Evolution and advancements in genomics and epigenomics in OA research: How far we have come.

OBJECTIVE: Osteoarthritis (OA) is the most prevalent musculoskeletal disease affecting articulating joint tissues, resulting in local and systemic changes that contribute to increased pain and reduced function. Diverse technological advancements have culminated in the advent of high throughput "omic" technologies, enabling identification of comprehensive changes in molecular mediators associated with the disease. Amongst these technologies, genomics and epigenomics - including methylomics and miRNomics, have emerged as important tools to aid our biological understanding of disease. DESIGN: In this narrative review, we selected articles discussing advancements and applications of these technologies to OA biology and pathology. We discuss how genomics, deoxyribonucleic acid (DNA) methylomics, and miRNomics have uncovered disease-related molecular markers in the local and systemic tissues or fluids of OA patients. RESULTS: Genomics investigations into the genetic links of OA, including using genome-wide association studies, have evolved to identify 100+ genetic susceptibility markers of OA. Epigenomic investigations of gene methylation status have identified the importance of methylation to OA-related catabolic gene expression. Furthermore, miRNomic studies have identified key microRNA signatures in various tissues and fluids related to OA disease. CONCLUSIONS: Sharing of standardized, well-annotated omic datasets in curated repositories will be key to enhancing statistical power to detect smaller and targetable changes in the biological signatures underlying OA pathogenesis. Additionally, continued technological developments and analysis methods, including using computational molecular and regulatory networks, are likely to facilitate improved detection of disease-relevant targets, in-turn, supporting precision medicine approaches and new treatment strategies for OA.

Prognostic factors and predictive models in hot gallbladder surgery: A prospective observational study in a high-volume center.

Backgrounds/Aims: The standard treatment for acute cholecystitis, biliary pancreatitis and intractable biliary colics ("hot gallbladder") is emergency laparoscopic cholecystectomy (LC). This paper aims to identify the prognostic factors and create statistical models to predict the outcomes of emergency LC for "hot gallbladder." Methods: A prospective observational cohort study was conducted on 466 patients having an emergency LC in 17 months. Primary endpoint was "suboptimal treatment," defined as the use of escape strategies due to the impossibility to complete the LC. Secondary endpoints were postoperative morbidity and length of postoperative stay. Results: About 10% of patients had a "suboptimal treatment" predicted by age and low albumin. Postop morbidity was 17.2%, predicted by age, admission day, and male sex. Postoperative length of stay was correlated to age, low albumin, and delayed surgery. Conclusions: Several predictive prognostic factors were found to be related to poor emergency LC outcomes. These can be useful in the decision-making process and to inform patients of risks and benefits of an emergency vs. delayed LC for hot gallbladder.

Three decades of advancements in osteoarthritis research: insights from transcriptomic, proteomic, and metabolomic studies.

OBJECTIVE: Osteoarthritis (OA) is a complex disease involving contributions from both local joint tissues and systemic sources. Patient characteristics, encompassing sociodemographic and clinical variables, are intricately linked with OA rendering its understanding challenging. Technological advancements have allowed for a comprehensive analysis of transcripts, proteomes and metabolomes in OA tissues/fluids through omic analyses. The objective of this review is to highlight the advancements achieved by omic studies in enhancing our understanding of OA pathogenesis over the last three decades. DESIGN: We conducted an extensive literature search focusing on transcriptomics, proteomics and metabolomics within the context of OA. Specifically, we explore how these technologies have identified individual transcripts, proteins, and metabolites, as well as distinctive endotype signatures from various body tissues or fluids of OA patients, including insights at the single-cell level, to advance our understanding of this highly complex disease. RESULTS: Omic studies reveal the description of numerous individual molecules and molecular patterns within OA-associated tissues and fluids. This includes the identification of specific cell (sub)types and associated pathways that contribute to disease mechanisms. However, there remains a necessity to further advance these technologies to delineate the spatial organization of cellular subtypes and molecular patterns within OA-afflicted tissues. CONCLUSIONS: Leveraging a multi-omics approach that integrates datasets from diverse molecular detection technologies, combined with patients' clinical and sociodemographic features, and molecular and regulatory networks, holds promise for identifying unique patient endophenotypes. This holistic approach can illuminate the heterogeneity among OA patients and, in turn, facilitate the development of tailored therapeutic interventions.

