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Abstract The development and progression of chronic lymphocytic leukemia (CLL) depend on genetic abnormalities and on the immunosuppressive microenvironment. We have explored the possibility that genetic drivers might be responsible for the immune cell dysregulation that shapes the protumor microenvironment. We performed a transcriptome analysis of coding and non-coding RNAs (ncRNAs) during leukemia progression in the Rag2−/−γc −/− MEC1-based xenotransplantation model. The DLEU2/miR-16 locus was found downmodulated in monocytes/macrophages of leukemic mice. To validate the role of this cluster in the tumor immune microenvironment, we generated a mouse model that simultaneously mimics the overexpression of hTCL1 and the germline deletion of the minimal deleted region (MDR) encoding the DLEU2/miR-15a/miR-16-1 cluster. This model provides an innovative and faster CLL system where monocyte differentiation and macrophage polarization are exacerbated, and T-cells are dysfunctional. MDR deletion inversely correlates with the levels of predicted target proteins including BCL2 and PD1/PD-L1 on murine CLL cells and immune cells. The inverse correlation of miR-15a/miR-16-1 with target proteins has been confirmed on patient-derived immune cells. Forced expression of miR-16-1 interferes with monocyte differentiation into tumor-associated macrophages, indicating that selected ncRNAs drive the protumor phenotype of non-malignant immune cells.

The outcome of bicondylar tibial plateau fractures treated with either external fixation (35 patients) or internal fixation (24 patients) was reviewed. Outcome measures included the Rasmussen score, clinical complications, development of osteoarthritis and the requirement for total knee replacement (TKR). Twenty-two (92%) anatomical reductions were achieved in the internal fixation group compared to 27 (77%) in the external fixation group. Infective complications were more common in the external fixation group (9 patients, 26%) due to pin tract infection. There were no deep infections in the internal fixation group. The mean Rasmussen score was not significantly different (mean score 32 in external fixation and 29 in internal fixation) between the two groups and the incidence of osteoarthritis was the same in both groups. Four patients in the external fixation group underwent a TKR compared to 5 patients in the internal fixation group. Bicondylar tibial plateau fractures have similar outcomes following external or internal fixation.

Abstract Genome-wide association studies (GWAS) have yielded significant insights into the genetic architecture of myocardial infarction (MI), although studies in non-European populations are still lacking. Saudi Arabian cohorts offer an opportunity to discover novel genetic variants impacting disease risk due to a high rate of consanguinity. Genome-wide genotyping (GWG), imputation and GWAS followed by meta-analysis were performed based on two independent Saudi Arabian studies comprising 3950 MI patients and 2324 non-MI controls. Meta-analyses were then performed with these two Saudi MI studies and the CardioGRAMplusC4D and UK BioBank GWAS as controls. Meta-analyses of the two Saudi MI studies resulted in 17 SNPs with genome-wide significance. Meta-analyses of all 4 studies revealed 66 loci with genome-wide significance levels of p 12% MAF). In conclusion, our results replicated many MI associations, whereas in Saudi-only GWAS (meta-analyses), several new loci were implicated that require future validation and functional analyses.

Abstract Background Oral microbiome sequencing has revealed key links between microbiome dysfunction and dental caries. However, these efforts have largely focused on Western populations, with few studies on the Middle Eastern communities. The current study aimed to identify the composition and abundance of the oral microbiota in saliva samples of children with different caries levels using machine learning approaches. Methods Oral microbiota composition and abundance were identified in 250 Saudi participants with high dental caries and 150 with low dental caries using 16 S rRNA sequencing on a NextSeq 2000 SP flow cell (Illumina, CA) using 250 bp paired-end reads, and attempted to build a classifier using random forest models to assist in the early detection of caries. Results The ADONIS test results indicate that there was no significant association between sex and Bray-Curtis dissimilarity (p ~ 0.93), but there was a significant association with dental caries status (p ~ 0.001). Using an alpha level of 0.05, five differentially abundant operational taxonomic units (OTUs) were identified between males and females as the main effect along with four differentially abundant OTUs between high and low dental caries. The mean metrics for the optimal hyperparameter combination using the model with only differentially abundant OTUs were: Accuracy (0.701); Matthew’s correlation coefficient (0.0509); AUC (0.517) and F1 score (0.821) while the mean metrics for random forest model using all OTUs were:0.675; 0.054; 0.611 and 0.796 respectively. Conclusion The assessment of oral microbiota samples in a representative Saudi Arabian population for high and low metrics of dental caries yields signatures of abundances and diversity.

