A computational pipeline for identifying gene targets and signalling pathways in cancer cells to improve lymphocyte infiltration and immune checkpoint therapy efficacy.

BACKGROUND: Tumour-infiltrating lymphocytes (TILs) are crucial for effective immune checkpoint blockade (ICB) therapy in solid tumours. However, ∼70% of these tumours exhibit poor lymphocyte infiltration, rendering ICB therapies less effective. METHODS: We developed a bioinformatics pipeline integrating multiple previously unconsidered factors or datasets, including tumour cell immune-related pathways, copy number variation (CNV), and single tumour cell sequencing data, as well as tumour mRNA-seq data and patient survival data, to identify targets that can potentially improve T cell infiltration and enhance ICB efficacy. Furthermore, we conducted wet-lab experiments and successfully validated one of the top-identified genes. FINDINGS: We applied this pipeline in solid tumours of the Cancer Genome Atlas (TCGA) and identified a set of genes in 18 cancer types that might potentially improve lymphocyte infiltration and ICB efficacy, providing a valuable drug target resource to be further explored. Importantly, we experimentally validated SUN1, which had not been linked to T cell infiltration and ICB therapy previously, but was one of the top-identified gene targets among 3 cancer types based on the pipeline, in a mouse colon cancer syngeneic model. We showed that Sun1 KO could significantly enhance antigen presentation, increase T-cell infiltration, and improve anti-PD1 treatment efficacy. Moreover, with a single-cell multiome analysis, we identified subgene regulatory networks (sub-GRNs) showing Stat proteins play important roles in enhancing the immune-related pathways in Sun1-KO cancer cells. INTERPRETATION: This study not only established a computational pipeline for discovering new gene targets and signalling pathways in cancer cells that block T-cell infiltration, but also provided a gene target pool for further exploration in improving lymphocyte infiltration and ICB efficacy in solid tumours. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Educational Paradigms in Islamic Medical History: A Review.

The rise of Islam in Arabia witnessed a scientific pursuit from 8th CE to 14th CE in its vast dominion. Medicine was one among many disciplines that was reshaped during the golden ages of Islamic world. Physicians and scholars from diverse faiths and background flocked in learning centers of Baghdad, Cordoba, and other cities. A multicultural environment of medical research was evolved with fundings from state. From medical teaching and clinical training to the licensing of physicians, many of the modern attributes of medical education were pioneered in Islamic world. The scholarly transfusion from European territories of Islamic world to the Western world in medieval era laid the foundation of modern medical education.

Aspirin-exacerbated respiratory disease is associated with variants in filaggrin, epithelial integrity, and cellular interactions.

Background: Previous studies have determined that up to 6% of patients with aspirin-exacerbated respiratory disease (AERD) have family history of AERD, indicating a possible link with genetic polymorphisms. However, whole exome sequencing (WES) studies of such associations are currently lacking. Objectives: We sought to examine whether WES can identify pathogenic variants associated with AERD. Methods: Diagnoses of AERD were confirmed in patients with nasal polyps and asthma. WES was performed using an Illumina sequencing platform. Human Phenotype Ontology terms were used to define the patients' phenotypes. Exomiser was used to annotate, filter, and prioritize possible disease-causing genetic variants. Results: Of 39 patients with AERD, 41% reported a family history of asthma and 5% reported a family history of AERD. Pathogenic exome variants in the filaggrin gene (FLG) were found in 2 patients (5%). Other variants not known to be pathogenic were detected in an additional 16 patients (41%) in genes related to epithelial integrity and cellular interactions, including genes encoding desmoglein 3 (DSG3), dynein axonemal heavy chain 9 (DNAH9), collagen type VII alpha 1 chain (COL7A1), collagen type XVII alpha 1 chain (COL17A1), chromodomain helicase DNA binding protein-7 (CHD7), TSC complex subunit 2/tuberous sclerosis-2 protein (TSC2), P-selectin (SELP), and platelet-derived growth factor receptor-alpha (PDGFRA). Conclusion: WES identified a monogenic susceptibility to AERD in 5% of patients with FLG pathogenic variants. Other variants not previously identified as pathogenic were found in genes relevant to epithelial integrity and cellular interactions and may further reveal genetic factors that contribute to this condition.