MicroRNAs as Prognostic Markers for Chondrogenic Differentiation Potential of Equine Mesenchymal Stromal Cells.

Mesenchymal stromal cells (MSCs) are a promising cell source for cartilage tissue regeneration in animals and humans but with large interdonor variation in their in vitro chondrogenic differentiation potential. Underlying molecular mechanisms responsible for culture-expanded MSC heterogeneity remain poorly understood. In this study, we sought to identify variations in microRNA (miRNA) signatures associated with cultured equine MSC chondrogenic differentiation potential from different donors. Neocartilage tissue generated from equine cord blood-derived MSCs was categorized as having either high or low chondrogenic potential (LCP) based on their histological appearance and quantification of glycosaminoglycan deposition. Using next-generation sequencing, we identified 30 differentially expressed miRNAs among undifferentiated MSC cultures that corresponded with their chondrogenic potential. Of note, MSCs with LCP upregulated miR-146a and miR-487b-3p, which was also observed by quantitative real-time polymerase chain reaction. Our findings suggest that miRNA profiling of equine MSC cultures may have prognostic value in selecting MSC donors with regard to their chondrogenic differentiation potential.

Characterization of miR-335-5p and miR-335-3p in human osteoarthritic tissues.

OBJECTIVE: We aimed to characterize the expression patterns, gene targets, and functional effects of miR-335-5p and miR-335-3p among seven primary human knee and hip osteoarthritic tissue types. METHODS: We collected synovial fluid, subchondral bone, articular cartilage, synovium, meniscus/labrum, infrapatellar/acetabular fat, anterior cruciate ligament/ligamentum teres, and vastus medialis oblique/quadratus femoris muscle (n = 7-20) from surgical patients with early- or late-stage osteoarthritis (OA) and quantified miR-335-5p and miR-335-3p expression by real-time PCR. Predicted gene targets were measured in knee OA infrapatellar fat following miRNA inhibitor transfection (n = 3), and prioritized gene targets were validated following miRNA inhibitor and mimic transfection (n = 6). Following pathway analyses, we performed Oil-Red-O staining to assess changes in total lipid content in infrapatellar fat. RESULTS: Showing a 227-fold increase in knee OA infrapatellar fat (the highest expressing tissue) versus meniscus (the lowest expressing tissue), miR-335-5p was more abundant than miR-335-3p (92-fold increase). MiR-335-5p showed higher expression across knee tissues versus hip tissues, and in late-stage versus early-stage knee OA fat. Exploring candidate genes, VCAM1 and MMP13 were identified as putative direct targets of miR-335-5p and miR-335-3p, respectively, showing downregulation with miRNA mimic transfection. Exploring candidate pathways, predicted miR-335-5p gene targets were enriched in a canonical adipogenesis network (p = 2.1e - 5). Modulation of miR-335-5p in late-stage knee OA fat showed an inverse relationship to total lipid content. CONCLUSION: Our data suggest both miR-335-5p and miR-335-3p regulate gene targets in late-stage knee OA infrapatellar fat, though miR-335-5p appears to be more prominent, with tissue-, joint-, and stage-specific effects.

The ChoCO-W prospective observational global study: Does COVID-19 increase gangrenous cholecystitis?

