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Type 1 diabetes (T1D) is associated with an increased risk of hip fracture beyond what can be explained by reduced bone mineral density, possibly due to changes in bone material from accumulation of advanced glycation end products (AGEs) and altered matrix composition, though data from human cortical bone in T1D are limited. The objective of this study was to evaluate cortical bone material behavior in T1D by examining specimens from cadaveric femora from older adults with long-duration T1D (≥50 years; n = 20) and age- and sex-matched non-diabetic controls (n = 14). Cortical bone was assessed by mechanical testing (4-point bending, cyclic reference point indentation, impact microindentation), AGE quantification (total fluorescent AGEs, pentosidine, carboxymethyl-lysine (CML)), and matrix composition via Raman spectroscopy. Cortical bone from older adults with T1D had diminished post-yield toughness to fracture (-30%, P=.036), elevated levels of AGEs (pentosidine, +17%, P=.039), lower mineral crystallinity (-1.4%, P=.010), greater proline hydroxylation (+1.9%, P=.009), and reduced glycosaminoglycan (GAG) content (-1.3%, P<.03) compared to non-diabetics. In multiple regression models to predict cortical bone toughness, cortical tissue mineral density (Ct.TMD), CML, and Raman spectroscopic measures of enzymatic collagen crosslinks and GAG content remained highly significant predictors of toughness, while diabetic status was no longer significant (adjusted R2 > 0.60, P<.001). Thus, impairment of cortical bone to absorb energy following long-duration T1D is well explained by AGE accumulation and modifications to the bone matrix. These results provide novel insight into the pathogenesis of skeletal fragility in individuals with T1D., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: A common genetic variant at the glutamate-ammonia ligase (GLUL) locus has been previously associated with an increased risk of coronary artery disease (CAD) as well as alterations of glutamic acid metabolism and the γ-glutamyl cycle in individuals with type 2 diabetes (T2D). Here we investigated whether less frequent variants in GLUL and 15 additional genes in these pathways are associated with differences in CAD risk in T2D., Methods: Coding sequences and regulatory elements of these genes were sequenced in 2,394 individuals with T2D from three CAD case/control sets., Results: Ninety-six variants with minor allele frequency [MAF]< 0.05 were identified as being nominally associated with CAD status. One of these variants (rs62447457, MAF 0.025), placed in a non-coding region flanking the γ-glutamylcyclotransferase (GGCT) gene, showed nominal evidence of replication in two other cases-control sets (n = 1,132), with summary OR of 0.54 (p = 2.5 × 10 -4 ). Another variant (rs145322388, MAF = 0.039), flanking the dipeptidase 2 (DPEP2) gene, showed association with CAD status across discovery and replications sets (summary OR 0.61, p = 2.5 × 10 -4 ). A third variant (rs1238275622, MAF 0.004), flanking the GLUL gene, was associated with increased risk of CAD (summary OR 1.84, p-value 2.1 × 10 -3 ). Based on their Regulome scores (2b, 2a, and 3a, respectively), all three variants are very likely to have regulatory functions., Conclusions: In summary, we have identified low-frequency variants associated with CAD in T2D at two loci involved in glutamic acid metabolism and the γ-glutamyl cycle. These findings provide further evidence for a role of these pathways in the link between T2D and CAD., Competing Interests: Declarations Ethics approval and consent to participate The study protocols of the JHS, JKS1, and JKS2 were approved by the Joslin Committee on Human Studies. The study protocols of the NHS and HPFS were approved by the Institutional Review Boards of the Brigham and Women's Hospital and the Harvard T.H. Chan School of Public Health. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Present study evaluates the usability of compaction simulation-based mechanical models as a material-sparing approach to predict tablet capping under processing compression conditions using Acetaminophen (APAP) and Ibuprofen (IBU). Measured mechanical properties were evaluated using principal component analysis (PCA) and principal component regression (PCR) models. PCR models were then utilized to predict the capping score (CS) from compression pressure (CP). APAP formulations displayed a quadratic correlation between CS and CP, with CS rank order following CP of 200MPa < 300MPa < 100MPa, indicating threshold compression pressure (TCP) limit between 200 and 300 MPa, resulting in higher CS at 300 than 200 MPa regardless of increased CP. IBU formulations displayed a linear correlation between CS and CP, with CS rank order following CP of 100MPa < 200MPa < 300MPa, indicating TCP limit between 100 and 200 MPa, resulting in higher CS at 200 and 300 than 100 MPa regardless of increased CP. Molecular models were developed as validation methods to predict capping from CP. Measured XRPD patterns of compressed tablets were linked with calculated Eatt and d-spacing of slip planes and analyzed using variable component least square methods to predict TCP triggering cleavage in slip planes and leading to capping. In APAP and IBU, TCP values were predicted at 245 and 175 MPa, meaning capped tablets above these TCP limits regardless of increased CP. A similar trend was observed in CS predictions from mechanical assessment, confirming that compaction simulation-based mechanical models can predict capping risk under desired compression conditions rapidly and accurately., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Latino/a/x sexual minority men (SMM) and transgender women remain disproportionately impacted by HIV, with higher HIV incidence and lower uptake of pre-exposure prophylaxis (PrEP) than their non-Hispanic White peers. Disparities in PrEP uptake among Latino/a/x populations have been found to be due to structural, social, and personal barriers. Social marketing interventions have been shown to effectively address barriers and increase PrEP uptake in other populations, and thus offer potential as a tool to increase PrEP uptake for Latino/a/x populations. The PrEPárate campaign was developed through community based participatory research and ran from April to September 2022 in Cook County, Illinois. We conducted a mixed methods evaluation through surveys (N = 515) and semi-structured interviews with survey participants and community partners (N = 14). We examined cross-sectional associations of campaign exposure with PrEP awareness and uptake in adjusted multivariable regression models. We used rapid qualitative methods to analyze interviews and assess implementation outcomes following the RE-AIM framework. The campaign reached over 118,000 people on social media, with additional reach over public transit and local events. PrEPárate exposure was associated with increased PrEP awareness (aOR = 5.23; 95% CI [2.58, 10.63]) and PrEP uptake (aOR = 1.69; 95% CI [1.09, 2.62]). Survey respondents expressed that the campaign name, visuals, ambassadors, and distribution were effective in engaging the target audience. Community partners felt the campaign was implemented with fidelity to the original vision and identified future directions for PrEPárate. Social marketing campaigns, anchored in community engagement, may be an effective strategy to increase PrEP awareness and uptake among underserved Latino/a/x populations., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Sepsis and atherosclerotic cardiovascular disease (ASCVD) are major health challenges involving complex processes like inflammation, renin-angiotensin system (RAS) dysregulation, and thrombosis. Despite distinct clinical symptoms, both conditions share mechanisms mediated by bradykinin. This review explores bradykinin's role in inflammation, RAS modulation, and thrombosis in sepsis and ASCVD. In sepsis, variable kininogen-bradykinin levels may correlate with disease severity and progression, though the effect of bradykinin receptor modulation on inflammation remains uncertain. RAS activation is present in both diseases, with sepsis showing variable or low levels of Ang II, ACE, and ACE2, while ASCVD consistently exhibits elevated levels. Bradykinin may act as a mediator for ACE2 and AT2 receptor effects in RAS regulation. It may influence clotting and fibrinolysis in sepsis-associated coagulopathy, but evidence for an antithrombotic effect in ASCVD is insufficient. Understanding bradykinin's role in these shared pathologies could guide therapeutic and monitoring strategies and inform future research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Latino, Latina, and Latinx (Latino/a/x) individuals remain disproportionately impacted by HIV, particularly sexual minority men and transgender women. Pre-exposure prophylaxis (PrEP) is an effective means of biomedical HIV prevention, but awareness and uptake remain low among marginalized Latino/a/x populations. Social marketing campaigns have demonstrated promise in promoting PrEP in other populations but are poorly studied in Latino/a/x sexual minority men and transgender women., Objective: This study aims to (1) adapt and pilot a PrEP social marketing campaign tailored to Latino/a/x populations with a focus on sexual minority men and transgender women through community-based participatory research (CBPR) and (2) evaluate the reach and ad performance of the adapted PrEP social marketing campaign., Methods: We used the ADAPT-ITT (assessment, decision, adaptation, production, topical experts-integration, training, and testing) framework for adapting evidence-based interventions for new settings or populations. This paper presents how each phase of the ADAPT-ITT framework was applied via CBPR to create the PrEPárate ("Be PrEPared") campaign. Key community engagement strategies included shared ownership with community partners, focus groups to guide content, crowdsourcing to name the campaign, design by local Latino/a/x artists, and featuring local influencers as the faces of PrEPárate. We evaluated campaign reach and advertisement performance using social media platform metrics (paid and organic reach, impressions, unique clicks, and click-through rates [CTR]) and website use statistics from Google Analytics., Results: The PrEPárate campaign ran in Cook County, Illinois, from April to September 2022. The campaign reached over 118,750 people on social media (55,750 on Facebook and Instagram [Meta Platforms Inc] and 63,000 on TikTok [ByteDance Ltd]). The Meta ads performed over the industry benchmark with ads featuring local transgender women (2% CTR) and cisgender sexual minority men (1.4% CTR). Of the different Grindr (Grindr Inc) ad formats piloted, the interstitial Grindr ads were the highest performing (1183/55,479, 2.13% CTR). YouTube (Google) ads were low performing at 0.11% (153/138,337) CTR and were stopped prematurely, given limits on sexual education-related content. In the first year, there were 5006 visitors to the website., Conclusions: Adaptation of an existing evidence-based intervention served as an effective method for developing a PrEP social marketing campaign for Latino/a/x audiences. CBPR and strong community partnerships were essential to tailor materials and provide avenues to systematically address barriers to PrEP access. Social marketing is a promising strategy to promote PrEP among underserved Latino/a/x populations., (©Harita S Shah, Pedro Alonso Serrano, Gregory Phillips II. Originally published in JMIR Formative Research (https://formative.jmir.org), 17.07.2024.)

