Granuloma annulare and possible relation to purified protein derivative administration: a case report.

BACKGROUND: Granuloma annulare is a noninfectious inflammatory granulomatous skin disease characterized by an erythematous or skin colored annulare plaque. The diagnosis of granuloma annulare may be challenging owing to its diverse morphology. In such cases, a correlation between the clinical findings and histologic findings are necessary. CASE PRESENTATION: We report a case of granuloma annulare after purified protein derivative administration. A 56-year-old Caucasian female patient complained of mildly pruritic rashes which started on both arms and lower extremities, and eventually spread to both thighs, the left popliteal region, left upper back, and the right abdominal area. About 6 weeks prior to the eruption of the rashes, the patient had been given a purified protein derivative tuberculin skin test. Biopsy specimens revealed dermal histiocytes palisading around areas of mucin and degenerated collagen, confirming granuloma annulare. After treatment with 0.1% topical triamcinolone acetanide and 500 mg oral metronidazole, the patient's lesions resolved. DISCUSSION: Relatively little is known about granuloma annulare's exact etiology. Granuloma annulare has four variations presenting as either localized, generalized, subcutaneous, or perforating and patch granuloma annulare. The clinical prognosis for granuloma annulare varies according to clinical subtypes. Proposed causal mechanisms of subcutaneous granuloma annulare include physical trauma, infections, immunizations, insect bites, diabetes mellitus, and alterations in the cell-mediated immune responses. The disease likely has an inflammatory component. Clinically, granuloma annulare may be confused with many other skin diseases. CONCLUSION: This case of subcutaneous granuloma annulare was reported since it is a rare dermatologic pathological condition that can be confused with other skin rash disorders. Although it is a benign self-limited disease, definitive diagnosis is important to rule out other pathologies with similar clinical appearances, such as cancer or human immunodeficiency virus (HIV) infection. Diagnostic confirmation is best made through skin biopsy.

Achieving Bone Healing Non-Operatively in Humeral Fractures in Two Patients with Risk Factors for Nonunion Utilizing a Specialized Orthosis.

We report the treatment of two patient with humeral fractures with one or more risk factors for nonunion. The first patient was elderly with a previously diagnosed central nervous sys-tem injury. The second elderly patient previously sustained a cerebral vascular accident affecting the fractured arm. The fracture was oblique in the proximal third of the humerus. We achieved bone healing non-operatively utilizing a spe-cialized plastic orthosis that included a deforming element made of dense foam. This device asymmetrically increases the soft tissue pressure around the fracture.

Genetic screening and metabolomics identify glial adenosine metabolism as a therapeutic target in Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder and lacks disease-modifying therapies. We developed a Drosophila model for identifying novel glial-based therapeutic targets for PD. Human alpha-synuclein is expressed in neurons and individual genes are independently knocked down in glia. We performed a forward genetic screen, knocking down the entire Drosophila kinome in glia in alpha-synuclein expressing flies. Among the top hits were five genes (Ak1, Ak6, Adk1, Adk2, and awd) involved in adenosine metabolism. Knockdown of each gene improved locomotor dysfunction, rescued neurodegeneration, and increased brain adenosine levels. We determined that the mechanism of neuroprotection involves adenosine itself, as opposed to a downstream metabolite. We dove deeper into the mechanism for one gene, Ak1, finding rescue of dopaminergic neuron loss, alpha-synuclein aggregation, and bioenergetic dysfunction after glial Ak1 knockdown. We performed metabolomics in Drosophila and in human PD patients, allowing us to comprehensively characterize changes in purine metabolism and identify potential biomarkers of dysfunctional adenosine metabolism in people. These experiments support glial adenosine as a novel therapeutic target in PD.

Comparison of Self-Reported and Capacity-Based Measures of Mobility in Community-Dwelling Older Adults in Nigeria: The Mediating Role of Age, Cognitive Status, and Chronic Conditions.