BACKGROUND: The incidence of the highly morbid and potentially lethal gangrenous cholecystitis was reportedly increased during the COVID-19 pandemic. The aim of the ChoCO-W study was to compare the clinical findings and outcomes of acute cholecystitis in patients who had COVID-19 disease with those who did not. METHODS: Data were prospectively collected over 6 months (October 1, 2020, to April 30, 2021) with 1-month follow-up. In October 2020, Delta variant of SARS CoV-2 was isolated for the first time. Demographic and clinical data were analyzed and reported according to the STROBE guidelines. Baseline characteristics and clinical outcomes of patients who had COVID-19 were compared with those who did not. RESULTS: A total of 2893 patients, from 42 countries, 218 centers, involved, with a median age of 61.3 (SD: 17.39) years were prospectively enrolled in this study; 1481 (51%) patients were males. One hundred and eighty (6.9%) patients were COVID-19 positive, while 2412 (93.1%) were negative. Concomitant preexisting diseases including cardiovascular diseases (p < 0.0001), diabetes (p < 0.0001), and severe chronic obstructive airway disease (p = 0.005) were significantly more frequent in the COVID-19 group. Markers of sepsis severity including ARDS (p < 0.0001), PIPAS score (p < 0.0001), WSES sepsis score (p < 0.0001), qSOFA (p < 0.0001), and Tokyo classification of severity of acute cholecystitis (p < 0.0001) were significantly higher in the COVID-19 group. The COVID-19 group had significantly higher postoperative complications (32.2% compared with 11.7%, p < 0.0001), longer mean hospital stay (13.21 compared with 6.51 days, p < 0.0001), and mortality rate (13.4% compared with 1.7%, p < 0.0001). The incidence of gangrenous cholecystitis was doubled in the COVID-19 group (40.7% compared with 22.3%). The mean wall thickness of the gallbladder was significantly higher in the COVID-19 group [6.32 (SD: 2.44) mm compared with 5.4 (SD: 3.45) mm; p < 0.0001]. CONCLUSIONS: The incidence of gangrenous cholecystitis is higher in COVID patients compared with non-COVID patients admitted to the emergency department with acute cholecystitis. Gangrenous cholecystitis in COVID patients is associated with high-grade Clavien-Dindo postoperative complications, longer hospital stay and higher mortality rate. The open cholecystectomy rate is higher in COVID compared with non -COVID patients. It is recommended to delay the surgical treatment in COVID patients, when it is possible, to decrease morbidity and mortality rates. COVID-19 infection and gangrenous cholecystistis are not absolute contraindications to perform laparoscopic cholecystectomy, in a case by case evaluation, in expert hands.

Can genetics guide exercise prescriptions in osteoarthritis?

Osteoarthritis (OA) is the most common form of arthritis and has a multifactorial etiology. Current management for OA focuses on minimizing pain and functional loss, typically involving pharmacological, physical, psychosocial, and mind-body interventions. However, there remain challenges in determining which patients will benefit most from which interventions. Although exercise-based interventions are recommended as first-line treatments and are known to be beneficial for managing both the disease and illness of OA, the optimal exercise "prescription" is unknown, due in part to our limited understanding of the precise mechanisms underlying its action. Here we present our perspective on the potential role of genetics in guiding exercise prescription for persons with OA. We describe key publications in the areas of exercise and OA, genetics and OA, and exercise and genetics, and point to a paucity of knowledge at the intersection of exercise, genetics, and OA. We suggest there is emerging evidence to support the use of genetics and epigenetics to explain the beneficial effects of exercise for OA. We identify missing links in the existing research relating to exercise, genetics, and OA, and highlight epigenetics as a promising mechanism through which environmental exposures such as exercise may impact OA outcomes. We anticipate future studies will improve our understanding of how genetic and epigenetic factors mediate exercise-based interventions to support implementation and ultimately improve OA patient care.

Contribution of MicroRNA-27b-3p to Synovial Fibrotic Responses in Knee Osteoarthritis.

OBJECTIVE: Synovial fibrosis contributes to osteoarthritis (OA) pathology, but the underlying mechanisms remain unknown. We have observed increased microRNA-27b-3p (miR-27b-3p) levels in synovial fluid of patients with late-stage radiographic knee OA. Here, we investigated the contribution of miR-27b-3p to synovial fibrosis in patients with severe knee OA and in a mouse model of knee OA. METHODS: We stained synovium sections obtained from patients with radiographic knee OA scored according to the Kellgren/Lawrence scale and mice that underwent destabilization of the medial meniscus (DMM) for miR-27b-3p using in situ hybridization. We examined the effects of intraarticular injection of miR-27b-3p mimic into naive mouse knee joints and intraarticular injection of a miR-27b-3p inhibitor into mouse knee joints after DMM. We performed transfection with miR-27b-3p mimic and miR-27b-3p inhibitor in human OA fibroblast-like synoviocytes (FLS) using reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) array, RNA sequencing, RT-qPCR, Western blotting, immunofluorescence, and migration assays. RESULTS: We observed increased miR-27b-3p expression in the synovium from patients with knee OA and in mice with DMM-induced arthritis. Injection of the miR-27b-3p mimic in mouse knee joints induced a synovial fibrosis-like phenotype, increased synovitis scores, and increased COL1A1 and α-smooth muscle actin (α-SMA) expression. In the mouse model of DMM-induced arthritis, injection of the miR-27b-3p inhibitor decreased α-SMA but did not change COL1A1 expression levels or synovitis scores. Transfection with the miR-27b-3p mimic in human OA FLS induced profibrotic responses, including increased migration and expression of key extracellular matrix (ECM) genes, but transfection with the miR-27b-3p inhibitor had the opposite effects. RNA sequencing identified a PPARG/ADAMTS8 signaling axis regulated by miR-27b-3p in OA FLS. Human OA FLS transfected with miR-27b-3p mimic and then treated with the PPARG agonist rosiglitazone or with ADAMTS8 small interfering RNA exhibited altered expression of select ECM genes. CONCLUSION: Our findings demonstrate that miR-27b-3p has a key role in ECM regulation associated with synovial fibrosis during OA.