Background: The role of glycemic control and its variability on the rate of kidney function decline after the onset of diabetic kidney disease (DKD) remains unclear., Methods: The association between baseline glycated hemoglobin (HbA1c) and rates of estimated glomerular filtration rate (eGFR) loss during follow-up was examined by mixed-effects linear regression in 530 individuals with type 1 diabetes and early-to-moderate DKD from the Preventing Early Renal Loss (PERL) trial and 2378 individuals with type 2 diabetes and established DKD from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. The benefit of intensive vs standard glycemic control in slowing eGFR decline was examined in ACCORD. The associations between continuous glucose monitoring-derived short-term glycemic variability indices and rate of eGFR decline were also evaluated in PERL., Results: A higher baseline HbA1c was associated with a more negative eGFR slope in both PERL and ACCORD (-0.87 and -0.27 mL/min/1.73 m2/year per Hba1c unit increment, P < .0001 and P = .0002, respectively). In both studies, the strength of this association progressively increased with increasing levels of albuminuria (P for interaction <.05). Consistent with this, the benefit of intensive glycemic control on eGFR decline was greater in ACCORD participants with severe rather than moderate albuminuria (+1.13 vs + 0.26 mL/min/1.73 m2/year, P = .01). No independent associations were found in PERL between short-term glycemic variability indices and rate of eGFR decline., Conclusion: In both type 1 and type 2 diabetes, poor glycemic control is associated with a more rapid rate of glomerular filtration rate decline after DKD onset, especially in persons with severe albuminuria., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Hydrates are often used as pharmaceutical active pharmaceutical ingredients (API), especially when anhydrates may not be feasible likely due to physicochemical properties concerns. Pharmaceutical hydrates, whereas water is present as crystal adduct, are feasible for drug products as they do not pose any safety concern. Hydrates can impart many different advantages; therefore, they are quite common and preferred solid forms for numerous pharmaceutical materials on market. However, hydrates may involve various phase transitions, which may impact the stability and processability of drug substance., Methods: Phase transitions, which include temperature-induced dehydration and moisture-facilitated rehydration are investigated by different solid-state analytical techniques such as powder x-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, polarized light microscopy, and single-crystal x-ray diffraction., Results: This research investigation focuses on the different phase transition behaviors of a newly discovered pharmaceutical compound with three channel hydrates, two of which confirmed by single-crystal analysis. The retention or rearrangement of crystal structures over the transitions are studied. Hydrate 3 exhibits a characteristic feature of channel hydrate that involves symmetric lattice relaxation. Unlike hydrate 3, hydrate 2 results in a potentially new unit cell upon dehydration due to asymmetric lattice relaxation, which converted back to Hydrate 2 in presence of water, a very unique behavior for a channel hydrate, rarely observed, which entails novelty of this research work., Conclusion: The relationship among crystal forms of different hydrates of this new compound is thus established. The current investigation is a vital part of drug product risk assessment for hydrates to avoid any challenges during manufacturing operations and/or stability studies. This investigation was successfully applied in the present study and can be expanded to other newly discovered APIs in future., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The prognosis of COVID-19 could influence by innate immune sensors such as toll-like receptors (TLRs). The purpose of this data was to investigate TLR3, 7, and 8 expression levels in COVID-19 patients and their relationship to outcome of disease. 75 confirm COVID-19 were included sequentially and separated into three groups: mild, severe, and critical. Peripheral blood mononuclear cells were isolated from the whole blood, and RNA was then extracted. The qRT-PCR technique was used to examine the expression of TLR3, TLR7, and TLR8 genes. The patients average ages were 52.69 ± 1.9 and 13 of the 25 individuals in each group were male. TLR3 ( p < 0.001), TLR7 ( p < 0.001), and TLR8 ( p < 0.001) expression levels were considerably greater in COVID-19 patients compared to the control group. The findings also showed that individuals with critical and severe COVID-19 disease had significantly greater TLR7 and TLR8 gene expression levels than patients in mild stage of disease ( p < 0.05). The data showed a significant difference ( p = 0.01) in the TLR3 transcript levels between critical and mild COVID-19 patients. Furthermore, male severe ( p = 0.02) and critical (p = 0.008) patients had significantly higher TLR8 expression levels than female patients in terms of gender. TLR3 ( p = 0.2) and TLR7 ( p = 0.08) transcripts were more elevated in males than females, but not significantly., (© 2024 Published by Elsevier Inc.)

Results of previous studies have suggested that cardiovascular autonomic neuropathy (CAN) may predict rapid kidney function decline among people with diabetes. We analyzed the association between baseline CAN and subsequent glomerular filtration rate (GFR) decline among individuals with type 1 diabetes (T1D) from the Preventing Early Renal Loss in Diabetes (PERL) study (N = 469) and with type 2 diabetes (T2D) from Action to Control Cardiovascular Risk in Diabetes (ACCORD) (N = 7,973). Baseline CAN was ascertained with electrocardiogram-derived heart rate variability indices. Its association with GFR slopes, rapid kidney function decline (GFR loss of ≥5 mL/min/1.73 m2/year), and ≥40% GFR loss was evaluated by linear mixed-effects, logistic, and Cox regression, respectively. Participants with CAN experienced more rapid GFR decline, by an excess 1.15 mL/min/1.73 m2/year (95% CI -1.93 to -0.37; P = 4.0 × 10-3) in PERL and 0.34 mL/min/1.73 m2/year (95% CI -0.49 to -0.19; P = 6.3 × 10-6) in ACCORD. This translated to 2.11 (95% CI 1.23-3.63; P = 6.9 × 10-3) and 1.39 (95% CI 1.20-1.61; P = 1.1 × 10-5) odds ratios of rapid kidney function decline in PERL and ACCORD, respectively. Baseline CAN was also associated with a greater risk of ≥40% GFR loss events during follow-up (hazard ratio 2.60 [95% CI 1.15-5.45], P = 0.02, in PERL and hazard ratio 1.54 [95% CI 1.28-1.84], P = 3.8 × 10-6, in ACCORD). These associations remained significant after adjustment for potential confounders, including baseline GFR and albuminuria. Our findings indicate that CAN is a strong, independent predictor of rapid kidney function decline in both T1D and T2D. Further studies of the link between these two complications may help with development of new therapies to prevent kidney function decline in patients with diabetes., (© 2024 by the American Diabetes Association.)