Background and Objectives: Although the association between self-reported and capacity-based mobility outcomes is prominently researched, the pathways through which self-reported measures affect capacity-based measures remains poorly understood. Therefore, our study examines the association between self-reported and capacity-based mobility measures and explores which mobility determinants mediate the association in Nigerian community-dwelling older adults. Research Design and Methods: This cross-sectional study included 169 older adults [mean age (SD) = 67.7 (7.0)]. Capacity-based mobility outcomes included the Short Physical Performance Battery (SPPB), the 6-Minute Walk Test (6MWT), and the 10-Meter Walk Test (10mWT), whereas the self-reported mobility outcomes included the Lower Extremity Functional scale (LEFS), the Life Space Questionnaire (LSQ), and the Mänty Preclinical Mobility scale (inability to walk 2 km, 0.5 km, or climb a flight of stairs). Spearman's correlations were conducted to examine the relationship between self-reported and capacity-based mobility measures, whereas structural equation modeling was used to determine the mediators. Results: The correlation between SPPB and LEFS (rho = 0.284) and 0.5 km (rho = -0.251) were fair, whereas the correlation between SPPB and inability to walk 2 km (rho = -0.244) and inability to climb a flight of stairs (rho = -0.190) were poor. Similarly, correlations between 6MWT and the LEFS (rho = 0.286), inability to walk 2 km (rho = -0.269), and 0.5 km (rho = -0.303) were fair. The 6WMT was poorly correlated with inability to climb one flight of stairs (rho = -0.233). The LSQ was not correlated with SPPB or 10mWT. Age was the only significant mediator, whereas the number of chronic conditions and cognitive status were not. Discussion and Implications: The correlation between self-reported and capacity-based mobility outcomes in older adults in Nigeria is lower than those in developed countries. Our analysis provides a foundation to explore mobility determinants that could be predictive mediators for mobility outcomes, making meaningful contributions to explaining mobility complexities.

Longitudinal Studies of Aging in Sub-Saharan Africa: Review, Limitations, and Recommendations in Preparation of Projected Aging Population.

Background and Objectives: The United Nations has projected a 218% increase in older people in Sub-Saharan Africa (SSA) between 2019 and 2050, underscoring the need to explore changes that would occur over this time. Longitudinal studies are ideal for studying and proffering solutions to these changes. This review aims to understand the breadth and use of longitudinal studies on aging in the SSA regions, proffering recommendations in preparation for the projected aging population. Research Design and Methods: This paper is the third of a four-part series paper of a previous systematic mapping review of aging studies in SSA. We updated the search (between 2021 and 2023) and screened the titles/abstracts and full-text articles by a pair of independent reviewers. Data were extracted using a standardized data-charting form, identifying longitudinal studies in SSA. Results: We identified 193 studies leveraging 24 longitudinal study data sets conducted at 28 unique sites. The World Health Organization's Study on Global AGEing and Adult Health (WHO-SAGE) (n = 59, 30.5%) and Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa (HAALSI) (n = 51, 26.4%) were the most used longitudinal data sets. Four studies used more than one longitudinal study data set. Eighteen of the longitudinal study data sets were used only in 1-4 studies. Most (n = 150, 77.7%) of the studies used a cross-sectional analytical approach. Discussion and Implications: Longitudinal studies on aging are sparingly being utilized in SSA. Most analyses conducted across the longitudinal data set were cross-sectional, which hindered the understanding of aging changes that occurred over time that could better inform aging policy and interventions. We call for funding bodies, such as WHO-SAGE, to develop funding competitions that focus on conducting longitudinal analyses, such as structural equation modeling, highlighting changes occurring among the aging population in SSA.

A population pharmacokinetic model using allometric scaling for baricitinib in patients with juvenile idiopathic arthritis.