Prognostic factors in the decision-making process for sigmoid volvulus: results of a single-centre retrospective cohort study.

BACKGROUND: Sigmoid volvulus is a common cause of emergency surgical admission. Those patients are often treated conservatively with a high rate of recurrence. We wondered if a more aggressive management might be indicated. METHODS: We have reviewed data of patients diagnosed with acute sigmoid volvulus over a 2-year period. The primary endpoint was patient survival. RESULTS: We analysed 332 admissions of 78 patients. 39.7% underwent resection. Survival was 54.9 ± 8.8 months from the first hospitalization, irrespective of the treatment. Long-term survival was positively influenced by being female, having a low "social score", a younger age and surgery. Multivariate analysis showed that only being female and surgery were independently associated with better survival. CONCLUSION: Early surgery may be the best approach in patients with recurrent sigmoid volvulus, as it ensures longer survival with a better quality of life, regardless of the patient's social and functional condition.

Circulating microRNAs differentiate fast-progressing from slow-progressing and non-progressing knee osteoarthritis in the Osteoarthritis Initiative cohort.

Introduction: The objective of this study is to identify circulating microRNAs that distinguish fast-progressing radiographic knee osteoarthritis (OA) in the Osteoarthritis Initiative cohort by applying microRNA-sequencing. Methods: Participants with Kellgren-Lawrence (KL) grade 0/1 at baseline were included (N = 106). Fast-progressors were defined by an increase to KL 3/4 by 4-year follow-up (N = 20), whereas slow-progressors showed an increase to KL 2/3/4 only at 8-year follow-up (N = 35). Non-progressors remained at KL 0/1 by 8-year follow-up (N = 51). MicroRNA-sequencing was performed on plasma collected at baseline and 4-year follow-up from the same participants. Negative binomial models were fitted to identify differentially expressed (DE) microRNAs. Penalized logistic regression (PLR) analyses were performed to select combinations of DE microRNAs that distinguished fast-progressors. Area under the receiver operating characteristic curves (AUC) were constructed to evaluate predictive ability. Results: DE analyses revealed 48 microRNAs at baseline and 2 microRNAs at 4-year follow-up [false discovery rate (FDR) < 0.05] comparing fast-progressors with both slow-progressors and non-progressors. Among these were hsa-miR-320b, hsa-miR-320c, hsa-miR-320d, and hsa-miR-320e, which were predicted to target gene families, including members of the 14-3-3 gene family, involved in signal transduction. PLR models included miR-320 members as top predictors of fast-progressors and yielded AUC ranging from 82.6 to 91.9, representing good accuracy. Conclusion: The miR-320 family is associated with fast-progressing radiographic knee OA and merits further investigation as potential biomarkers and mechanistic drivers of knee OA.

A Network Biology Approach to Understanding the Tissue-Specific Roles of Non-Coding RNAs in Arthritis.

Discovery of non-coding RNAs continues to provide new insights into some of the key molecular drivers of musculoskeletal diseases. Among these, microRNAs have received widespread attention for their roles in osteoarthritis and rheumatoid arthritis. With evidence to suggest that long non-coding RNAs and circular RNAs function as competing endogenous RNAs to sponge microRNAs, the net effect on gene expression in specific disease contexts can be elusive. Studies to date have focused on elucidating individual long non-coding-microRNA-gene target axes and circular RNA-microRNA-gene target axes, with a paucity of data integrating experimentally validated effects of non-coding RNAs. To address this gap, we curated recent studies reporting non-coding RNA axes in chondrocytes from human osteoarthritis and in fibroblast-like synoviocytes from human rheumatoid arthritis. Using an integrative computational biology approach, we then combined the findings into cell- and disease-specific networks for in-depth interpretation. We highlight some challenges to data integration, including non-existent naming conventions and out-of-date databases for non-coding RNAs, and some successes exemplified by the International Molecular Exchange Consortium for protein interactions. In this perspective article, we suggest that data integration is a useful in silico approach for creating non-coding RNA networks in arthritis and prioritizing interactions for further in vitro and in vivo experimentation in translational research.