The purpose of this study was to produce hyaluronic acid customized nanoparticles with chitosan for the delivery of chebulinic acid (CLA) to enhance its anticancer potential against breast cancer. A significant portion of CLA was encapsulated (89.72 ± 4.38 %) and loaded (43.15 ± 5.61 %) within hybrid nanoparticles. The colloidal hybrid nanoparticles demonstrated a polydispersity index (PDI) of about 0.379 ± 0.112, with zeta capacitance of 32.69 ± 5.12 (mV), and an average size of 115 ± 8 (nm). It was found that CLA-CT-HA-NPs had stronger anticancer effects on MCF-7 cells (IC 50  = 8.18 ± 3.02 μM) than pure CLA (IC 50  = 17.15 ± 5.11 μM). The initial cytotoxicity findings were supported by additional investigations based on comet assay and flow cytometry analysis. Tumor remission and survival were evaluated in five separate groups of mice. When juxtaposed with pure CLA (3.17 ± 0.419 %), CLA-CT-HA-NPs improved survival rates and reduced tumor burden by 3.76 ± 0.811(%). Furthermore, in-silico molecular docking investigations revealed that various biodegradable polymers had several levels of compatibility with CLA. The outcomes of this study might potentially served as an effective strategy for delivering drugs in the context of breast cancer therapy., Competing Interests: Declaration of competing interest The authors state that there are no competing interests involved., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Living with HIV/AIDS is more difficult for gay, bisexual, and queer (GBQ) people as they face stigma on both the disease and sexuality, which puts significant stress on coping with stressors, and online platforms have become an alternative coping channel., Methods: This study investigated the use of online coping strategies in moderating the HIV stigma mediated by sexual identity stigma on mental health in Malaysia. 123 GBQ people living with HIV between the ages of 20 and 39 participated in the study, responding to the HIV Stigma - Short Form Scale, adapted China MSM Stigma Scale, Online Coping Inventory, and DASS-21., Result: Results were analyzed using OLS, and logistic regression path modeling showed a statistically significant indirect effect of sexual identity stigma mediating HIV stigma on depressive (ab = 0.1362), anxiety (ab = 0.1259), and stress (ab = 0.1636) levels. Problem-focused online coping strategy was found to moderate the indirect association between HIV stigma and depression levels via sexual identity stigma at low (β = 0.2110, SE = 0.0741, p<.05) and moderate levels (β = 0.1168, SE = 0.0465, p<.05). The findings demonstrated the compounding link between HIV and sexual identity stigmas on mental health and how online coping strategies can be used as a helpful coping resource to manage depressive symptoms for this community and mental health practitioners., Conclusion: These findings can be beneficial to generate a better understanding of how double stigmas play a role in mental health and the types of online coping strategies adopted to process the stressors for GBQ individuals living with HIV in Malaysia., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The discovery of effective therapeutic approaches with minimum side effects and their tendency to completely eradicate the disease is the main challenge in the history of cancer treatment. Fenugreek (FGK) seeds are a rich source of phytochemicals, especially Diosgenin (DGN), which shows outstanding anticancer activities. In the present study, chitosan-silver nanoparticles (ChAgNPs) containing Diosgenin (DGN-ChAgNPs) were synthesized and evaluated for their anticancer activity against breast cancer cell line (MCF-7). For the physical characterization, the hydrodynamic diameter and zeta potential of DGN-ChAgNPs were determined to be 160.4 ± 12 nm and +37.19 ± 5.02 mV, respectively. Transmission electron microscopy (TEM) showed that nanoparticles shape was mostly round with smooth edges. Moreover, DGN was efficiently entrapped in nanoformulation with good entrapment efficacy (EE) of ~88 ± 4 %. The in vitro anti-proliferative activity of DGN-ChAgNPs was performed by sulforhodamine B (SRB) assay with promising inhibitory concentration of 6.902 ± 2.79 μg/mL. DAPI staining, comet assay and flow cytometry were performed to validate the anticancer potential of DGN-ChAgNPs both qualitatively and quantitatively. The percentage of survival rate and tumor reduction weight was evaluated in vivo in different groups of mice. Cisplatin was used as a standard anticancer drug. The DGN-ChAgNPs (12.5 mg/kg) treated group revealed higher percentage of survival rate and tumor reduction weight as compared to pure DGN treated group. These findings suggest that DGN-ChAgNPs could be developed as potential treatment therapy for breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Cancer contributes to a high mortality rate worldwide spanning its diversity from genetics to resistant therapeutic response. To date emerging strategies to combat and manage cancer are particularly focused on the development of targeted therapies as conventional treatments account for the destruction of normal cells as well. In this regard, medicinal plant-based therapies are quite promising in imposing minimal side effects; however, limitations like poor bioavailability and stability of bioactive phytochemicals are associated with them. In parallel, nanotechnology provides nominal solution to deliver particular therapeutic agent without compromising its stability. Methods: In this study, Solanum nigrum , an effective medicinal plant, loaded arabinoxylan cross-linked β-cyclodextrin nanosponges (SN-AXCDNS) were designed to evaluate antitumor activity against breast cancer. Therefore, SN-AXCDNS were prepared by using cross-linker melt method and characterized by physicochemical and pharmacological parameters. Results: Hydrodynamic size, zeta potential and entrapment efficiency (EE%) were estimated as 226 ± 4 nm, -29.15 ± 5.71 mV and 93%, respectively. Surface morphology of nanocomposites showed spherical, smooth, and porous form. Antitumor pharmacological characterization showed that SN loaded nanosponge demonstrated higher cytotoxicity (22.67 ± 6.11 μg/mL), by inducing DNA damage as compared to void SN extract. Flow cytometry analysis reported that encapsulated extract promoted cell cycle arrest at sub-G1 (9.51%). Moreover, in vivo analysis demonstrates the reduction in tumor weight and 85% survival chances in nanosponge treated mice featuring its effectiveness. In addition, in silico analysis revealed that β-cyclodextrin potentially inhibits MELK in breast cancer cell lines (B.E = -10.1 Kcal/mol). Conclusion: Therefore, findings of current study elucidated the therapeutic potential of β-cyclodextrin based nanosponges to be an alternative approach regarding the delivery and solubilization of antitumor drugs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Shah, Zaib, Khan, Sliem, Alharbi, Al-Ghorbani, Jawad, Shahzadi and Awan.)