We sought to investigate the lower-extremity biomechanics underlying increased gait velocity following high-cadence cycling. Ground reaction forces (GRF) and lower-extremity kinematics and kinetics were recorded as 15 healthy adults walked at a self-selected pace prior to and immediately following a 15 min bout of cycling at a cadence of 75 rotations per minute. Propulsive GRF and stance-phase peak dorsiflexion and knee extension angles increased, while peak plantarflexion and hip extension angles decreased. Swing-phase peak dorsiflexion, plantarflexion, knee flexion, and hip flexion angles increased, while peak knee extension angle decreased. Peak dorsiflexion, knee extension, and hip extension angular velocity also increased during swing. No changes in peak joint moments were observed; however, peak positive ankle, knee, and hip joint power generation increased following cycling. Completing high-cadence cycling improves gait velocity by increasing propulsive GRF; increasing joint angular velocity during the swing phase of gait for the ankle, knee, and hip; and increasing positive power production by the ankle, knee, and hip during the stance phase. Increased gait velocity post cycling exercise did not increase lower-extremity joint moments. Cycling may be a viable exercise-based modality for increasing gait velocity, especially in populations where gait ability or joint loading is of particular concern.

It has been known for decades that the incidence of chronic lymphocytic leukemia (CLL) is significantly lower in Asia than in Western countries, but the reason responsible for this difference still remains a major knowledge gap. Using GeneChip® miRNA array to analyze the global microRNA expression in B lymphocytes from Asian and Western CLL patients and healthy individuals, we have identified microRNA with CLL-promoting or suppressive functions that are differentially expressed in Asian and Western individuals. In particular, miR-4485 is upregulated in CLL patients of both ethnic groups, and its expression is significantly lower in Asian healthy individuals. Genetic silencing of miR-4485 in CLL cells suppresses leukemia cell growth, whereas ectopic expression of miR-4485 promotes cell proliferation. Mechanistically, miR-4485 exerts its CLL-promoting activity by inhibiting the expression of TGR5 and activating the ERK1/2 pathway. In contrast, miR-138, miR-181a, miR- 181c, miR-181d, and miR-363 with tumor-suppressive function are highly expressed in Asian healthy individuals. Our study suggests that differential expression of several important microRNA with pro- or anti-CLL functions in Asian and Western B lymphocytes likely contributes to the difference in CLL incidence between the two ethnic groups, and that miR-4485 and its downstream molecule TGR5 could be potential therapeutic targets.

(1) Background: Few studies have examined risk factors of frailty during early life and mid-adulthood, which may be critical to prevent frailty and/or postpone it. The aim was to identify early life and adulthood risk factors associated with frailty. (2) Methods: A systematic review of cohort studies (of at least 10 years of follow-up), using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA). A risk of confounding score was created by the authors for risk of bias assessment. Three databases were searched from inception until 1 January 2023 (Web of Science, Embase, PubMed). Inclusion criteria were any cohort study that evaluated associations between any risk factor and frailty. (3) Results: Overall, a total of 5765 articles were identified, with 33 meeting the inclusion criteria. Of the included studies, only 16 were categorized as having a low risk of confounding due to pre-existing diseases. The long-term risk of frailty was lower among individuals who were normal weight, physically active, consumed fruits and vegetables regularly, and refrained from tobacco smoking, excessive alcohol intake, and regular consumption of sugar or artificially sweetened drinks. (4) Conclusions: Frailty in older adults might be prevented or postponed with behaviors related to ideal cardiovascular health.