Tissue Collection and RNA Extraction from the Human Osteoarthritic Knee Joint.

Osteoarthritis (OA) is a chronic and degenerative joint disease most often affecting the knee. As there is currently no cure, total knee arthroplasty (TKA) is a common surgical intervention. Experiments using primary human OA tissues obtained from TKA provide the capability to investigate disease mechanisms ex vivo. While OA was previously thought to impact mainly the cartilage, it is now known to impact multiple tissues in the joint. This protocol describes patient selection, sample processing, tissue homogenization, RNA extraction, and quality control (based on RNA purity, integrity, and yield) from each of seven unique tissues to support disease mechanism investigation in the knee joint. With informed consent, samples were obtained from patients undergoing TKA for OA. Tissues were dissected, washed, and stored within 4 h of surgery by flash freezing for RNA or formalin fixation for histology. Collected tissues included articular cartilage, subchondral bone, meniscus, infrapatellar fat pad, anterior cruciate ligament, synovium, and vastus medialis oblique muscle. RNA extraction protocols were tested for each tissue type. The most significant modification involved the method of disintegration used for low-cell, high-matrix, hard tissues (considered as cartilage, bone, and meniscus) versus relatively high-cell, low-matrix, soft tissues (considered as fat pad, ligament, synovium, and muscle). It was found that pulverization was appropriate for hard tissues, and homogenization was appropriate for soft tissues. A proclivity for some subjects to yield higher RNA integrity number (RIN) values than other subjects consistently across multiple tissues was observed, suggesting that underlying factors such as disease severity may impact RNA quality. The ability to isolate high-quality RNA from primary human OA tissues provides a physiologically relevant model for sophisticated gene expression experiments, including sequencing, that can lead to clinical insights that are more readily translated to patients.

COVID-19 infection risk by open and laparoscopic surgical smoke: A systematic review of the literature.

BACKGROUND: The current COVID-19 pandemic has greatly changed the way surgery is delivered. In particular, current guidelines and policies have highlighted the need to use high level Personal Protective Equipment to reduce the risk of viral infection during open and laparoscopic surgical procedures. In particular, it was felt that the laparoscopic approach was at higher risk of viral transmission due to the chimney effect of the smoke escape from the trocars during and after the procedure. However, with this being a new and largely unknown viral agent, guidelines have been based on speculation and extrapolation from previous studies conducted in completely different situations, and led to anxiety amongst surgeons and theatre staff. We decided to conduct a systematic review of the Literature to try to clarify whether inhalation of surgical smoke can increase the risk of COVID-19 infection. METHODS: A thorough search of the relevant Literature was performed following the PRISMA guidelines and the most relevant papers on this topic were selected for qualitative analysis. Duplicates, review, personal opinions and guidelines have been excluded. Quantitative analysis has not been performed due to the lack of homogeneous high-quality studies. RESULTS: Literature search identified 740 papers but only 34 of them were suitable for qualitative analysis. The quality of those studies is generally quite low. We were not able to find any evidence directly linking surgical smoke with viral transmission, other than in patients with active HPV infection. DISCUSSION: Inhalation of surgical smoke can be generally hazardous, and therefore the use of PPE during surgical operations must be recommended in any case. However, the present systematic review of the existent Literature did not identify any significant evidence of the risk of viral transmission with the surgical smoke, therefore the current guidelines restricting the use of laparoscopy and/or diathermy during the current Covid-19 pandemic may be considered excessive and non-evidence based.

Case-report: A rare cause of intestinal obstruction in late pregnancy.