Baricitinib is approved for the treatment of rheumatoid arthritis (RA) in more than 70 countries, and juvenile idiopathic arthritis (JIA) in the European Union. Population pharmacokinetic (PK) models were developed in a phase 3 trial to characterize PK in pediatric patients with JIA and identify weight-based dosing regimens. The phase 3, randomized, double-blind, placebo-controlled withdrawal, efficacy and safety trial, JUVE-BASIS, enrolled patients (aged 2 to <18 years) with polyarticular course JIA. During a safety/PK period, baricitinib concentration data from age-based dose cohorts were compared to concentrations from adult patients receiving 4-mg QD. PK data were used to develop a population PK model with allometric scaling to determine a weight-based posology in pediatric patients with JIA that matched the adult 4-mg exposure. Baricitinib plasma concentrations from 217 pediatric patients were used to characterize PK. Based on the adult model, pediatric PK was best described using a 2-compartment model with allometric scaling on clearance and volume of distribution and renal function (estimated with glomerular filtration rate [GFR], a known covariate affecting PK of baricitinib) on clearance. The PK modeling suggested the optimal dosing regimen based on weight for pediatric patients as: 2-mg QD for patients 10 to <30 kg and 4-mg QD for patients ≥30 kg. The use of a population PK model of baricitinib treatment in adult patients with RA, with the addition of allometric scaling for weight on clearance and volume terms, was useful to predict exposures and identify weight-based dosing in pediatric patients with JIA.

A Multidimensional Model to Facilitate Within Person Comparison of Attributes.

In psychological research and practice, a person's scores on two different traits or abilities are often compared. Such within-person comparisons require that measurements have equal units (EU) and/or equal origins: an assumption rarely validated. We describe a multidimensional SEM/IRT model from the literature and, using principles of conjoint measurement, show that its expected response variables satisfy the axioms of additive conjoint measurement for measurement on a common scale. In an application to Quality of Life data, the EU analysis is used as a pre-processing step to derive a simple structure Quality of Life model with three dimensions expressed in equal units. The results are used to address questions that can only be addressed by scores expressed in equal units. When the EU model fits the data, scores in the corresponding simple structure model will have added validity in that they can address questions that cannot otherwise be addressed. Limitations and the need for further research are discussed.

Quantifying anterior pelvic roll during total hip arthroplasty in the lateral decubitus position.

BACKGROUND: Unintended pelvic positional change is an acknowledged intra-operative problem for hip arthroplasty, seen commonly with procedures performed in the lateral position. If unrecognised, such changes can dramatically alter final acetabular component anteversion potentially resulting in suboptimal construct performance. It has previously been suggested that pelvic roll of just 13° may be enough to place an otherwise perfectly orientated cup outside of conventional ± 10° safe zones. Using the real-time tracking capacity of a commercially available optical navigation system, we aimed to accurately quantify pelvic roll occurring during total hip arthroplasties (THAs) performed in the decubitus position. METHODS: Prospectively collected data for 107 consecutive, unilateral, THAs were interrogated to determine the magnitude of pelvic movement around a central longitudinal axis (i.e. AP roll). Correlation statistics with patient age and body mass index (BMI) were also calculated. RESULTS: A mean pelvic roll of 9.5° was observed, being anterior in 96% of cases. Of these, 18.3% of hips had a magnitude of roll greater than 13°. There were no statistically significant independent correlations observed between age (p = 0.87) or BMI (p = 0.59) and mean roll. CONCLUSIONS: Errors in achieving acetabular target version may result in numerous post-operative concerns including instability/dislocation, bearing wear, squeaking, range-of-movement limitation and increased revision rate. In a general cohort, our findings suggest a mean anterior pelvic roll during THA of nearly 10°. Without purposeful correction, this may cause substantial deviation from intended target positions. Future work is indicated to map changing pelvic roll during THA which is likely to follow a nonlinear trajectory. Level of evidence: IV. .

Combined Experimental and Computational Study of V-Substituted Lindqvist Polyoxotungstate: Screening by Docking for Potential Antidiabetic Activity.

