and to customize the magnetic properties of nanoparticles. The combination of magneto-impedance sensors with ad hoc microfluidic systems favors the design of integrated portable devices with high specificity towards magnetic ferrofluids, allowing the use of very small sample volumes and making measurements faster and more reliable. In this work, a magneto-impedance sensor based on an amorphous Fe73.5Nb3Cu1Si13.5B9 wire as the sensing element is integrated into a customized millifluidic chip. The sensor detects the presence of magnetic nanoparticles in the ferrofluid and distinguishes the different stray fields generated by single-domain superparamagnetic iron oxide nanoparticles or magnetically blocked Co-ferrite nanoparticles.
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A series of structurally similar trinuclear macrocyclic copper(I) and silver(I) pyrazolate complexes bearing various short-bite diphosphine R2PCH(R')PR2 ligands are reported. Upon diphosphine coordination, the planar geometry of the initial complexes undergoes bending along the line between two metal atoms coordinated to the phosphorus moieties. The complexes based on dcpm ligands (R = cyclohexyl, R' = H, Ph) do not exhibit dynamic behavior in solution at room temperature on the 31P NMR time scale as it was previously observed for similar trinuclear copper complexes bearing the dppm (R = Ph, R' = H) scaffold. All copper(I) complexes exhibit thermally activated delayed fluorescence (TADF) behavior in the solid state. Importantly, the use of aliphatic substituents on the phosphorus atoms instead of aromatic ones leads to an almost double increase in the quantum efficiency (ΦPL) of photoluminescence by eliminating nonradiative decay from the 3LCPh states of the dppm aromatic rings. The higher donating ability of the substituents in the pyrazolate ligand (CF3 vs CH3) lowers the energy of the metal-centered excited state, allowing for a significant metal impact on the T1 state. Finally, the Ag(I) complex displays an emission efficiency of approximately 14%, being the highest among known trinuclear silver(I) pyrazolate homometallic derivatives.
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The present computational study provides a benchmark of density functional theory (DFT) methods in describing hydrogen evolution processes catalyzed by [Cp*Rh]-containing organometallic complexes. A test set was composed of 26 elementary reactions featuring chemical transformations and bonding situations essential for the field, including the emerging concept of non-innocent Cp* behavior. Reference values were obtained from a highly accurate 3/4 complete basis set and 6/7 complete PNO space extrapolated DLPNO-CCSD(T) energies. The performance of lower-level extrapolation procedures was also assessed. We considered 84 density functionals (DF) (including 13 generalized gradient approximations (GGA), nine meta-GGAs, 33 hybrids, and 29 double-hybrids) and three composite methods (HF-3c, PBEh-3c, and r2SCAN-3c), combined with different types of dispersion corrections (D3(0), D3BJ, D4, and VV10). The most accurate approach is the PBE0-DH-D3BJ (MAD of 1.36 kcal mol-1) followed by TPSS0-D3BJ (MAD of 1.60 kcal mol-1). Low-cost r2SCAN-3c composite provides a less accurate but much faster alternative (MAD of 2.39 kcal mol-1). The widely used Minnesota-family M06-L, M06, and M06-2X DFs should be avoided (MADs of 3.70, 3.94, and 4.01 kcal mol-1, respectively).
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Immunotherapies have demonstrated limited clinical efficacy in malignant mesothelioma treatment. We conducted multiplex immunofluorescence analyses on tissue microarrays (n = 3) from patients with malignant pleural mesothelioma (MPM, n = 88) and malignant peritoneal mesothelioma (MPeM, n = 25). Our study aimed to elucidate spatial distributions of key immune cell populations and their association with lymphocyte activation gene 3 (LAG3), BRCA1-associated protein 1 (BAP1), neurofibromatosis type 2 (NF2), and methylthioadenosine phosphorylase (MTAP), with MTAP serving as a cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/B) surrogate marker. Additionally, we examined the relationship between the spatial distribution of major immune cell types and prognosis and clinical characteristics of patients with malignant mesothelioma. We observed a higher degree of interaction between immune cells and tumor cells in MPM compared with MPeM. Notably, within MPM tumors, we detected a significantly increased interaction between tumor cells and CD8+ T cells in tumors with low BAP1 expression compared with those with high BAP1 expression. To support the broader research community, we have developed The Human Spatial Atlas of Malignant Mesothelioma, containing hematoxylin and eosin and multiplex immunofluorescence images with corresponding metadata. SIGNIFICANCE: Considering the limited therapeutic options available to patients with malignant mesothelioma, there is substantial translational potential in understanding the correlation between the spatial architecture of the malignant mesothelioma tumor immune microenvironment and tumor biology. Our investigation reveals critical cell-cell interactions that may influence the immune response against malignant mesothelioma tumors, potentially contributing to the differential behaviors observed in MPM and MPeM. These findings represent a valuable resource for the malignant mesothelioma cancer research community.