INTRODUCTION: Caecal volvulus represents a rare and often life-threatening cause of intestinal obstruction. Diagnosis and management of caecal volvulus remains a clinical challenge, since those presenting with symptoms can have vague nonspecific presentations. Symptoms eventually occur, usually secondary to obstruction or ischaemia. This case report will discuss the presentation, investigation and management options available. PRESENTATION: A 31-year-old multigravida, at 38 weeks and 6 days gestation; presented to hospital with a 2-day history of diffuse abdominal pain and distension. Initial examination was unremarkable aside from mild epigastric tenderness. Raised inflammatory markers and concerns for foetal health resulted in an emergency caesarean section. Symptoms however worsened and the patient underwent colonoscopy and computerised tomography (CT) of the abdomen and pelvis with contrast; showing caecal volvulus. The patient was taken to the operating theatres for an emergency right hemicolectomy with formation of end ileostomy. Intra-operatively, areas of necrosis were noted within the caecum suggestive of impending perforation. The patient recovered well post reversal of end ileostomy, with no complications to date. DISCUSSION: Caecal volvulus represents a rare, but potentially fatal cause of intestinal obstruction and ischaemia. High mortality rates are attributed to delayed diagnosis and treatment. Patients may initially present with vague symptoms, which rapidly progress with the development of ischaemia. Multiple management modalities exist. Central to prognosis is early diagnosis. CONCLUSION: Early diagnosis and intervention are paramount. Imaging via abdominal x-rays and CT are of particular importance. Surgical management is widely reported as the mainstay of treatment. We advise clinicians to remember this rare diagnosis, as a potential cause of abdominal pain and intestinal obstruction; especially in those with predisposing risk factors.

The future of deep phenotyping in osteoarthritis: How can high throughput omics technologies advance our understanding of the cellular and molecular taxonomy of the disease?

Osteoarthritis (OA) is the most common form of musculoskeletal disease with significant healthcare costs and unmet needs in terms of early diagnosis and treatment. Many of the drugs that have been developed to treat OA failed in phase 2 and phase 3 clinical trials or produced inconclusive and ambiguous results. High throughput omics technologies are a powerful tool to better understand the mechanisms of the development of OA and other arthritic diseases. In this paper we outline the strategic reasons for increasingly applying deep phenotyping in OA for the benefit of gaining a better understanding of disease mechanisms and developing targeted treatments. This editorial is intended to launch a special themed issue of Osteoarthritis and Cartilage Open addressing the timely topic of "Advances in omics technologies for deep phenotyping in osteoarthritis". High throughput omics technologies are increasingly being applied in mechanistic studies of OA and other arthritic diseases. Applying multi-omics approaches in OA is a high priority and will allow us to gather new information on disease pathogenesis at the cellular level, and integrate data from diverse omics technology platforms to enable deep phenotyping. We anticipate that new knowledge in this area will allow us to harness the power of Big Data Analytics and resolve the extremely complex and overlapping clinical phenotypes into molecular endotypes, revealing new information about the cellular taxonomy of OA and "druggable pathways", thus facilitating future drug development.

Applying the International Classification of Functioning, Disability and Health to understand osteoarthritis management in urban and rural community-dwelling seniors.

Objectives: The objectives of this study were to identify contextual factors as barriers or facilitators of osteoarthritis management in urban- and rural-dwelling seniors by applying the World Health Organization's International Classification of Functioning, Disability and Health (ICF). Design: Secondary analysis was performed on interview transcripts from urban- (n â€‹= â€‹11) and rural-dwelling (n â€‹= â€‹9) seniors living with osteoarthritis in Canada. Meaningful concepts were linked to ICF codes (Environmental Factors) according to established linking rules. Unclassified content (including Personal Factors) was subjected to qualitative content analysis. Results: A total of 481 and 410 meaningful concepts were identified in interview transcripts from urban and rural groups, respectively. For Environmental Factors, the majority of meaningful concepts linked to "Environmental Factors", then "Activities and Participation", and then "Body Functions" in the ICF. The most frequently linked codes were "e355 Health professionals", "e5801 Health systems", "e5800 Health services", and "e398 Support and relationships, other specified". The most salient barrier and facilitator to osteoarthritis management reflected in our results were "e5801 Health systems" and "e398 Support and relationships, other specified", respectively, for both urban and rural groups. For Personal Factors, qualitative content analysis of unclassified content revealed 3 key themes including (1) Coping Strategies; (2) Age of Osteoarthritis Diagnosis; and (3) Individual Circumstances. Conclusion: Beyond physical limitations, community-dwelling seniors with osteoarthritis encounter a wide range of biopsychosocial factors that can impact disease management. Applying the ICF, we identify "Environmental Factors" as a significant contextual factor impacting osteoarthritis management in both urban and rural communities.