Introduction: The screening of multicomponent crystal system (MCC) is a key method for improving physicochemical properties of active pharmaceutical ingredients (APIs). The challenges associated with experimental salt screening include a large number of potential counterions and solvent systems and tendency to undergo disproportionation to produce free form during crystallization. These challenges may be mitigated by a combination of experimental and computational approaches to salt screening. The goal of this study is to evaluate performance of the counterion screening methods and propose and validate novel approaches to virtual solvent screening for MCC crystallization., Methods: The actual performance of the ΔpK a  > 3 rule for counterion selection was validated using multiple screenings reports. Novel computational models for virtual solvent screening to avoid MCC incongruent crystallization were proposed. Using the ΔpK a rule, 10 acid counterions were selected for experimental aripiprazole (APZ) salt screening using 10 organic solvents. The experimental results were used to validate the proposed novel virtual solvent screen models., Results: Experimental APZ salt screening resulted in a total of eight MCCs which included glucuronate, mesylate, oxalate, tartrate, salicylate and mandelate. The new model to virtually screen solvents provided a general agreement with APZ experimental findings in terms of selecting the optimal solvent for MCC crystallization., Conclusion: The rational selection of counterions and organic solvents for MCC crystallization was presented using combined novel computational model as well as experimental studies. The current virtual solvent screen model was successfully implemented and validated which can be easily applied to newly discovered APIs., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Solid lipid nanoparticles (SLNs) have the advantages of a cell-specific delivery and sustained release of hydrophobic drugs that can be exploited against infectious diseases. The topical delivery of hydrophobic drugs needs pharmaceutical strategies to enhance drug permeation, which is a challenge faced by conventional formulations containing a drug suspended in gel, creams or ointments. We report the fabrication and optimization of SLNs with sulconazole (SCZ) as a model hydrophobic drug and then a formulation of an SLN-based topical gel against fungal infections. The SLNs were optimized through excipients of glyceryl monostearate and Phospholipon ® 90 H as lipids and tween 20 as a surfactant for its size, drug entrapment and sustained release and resistance against aggregation. The SCZ-SLNs were physically characterized for their particle size (89.81 ± 2.64), polydispersity index (0.311 ± 0.07), zeta potential (-26.98 ± 1.19) and encapsulation efficiency (86.52 ± 0.53). The SCZ-SLNs showed sustained release of 85.29% drug at the 12 h timepoint. The TEM results demonstrated spherical morphology, while DSC, XRD and FTIR showed the compatibility of the drug inside SLNs. SCZ-SLNs were incorporated into a gel using carbopol and were further optimized for their rheological behavior, pH, homogeneity and spreadability on the skin. The antifungal activity against Candida albicans and Trichophyton rubrum was increased in comparison to a SCZ carbopol-based gel. In vivo antifungal activity in rabbits presented faster healing of skin fungal infections. The histopathological examination of the treated skin from rabbits presented restoration of the dermal architecture. In summary, the approach of formulating SLNs into a topical gel presented an advantageous drug delivery system against mycosis.

Tioconazole (TCZ) is a broad-spectrum fungicidal BCS class II drug with reported activity against Candida albicans , dermatophytes , and certain Staphylococci bacteria. We report the use of TCZ-loaded transethosomes (TEs) to overcome the skin's barrier function. TCZ-loaded TEs were fabricated by using a cold method with slight modification. Box-Behnken composite design was utilized to investigate the effect of independent variables. The fabricated TEs were assessed with various physicochemical characterizations. The optimized formulation of TCZ-loaded TEs was incorporated into gel and evaluated for pH, conductivity, drug content, spreadability, rheology, in vitro permeation, ex vivo permeation, and in vitro and in vivo antifungal activity. The fabricated TCZ-loaded TEs had a % EE of 60.56 to 86.13, with particle sizes ranging from 219.1 to 757.1 nm. The SEM images showed spherically shaped vesicles. The % drug permeation was between 77.01 and 92.03. The kinetic analysis of all release profiles followed Higuchi's diffusion model. The FTIR, DSC, and XRD analysis showed no significant chemical interactions between the drug and excipients. A significantly higher antifungal activity was observed for TCZ-loaded transethosomal gel in comparison to the control. The in vivo antifungal study on albino rats indicated that TCZ-loaded transethosomal gel showed a comparable therapeutic effect in comparison to the market brand Canesten ® . Molecular docking demonstrated that the TCZ in the TE composition was surrounded by hydrophobic excipients with increased overall hydrophobicity and better permeation. Therefore, TCZ in the form of transethosomal gel can serve as an effective drug delivery system, having the ability to penetrate the skin and overcome the stratum corneum barrier with improved efficacy.

The expanding global cancer burden necessitates a comprehensive strategy to promote possible therapeutic interventions. Nanomedicine is a cutting-edge approach for treating cancer with minimal adverse effects. In the present study, chitosan-silver nanoparticles (ChAgNPs) containing Eugenol (EGN) were synthesized and evaluated for their anticancer activity against breast cancer cells (MCF-7). The physical, pharmacological, and molecular docking studies were used to characterize these nanoparticles. EGN had been effectively entrapped into hybrid NPs (84 ± 7%). The EGN-ChAgNPs had a diameter of 128 ± 14 nm, a PDI of 0.472 ± 0.118, and a zeta potential of 30.58 ± 6.92 mV. Anticancer activity was measured in vitro using an SRB assay, and the findings revealed that EGN-ChAgNPs demonstrated stronger anticancer activity against MCF-7 cells (IC 50  = 14.87 ± 5.34 µg/ml) than pure EGN (30.72 ± 4.91 µg/ml). To support initial cytotoxicity findings, advanced procedures such as cell cycle analysis and genotoxicity were performed. Tumor weight reduction and survival rate were determined using different groups of mice. Both survival rates and tumor weight reduction were higher in the EGN-ChAgNPs (12.5 mg/kg) treated group than in the pure EGN treated group. Based on protein-ligand interactions, it might be proposed that eugenol had a favorable interaction with Aurora Kinase A. It was observed that C9 had the highest HYDE score of any sample, measuring at -6.8 kJ/mol. These results, in conjunction with physical and pharmacological evaluations, implies that EGN-ChAgNPs may be a suitable drug delivery method for treating breast cancer in a safe and efficient way., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Great saphenous vein insufficiency is linked to 80% of all remarkable lower limb varicosities. A total of 30 patients were enrolled from OPD fulfilling the inclusion criteria after the approval of the hospital's ethical committee. Patients had compression dressing for seven days after surgery. The patients were divided into two groups-Group-A (Compression dressing for two days) and Group-B (Compression dressing for seven days). Stratification of pain score was done against age, gender, and grades of varicose veins, and after dividing into groups t- test was put into use. A p 20 value ≤0.05 was contemplated to be remarkable. Thirty patients with primary varicose vein were enrolled in this study. The mean age of patients was 35.4±9.9 years. Mean pain score in these patients was 2.9±0.8 years. Pain score after seven days of compression dressing after the surgery for varicose veins depend upon the gender, age, and grades of the varicosity of the veins. It is lesser in the females, younger age groups, and in those who had initially lesser severity of the varicose veins.

Establishing the absolute configuration of chiral active pharmaceutical ingredients (APIs) is of great importance. Single crystal X-ray diffraction (scXRD) has traditionally been the method of choice for such analysis, but scXRD requires the growth of large crystals, which can be challenging. Here, we present a method for determining absolute configuration that does not rely on the growth of large crystals. By examining microcrystals formed with chiral probes (small chiral compounds such as amino acids), absolute configuration can be unambiguously determined by microcrystal electron diffraction (MicroED). Our streamlined method employs three steps: (1) virtual screening to identify promising chiral probes, (2) experimental cocrystal screening and (3) structure determination by MicroED and absolute configuration assignment. We successfully applied this method to analyze two chiral API molecules currently on the market for which scXRD was not used to determine absolute configuration., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

End-of-life vehicles (ELV) management is becoming a global concern in the automotive industry. However, there is still limited study on supply chain optimisation that focusses on specific ELV treatments. Therefore, this mini-review article analyses the supply chain optimisation for recycling and remanufacturing sustainable management in ELV. A total of 51 papers were reviewed from the year 2016 to 2021. The key topics in each article were assessed and classified into various themes, followed by the content analysis. The percentage breakdown for the six main themes are ELV recovery management system (37.25%), reverse logistic network design (29.41%), ELV economy analysis (15.69%), government regulation or subsidies (7.84%), ELV quantity forecast (5.88%) and ELV part design (3.92%). It can be concluded that ELV recovery management and reverse logistic network design are the top two key focusses of supply chain optimisation priorities that have been extensively applied to improve ELV development. The literature gap has shown that the study on remanufacturing in the ELV supply chain is minimal compared to recycling. The classification of ELV recycling and remanufacturing supply chain optimisation in this study will be beneficial in supporting real-life problem-solving for industrial applications. This study serves as a valuable reference guide to identifying more sustainable solutions in ELV management and promoting the critical focus area for academicians and industry players.