In the current work, a novel vanadotungstate compound, (C6H9N2)4[V2W4O19]·2H2O (1), is isolated by a simple stepwise synthesis method and characterized by a combined experimental and computational study. Molecular docking is conducted for the first time for this kind of substituted Lindqvist polyoxometalates to elucidate for potential antidiabetic activity. Hence, the modeling results revealed a significant docking score of the reported compound to bind to the active sites of α-glucosidase with the lowest binding energy of -5.7 kcal/mol, where the standard drug acarbose (ACB) had -4.6 kcal/mol binding energy. The stability of binding was enhanced by strong H-bonding, van der Waals, and electrostatic interactions occurring in the three-dimensional (3D) supramolecular network of polyanionic vanadotungstate subunits templated with organic moieties as shown by X-ray diffraction and Hirshfeld analyses. Furthermore, density functional theory (DFT) calculations supported with photophysical measurements are also discussed to predict the most chemical and biological reactivity. In this view, the complete description of electronic and biological features of (1) is enhanced by determination of the highest occupied molecular orbital (HOMO)/least unoccupied molecular orbital (LUMO) energy, electronic density, ionization potential, electron affinity, etc. These chemical descriptors, intermolecular interactions, docking score, and binding free energy estimation are essential in understanding the reactivity of this bioactive compound offering potential inhibition of the α-glucosidase enzyme.

First-principle study of Cu-, Ag-, and Au-decorated Si-doped carbon quantum dots (Si@CQD) for CO2 gas sensing efficacies.

CONTEXT: Nanosensor materials for the trapping and sensing of CO2 gas in the ecosystem were investigated herein to elucidate the adsorption, sensibility, selectivity, conductivity, and reactivity of silicon-doped carbon quantum dot (Si@CQD) decorated with Ag, Au, and Cu metals. The gas was studied in two configurations on its O and C sites. When the metal-decorated Si@CQD interacted with the CO2 gas on the C adsorption site of the gas, there was a decrease in all the interactions with the lowest energy gap of 1.084 eV observed in CO2_C_Cu_Si@CQD followed by CO2_C_Au_Si@CQD which recorded a slightly higher energy gap of 1.094 eV, while CO2_C_Ag_Si@CQD had an energy gap of 2.109 eV. On the O adsorption sites, a decrease was observed in CO2_O_Au_Si@CQD which had the least energy gap of 1.140 eV, whereas there was a significant increase after adsorption in CO2_O_Ag_Si@CQD and CO2_O_Cu_Si@CQD with calculated ∆E values of 2.942 eV and 3.015 eV respectively. The adsorption energy alongside the basis set supposition error (BSSE) estimation reveals that CO2_C_Au_Si@CQD, CO2_C_Ag_Si@CQD, and CO2_C_Cu_Si@CQD were weakly adsorbed, while chemisorption was present in the CO2_O_Ag_Si@CQD, CO2_O_Cu_Si@CQD, and CO2_O_Au_Si@CQD interactions. Indeed, the adsorption of CO2 on the different metal-decorated quantum dots affects the Fermi level (Ef) and the work function (Φ) of each of the decorated carbon quantum dots owed to their low Ef values and high ∆Φ% which shows that they can be a prospective work function-based sensor material. METHODS: Electronic structure theory method based on first-principle density functional theory (DFT) computation at the B3LYP-GD3(BJ)/Def2-SVP level of theory was utilized through the use of the Gaussian 16 and GaussView 6.0.16 software packages. Post-processing computational code such as multi-wavefunction was employed for result analysis and visualization.

Molecular simulation of Cu, Ag, and Au-decorated Si-doped graphene quantum dots (Si@QD) nanostructured as sensors for SO2 trapping.

In view of the numerous environmental hazards and health challenges linked to sulfur (iv) oxide (SO2), an indirect greenhouse gas, and the resultant need to develop efficient gas nanosensor devices, this research had as its principal focus on the theoretical evaluation of the gas sensing potential of metals: Ag, Au and Cu functionalized silicon-doped quantum dots (Si@QD) for the detection and adsorption of SO2 gas investigated using the first-principles density functional theory (DFT) computation at the B3LYP-D3(BJ)/def2-SVP level of theory. Eight (8) possible adsorption modes: SO2_O_Si@QD, SO2_O_Ag_Si@QD, SO2_O_Au_Si@QD, SO2_O_Cu_Si@QD, SO2_S_Si@QD, SO2_S_Ag_Si@QD, SO2_S_Au_Si@QD, and SO2_S_Cu_Si@QD were considered based on SO2 interactions with the studied materials at the -S and -O sites of the SO2 molecule. The counterpoise correction (BSSE) showed that five of the eight interactions had favorable Ead + BSSE values ranging from -0.31 to -1.98 eV. All the eight interactions were observed to be thermodynamically favorable with ΔG and ΔH ranging from -129.01 to -200.24 kcal/mol and -158.26 to -229.73 kcal/mol respectively. Results from the topology analysis reveal that van der Waals forces occurred the greatest at the gas-sensor interphase while SO2_S_ Cu_Si@QD is predicted to have the highest sensing potency based on the conductivity and recovery time estimations. These results confirm the potential efficient feasibility of real-world device application of the metals (Ag, Au, Cu) functionalized Si-doped QDs.