Factors limiting women's adherence to venous thromboembolism prophylaxis after cesarean section in the Gaza Strip: A cross-sectional study.

OBJECTIVES: We evaluate the rates and limitations of women's adherence to low molecular weight heparin (LMWH) after cesarean section (CS) in the Gaza Strip. METHODS: Women who underwent CS were recruited consecutively. Communication offered to women, adherence to Venous thromboembolism (VTE), and its limiting factors were surveyed. RESULTS: 281 women participated (mean age 27.9 years). 51.95% fully adhered to VTE prophylaxis. Causes of suboptimal adherence were: 51.1% did not feel VTE prophylaxis was important, 37.8% due to high drug cost, and 11.1% didn't receive a prescription for LMWH at discharge. Poor communication was evident as 48.8% of the sample did not receive any instructions about the technical method of LMWH injection, 45.6% did not receive any information about the clinical significance of heparin, and 74.7% were unaware of LMWH side effects. CONCLUSION: There is inadequate adherence to VTE prophylaxis after CS among Gaza women, mostly due to a lack of appropriate communication but also due to drug costs.

Distinct immune escape and microenvironment between RG-like and pri-OPC-like glioma revealed by single-cell RNA-seq analysis.

The association of neurogenesis and gliogenesis with glioma remains unclear. By conducting single-cell RNA-seq analyses on 26 gliomas, we reported their classification into primitive oligodendrocyte precursor cell (pri-OPC)-like and radial glia (RG)-like tumors and validated it in a public cohort and TCGA glioma. The RG-like tumors exhibited wild-type isocitrate dehydrogenase and tended to carry EGFR mutations, and the pri-OPC-like ones were prone to carrying TP53 mutations. Tumor subclones only in pri-OPC-like tumors showed substantially down-regulated MHC-I genes, suggesting their distinct immune evasion programs. Furthermore, the two subgroups appeared to extensively modulate glioma-infiltrating lymphocytes in distinct manners. Some specific genes not expressed in normal immune cells were found in glioma-infiltrating lymphocytes. For example, glial/glioma stem cell markers OLIG1/PTPRZ1 and B cell-specific receptors IGLC2/IGKC were expressed in pri-OPC-like and RG-like glioma-infiltrating lymphocytes, respectively. Their expression was positively correlated with those of immune checkpoint genes (e.g., LGALS33) and poor survivals as validated by the increased expression of LGALS3 upon IGKC overexpression in Jurkat cells. This finding indicated a potential inhibitory role in tumor-infiltrating lymphocytes and could provide a new way of cancer immune evasion.

Is the C-Terminal Domain an Effective and Selective Target for the Design of Hsp90 Inhibitors against Candida Yeast?

Improving the armamentarium to treat invasive candidiasis has become necessary to overcome drug resistance and the lack of alternative therapy. In the pathogenic fungus Candida albicans, the 90-kDa Heat-Shock Protein (Hsp90) has been described as a major regulator of virulence and resistance, offering a promising target. Some human Hsp90 inhibitors have shown activity against Candida spp. in vitro, but host toxicity has limited their use as antifungal drugs. The conservation of Hsp90 across all species leads to selectivity issues. To assess the potential of Hsp90 as a druggable antifungal target, the activity of nine structurally unrelated Hsp90 inhibitors with different binding domains was evaluated against a panel of Candida clinical isolates. The Hsp90 sequences from human and yeast species were aligned. Despite the degree of similarity between human and yeast N-terminal domain residues, the in vitro activities measured for the inhibitors interacting with this domain were not reproducible against all Candida species. Moreover, the inhibitors binding to the C-terminal domain (CTD) did not show any antifungal activity, with the exception of one of them. Given the greater sequence divergence in this domain, the identification of selective CTD inhibitors of fungal Hsp90 could be a promising strategy for the development of innovative antifungal drugs.