To address disparities in COVID-19 outcomes among Latinos with limited English proficiency in Maryland, our team developed a culturally congruent intervention that coupled a statewide social marketing campaign with community-based COVID-19 services. In the first year, we reached 305 122 people through social media advertisements and had 9607 visitors to the Web site. Social marketing campaigns represent an opportunity to promote COVID-19 testing and vaccine uptake among Latino populations, especially when they are paired with community services that simultaneously address structural barriers to care. ( Am J Public Health . 2023;113(3):263-266. https://doi.org/10.2105/10.2105/AJPH.2022.307191).

Incompetence of the great saphenous vein (GSV) is a global issue and the most prevalent cause of chronic venous disease of the leg. Clinical manifestations range from moderate to severe, including tiredness, heaviness, and irritation, as well as hyperpigmentation and leg ulcers. A study was conducted to address this controversy,1 i.e. to determine the outcome of compression dressing after varicose vein surgery in terms of postoperative pain, on the Surgical floor, of Mayo Hospital, Lahore, from October 1, 2020, to April 1, 2021. A total of 60 patients with Primary varicose veins were enrolled in this study, fulfilling the inclusion criteria after obtaining approval from the ethical committee of the hospital. The patients were divided in two groups. Group A wore compression dressing for two days after surgery and Group B wore compression dressing for seven days after surgery. All the patients received 1gm Paracetamol I/V eight hourly followed by tablet Paracetamol 500mg P/O eight hourly. Then the outcome of compression dressing was analysed in the form of mean postoperative pain. The mean pain score was assessed on one week. Data were entered in SSPS v23.0. Stratification of pain score was done against age, gender, and grades of varicose veins. A comparison of the two groups was done by applying a t-test. A p-value of ≤ 0.05 was considered significant. Prescribing compression stockings for longer than two days after Trendelenburg's procedure leads to reduced pain and improved physical function during the first week after treatment.

Lung cancer is the leading cause of cancer death in the United States. It has the lowest 5-year survival rate among the most common cancers and therefore, early diagnosis is critical to improve the survival rate. In this paper, a new handheld electronic device is proposed to detect nine lung cancer biomarkers in the exhaled breath. An electrochemical gas sensor was produced through deposition of a thin layer of graphene and Prussian blue on a chromium-modified silicon substrate. Selective binding of the analyte was formed by molecular imprinting polymer (MIP). Subsequent polymerization and removal of the analyte yielded a layer of a conductive polymer on top of the sensor containing molecularly imprinted cavities selective for the target molecule. The sensors were tested over 1-20 parts per trillion (ppt) level of concentration while the sensor resistance has been monitored as the sensors react to the analyte by resistance change. Pentane sensor was also tested for selectivity. A printed circuit board was designed to measure the resistance of each sensor and send the data to a developed application in smartphone through Bluetooth. This handheld device has the potential to be used as a diagnostic method in the near future., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Successful drug therapy in children is contingent upon hassle-free administration of pediatric dosage forms. Pediatric patients suffer from difficulty in swallowing due to weak esophagus muscles in their early age. Considering this challenge liquid formulations are preferred over solid dosage form among pediatric patients to avoid the possibility of choking which can be a serious life-threatening condition in children. The main aim of the present research work was to develop a reconstitutable amorphous acetaminophen spray-dried milk powder (ASDM) as novel pediatric formulation., Methods: ASDM was prepared by spray drying process and the spray drying process was optimized using Box-Behnken design to study the effect of spray drying process parameters at X 1 [inlet temperature], X 2 [aspiration rate] and X 3 [feed rate] to Y 1 [% yield], Y 2 [angle of repose], Y 3 [Hausner's Ratio] and Y 4 [Carr's Index] as dependent variables of ASDM. In addition, each batch was characterized for particle size by polarized light microscopy and drug entrapment., Results: Predicted parameters from optimized spray drying process model were successfully employed to manufacture a scale up cum validation batch of ASDM, which showed notably improved yield and desirable flow properties. The scale-up validation batch was further characterized using thermal analysis, diffraction studies, spectroscopic analysis, dispersion studies, stability APAP in dispersion formulation and formulation stability studies to confirm the physico-chemical stability of ASDM., Conclusions: Thus, ASDM for oral use can serve as a promising pediatric formulation and the developed prototype formulation can be further extended to future newly discovered drugs with similar characteristics., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Inflammation related to cancer occurs in the cellular vicinity of the tumour and is involved with predictions related to the course of disease and survival prognosis in varioua malignancies. These inflammatory markers affect different phases of tumourigenesis, i.e. carcinogenesis, tumour expansion, lymphovascular invasion, and distant metastasis, and, as a result, tumour cells can activate immune mediators and cells directly and/or chemokines as well as prostaglandins. Numbers of circulating different blood cells, i.e. lymphocytes, platelets, neutrophils and levels of plasma proteins, like C-reactive protein and interleukins that are components of inflammatory responses, are hallmarks of pathways leading to tumourigenesis. Thus, they can provide vital information in stratifying patients according to the risk and precisely targeted clinical care and outcome in malignancies. The current narrartive review was planned to discuss the role of platelet-to-lymphocyte ratio alongside the use of systemic immune inflammation index as the inflammatory mediators of malignancies along with overview of their role in different studies. It was also planned to recommend what the future studies should should aim at, including multiple risk factors, exposures and inflammatory profiles and as well as their combined interactions, for a better understanding of the role of the inflammatory mediators in malignancy.

HIV-related stigma exacerbates Latino immigrants' risk of HIV infection and delayed care. Following the implementation of the social marketing campaign Sólo Se Vive Una Vez (You Only Live Once) to increase HIV testing that addressed stigmatizing beliefs, we conducted a survey among Latinos in Baltimore, Maryland (N = 357). The aims of this paper are to 1) characterize the sociodemographic characteristics, HIV-related stigma beliefs, and testing behaviors of the survey respondents by campaign exposure, and 2) model the effects of Vive exposure on stigma beliefs and testing behaviors. Comparing post-campaign survey respondents exposed and unexposed to the campaign to survey findings previously obtained and reported before the campaign implementation, respondents to the post-Vive survey continued to hold high levels of stigma beliefs, and compared to the pre-Vive survey sample, were more likely to hold four or more stigmatizing beliefs (from the six survey items). Among the post-Vive survey respondents, those for whom religion was important or very important had an increased odds of 1.6 of holding four or more stigmatizing beliefs. Survey respondents who were exposed to the campaign, however, had an increased odds of 2.25 of reporting ever having been tested for HIV. Our findings demonstrate the importance of the changing social context in addressing stigma within emerging immigrant communities and highlight the critical role of religious leaders in efforts to address HIV-related stigma., Competing Interests: The authors have declared that no competing interests exist.