Insights into in-vitro studies and molecular modelling of the antimicrobial efficiency of 4-chlorobenzaldehyde and 4-methoxybenzaldehyde derivatives.

Owing to the significant gap in the knowledge and understanding of the mechanisms of antimicrobial action and the development of resistance, the optimization of antimicrobial therapies therefore becomes a necessity. It is on this note, that this study seeks to both experimentally and theoretically investigate the antimicrobial efficiency of two synthesized compounds namely; 1-((4-methoxyphenyl) (morpholino)methyl)thiourea (MR1) and diethyl 4-(4-chlorophenyl)-2,6-diphenyl-1,4-dihydropyridine-3,5-dicarboxylate (HRC). Utilizing the density functional theory (DFT), the compounds were optimized at ωB97XD/6-31++G(2d, 2p) level of theory. This provided a clear explanation for their distinct reactivity and stability potentials. More so, the natural bond orbital (NBO) analysis confirmed strong intra and intermolecular interactions, which agreed with the calculated reactivity parameters and density of states (DOS). Upon assessing the antimicrobial efficacy of the synthesized compounds, it was found that they exhibited lower activity against Enterobacter and A. niger, but considerable activity against Moraxella. In contrast, they showed higher activity against B. subtilis and Trichophyton, indicating that the compounds are more effective against gram-positive bacteria than gram-negative ones. Hence, it can be asserted that the synthesized compounds have superior antifungal action than antibacterial activity. A fascinating aspect of the data is that they show interactions that are incredibly insightful, totally correlating with the simulations of both molecular docking and molecular dynamics. Therefore, the alignment between experimental findings and computational simulations strengthens the validity of the study's conclusions, emphasizing the significance of the synthesized compounds in the context of optimizing antimicrobial therapies.Communicated by Ramaswamy H. Sarma.

Donanemab exposure and efficacy relationship using modeling in Alzheimer's disease.

INTRODUCTION: Donanemab is an amyloid-targeting therapy that specifically targets brain amyloid plaques. The objective of these analyses was to characterize the relationship of donanemab exposure with plasma biomarkers and clinical efficacy through modeling. METHODS: Data for the analyses were from participants with Alzheimer's disease from the phase 1 and TRAILBLAZER-ALZ studies. Indirect-response models were used to fit plasma phosphorylated tau 217 (p-tau217) and plasma glial fibrillated acidic protein (GFAP) data over time. Disease-progression models were developed using pharmacokinetic/pharmacodynamic modeling. RESULTS: The plasma p-tau217 and plasma GFAP models adequately predicted the change over time, with donanemab resulting in decreased plasma p-tau217 and plasma GFAP concentrations. The disease-progression models confirmed that donanemab significantly reduced the rate of clinical decline. Simulations revealed that donanemab slowed disease progression irrespective of baseline tau positron emission tomography (PET) level within the evaluated population. DISCUSSION: The disease-progression models show a clear treatment effect of donanemab on clinical efficacy regardless of baseline disease severity.

Modeling of magnesium-decorated graphene quantum dot nanostructure for trapping AsH3, PH3 and NH3 gases.