Clinically impactful metabolic subtypes of pancreatic ductal adenocarcinoma (PDAC).

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease characterized by a diverse tumor microenvironment. The heterogeneous cellular composition of PDAC makes it challenging to study molecular features of tumor cells using extracts from bulk tumor. The metabolic features in tumor cells from clinical samples are poorly understood, and their impact on clinical outcomes are unknown. Our objective was to identify the metabolic features in the tumor compartment that are most clinically impactful. Methods: A computational deconvolution approach using the DeMixT algorithm was applied to bulk RNASeq data from The Cancer Genome Atlas to determine the proportion of each gene's expression that was attributable to the tumor compartment. A machine learning algorithm designed to identify features most closely associated with survival outcomes was used to identify the most clinically impactful metabolic genes. Results: Two metabolic subtypes (M1 and M2) were identified, based on the pattern of expression of the 26 most important metabolic genes. The M2 phenotype had a significantly worse survival, which was replicated in three external PDAC cohorts. This PDAC subtype was characterized by net glycogen catabolism, accelerated glycolysis, and increased proliferation and cellular migration. Single cell data demonstrated substantial intercellular heterogeneity in the metabolic features that typified this aggressive phenotype. Conclusion: By focusing on features within the tumor compartment, two novel and clinically impactful metabolic subtypes of PDAC were identified. Our study emphasizes the challenges of defining tumor phenotypes in the face of the significant intratumoral heterogeneity that typifies PDAC. Further studies are required to understand the microenvironmental factors that drive the appearance of the metabolic features characteristic of the aggressive M2 PDAC phenotype.

Pharmacophore-Based Screening, Molecular Docking, and Dynamic Simulation of Fungal Metabolites as Inhibitors of Multi-Targets in Neurodegenerative Disorders.

Neurodegenerative disorders, such as Alzheimer's disease (AD), negatively affect the economic and psychological system. For AD, there is still a lack of disease-altering treatments and promising cures due to its complex pathophysiology. In this study, we computationally screened the natural database of fungal metabolites against three known therapeutic target proteins of AD. Initially, a pharmacophore-based, drug-likeness category was employed for screening, and it filtered the 14 (A-N) best hits out of 17,544 fungal metabolites. The 14 best hits were docked individually against GSK-3ß, the NMDA receptor, and BACE-1 to investigate the potential of finding a multitarget inhibitor. We found that compounds B, F, and L were immuno-toxic, whereas E, H, I, and J had a higher LD50 dose (5000 mg/kg). Among the examined metabolites, the Bisacremine-C (compound I) was found to be the most active molecule against GSK-3ß (ΔG: -8.7 ± 0.2 Kcal/mol, Ki: 2.4 × 106 M-1), NMDA (ΔG: -9.5 ± 0.1 Kcal/mol, Ki: 9.2 × 106 M-1), and BACE-1 (ΔG: -9.1 ± 0.2 Kcal/mol, Ki: 4.7 × 106 M-1). It showed a 25-fold higher affinity with GSK-3ß, 6.3-fold higher affinity with NMDA, and 9.04-fold higher affinity with BACE-1 than their native ligands, respectively. Molecular dynamic simulation parameters, such as RMSD, RMSF, Rg, and SASA, all confirmed that the overall structures of the targeted enzymes did not change significantly after binding with Bisacremine-C, and the ligand remained inside the binding cavity in a stable conformation for most of the simulation time. The most significant hydrophobic contacts for the GSK-3ß-Bisacremine-C complex are with ILE62, VAL70, ALA83, and LEU188, whereas GLN185 is significant for H-bonds. In terms of hydrophobic contacts, TYR184 and PHE246 are the most important, while SER180 is vital for H-bonds in NMDA-Bisacremine-C. THR232 is the most crucial for H-bonds in BACE-1-Bisacremine-C and ILE110-produced hydrophobic contacts. This study laid a foundation for further experimental validation and clinical trials regarding the biopotency of Bisacremine-C.