An Embryonic stem line was engineered with CRISPR mediated knock-in to tag the endogenous locus of Sox2 with tdTomato and Gata6 with GFP. The site-specific knock-ins were genotyped by PCR and DNA sequencing. The timely expression of Gata6 and loss of Sox2 upon differentiation in cells and Embryoid bodies (EBs) were studied by microscopy. The GFP and tdtomato expressing population from day 4 EBs showed exclusive expression of GATA6 and SOX2 protein, confirming the appropriate expression of the fluorescent reporters in the cell line., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

The determination of the variability of critical dosage form attributes has been a challenge in establishing the quality of pharmaceutical products. During the development process knowledge is minimal. Consequently, ad hoc statistical tools such as hypothesis or significance tests, with calibrated decision error rates are often used in an effort to vet CQAs (Critical Quality Attributes) and keep their levels "between the curbs". As progress moves towards product launch, process and mechanistic understanding grows considerably and there are opportunities to leverage that knowledge for predictive modeling. Bayesian models offer a coherent strategy for integrating prior knowledge into both experimental design as well as predictive analysis for optimal risk-based decision making. This is because the Bayesian paradigm, unlike the frequentist paradigm, can assign probabilities to underlying states of nature that directly impact safety and efficacy such as the population distribution of tablet potencies or dissolution profiles in a batch. However, there are challenges and reluctance in switching to a predictive modeling quality framework once regulatory approval has been attained. This paper offers encouragement to make this switch. In this paper, we review a joint Long Island University - Purdue University (LIU-PU) FDA funded project whose purpose was to further integrate the concepts of this adaptive approach to lot release with the rationale and methods for data generation and curation and to extend the testing of this approach. We discuss the utility of the approach in product development. We consider the regulatory compliance implications, with examples, and establish a potential way forward toward implementation of this approach for both industry and regulatory stake-holders., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Multiple myeloma (MM) is a complex hematologic malignancy characterized by the uncontrolled proliferation of clonal plasma cells in the bone marrow that secrete large amounts of immunoglobulins and other non-functional proteins. Despite decades of progress and several landmark therapeutic advancements, MM remains incurable in most cases. Standard of care frontline therapies have limited durable efficacy, with the majority of patients eventually relapsing, either early or later. Induced drug resistance via up-modulations of signaling cascades that circumvent the effect of drugs and the emergence of genetically heterogeneous sub-clones are the major causes of the relapsed-refractory state of MM. Cytopenias from cumulative treatment toxicity and disease refractoriness limit therapeutic options, hence creating an urgent need for innovative approaches effective against highly heterogeneous myeloma cell populations. Here, we present a comprehensive overview of the current and future treatment paradigm of MM, and highlight the gaps in therapeutic translations of recent advances in targeted therapy and immunotherapy. We also discuss the therapeutic potential of emerging preclinical research in multiple myeloma.

Introduction and Aims: There is paucity of prospective studies on conversion total hip arthroplasty (CTHA) for failed proximal femoral nailing. The objective of this study is to evaluate the functional outcome of CTHA using extensively porous coated distal loading stem for failed proximal femoral nailing., Patients and Methods: Fifteen consecutively operated patients for failed proximal femoral nail treated with single stage procedure of nail extraction and CTHA were included in this prospective observational study. All patients received metal-on-polyethylene bearing with uncemented press-fit acetabular cup (Pinnacle cup; DePuy, Warsaw [IN], USA) and extensively porous coated distally loading revision stem (Solution stem; DePuy, Warsaw [IN], USA). All patients were assessed preoperatively and postoperatively at one, three, six and more than twelve months using the Harris Hip Score (HHS). The responsiveness of HHS was assessed using Effect Size (ES) and Standardised Response Mean (SRM). ES and SRM >0.8 indicates adequate responsiveness., Results: The mean duration of follow-up was 16.9 months for the overall cohort (SD: 7.9; range: 6-28 months). The mean preoperative HHS was 32 ± 6.1, the mean HHS at six months follow-up was 89.7 ± 4.0 and the mean HHS at final follow-up of atleast one year was 93.7 ± 3.0. There was a statistically and clinically significant improvement in the HHS from preoperatively to final follow-up postoperatively (p < 0.0001). At the final follow-up, twelve patients (80%) had an excellent outcome and three patients (20%) had a good outcome as per HHS grading. The ES was 9.87 and the SRM was 8.86 thereby suggesting adequate responsiveness. One patient developed surgical site infection and another patient developed dislocation. Both were successfully treated and subsequently the patients made uneventful recovery. None of the patients required revision surgery., Conclusion: HHS has adequate responsiveness for assessing the functional outcome of CTHA. We recommend the use of an uncemented cup and uncemented extensively porous coated, distal loading stem for failed PFN fixation in intertrochanteric hip fractures., Competing Interests: None to declare., (© 2022 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.)

Objective: To identify novel biomarkers of cardiovascular disease (CVD) risk in type 2 diabetes (T2D) via a hypothesis-free global metabolomics study, while taking into account renal function, an important confounder often overlooked in previous metabolomics studies of CVD., Research Design and Methods: We conducted a global serum metabolomics analysis using the Metabolon platform in a discovery set from the Joslin Kidney Study having a nested case-control design comprising 409 individuals with T2D. Logistic regression was applied to evaluate the association between incident CVD events and each of the 671 metabolites detected by the Metabolon platform, before and after adjustment for renal function and other CVD risk factors. Significant metabolites were followed up with absolute quantification assays in a validation set from the Joslin Heart Study including 599 individuals with T2D with and without clinical evidence of significant coronary heart disease (CHD)., Results: In the discovery set, serum orotidine and 2-piperidinone were significantly associated with increased odds of incident CVD after adjustment for glomerular filtration rate (GFR) (odds ratio [OR] per SD increment 1.94 [95% CI 1.39-2.72], P = 0.0001, and 1.62 [1.26-2.08], P = 0.0001, respectively). Orotidine was also associated with increased odds of CHD in the validation set (OR 1.39 [1.11-1.75]), while 2-piperidinone did not replicate. Furthermore, orotidine, being inversely associated with GFR, mediated 60% of the effects of declining renal function on CVD risk. Addition of orotidine to established clinical predictors improved (P < 0.05) C statistics and discrimination indices for CVD risk (ΔAUC 0.053, rIDI 0.48, NRI 0.42) compared with the clinical predictors alone., Conclusions: Through a robust metabolomics approach, with independent validation, we have discovered serum orotidine as a novel biomarker of increased odds of CVD in T2D, independent of renal function. Additionally, orotidine may be a biological mediator of the increased CVD risk associated with poor kidney function and may help improve CVD risk prediction in T2D., (© 2022 by the American Diabetes Association.)

Voriconazole (VRC) is a broad-spectrum antifungal agent belonging to BCS class II (biopharmaceutical classification system). Despite many efforts to enhance its solubility, this primary issue still remains challenging for formulation scientists. Transethosomes (TELs) are one of the potential innovative nano-carriers for improving the solubility and permeation of poorly soluble and permeable drugs. We herein report voriconazole-loaded transethosomes (VRCT) fabricated by the cold method and followed by their incorporation into carbopol 940 as a gel. The prepared VRCT were evaluated for % yield, % entrapment efficiency (EE), surface morphology, possible chemical interaction, particle size, zeta potential, and polydispersity index (PDI). The optimized formulation had a particle size of 228.2 nm, a zeta potential of -26.5 mV, and a PDI of 0.45 with enhanced % EE. Rheology, spreadability, extrudability, in vitro release, skin permeation, molecular docking, antifungal, and antileishmanial activity were also assessed for VRCT and VRC loaded transethosomal gel (VTEG). Ex-vivo permeation using rat skin depicted a transdermal flux of 22.8 µg/cm 2 /h with enhanced efficiency up to 4-fold. A two-fold reduction in inhibitory as well as fungicidal concentration was observed against various fungal strains by VRCT and VTEG besides similar results against L-donovani. The development of transethosomal formulation can serve as an efficient drug delivery system through a topical route with enhanced efficacy and better patient compliance.