Subject(s)
Mesothelioma, Malignant , Mesothelioma , Peritoneal Neoplasms , Pleural Neoplasms , Purine-Nucleoside Phosphorylase , Tumor Microenvironment , Ubiquitin Thiolesterase , Humans , Tumor Microenvironment/immunology , Mesothelioma, Malignant/immunology , Mesothelioma, Malignant/pathology , Pleural Neoplasms/immunology , Pleural Neoplasms/pathology , Male , Female , Peritoneal Neoplasms/immunology , Peritoneal Neoplasms/pathology , Purine-Nucleoside Phosphorylase/metabolism , Purine-Nucleoside Phosphorylase/genetics , Middle Aged , Ubiquitin Thiolesterase/metabolism , Mesothelioma/immunology , Mesothelioma/pathology , Aged , Tumor Suppressor Proteins/metabolism , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Neurofibromin 2/genetics , Biomarkers, Tumor , Prognosis , Antigens, CD , CD8-Positive T-Lymphocytes/immunologyABSTRACT
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease. Global Burden of Disease (GBD) data from 1990 to 2019 reported a rise in prevalence (9-13%) in Australia, which also ranked third highest for NAFLD prevalence compared to 14 similar countries. As a result of underdiagnosis, NAFLD burden is underestimated by GBD.
Subject(s)
Global Burden of Disease , Non-alcoholic Fatty Liver Disease , Non-alcoholic Fatty Liver Disease/epidemiology , Humans , Australia/epidemiology , Prevalence , Male , Female , Cost of Illness , Middle Aged , AdultABSTRACT
OBJECTIVE: Explore the experiences of people with knee osteoarthritis (OA) who received a very low energy diet (VLED) and exercise program from a physiotherapist. METHODS: Mixed methods study involving questionnaires (n = 42) and semistructured interviews (n = 22) with randomized control trial participants with knee OA who had received a 6-month physiotherapist-delivered VLED weight loss and exercise intervention. Questionnaires measured participant satisfaction and perceptions about physiotherapist's skills/knowledge in delivery of the dietary intervention (measured on 5-7 point Likert scales). Interviews explored participant's experiences and were analyzed based on the principles of reflexive thematic analysis. RESULTS: Questionnaire response: 90%. Participants were satisfied with the program (95%), confident their physiotherapist had the required skills (84%) and knowledge (79%) to deliver the dietary intervention, felt comfortable talking to the physiotherapist about weight (74%), and would recommend others see a physiotherapist for the intervention they undertook (71%). The following four themes were developed from the interviews: (1) one-stop-shop of exercise and diet; (2) physiotherapist-delivered weight loss works (unsure initially; successfully lost weight); (3) physiotherapists knowledge and skills (exercise is forte; most thought physiotherapists had the necessary weight loss skills/knowledge, but some disagreed); and (4) physiotherapists have a role in weight loss (physiotherapists are intelligent, credible, and trustworthy; specific training in weight loss necessary). CONCLUSION: This study provides, to our knowledge, the first documented perspectives from people with OA who have received a physiotherapist-delivered weight loss intervention. Findings suggest physiotherapists may have a role in delivering a protocolized dietary intervention for some people with knee OA with overweight and obesity.
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Hepatitis B virus (HBV) is an obligate human hepatotropic DNA virus causing both transient and chronic infection. The livers of chronic hepatitis B patients have a high risk of developing liver fibrosis, cirrhosis, and hepatocellular carcinoma. The nuclear episomal viral DNA intermediate, covalently closed circular DNA (cccDNA), forms a highly stable complex with host and viral proteins to serve as a transcription template and support HBV infection chronicity. Thus, characterization of the composition and dynamics of cccDNA nucleoprotein complexes providing cccDNA stability and gene regulation is of high importance for both basic and medical research. The presented method for chromatin immunoprecipitation coupled with qPCR (ChIP-qPCR) allows to assess provisional physical interaction of the protein of interest (POI) with cccDNA using POI-specific antibody, the level of enrichment of a POI on cccDNA versus control/background is characterized quantitatively using qPCR.