A magnesium-decorated graphene quantum dot (C24H12-Mg) surface has been examined theoretically using density functional theory (DFT) computations at the ωB97XD/6-311++G(2p,2d) level of theory to determine its sensing capability toward XH3 gases, where X = As, N and P, in four different phases: gas, benzene solvent, ethanol solvent and water. This research was carried out in different phases in order to predict the best possible phase for the adsorption of the toxic gases. Analysis of the electronic properties shows that in the different phases the energy gap follows the order NH3@C24H12-Mg < PH3@C24H12-Mg < AsH3@C24H12-Mg. The results obtained from the adsorption studies show that all the calculated adsorption energies are negative, indicating that the nature of the adsorption is chemisorption. The adsorption energies can be arranged in an increasing trend of NH3@C24H12-Mg < PH3@C24H12-Mg < AsH3@C24H12-Mg. The best adsorption performance was noted in the gas phase compared to the other studied counterparts. The interaction between the adsorbed gases and the surfaces shows a non-covalent interaction nature, as confirmed by the quantum theory of atoms-in-molecules (QTAIM) and non-covalent interactions (NCI) analysis. The overall results suggest that we can infer that the surface of the magnesium-decorated graphene quantum dot C24H12-Mg is more efficient for sensing the gas AsH3 than PH3 and NH3.

Testing the Webber's Comprehensive Mobility Framework Using Self-Reported and Performance-Based Mobility Outcomes Among Community-Dwelling Older Adults in Nigeria.

Background and Objectives: In 2010, Webber and colleagues conceptualized the interrelationships between mobility determinants, and researchers tested Webber's framework using data from developed countries. No studies have tested this model using data from developing nations (e.g., Nigeria). This study aimed to simultaneously explore the cognitive, environmental, financial, personal, physical, psychological, and social influences and their interaction effects on the mobility outcomes among community-dwelling older adults in Nigeria. Research Design and Methods: This cross-sectional study recruited 227 older adults (mean age [standard deviation] = 66.6 [6.8] years). Performance-based mobility outcomes included gait speed, balance, and lower extremity strength, and were assessed using the Short Physical Performance Battery, whereas the self-reported mobility outcomes included inability to walk 0.5 km, 2 km, or climb a flight of stairs, assessed using the Manty Preclinical Mobility Limitation Scale. Regression analysis was used to determine the predictors of mobility outcomes. Results: The number of comorbidities (physical factor) negatively predicted all mobility outcomes, except the lower extremity strength. Age (personal factor) negatively predicted gait speed (ß = -0.192), balance (ß = -0.515), and lower extremity strength (ß = -0.225), and a history of no exercise (physical factor) positively predicted inability to walk 0.5 km (B = 1.401), 2 km (B = 1.295). Interactions between determinants improved the model, explaining the most variations in all the mobility outcomes. Living arrangement is the only factor that consistently interacted with other variables to improve the regression model for all mobility outcomes, except balance and self-reported inability to walk 2 km. Discussion and Implications: Interactions between determinants explain the most variations in all mobility outcomes, highlighting the complexity of mobility. This finding highlighted that factors predicting self-reported and performance-based mobility outcomes might differ, but this should be confirmed with a large data set.

Anticancer Activities of Re(I) Tricarbonyl and Its Imidazole-Based Ligands: Insight from a Theoretical Approach.

Rhenium complexes have been observed experimentally to exhibit good inhibitory activity against malignant cells. Hence, our motivation is to explore this activity from a theoretical perspective. In the present study, density functional theory (DFT) and in silico molecular docking approaches were utilized to unravel the unique properties of metal-based rhenium tricarbonyl complexes as effective anticancer drugs. All DFT calculations and geometric optimizations were conducted using the well-established hybrid functional B3LYP-GD(BJ)/Gen/6-311++G(d,p)/LanL2DZ computational method. The FT-IR spectroscopic characterization of the complexes: fac-[Re(Pico)(CO)3(Pz)] (R1), fac-[Re(Pico)(CO)3(Py)] (R2), fac-[Re(Dfpc)(CO)3(H2O)] (R3), fac-[Re(Dfpc)(CO)3(Pz)] (R4), fac-[Re(Dfpc)(CO)3(Py)] (R5), fac-[Re(Tfpc)(CO)3(H2O)] (R6), fac-[Re(Tfpc)(CO)3(Py)] (R7), and fac-[Re(Tfpc)(CO)3(Im)] (R8) was explored. To gain insights into the electronic structural properties, bioactivity, and stability of these complexes, the highest occupied molecular orbital-lowest unoccupied molecular orbital analysis, binding energy, and topological analysis based on quantum theory of atoms-in-molecules were considered. The anticancer activities of the complexes were measured via in silico molecular docking against human BCL-2 protein (IG5M) and proapoptotic (agonist) BAX 1 protein (450O). The results showed that the studied complexes exhibited good binding affinity (-3.25 to -10.16 kcal/mol) and could cause significant disruption of the normal physiological functions of the studied proteins. The results of DFT calculations also showed that the studied complexes exhibited good stability and are suitable candidates for the development of anticancer agents.