Exploring the impact of integrated polyvagal exercises and knee reinforcement in females with grade II knee osteoarthritis: a randomized controlled trial.

This study aimed to compare the effects of knee strengthening exercises to those of polyvagal theory-based exercises combined with knee strengthening exercises on selected outcomes in women with grade II knee osteoarthritis (OA). A randomized controlled trial was conducted, in which 60 female participants diagnosed with grade II knee OA, with a mean age of 57.27 ± 7.81 years and knee pain rated between 4 and 7 on the visual analog scale (VAS), were assigned to either the knee strengthening exercise group (Group 1, n = 30) or the polyvagal theory-based exercise plus knee strengthening exercise group (Group 2, n = 30). Pre- and posttreatment assessment of outcome variables, including WOMAC scores (joint pain, joint stiffness, functional limitations, and the overall index), WHOQOL scores (overall quality of life, general health, physical, psychological, social, and environmental domains), and heart rate variability (HRV, time and frequency domains), were analyzed. Group 2 demonstrated significantly greater reductions in joint pain, stiffness, and functional limitations than Group 1 after the intervention. Group 2 presented with significantly improved WOMAC scores, indicating better overall outcomes. Group 2 showed significant improvements in the psychological and social domains regarding quality of life. There were no significant differences in the physical domain or the environmental domain. Group 2 showed a significant increase in high-frequency power (HF) and a significant decrease in the LF/HF ratio, suggesting improved autonomic regulation. A combination of polyvagal exercise and knee strengthening training resulted in superior outcomes compared to knee strengthening exercises alone in women with grade II knee OA. These findings support the potential effectiveness of incorporating polyvagal exercises as an adjunctive intervention for osteoarthritis management.

Multi-Year Retrospective Analysis of Mortality and Readmissions Correlated with STOPP/START and the American Geriatric Society Beers Criteria Applied to Calgary Hospital Admissions.

Introduction: The goals of this retrospective cohort study of 129,443 persons admitted to Calgary acute care hospitals from 2013 to 2021 were to ascertain correlations of "potentially inappropriate medications" (PIMs), "potential prescribing omissions" (PPOs), and other risk factors with readmissions and mortality. Methods: Processing and analysis codes were built in Oracle Database 19c (PL/SQL), R, and Excel. Results: The percentage of patients dying during their hospital stay rose from 3.03% during the first admission to 7.2% during the sixth admission. The percentage of patients dying within 6 months of discharge rose from 9.4% after the first admission to 24.9% after the sixth admission. Odds ratios were adjusted for age, gender, and comorbidities, and for readmission, they were the post-admission number of medications (1.16; 1.12-1.12), STOPP PIMs (1.16; 1.15-1.16), AGS Beers PIMs (1.11; 1.11-1.11), and START omissions not corrected with a prescription (1.39; 1.35-1.42). The odds ratios for readmissions for the second to thirty-ninth admission were consistently higher if START PPOs were not corrected for the second (1.41; 1.36-1.46), third (1.41;1.35-1.48), fourth (1.35; 1.28-1.44), fifth (1.38; 1.28-1.49), sixth (1.47; 1.34-1.62), and seventh admission to thirty-ninth admission (1.23; 1.14-1.34). The odds ratios for mortality were post-admission number of medications (1.04; 1.04-1.05), STOPP PIMs (0.99; 0.96-1.00), AGS Beers PIMs (1.08; 1.07-1.08), and START omissions not corrected with a prescription (1.56; 1.50-1.63). START omissions for all admissions corrected with a prescription by a hospital physician correlated with a dramatic reduction in mortality (0.51; 0.49-0.53) within six months of discharge. This was also true for the second (0.52; 0.50-0.55), fourth (0.56; 0.52-0.61), fifth (0.63; 0.57-0.68), sixth (0.68; 0.61-0.76), and seventh admission to thirty-ninth admission (0.71; 0.65-0.78). Conclusions: "Potential prescribing omissions" (PPOs) consisted mostly of needed cardiac medications. These omissions occurred before the first admission of this cohort, and many persisted through their readmissions and discharges. Therefore, these omissions should be corrected in the community before admission by family physicians, in the hospital by hospital physicians, and if they continue after discharge by teams of family physicians, pharmacists, and nurses. These community teams should also meet with patients and focus on patients' understanding of their illnesses, medications, PPOs, and ability for self-care.