Abstract Background We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

The community spread of COVID-19 is well known and has been rigorously studied since the onset of the pandemic; however, little is known about the risk of transmission to hospitalized patients. Many practices have been adopted by healthcare facilities to protect patients and staff by attempting to mitigate internal spread of the disease; however, these practices are highly variable among institutions, and it is difficult to identify which interventions are both practical and impactful. Our institution, for example, adopted the most rigorous infection control methods in an effort to keep patients and staff as safe as possible throughout the pandemic. This case report details the hospital courses of two trauma patients, both of whom tested negative for the COVID-19 virus multiple times prior to producing positive tests late in their hospital courses. The two patients share many common features including history of psychiatric illness, significant injuries, ICU stays, one-to-one observers, multiple consulting services, and a prolonged hospital course prior to discharge to a rehabilitation facility. Analysis of these hospital courses can help provide a better understanding of potential risk factors for acquisition of a nosocomial COVID-19 infection and insight into which measures may be most effective in preventing future occurrences. This is important to consider not only for COVID-19 but also for future novel infectious diseases.

This study quantifies future changes in tropospheric ozone (O3) using a simple parameterisation of source–receptor relationships based on simulations from a range of models participating in the Task Force on Hemispheric Transport of Air Pollutants (TF-HTAP) experiments. Surface and tropospheric O3 changes are calculated globally and across 16 regions from perturbations in precursor emissions (NOx, CO, volatile organic compounds – VOCs) and methane (CH4) abundance only, neglecting any impact from climate change. A source attribution is provided for each source region along with an estimate of uncertainty based on the spread of the results from the models. Tests against model simulations using the Hadley Centre Global Environment Model version 2 – Earth system configuration (HadGEM2-ES) confirm that the approaches used within the parameterisation perform well for most regions. The O3 response to changes in CH4 abundance is slightly larger in the TF-HTAP Phase 2 than in the TF-HTAP Phase 1 assessment (2010) and provides further evidence that controlling CH4 is important for limiting future O3 concentrations. Different treatments of chemistry and meteorology in models remain one of the largest uncertainties in calculating the O3 response to perturbations in CH4 abundance and precursor emissions, particularly over the Middle East and south Asia regions. Emission changes for the future Evaluating the CLimate and Air Quality ImPacts of Short-livEd Pollutants (ECLIPSE) scenarios and a subset of preliminary Shared Socioeconomic Pathways (SSPs) indicate that surface O3 concentrations will increase regionally by 1 to 8 ppbv in 2050. Source attribution analysis highlights the growing importance of CH4 in the future under current legislation. A change in the global tropospheric O3 radiative forcing of +0.07 W m−2 from 2010 to 2050 is predicted using the ECLIPSE scenarios and SSPs, based solely on changes in CH4 abundance and tropospheric O3 precursor emissions and neglecting any influence of climate change. Current legislation is shown to be inadequate in limiting the future degradation of surface ozone air quality and enhancement of near-term climate warming. More stringent future emission controls provide a large reduction in both surface O3 concentrations and O3 radiative forcing. The parameterisation provides a simple tool to highlight the different impacts and associated uncertainties of local and hemispheric emission control strategies on both surface air quality and the near-term climate forcing by tropospheric O3.