A bioinformatics approach to microRNA-sequencing analysis.

The rapid expansion of Next Generation Sequencing (NGS) data availability has made exploration of appropriate bioinformatics analysis pipelines a timely issue. Since there are multiple tools and combinations thereof to analyze any dataset, there can be uncertainty in how to best perform an analysis in a robust and reproducible manner. This is especially true for newer omics applications, such as miRNomics, or microRNA-sequencing (miRNA-sequencing). As compared to transcriptomics, there have been far fewer miRNA-sequencing studies performed to date, and those that are reported seldom provide detailed description of the bioinformatics analysis, including aspects such as Unique Molecular Identifiers (UMIs). In this article, we attempt to fill the gap and help researchers understand their miRNA-sequencing data and its analysis. This article will specifically discuss a customizable miRNA bioinformatics pipeline that was developed using miRNA-sequencing datasets generated from human osteoarthritis plasma samples. We describe quality assessment of raw sequencing data files, reference-based alignment, counts generation for miRNA expression levels, and novel miRNA discovery. This report is expected to improve clarity and reproducibility of the bioinformatics portion of miRNA-sequencing analysis, applicable across any sample type, to promote sharing of detailed protocols in the NGS field.

Inotropic Agents and Vasopressors in the Treatment of Cardiogenic Shock.

BACKGROUND: Worldwide, cardiogenic shock (CS) is the leading cause of death in patients admitted with an acute myocardial infarction (AMI). CS is characterised by reduced cardiac output secondary to systolic dysfunction which can lead to multi-organ failure. The mainstay of medical treatment in CS are inotropes and vasopressors to improve cardiac output. However, current clinical guidelines do not direct clinicians as to which agents to use and in what combinations. This article aims to review the current evidence on the management of CS with a major focus on the use of inotropes and vasopressors. METHOD: A literature review was conducted analysing published literature from the following databases: PubMed, MedLine, Cochrane Library and Embase, as well as a manual search of articles that were deemed relevant. Relevant articles were identified by using keywords such as "cardiogenic shock". RESULTS: Literature was assessed to review the use of inotropes and vasopressors in CS. Dopamine and adrenaline were associated with increased mortality and arrhythmias. Dobutamine was associated with an improvement in cardiac output, at the determinant of causing arrhythmias. Conversely, noradrenaline was associated with a lower likelihood of arrhythmias and most importantly decreased mortality in CS. Compared to other inotropes, levosimendan appears to have a better safety profile and is associated with decreased mortality in CS, particularly when combined with a vasopressor. Our literature review suggests that treatment combination of the inotrope levosimendan with the vasopressor noradrenaline may be the most effective management option in CS.

Antisense oligonucleotide-based therapies for the treatment of osteoarthritis: Opportunities and roadblocks.

Osteoarthritis (OA) is a debilitating disease with no approved disease-modifying therapies. Among the challenges for developing treatment is achieving targeted drug delivery to affected joints. This has contributed to the failure of several drug candidates for the treatment of OA. Over the past 20 years, significant advances have been made in antisense oligonucleotide (ASO) technology for achieving targeted delivery to tissues and cells both in vitro and in vivo. Since ASOs are able to bind specific gene regions and regulate protein translation, they are useful for correcting aberrant endogenous mechanisms associated with certain diseases. ASOs can be delivered locally through intra-articular injection, and can enter cells through natural cellular uptake mechanisms. Despite this, ASOs have yet to be successfully tested in clinical trials for the treatment of OA. Recent chemical modification to ASOs have further improved cellular uptake and reduced toxicity. Among these are locked nucleic acid (LNA)-based ASOs, which have shown promising results in clinical trials for diseases such as hepatitis and dyslipidemia. Recently, LNA-based ASOs have been tested both in vitro and in vivo for their therapeutic potential in OA, and some have shown promising joint-protective effects in preclinical OA animal models. In order to accelerate the testing of ASO therapies in a clinical trial setting for OA, further investigation into delivery mechanisms is required. In this review article, we discuss opportunities for viral-, particle-, biomaterial-, and chemical modification-based therapies, which are currently in preclinical testing. We also address potential roadblocks in the clinical translation of ASO-based therapies for the treatment of OA, such as the limitations associated with OA animal models and the challenges with drug toxicity. Taken together, we review what is known and what would be useful to accelerate translation of ASO-based therapies for the treatment of OA.