Role of Living Anatomy in Medical Education: A Narrative Review.

Introduction: There has been a significant change noticed in the way in how anatomy is taught and learned in last two decades. The use of teaching approaches such as body painting, peer physical examination, medical imaging, and virtual anatomy software in the teaching and learning of living anatomy was made possible by advancements in medical technology. This study focuses on a review of the historical context and contemporary developments in teaching and learning of live and surface anatomy with a special emphasis on its pedagogical elements, some opinions of medical educationists, and undergraduates. Conclusions: It is suggested that living anatomy be included as a core subject in the curriculum. Learning about living anatomy will be improved in an integrated and pertinent framework with the inclusion and execution of teaching and learning modalities such as body painting, peer physical examination, medical imaging, and virtual anatomy software.

Application of low-, and medium-molecular weight chitosan for preparation of spray-dried microparticles loaded with Ferulago angulata essential oil: Physicochemical, antioxidant, antibacterial and in-vitro release properties.

The present work aimed at spray-drying encapsulation of Chavir (Ferulago angulata) essential oil (EO) using low-, and medium-molecular weight chitosan. The obtained EO was observed to be mainly composed of ß-ocimene, α-pinene, and bornyl acetate with antioxidant, and antimicrobial activity. The results indicated that stable emulsions with uniform particle size distribution and encapsulation efficiencies higher than 93 % could be prepared using chitosan as feed for spray-drying. In addition, spray-drying resulted in fabricating stable microspheres with yields higher than 50 %, uniform particle size, and encapsulation efficiency exceeding 70 %. The microspheres were fairly soluble and hygroscopic, and exhibited antioxidant and bacteriostatic activities with a biphasic release pattern. FTIR characterisation confirmed successful encapsulation of EO and thermal properties of microspheres indicated enhanced stability of EO after microencapsulation. Overall, it was revealed that molecular weight of chitosan and EO:chitosan ratio affects some physicochemical properties of obtained chitosan microspheres.

Green synthesis of heterocyclic alkenes using MCM 41 supported perchloric acid catalytic system: characterization and DFT studies.

CONTEXT: In this work, a series of heterocyclic alkenes were prepared by the reaction of 2-hydroxy-1-naphthaldehyde with various heterocyclic active methylene compounds via Knoevenagel condensation reaction using mesoporous silica, MCM 41, supported perchloric acid as an efficient green catalytic system under solvent-free conditions. A comparative study of the conventional method vs the green method was also reported with the same raw materials. 1H NMR, 13C NMR, IR, and mass spectroscopic techniques were used for the characterization of synthesized compounds. METHODS: Computational study was performed for these compounds by applying density functional theory (DFT) at M06 functional and 6-311G (d,p) basis set to interpret the electronic structures and counter check the experimental findings. The frequency analysis with aforementioned levels of DFT was performed to confirm the stability associated with optimized geometries. The true minimum for the optimized geometries for 1, 2, and 3 was achieved as indicated by the absence of negative eigenvalues in all the calculated frequencies. Additionally, natural bond orbitals (NBOs) and nonlinear optical (NLO) properties were explored utilizing the aforementioned level and basis set combination via DFT, whereas the frontier molecular orbitals (FMOs) evaluation was done at time-dependent density functional theory TDDFT at M06/6-311G(d,p). The global reactivity parameters were also calculated using the FMO data. These computation-based outcomes were found in good agreement with the experimental findings.

Real-World Effectiveness of Four Types of COVID-19 Vaccines.