Subject(s)
Chromatin Immunoprecipitation , DNA, Circular , DNA, Viral , Hepatitis B virus , Hepatitis B virus/genetics , DNA, Circular/genetics , DNA, Circular/metabolism , Humans , DNA, Viral/genetics , Chromatin Immunoprecipitation/methods , Real-Time Polymerase Chain Reaction/methods , Hepatitis B/virology , Hepatitis B/geneticsABSTRACT
This systematic review assesses the knowledge, attitudes, and behaviors (KAB) surrounding dietary fat intake among people with type 2 diabetes mellitus (T2DM) and healthcare professionals. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, four databases were searched to identify studies published between 1995 and 2023 reporting people with T2DM or healthcare professionals that measured KAB towards dietary fat. This work was registered at PROSPERO (CRD42020140247). Twenty-four studies were included. Studies assessed knowledge of people with T2DM and reported poor nutrition knowledge regarding the health effect of fat consumption. Two opposing attitudes towards dietary fat was reported: (1) dietary fat should be limited, (2) promoted dietary fat intake through a low-carbohydrate diet. Participants reported behaviors of limiting fat intake, including trimming visible fat or choosing lower-fat alternatives. Total fat intake ranged between 10 and 66% of participants' total energy intake, while saturated fat intake ranged between 10 and 17%. People with T2DM reported poor knowledge of dietary fats in particular, and they were frequently unable to identify high-fat food. Attitudes towards dietary fat were heterogenous, and regarding behaviors, saturated fat intake was higher than recommended. Future studies should assess the KAB of people with T2DM based on dietary fat subtypes.
Subject(s)
Diabetes Mellitus, Type 2 , Dietary Fats , Health Knowledge, Attitudes, Practice , Humans , Diabetes Mellitus, Type 2/psychology , Diabetes Mellitus, Type 2/diet therapy , Dietary Fats/administration & dosage , Female , Male , Middle Aged , Feeding Behavior/psychology , AdultABSTRACT
The formation of an aneurysm in the false lumen (FL) is a long-term complication in a significant percentage of type B aortic dissection (AD) patients. The ability to predict which patients are likely to progress to aneurysm formation is key to justifying the risks of interventional therapy. The investigation of patient-specific hemodynamics has the potential to enable a patient-tailored approach to improve prognosis by guiding disease management for type B dissection. CFD-derived hemodynamic descriptors and geometric features were used to retrospectively assess individual aortas for a population of residual type B AD patients and analyze correlations with known outcomes (i.e., rapid aortic growth, death). The results highlight great variability in flow patterns and hemodynamic descriptors. A rapid aortic expansion was found to be associated with a larger FL. Time-averaged wall shear stress at the tear region emerged as a possible indicator of the dynamics of flow exchange between lumens and its effect on the evolution of individual aortas. High FL flow rate and tortuosity were associated with adverse outcomes suggesting a role as indicators of risk. AD induces complex changes in vessel geometry and hemodynamics. The reported findings emphasize the need for a patient-tailored approach when evaluating uncomplicated type B AD patients and show the potential of CFD-derived hemodynamics to complement anatomical assessment and help disease management.
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Enzymatic transglycosylation of the fleximer base 4-(4-aminopyridine-3-yl)-1H-pyrazole using recombinant E. coli purine nucleoside phosphorylase (PNP) resulted in the formation of "non-typical" minor products of the reaction. In addition to "typical" N1-pyrazole nucleosides, a 4-imino-pyridinium riboside and a N1-pyridinium-N1-pyrazole bis-ribose derivative were formed. N1-Pyrazole 2'-deoxyribonucleosides and a N1-pyridinium-N1-pyrazole bis-2'-deoxyriboside were formed. But 4-imino-pyridinium deoxyriboside was not formed in the reaction mixture. The role of thermodynamic parameters of key intermediates in the formation of reaction products was elucidated. To determine the mechanism of binding and activation of heterocyclic substrates in the E. coli PNP active site, molecular modeling of the fleximer base and reaction products in the enzyme active site was carried out. As for N1-pyridinium riboside, there are two possible locations for it in the PNP active site. The presence of a relatively large space in the area of amino acid residues Phe159, Val178, and Asp204 allows the ribose residue to fit into that space, and the heterocyclic base can occupy a position that is suitable for subsequent glycosylation. Perhaps it is this "upside down" arrangement that promotes secondary glycosylation and the formation of minor bis-riboside products.