Abstract Background The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG). Results Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p

The recent update on the US National Ambient Air Quality Standards (NAAQS) of the ground-level ozone (O3) can benefit from a better understanding of its source contributions in different US regions during recent years. In the Hemispheric Transport of Air Pollution experiment phase 1 (HTAP1), various global models were used to determine the O3 source–receptor (SR) relationships among three continents in the Northern Hemisphere in 2001. In support of the HTAP phase 2 (HTAP2) experiment that studies more recent years and involves higher-resolution global models and regional models' participation, we conduct a number of regional-scale Sulfur Transport and dEposition Model (STEM) air quality base and sensitivity simulations over North America during May–June 2010. STEM's top and lateral chemical boundary conditions were downscaled from three global chemical transport models' (i.e., GEOS-Chem, RAQMS, and ECMWF C-IFS) base and sensitivity simulations in which the East Asian (EAS) anthropogenic emissions were reduced by 20 %. The mean differences between STEM surface O3 sensitivities to the emission changes and its corresponding boundary condition model's are smaller than those among its boundary condition models, in terms of the regional/period-mean (3 sensitivities to the size of the emission perturbation is spatially varying, and the full (i.e., based on a 100 % emission reduction) source contribution obtained from linearly scaling the North American mean O3 sensitivities to a 20 % reduction in the EAS anthropogenic emissions may be underestimated by at least 10 %. The three boundary condition models' mean O3 sensitivities to the 20 % EAS emission perturbations are ∼ 8 % (May–June 2010)/∼ 11 % (2010 annual) lower than those estimated by eight global models, and the multi-model ensemble estimates are higher than the HTAP1 reported 2001 conditions. GEOS-Chem sensitivities indicate that the EAS anthropogenic NOx emissions matter more than the other EAS O3 precursors to the North American O3, qualitatively consistent with previous adjoint sensitivity calculations. In addition to the analyses on large spatial–temporal scales relative to the HTAP1, we also show results on subcontinental and event scales that are more relevant to the US air quality management. The EAS pollution impacts are weaker during observed O3 exceedances than on all days in most US regions except over some high-terrain western US rural/remote areas. Satellite O3 (TES, JPL–IASI, and AIRS) and carbon monoxide (TES and AIRS) products, along with surface measurements and model calculations, show that during certain episodes stratospheric O3 intrusions and the transported EAS pollution influenced O3 in the western and the eastern US differently. Free-running (i.e., without chemical data assimilation) global models underpredicted the transported background O3 during these episodes, posing difficulties for STEM to accurately simulate the surface O3 and its source contribution. Although we effectively improved the modeled O3 by incorporating satellite O3 (OMI and MLS) and evaluated the quality of the HTAP2 emission inventory with the Royal Netherlands Meteorological Institute–Ozone Monitoring Instrument (KNMI–OMI) nitrogen dioxide, using observations to evaluate and improve O3 source attribution still remains to be further explored.

The emergence of B cell receptor (BCR) kinase inhibitors has recently changed the treatment landscape in chronic lymphocytic leukaemia (CLL). The inhibitors that selectively target potential kinases downstream from BCR (particularly Bruton’s tyrosine kinase [BTK] and phosphoinositide 3-kinase [PI3K]) have replaced conventional chemotherapy for high-risk CLL. Ibrutinib and idelalisib are the respective first-in-class BTK and PI3K-δ inhibitors that are US Food and Drug Administration (FDA) approved for CLL treatment, with promising second-generation molecules under development. Differing from idelalisib, duvelisib (IPI-145) inhibits both delta and gamma isoforms of PI3K. Kinase inhibitors have gained popularity in the clinic primarily due to their ability to induce remissions in the vast majority of patients, even in patients with high-risk disease features, without causing haematotoxicity. In particular, they interfere with the homing capabilities of CLL cells residing in their respective microenvironments and cause lymphocytosis via redistribution of tissue-resident CLL cells into the peripheral blood. Thereby, BCR inhibitors can seek out and target hiding CLL cells in the lymph node and marrow niches. In this review, we discuss laboratory and clinical aspects of the BCR inhibitors that have recently advanced the treatment of B cell malignancies, with a particular emphasis on CLL. Despite the excitement about this new class of compounds targeting BCR signalling, single agent therapy with kinase inhibitors has limitations, requiring continuous kinase suppression to maintain remissions, which generally are partial remissions, indicating that combination strategies will become important for moving the field forward.