BACKGROUND: There is a scarcity of evidence regarding the real-world effectiveness of coronavirus disease 2019 (COVID-19) vaccines. This was the first study to evaluate the effectiveness of four types of vaccines against asymptomatic and symptomatic infection, and COVID-19 outcomes among the general population. METHODS: This was a matched comparison group quasi-experimental study conducted in Jordan between 1 January and 29 August 2021. In the first part of the study, 1200 fully vaccinated individuals were matched with 1200 unvaccinated control participants. In order to measure vaccine effectiveness, the infection rates of both vaccinated and unvaccinated groups were calculated. The second part of the study included measuring specific anti-SARS CoV-2 immune cells and antibodies. RESULTS: BNT162b2 (Pfizer, New York, NY, USA) showed a significantly higher effectiveness against asymptomatic COVID-19 infection (91.7%) and hospitalization (99.5%) than BBIBP-CorV (Sinopharm, Beijing, China) (88.4% and 98.7%, respectively) and ChAdOx1 nCoV-19 (AstraZeneca, Cambridge, UK) (84.3%, and 98.9%, respectively). The effectiveness rates of the Sputnik V (Gamaleya Research Institute, Moscow, Russia) vaccine against asymptomatic, symptomatic, and hospitalization were 100%, 100%, and 66.7%, respectively. The highest median anti-spike (S) IgG values were seen in individuals who received BNT162b2 (2.9 AU/mL) and ChAdOx1 nCoV-19 (2.8 AU/mL) vaccines. The levels of anti-S IgG were significantly decreased after 7 months of vaccination with BNT162b2 and BBIBP-CorV. There were significant decreases in the median number of neutralizing antibodies one month and seven months after receiving BNT162b2 (from 88.5 to 75.2 4 Bioequivalent Allergen Unit per milliliter/mL), BBIBP-CorV (from 69.5 to 51.5 BAU/mL), and ChAdOx1 nCoV-19 (from 69.2 to 58.BAU/mL) vaccines. The highest percentage of T cells specific to COVID-19 vaccine was found in individuals who received BNT162b2 (88.5%). CONCLUSION: All four vaccines evaluated in this study showed effectiveness against asymptomatic COVID-19 infection, symptomatic infection, hospitalization, and death. Furthermore, BNT162b2, BBIBP-CorV, and ChAdOx1 nCoV-19 induced high levels of immunology markers within one month of vaccination.

Medical Faculty Perspectives Toward Cadaveric Dissection as a Learning Tool for Anatomy Education: A Survey Study in India.

Cadaveric dissection, as a learning tool, has been a part of Indian medical education. Worldwide, with reforms in medical education and the introduction of new learning modalities, cadaveric dissection has been complemented with other modalities such as living anatomy and virtual anatomy. This study aims to collect the feedback of faculty members regarding the role of dissection in the present context of medical education. The method of the study involved a 32-item questionnaire to collect responses; they were collected using the 5-point Likert scale along with two open-ended questions. In general, the closed questions covered these sections: learning styles, interpersonal skills, teaching and learning, dissection, and other learning modes. The principal component analysis was used to explore the multivariate relationships among the items' perceptions. The multivariate regression analysis was conducted between the construct and the latent variable to develop the structural equation model. Four themes, PC1 (learning ability with structural orientation), PC2 (interpersonal skill), PC3 (multimedia-virtual tool), and PC5 (associated factors) had positive relation and were treated as a latent variable motivation for dissection, and theme 4 (PC4, safety) had a negative correlation and was treated as a latent variable repulsion for dissection. It was found that the dissection room is an important place for learning clinical and personal skills, along with empathy, in anatomy education. Safety issues and implementation of stress-coping activities during the induction phase are required. There is also a need to use mixed-method approaches that integrate technology-enhanced learning such as virtual anatomy, living anatomy, and radiological anatomy with cadaveric dissection.

Enhancing the Photovoltaic Properties via Incorporation of Selenophene Units in Organic Chromophores with A2-π2-A1-π1-A2 Configuration: A DFT-Based Exploration.