Background: Latino communities are among the most heavily impacted populations by the COVID-19 pandemic in the United States due to intersectional barriers to care. Crowdsourcing open contests can be an effective means of community engagement but have not been well studied in Latino populations nor in addressing the COVID-19 pandemic., Objective: The aims of this study are to (1) implement and evaluate a crowdsourcing open contest to solicit a name for a COVID-19 social marketing campaign for Latino populations in Maryland and (2) conduct a thematic analysis of submitted entries to guide campaign messaging., Methods: To assess the level of community engagement in this crowdsourcing open contest, we used descriptive statistics to analyze data on entries, votes, and demographic characteristics of participants. The submitted text was analyzed through inductive thematic analysis., Results: We received 74 entries within a 2-week period. The top 10 entries were chosen by community judges and the winner was decided by popular vote. We received 383 votes within 1 week. The most common themes were collective efficacy, self-efficacy, and perceived benefits of COVID-19 testing. We used these themes to directly inform our social marketing intervention and found that advertisements based on these themes became the highest performing., Conclusions: Crowdsourcing open contests are an effective means of community engagement and an agile tool for guiding interventions to address COVID-19, including in populations impacted by health care disparities, such as Latino communities. The thematic analysis of contest entries can be a valuable strategy to inform the development of social marketing campaign materials., (©Harita S Shah, Suzanne Dolwick Grieb, Alejandra Flores-Miller, Katherine H Phillips, Kathleen R Page, Ana Cervantes, Cui Yang. Originally published in JMIR Formative Research (https://formative.jmir.org), 12.05.2022.)

This study aimed to develop the Fenugreek seed mucilage-based pH-responsive hydrogel system in order to improve the oral bioavailability of methotrexate (MTX). Fenugreek seed mucilage (FSM) was extracted from Trigonella foenum-graecum seeds. F1-F9 formulations of pH-responsive hydrogels were prepared using various FSM ratios, methacrylic acid (MAA), and methylene bis acrylamide (MBA) via free radical polymerization technique. Swelling behavior and in vitro drug release studies of prepared hydrogels were evaluated. Toxicity studies of prepared hydrogels were performed on normal cells and on Wistar rats (n = 6). Moreover, in vivo pharmacokinetics parameters were studied on albino rabbits. Hydrogels formation was confirmed by FTIR analysis, thermal analysis and SEM studies. The maximum swelling of hydrogel was found to be 384.7% at pH 7.4. MTX-loaded hydrogel showed the controlled release of MTX up to 24 h following Super Case II transport. Prepared hydrogels exhibited no toxicity in normal cells as well as in experimental subjects. MTX loaded hydrogels exhibited less inhibition compared to free MTX on Hela cells. In Vivo studies revealed 7.5-fold improved oral bioavailability of MTX with higher C max (928 ng/mL). These results indicate that the pH-responsive hydrogel system based on FSM is a promising tool for the controlled delivery of MTX., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The molecular basis of adhesion leading to sticking was investigated by exploring the correlation between thermal analysis and molecular simulations. It is hypothesized that intermolecular interactions between a drug molecule and a punch face are the first step in the adhesion process and the rank order of adhesion during tablet compression should correspond to the rank order of the energies of these interactions. In the present study, the sticking propensity was investigated using ibuprofen, flurbiprofen, and ketoprofen as model substances. At the intermolecular level, a thermal analysis model was proposed as an experimental technique to estimate the work of adhesion between ibuprofen, flurbiprofen, and ketoprofen in a DSC aluminum pan. The linear relationship was established between the enthalpy of vaporization and sample mass to demonstrate the accuracy of the instruments used. The threshold mass for ibuprofen, flurbiprofen, and ketoprofen was determined to be 107, 112, and 222 μg, respectively, after three replicate measurements consistent with the experimental results. Ketoprofen showed a 2-fold higher threshold mass compared to ibuprofen and flurbiprofen, which predicts that ketoprofen should have the highest sticking propensity. Computationally, the rank order of the work of adhesion between ibuprofen, flurbiprofen, and ketoprofen with the metal surface was simulated to be -75.91, 44.75, and -96.91 kcal/mol, respectively, using Materials Studio. The rank order of the interaction between the drug molecule and the iron superlattice decreases in the order ketoprofen > ibuprofen > flurbiprofen. The results indicate that the thermal model can be successfully implemented to assess the sticking propensity of a drug at the molecular level. Also, a new molecular simulation script was successfully applied to determine the interaction energy of the drug molecule upon contact with iron.

The rapidly growing global burden of cancer poses a major challenge to public health and demands a robust approach to access promising anticancer therapeutics. In parallel, nanotechnology approaches with various pharmacological properties offer efficacious clinical outcomes. The use of new artificial variants of nanosponges (NS) as a transporter of chemotherapeutic drugs to target cells has emerged as a very promising tool. Therefore, in this research, ethylcellulose (EC) NS were prepared using the ultrasonication assisted-emulsion solvent evaporation technique. Withaferin-A (WFA), an active ingredient in Withania somnifera , has been implanted into the nanospongic framework with enhanced anticancer properties. Inside the polymeric structure, WFA was efficiently entrapped (85 ± 11%). The drug (WFA) was found to be stable within polymeric nanosponges, as demonstrated by Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) studies. The WFA-NS had a diameter of 117 ± 4 nm and zeta potential of -39.02 ± 5.71 mV with a polydispersity index (PDI) of 0.419 ± 0.073. In addition, scanning electron microscopy (SEM) revealed the porous surface texture of WFA-NS. In vitro anticancer activity (SRB assay) results showed that WFA-NS exhibited almost twice the anticancer efficacy against MCF-7 cells (IC 50 = 1.57 ± 0.091 µM), as quantified by flow cytometry and comet tests. Moreover, fluorescence microscopy with DAPI staining and analysis of DNA fragmentation revealed apoptosis as a mechanism of cancer cell death. The anticancer activity of WFA-NS was further determined in vivo and results were compared to cisplatin. The anticancer activity of WFA-NS was further investigated in vivo, and the data were consistent to those obtained with cisplatin. At Day 10, WFA-NS (10 mg/kg) significantly reduced tumour volume to 72 ± 6%, which was comparable to cisplatin (10 mg/kg), which reduced tumour volume to 78 ± 8%. Finally, the outcomes of molecular modeling (in silico) also suggested that WFA established a stable connection with nanosponges, generating persistent hydrophobic contacts (polar and nonpolar) and helping with the attractive delayed-release features of the formulation. Collectively, all the findings support the use of WFA in nanosponges as a prototype for cancer treatment, and opened up new avenues for increasing the efficacy of natural product-derived medications.

Type 2 diabetes mellitus has been a major health issue with increasing morbidity and mortality due to macrovascular and microvascular complications. The urgent need for improved methods to control hyperglycemic complications reiterates the development of innovative preventive and therapeutic treatment strategies. In this perspective, xanthone compounds in the pericarp of the mangosteen fruit, especially α-mangostin (MGN), have been recognized to restore damaged pancreatic β-cells for optimal insulin release. Therefore, taking advantage of the robust use of nanotechnology for targeted drug delivery, we herein report the preparation of MGN loaded nanosponges for anti-diabetic therapeutic applications. The nanosponges were prepared by quasi-emulsion solvent evaporation method. Physico-chemical characterization of formulated nanosponges with satisfactory outcomes was performed with Fourier transform infra-red (FTIR) spectroscopy, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Zeta potential, hydrodynamic diameter, entrapment efficiency, drug release properties, and stability studies at stress conditions were also tested. Molecular docking analysis revealed significant interactions of α-glucosidase and MGN in a protein-ligand complex. The maximum inhibition by nanosponges against α-glucosidase was observed to be 0.9352 ± 0.0856 µM, 3.11-fold higher than acarbose. In vivo studies were conducted on diabetic rats and plasma glucose levels were estimated by HPLC. Collectively, our findings suggest that MGN-loaded nanosponges may be beneficial in the treatment of diabetes since they prolong the antidiabetic response in plasma and improve patient compliance by slowly releasing MGN and requiring less frequent doses, respectively.