Richter syndrome is the name given to the transformation of the most frequent type of leukemia, chronic lymphocytic leukemia, into an aggressive lymphoma. Patients with Richter syndrome have limited response to therapies and dismal survival. The underlying mechanisms of transformation are insufficiently understood and there is a major lack of knowledge regarding the roles of microRNA that have already proven to be causative for most cases of chronic lymphocytic leukemia. Here, by using four types of genomic platforms and independent sets of patients from three institutions, we identified microRNA involved in the transformation of chronic lymphocytic leukemia to Richter syndrome. The expression signature is composed of miR-21, miR-150, miR-146b and miR-181b, with confirmed targets significantly enriched in pathways involved in cancer, immunity and inflammation. In addition, we demonstrated that genomic alterations may account for microRNA deregulation in a subset of cases of Richter syndrome. Furthermore, network analysis showed that Richter transformation leads to a complete rearrangement, resulting in a highly connected microRNA network. Functionally, ectopic overexpression of miR-21 increased proliferation of malignant B cells in multiple assays, while miR-150 and miR-26a were downregulated in a chronic lymphocytic leukemia xenogeneic mouse transplantation model. Together, our results suggest that Richter transformation is associated with significant expression and genomic loci alterations of microRNA involved in both malignancy and immunity.

The microbial community of the gut conveys significant benefits to host physiology. A clear relationship has now been established between gut bacteria and host metabolism in which microbial-mediated gut hormone release plays an important role. Within the gut lumen, bacteria produce a number of metabolites and contain structural components that act as signaling molecules to a number of cell types within the mucosa. Enteroendocrine cells within the mucosal lining of the gut synthesize and secrete a number of hormones including CCK, PYY, GLP-1, GIP, and 5-HT, which have regulatory roles in key metabolic processes such as insulin sensitivity, glucose tolerance, fat storage, and appetite. Release of these hormones can be influenced by the presence of bacteria and their metabolites within the gut and as such, microbial-mediated gut hormone release is an important component of microbial regulation of host metabolism. Dietary or pharmacological interventions which alter the gut microbiome therefore pose as potential therapeutics for the treatment of human metabolic disorders. This review aims to describe the complex interaction between intestinal microbiota and their metabolites and gut enteroendocrine cells, and highlight how the gut microbiome can influence host metabolism through the regulation of gut hormone release.

Although trisomy 12 (+12) chronic lymphocytic leukemia (CLL) comprises about 20% of cases, relatively little is known about its pathophysiology. These cases often demonstrate atypical morphological and immunophenotypic features, high proliferative rates, unmutated immunoglobulin heavy chain variable region genes, and a high frequency of NOTCH1 mutation. Patients with +12 CLL have an intermediate prognosis, and show higher incidences of thrombocytopenia, Richter transformation, and other secondary cancers. Despite these important differences, relatively few transcriptional profiling studies have focused on identifying dysregulated pathways that characterize +12 CLL, and most have used a hierarchical cytogenetic classification in which cases with more than one recurrent abnormality are categorized according to the abnormality with the poorest prognosis. In this study, we sought to identify protein-coding genes whose expression contributes to the unique pathophysiology of +12 CLL. To exclude the likely confounding effects of multiple cytogenetic abnormalities on gene expression, our +12 patient cohort had +12 as the sole abnormality. We profiled samples obtained from 147 treatment-naïve patients. We compared cases with +12 as the only cytogenetic abnormality to cases with only del(13q), del(11q), or diploid cytogenetics using independent discovery (n=97) and validation (n=50) sets. We demonstrate that CLL cases with +12 as the sole abnormality express a unique set of activated pathways compared to other cytogenetic subtypes. Among these pathways, we identify the NFAT signaling pathway and the immune checkpoint molecule, NT5E (CD73), which may represent new therapeutic targets.