Currently, polymer organic solar cells (POSCs) are widely utilized due to their significant application, such as low-cost power conversion efficiencies (PCEs). Therefore, we designed a series of photovoltaic materials (D1, D2, D3, D5 and D7) by the incorporation of selenophene units (n = 1-7) as π1-spacers by considering the importance of POSCs. Density functional theory (DFT) calculations were accomplished at MPW1PW91/6-311G (d, p) functional to explore the impact of additional selenophene units on the photovoltaic behavior of the above-mentioned compounds. A comparative analysis was conducted for designed compounds and reference compounds (D1). Reduction in energy gaps (∆E = 2.399 - 2.064 eV) with broader absorption wavelength (λmax = 655.480 - 728.376 nm) in chloroform along with larger charge transference rate was studied with the addition of selenophene units as compared to D1. A significantly higher exciton dissociation rate was studied as lower values of binding energy (Eb = 0.508 - 0.362 eV) were noted in derivatives than in the reference (Eb = 0.526 eV). Moreover, transition density matrix (TDM) and density of state (DOS) data also supported the efficient charge transition origination from HOMOs to LUMOs. Open circuit voltage (Voc) was also calculated for all the aforesaid compounds to check the efficiency, and significant results were seen (1.633-1.549 V). All the analyses supported our compounds as efficient POSCs materials with significant efficacy. These compounds might encourage the experimental researchers to synthesize them due to proficient photovoltaic materials.

Instrument-Assisted Soft Tissue Mobilization Technique versus Static Stretching in Patients with Pronated Dominant Foot: A Comparison in Effectiveness on Flexibility, Foot Posture, Foot Function Index, and Dynamic Balance.

BACKGROUND: Pronated foot is a deformity with various degrees of physical impact. Patients with a pronated foot experience issues such as foot pain, ankle pain, heel pain, shin splints, impaired balance, plantar fasciitis, etc. Objective: The study intended to compare the effectiveness of IASTM (instrument-assisted soft tissue mobilization) and static stretching on ankle flexibility, foot posture, foot function, and balance in patients with a flexible pronated foot. METHODS: Seventy-two participants between the ages of 18-25 years with a flexible pronated foot were included and allocated into three groups: Control, stretching, and IASTM group using single-blinded randomization. Range of motion (ROM) measuring ankle flexibility, foot posture index (FPI), foot function index (FFI), and dynamic balance was measured at baseline and after 4 weeks of intervention. Soft tissue mobilization was applied on to the IASTM group, while the stretching group was directed in static stretching of the gastrocnemius-soleus complex, tibialis anterior, and Achilles tendon in addition to the foot exercises. The control group received only foot exercises for 4 weeks. RESULTS: The result shows the significant improvement of the right dominant foot in ROM plantar flexion, (F = 3.94, p = 0.03), dorsiflexion (F = 3.15, p = 0.05), inversion (F = 8.54, p = 0.001) and eversion (F = 5.93, p = 0.005), FFI (control vs. IASTM, mean difference (MD) = 5.9, p < 0.001), FPI (right foot, control vs. IASTM MD = 0.88, p = 0.004), and in dynamic balance of the right-leg stance (anterior, pre vs. post = 88.55 ± 2.28 vs. 94.65 ± 2.28; anteromedial, pre vs. post = 80.65 ± 2.3 vs. 85.55 ± 2.93; posterior, pre vs. post = 83 ± 3.52 vs. 87 ± 2.99 and lateral, pre vs. post = 73.2 ± 5.02 vs. 78.05 ± 4.29) in the IASTM group. The FFI was increased remarkably in the stretching group as compared to the control group. CONCLUSIONS: Myofascial release technique, i.e., IASTM with foot exercises, significantly improves flexibility, foot posture, foot function, and dynamic balance as compared to stretching, making it a choice of treatment for patients with a flexible pronated foot.

Chitosan-Cu Catalyzed Novel Ferrocenated Spiropyrrolidines: Green Synthesis, Single Crystal X-ray Diffraction, Hirshfeld Surface and Antibacterial Studies.