Precisely developed computational methodologies can allow the drug product lifecycle process to be time-efficient, cost-effective and reliable through a thorough fundamental understanding at the molecular level. Computational methodologies include computational simulations, virtual screening, mathematical modeling and predictive tools. In light of current trends and increased expectations of product discovery in early pharmaceutical development, we have discussed different case studies. These case studies clearly demonstrate the successful application of predictive tools alone or in combination with analytical techniques to predict the physicochemical properties of drug substances and drug products, thereby shortening research and development timelines. The overall goal of this report is to summarize unique predictive methodologies, which can assist pharmaceutical scientists in achieving time-sensitive research goals and avoiding associated risks that can potentially affect the drug product quality.

Covid-19 pandemic has created crises among some Malaysians. The crises have both opportunity and threat impacts. Without proper intervention, some people will develop stress, anxiety, and depression. This study aims to explore the emotional anxiety that exists in the society due to Covid-19 pandemic and the roles of social media and counselling support in reducing anxiety among Malaysians. This quantitative research involved online survey throughout the country. The online survey is administered during the First Phase and the Second Phase of Movement Control Order (MCO). The survey contains 13 items which cover three domain: i) anxiety, ii) roles of social media, and iii) roles of counselling support in reducing anxiety among members of the society. There were 8375 respondents from various age groups, locations, as well as economic and educational statuses involved in the study. Data were analysed using descriptive and inferential analysis. Majority of 7233 (86.6%) respondents felt anxious due to Covid-19 pandemic. A total of 7871 respondents (94%) followed the latest updates on Covid-19 to reduce their anxiety. They used social media such as Facebook, Instagram and Twitter to gather information and follow the updates through television and press conference. A total of 5251 respondents (62.7%) were aware of the counselling support provided during the MCO, and 4603 respondents (55%) felt comfortable to have counselling support by phone. The findings will contribute to knowledge on the society's emotional anxiety in facing Covid-19. It reflects the actual situation happened in Malaysia during Covid-19 and MCO., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Elsevier Ltd. All rights reserved.)

Latinxs in the U.S. are disproportionately affected by HIV and more likely to have delayed diagnosis than their non-Latinx peers. We developed and implemented Sólo Se Vive Una Vez (You Only Live Once), the first Spanish-language campaign aimed at improving HIV testing and prevention among Latinx immigrants in Baltimore, Maryland. Sólo Se Vive Una Vez featured a website ( www.solovive.org ) and social marketing campaign promoting free HIV testing through the Baltimore City Health Department (BCHD) clinic and Latinx outreach team. The campaign was not associated with a change in the overall number of Latinxs obtaining HIV testing. However, Latinx HIV testers who reported being exposed to the campaign had significantly higher rates of high-risk sexual behaviors, mean number of sexual partners, and substance use. The campaign was also associated with increased PrEP referrals through the BCHD Latinx outreach team., (© 2021. The Author(s).)

Backgrounds: Accurate measurement and suitable strategies facilitate people regulate their sadness in an effective manner. Regulating or mitigating negative emotions, particularly sadness, is crucial mainly because constant negative emotions may lead to psychological disorders, such as depression and anxiety. This paper presents an overview of sadness regulation strategies and related measurement., Method: Upon adhering to five-step scoping review, this study combed through articles that looked into sadness regulation retrieved from eight databases., Results: As a result of reviewing 40 selected articles, 110 strategies were identified to regulate emotions, particularly sadness. Some of the most commonly reported strategies include expressive suppression, cognitive reappraisal, distraction, seeking social or emotional support, and rumination. The four types of measures emerged from the review are self-reported, informant report (parents or peers), open-ended questions, and emotion regulation instructions. Notably, most studies had tested psychometric properties using Cronbach's alpha alone, while only a handful had assessed validity (construct and factorial validity) and reliability (Cronbach's alpha or test-retest) based on responses captured from questionnaire survey., Conclusion: Several sadness regulation strategies appeared to vary based on gender, age, and use of strategy. Despite the general measurement of emotion regulation, only one measure was developed to measure sadness regulation exclusively for children. Future studies may develop a comprehensive battery of measures to assess sadness regulation using multi-component method., Competing Interests: The authors have declared that no competing interests exist.

A present investigation aimed for multivariate modeling as a solution to resolve inaccuracy in dissolution testing experienced in the use of in-situ UV fiber optics dissolution systems (FODS) due to signal saturation problems. This problem is specifically encountered with high absorbance of moderate to high dose formulations. A high absorbance not only impede a real-time assessment but can also result in inaccurate dissolution profiles. Full spectra (F) and low absorbance regions (L) were employed to develop linear and quadratic (Q) partial least squares (PLS) and principal component regression (PCR) models. The conventional dissolution of atenolol, ibuprofen, and metformin HCl immediate-release (IR) tablets followed by HPLC analysis was used as a reference method to gauge multivariate models' performance in the 'built-in' Opt-Diss model. The linear multivariate modeling outputs resulted in accurate dissolution profiles, despite the potentially high UV signal saturation at later time points. Conversely, the 'built-in' Opt-Diss model and multivariate quadratic models failed to predict dissolution profiles accurately. The current studies show a good agreement in the predictions across both low absorbance region and full spectra, demonstrating the multivariate models' robust predictability. Overall, linear PLS and PCR models showed statistically similar results, which demonstrated their applicative flexibility for using FODS despite signal saturation and provides a unique alternative to traditional and labor-intensive UV or HPLC dissolution testing., (Copyright © 2021. Published by Elsevier B.V.)

The current research work focuses on understanding the reported discrepancies and our observations in the dissolution profiles of warfarin sodium tablets and potential patient-based failure modes during oral warfarin therapy. It was hypothesized that freely soluble crystalline warfarin sodium (WAR C ) at first transforms into noncrystalline warfarin sodium (WAR NC ) under stress conditions. The WAR C → WAR NC conversion facilitates the rapid formation of the poorly soluble unionized form, which could lead to dissolution failures and potential poor in vivo performance. Depressed warfarin concentrations locally in the gastrointestinal tract (GIT) may in turn lead to inadequate absorption and thereby affect bioavailability. A low volume two-stage dissolution method was developed to mimic in vivo GIT conditions. Warfarin sodium tablets exposed to room temperature and 75% relative humidity for 1 week showed approximately 23% decrease in drug release. The decline in drug release supports the hypothesis that WAR NC is converted to the unionized form faster than WAR C does under the same conditions. Solid state characterization (powder X-ray diffractometry and differential scanning calorimetry) data demonstrated the disproportionation of warfarin sodium to unionized warfarin after solubility and dissolution studies. The findings support the hypothesis and a possible failure mode of warfarin sodium tablets. This work is a second case study from our laboratory on narrow therapeutic index drug products in which the instability of the solid state of the drug substance is potentially responsible for observed clinical failures.

Purpose: To assess the stability of insulin detemir at controlled room temperature (RT) at 25°C in different packaging systems over 7 days., Methods: The degradation characteristics of insulin detemir were determined based on the assay results in different packaging systems (pinhole glass vial, closed glass vial, glass syringe, and plastic syringe) at RT using a reverse-phase high-performance liquid chromatography (HPLC) assay method for insulin injection. Each packaging system was compared to insulin detemir stored in the original packaged closed glass vial at 2°C to 8°C., Results: Insulin detemir stored in a closed glass vial and a glass syringe showed minor degradation at the end of day 7 (98.96% ± 1.49% and 99.78% ± 0.10%, respectively). Insulin detemir stored in plastic syringe decreased to 94.90% ± 2.50% by day 3 and to 93.52% ± 0.29% by day 7. Storage in pin-hole glass vial showed an increase in the assay (152.13% ± 0.12%) by day 7., Conclusion: Stability studies in different packaging systems demonstrated that insulin detemir remained stable for at least 7 days in a closed glass vial or glass syringe, but for only 3 days in a plastic syringe at RT. This study will allow pharmacists in the hospital setting to deliver patient-specific insulin doses into an insulin syringe with confidence in the stability.