Donanemab Population Pharmacokinetics, Amyloid Plaque Reduction, and Safety in Participants with Alzheimer's Disease.

Donanemab is an amyloid-targeting therapy that resulted in robust amyloid plaque reduction and slowed Alzheimer's disease (AD) progression compared with placebo in the phase II TRAILBLAZER-ALZ study (NCT03367403). The objectives of the current analyses are to characterize (i) the population pharmacokinetics of donanemab, (ii) the relationship between donanemab exposure and amyloid plaque reduction (response), and (iii) the relationship between donanemab exposure and amyloid-related imaging abnormalities with edema or effusions (ARIA-E). Model development included data from participants with mild cognitive impairment or mild to moderate dementia due to AD from the phase Ib study on donanemab (NCT02624778) and participants with early symptomatic AD from the TRAILBLAZER-ALZ study. The analysis showed donanemab has a terminal elimination half-life of 11.8 days. Body weight and antidrug antibody titer impact donanemab exposure but not the pharmacodynamic response. Maintaining a donanemab serum concentration above 4.43 µg/mL (95% confidence interval: 0.956, 10.4) is associated with amyloid plaque reduction. The time to achieve amyloid plaque clearance (amyloid plaque level < 24.1 Centiloids) varied depending on the baseline amyloid level, where higher baseline levels were associated with fewer participants achieving amyloid clearance. The majority of participants achieved amyloid clearance by 52 weeks on treatment. Apolipoprotein ε4 carriers, irrespective of donanemab serum exposure, were 4 times more likely than noncarriers to have an ARIA-E event by 24 weeks.

High-performance non-fullerene acceptor-analogues designed from dithienothiophen [3,2-b]-pyrrolobenzothiadiazole (TPBT) donor materials.

CONTEXT: Density functional theory (DFT) method was employed to investigate the electronic structure properties, excited state dynamics, charge transfer, and photovoltaic potential of benzo [1,2,5] thiadiazole fused to 3,7-dimethyl-3a,6,7,7b-tetrahydro-5H-thieno[2',3':4,5]thieno[3,2-b]pyrrole to form 3,9,12,13-tetramethyl-12,13-dihydro-[1,2,5]thiadiazolo[3,4-e]thieno[2″,3″:4,5]pyrrolo[3.2-g]thieno[2',3':4,5]thieno[3,2-b]indole as the acceptor (A), bridge with thiophene as π-spacer to the donor moieties (D) which are 2,3-dihydrobenzo [b]thiophene-6-carboxylic acid (M4) and functionalized R, M1, M2, M3, and M5 to give a D-π-A-π-D. Here is the reverse combination for our molecules: the A-π-D-π-A type of chromophore configuration. It is also observed that tuning the dono-bridge configuration significantly increases the ease of charge transfer as the energy gap decreases in the order of 1.29 eV in M4 < 1.59 eV in M3 < 1.67 eV < 1.99 in M2 and 2.06 eV. The reorganization energy (RE) of M3 (0.0031) and M5 (0.0031) indicates an increase in the order of M3 > M5 > R > M2 > M4 > M1. The HOMO-LUMO indicates that the reactivity decreased, while the stability increased for the reference R at 0.990 eV, compared to the designed molecules M1-M5, with M1 being the least stable at 0.970 eV, while M4 exhibited the highest stability at 1.550 eV. The stability of the designed molecule decreased in the order of M4:1.550 > M3:1.257 > M5:1.197 > M2:1.010 > M1:0.970. Therefore, all results point to the electron-deficient core as an effective end-capped electron acceptor in M1-M5 compounds. As the ideal pair for successfully optimizing optoelectronic properties by reducing the HOMO-LUMO energy levels, reorganization energy, and binding energy and enhancing the absorption maximum and open-circuit voltage values in these designed molecules. METHODS: DFT and TDDFT calculations were performed with Gaussian 16 program. The modelled compounds were optimized fully using the CAM-B3LYP, WB97XD, B3LYP, and MPW1PW91 functionals with the 6-31 G (d,p) basis set. The graphs for the density of states were plotted using the PyMOlyze software. Other molecular properties like the transition density matrix (TDM) and electron density difference maps (EDD) were rendered via the Multiwfn software.