Subject(s)
Escherichia coli , Purine-Nucleoside Phosphorylase , Purine-Nucleoside Phosphorylase/metabolism , Purine-Nucleoside Phosphorylase/chemistry , Purine-Nucleoside Phosphorylase/genetics , Glycosylation , Escherichia coli/genetics , Escherichia coli/enzymology , Escherichia coli/metabolism , Recombinant Proteins/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Catalytic Domain , Nucleosides/chemistry , Nucleosides/metabolism , Models, MolecularABSTRACT
Despite the significance of H2O2-metal adducts in catalysis, materials science and biotechnology, the nature of the interactions between H2O2 and metal cations remains elusive and debatable. This is primarily due to the extremely weak coordinating ability of H2O2, which poses challenges in characterizing and understanding the specific nature of these interactions. Herein, we present an approach to obtain H2O2-metal complexes that employs neat H2O2 as both solvent and ligand. SnCl4 effectively binds H2O2, forming a SnCl4(H2O2)2 complex, as confirmed by 119Sn and 17O NMR spectroscopy. Crystalline adducts, SnCl4(H2O2)2·H2O2·18-crown-6 and 2[SnCl4(H2O2)(H2O)]·18-crown-6, are isolated and characterized by X-ray diffraction, providing the complete characterization of the hydrogen bonding of H2O2 ligands including geometric parameters and energy values. DFT analysis reveals the synergy between a coordinative bond of H2O2 with metal cation and its hydrogen bonding with a second coordination sphere. This synergism of primary and secondary interactions might be a key to understanding H2O2 reactivity in biological systems.
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Epithelial ovarian cancer (EOC) has a low overall survival rate, largely due to frequent recurrence and acquiring resistance to platinum-based chemotherapy. EOC with homologous recombination (HR) deficiency has increased sensitivity to platinum-based chemotherapy because platinum-induced DNA damage cannot be repaired. Mutations in genes involved in the HR pathway are thought to be strongly correlated with favorable response to treatment. Patients with these mutations have better prognosis and an improved survival rate. On the other hand, mutations in non-HR genes in EOC are associated with increased chemoresistance and poorer prognosis. For this reason, accurate predictions in response to treatment and overall survival remain challenging. Thus, analyses of 360 EOC cases on NCI's The Cancer Genome Atlas (TCGA) program were conducted to identify novel gene mutation signatures that were strongly correlated with overall survival. We found that a considerable portion of EOC cases exhibited multiple and overlapping mutations in a panel of 31 genes. Using logistical regression modeling on mutational profiles and patient survival data from TCGA, we determined whether specific sets of deleterious gene mutations in EOC patients had impacts on patient survival. Our results showed that six genes that were strongly correlated with an increased survival time are BRCA1, NBN, BRIP1, RAD50, PTEN, and PMS2. In addition, our analysis shows that six genes that were strongly correlated with a decreased survival time are FANCE, FOXM1, KRAS, FANCD2, TTN, and CSMD3. Furthermore, Kaplan-Meier survival analysis of 360 patients stratified by these positive and negative gene mutation signatures corroborated that our regression model outperformed the conventional HR genes-based classification and prediction of survival outcomes. Collectively, our findings suggest that EOC exhibits unique mutation signatures beyond HR gene mutations. Our approach can identify a novel panel of gene mutations that helps improve the prediction of treatment outcomes and overall survival for EOC patients.