Chitosan-bounded copper (chitosan-Cu) was introduced for green synthesis of novel ferrocenated spiropyrrolidine hybrids, namely 3'-(4-.bromobenzoyl)-5'-(4-hydroxybenzyl)-4'-ferrocenylspiro[indoline-3,2'-pyrrolidin]-2-one and 3'-(4-bromobenzoyl)-4'-ferrocenylspiro[indoline-3,2'-pyrrolidin]-2-one, in good yield. A one-pot three-component 1,3-dipolar cycloaddition reaction was employed for the formation of spiropyrrolidines from 1-(4-bromophenyl)-ferrocene-prop-2-en-1-one and azomethine ylides, which were developed in situ from tyrosine, glycine, and isatin, respectively. Various spectroscopic methods were used to establish the structures of spiropyrrolidines, and a single crystal X-ray diffraction study of a spiropyrrolidine provided additional confirmation. The crystallographic study revealed that compound 3a has one independent molecule in its unit cell, which is correlated with Hirshfeld surface analysis, and describes intramolecular contacts adversely. The highly yielded products in green conditions were determined for their antibacterial significance and were found to have good activity against Gram-positive and Gram-negative bacterial strains.

Comparing the associations between host and tumor factors with survival outcomes with anti-PD-1 immunotherapy in metastatic melanoma.

BACKGROUND: Anti-programmed death-1 (PD-1) immunotherapy has drastically improved survival for metastatic melanoma; however, 50% of patients have progression within 6 months despite treatment. In this study, we investigated host, and tumor factors for metastatic melanoma patients treated with anti-PD-1 immunotherapy. METHODS: Patients treated with the anti-PD-1 immunotherapy between 2014 and 2017 were identified in Alberta, Canada. All patients had Stage IV melanoma. Patient characteristics, investigations, treatment, and clinical outcomes were obtained from electronic medical records. RESULTS: We identified 174 patients treated with anti-PD-1 immunotherapy. At 37.1 months median follow-up time 135 (77.6%) individuals had died and 150 (86.2%) had progressed. An elevated lactate dehydrogenase (LDH) had a response rate of 21.0% versus 41.0% for those with a normal LDH (p = 0.017). Host factors associated with worse median progression-free survival (mPFS) and median overall survival (mOS) included liver metastases, >3 sites of disease, elevated LDH, thrombocytosis, neutrophilia, anemia, lymphocytopenia, and an elevated neutrophil/lymphocyte ratio. Primary ulcerated tumors had a worse mOS of 11.8 versus 19.3 months (p = 0.042). We identified four prognostic subgroups in advanced melanoma patients treated with anti-PD-1 therapy. (1) Normal LDH with <3 visceral sites, (2) normal LDH with ≥3 visceral sites, (3) LDH 1-2x upper limit of normal (ULN), (4) LDH ≥2x ULN. The mPFS each group was 14.0, 6.5, 3.3, and 1.9 months, while the mOS for each group was 33.3, 15.7, 7.9, and 3.4 months. CONCLUSION: Our study reports that host factors measuring the general immune function, markers of systemic inflammation, and tumor burden and location are the most prognostic for survival.

An ensemble prediction model for COVID-19 mortality risk.

Background: It's critical to identify COVID-19 patients with a higher death risk at early stage to give them better hospitalization or intensive care. However, thus far, none of the machine learning models has been shown to be successful in an independent cohort. We aim to develop a machine learning model which could accurately predict death risk of COVID-19 patients at an early stage in other independent cohorts. Methods: We used a cohort containing 4711 patients whose clinical features associated with patient physiological conditions or lab test data associated with inflammation, hepatorenal function, cardiovascular function, and so on to identify key features. To do so, we first developed a novel data preprocessing approach to clean up clinical features and then developed an ensemble machine learning method to identify key features. Results: Finally, we identified 14 key clinical features whose combination reached a good predictive performance of area under the receiver operating characteristic curve 0.907. Most importantly, we successfully validated these key features in a large independent cohort containing 15 790 patients. Conclusions: Our study shows that 14 key features are robust and useful in predicting the risk of death in patients confirmed SARS-CoV-2 infection at an early stage, and potentially useful in clinical settings to help in making clinical decisions.