Linear equality constraints: Reformulations of criterion related profile analysis with extensions to moderated regression for multiple groups.

Criterion-related profile analysis (CPA) is a least squares linear regression technique for identifying a criterion-related pattern (CRP) among predictor variables and for quantifying the variance accounted for by the pattern. A CRP is a pattern, described by a vector of contrast coefficients, such that predictor profiles with higher similarity to the pattern have higher expected criterion scores. A review of applications shows that researchers have extended the analysis to meta-analyses, logit regression, canonical regression, and structural equation modeling. It also reveals a need for better methods of comparing CRPs across populations. While the original method for identifying the CRP tends to underestimate the variance accounted for by pattern only, both the pattern identified by the original method and the pattern identified by the new method proposed here have useful and complementary interpretations. Imposing linear equality constraints on regression coefficients yields a more accurate method of estimating the variance accounted for by pattern only, and this constrained approach leads to moderated regression models for investigating whether the CRP is the same in two or more populations. Finally, we show how the elements in Cronbach and Gleser's (1953) classic profile decomposition are related to the linear regression model and the CPA model. Academic ability tests as predictors of college GPA are used to illustrate the analyses. Implications of the profile pattern models for psychological theory and applied decision-making are discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Anti-inflammatory biomolecular activity of chlorinated-phenyldiazenyl-naphthalene-2-sulfonic acid derivatives: perception from DFT, molecular docking, and molecular dynamic simulation.

In this study, two novel derivatives of naphthalene-2-sulfonic acid: 6-(((1S,5R)-3,5-dichloro-2,4,6-triazabicyclo [z3.1.0]hex-3-en-1-yl)amino)-5-((E)-phenyldiazenyl)naphthalene-2-sulfonic acid (DTPS1) and (E)-6-((4,6-dichloro-1,3,5-triazine2-yl)amino)-4-hydroxy-3-(phenyldiazenyl)naphthalene-2-sulfonic acid (DTPS2) have been synthesized and characterized using FT-IR, UV-vis, and NMR spectroscopic techniques. Applying density functional theory (DFT) at the B3LYP, APFD, PBEPBE, HCTH, TPSSTPSS, and ωB97XD/aug-cc-pVDZ level of theories for the electronic structural properties. In-vitro analysis, molecular docking, molecular dynamic (MD) simulation of the compounds was conducted to investigate the anti-inflammatory potential using COXs enzymes. Docking indicates binding affinity of -9.57, -9.60, -6.77 and -7.37 kcal/mol for DTPS1, DTPS2, Ibuprofen and Diclofenac which agrees with in-vitro assay. Results of MD simulation, indicates sulphonic group in DTPS1 has > 30% interaction with the hydroxyl and oxygen atoms in amino acid residues, but > 35% interaction with the DTPS2. It can be said that the DTPS1 and DTPS2 can induce inhibitory effect on COXs to halt biosynthesis of prostaglandins (PGs), a chief mediator of inflammation and pain in mammals.Communicated by Ramaswamy H. Sarma.