Subject(s)
Carcinoma, Ovarian Epithelial , Mutation , Neoplasms, Glandular and Epithelial , Ovarian Neoplasms , Humans , Ovarian Neoplasms/genetics , Ovarian Neoplasms/mortality , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Female , Carcinoma, Ovarian Epithelial/genetics , Carcinoma, Ovarian Epithelial/mortality , Carcinoma, Ovarian Epithelial/pathology , Neoplasms, Glandular and Epithelial/genetics , Neoplasms, Glandular and Epithelial/mortality , Neoplasms, Glandular and Epithelial/drug therapy , Neoplasms, Glandular and Epithelial/pathology , Prognosis , Middle Aged , Aged , RNA Helicases , Fanconi Anemia Complementation Group ProteinsABSTRACT
We study the influence of core-shell morphology on the structural characteristics of nanogels. Using computer simulations, we examine three different types of systems, distinguished by their intermonomer interactions: those with excluded volume only; those with charged monomers and excluded volume; and those with excluded volume combined with a certain number of magnetised nanoparticles incorporated within the nanogel. We observe that if the polymers in the shell are short and dense, they tend to penetrate the core. This effect of backfolding is enhanced in charged nanogels, regardless of whether all monomers are charged, or only the core or shell ones. The presence of an experimentally available amount of magnetic nanoparticles in a gel, on the one hand, does not lead to any significant morphological changes. On the other hand, the morphology of the nanogel with magnetic particles has an impact on its magnetic susceptibility. Particular growth of the magnetic response is observed if a long shell of a nanogel is functionalised.
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Wildfire smoke (WFS) is an urgent and rapidly growing threat to global health. Aside from obvious threats to pulmonary function, increases in cardiac abnormalities or myocardial infarction have been documented during WF season, but little is known about the effects of WFS on cardiovascular health. We investigated the effect of nonoccupational WFS exposure on cardiovascular and pulmonary function at rest and during graded handgrip exercise through a case series of young, healthy adults (n = 4, 25 ± 6 years) assessed after ≥3 days of bad or good air quality. Peripheral and estimated central blood pressures, vascular stiffness, and microvascular function (Near infrared spectroscopy, NIRS) were assessed at rest, and during rhythmic handgrip exercise. WFS did not appear to alter resting peripheral, central BP, or vascular stiffness (all, p > 0.05). Slope 1 and slope 2 from the NIRS-vascular occlusion test (NIRS-VOT) were not different between conditions (p > 0.05). The change in SmO2 during exercise was lower (p = 0.02, η p 2 $$ {\eta}_{\mathrm{p}}^2 $$ = 0.62) with bad air quality. These preliminary findings suggest modest effects of environmental WFS exposure on muscle microvascular function during exercise in healthy adults. Future work is needed to elucidate the physiological changes with WFS exposure and the increased risk of cardiovascular events, perhaps exacerbated through physical activity.
Subject(s)
Exercise , Hand Strength , Smoke , Wildfires , Humans , Hand Strength/physiology , Adult , Male , Smoke/adverse effects , Female , Exercise/physiology , Environmental Exposure/adverse effects , Microcirculation/physiology , Microcirculation/drug effects , Young Adult , Oxygen Consumption/physiology , Vascular Stiffness , Spectroscopy, Near-Infrared , Blood PressureABSTRACT
Pathogenic variants in the FKBP10 gene lead to a spectrum of rare autosomal recessive phenotypes, including osteogenesis imperfecta (OI) Type XI, Bruck syndrome Type I (BS I), and the congenital arthrogryposis-like phenotype (AG), each with variable clinical manifestations that are crucial for diagnosis. This study analyzed the clinical-genetic characteristics of patients with these conditions, focusing on both known and newly identified FKBP10 variants. We examined data from 15 patients, presenting symptoms of OI and joint contractures. Diagnostic methods included genealogical analysis, clinical assessments, radiography, whole exome sequencing, and direct automated Sanger sequencing. We diagnosed 15 patients with phenotypes due to biallelic FKBP10 variants-4 with OI Type XI, 10 with BS I, and 1 with the AG-like phenotype-demonstrating polymorphism in disease severity. Ten pathogenic FKBP10 variants were identified, including three novel ones, c.1373C>T (p.Pro458Leu), c.21del (p.Pro7fs), and c.831_832insCG (p.Gly278Argfs), and a recurrent variant, c.831dup (p.Gly278Argfs). Variant c.1490G>A (p.Trp497Ter) was found in two unrelated patients, causing OI XI in one and BS I in the other. Additionally, two unrelated patients with BS I and epidermolysis bullosa shared identical homozygous FKBP10 and KRT14 variants. This observation illustrates the diversity of FKBP10-related pathology and the importance of considering the full spectrum of phenotypes in clinical diagnostics.