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Potent and selective ligands for the human EP3 prostanoid receptor are described. Biaryl compounds bearing a tethered ortho substituted acidic moiety were identified as potent EP3 antagonists based on the SAR described herein. The binding affinity of key compounds on all eight human prostanoid receptors is reported. [Copyright &y& Elsevier]

Moral or ethical questions are vital because they affect our daily lives: what is the best choice we can make, the best action to take in a given situation, and ultimately, the best way to live our lives? Health ethics has contributed to moving ethics toward a more experience-based and user-oriented theoretical and methodological stance but remains in our practice an incomplete lever for human development and flourishing. This context led us to envision and develop the stance of a "living ethics", described in this inaugural collective and programmatic paper as an effort to consolidate creative collaboration between a wide array of stakeholders. We engaged in a participatory discussion and collective writing process known as instrumentalist concept analysis. This process included initial local consultations, an exploratory literature review, the constitution of a working group of 21 co-authors, and 8 workshops supporting a collaborative thinking and writing process. First, a living ethics designates a stance attentive to human experience and the role played by morality in human existence. Second, a living ethics represents an ongoing effort to interrogate and scrutinize our moral experiences to facilitate adaptation of people and contexts. It promotes the active and inclusive engagement of both individuals and communities in envisioning and enacting scenarios which correspond to their flourishing as authentic ethical agents. Living ethics encourages meaningful participation of stakeholders because moral questions touch deeply upon who we are and who we want to be. We explain various aspects of a living ethics stance, including its theoretical, methodological, and practical implications as well as some barriers to its enactment based on the reflections resulting from the collaborative thinking and writing process., (© 2024. The Author(s).)

Living labs are interdisciplinary and participatory initiatives aimed at bringing research closer to practice by involving stakeholders in all stages of research. Living labs align with the principles of participatory research methods as well as recent insights about how participatory ways of generating knowledge help to change practices in concrete settings with respect to specific problems. The participatory, open, and discussion-oriented nature of living labs could be ideally suited to accompany ethical reflection and changes ensuing from reflection. To our knowledge, living labs have not been explicitly trialed and reported in ethics literature. In this discussion paper, we report and discuss four initial issues that marked the process of setting up a living lab in ethics: (1) determining the goals and expected outcomes of an ethics living lab; (2) establishing operational procedures; (3) selecting communities and defining pilot projects; and (4) adopting a lens to tackle emerging questions and challenges. We explain these four issues and present the paths taken based on the novel and specific orientation, that is, living ethics, at the basis of this project. In alignment with living ethics and É-LABO, we approach challenges as learning opportunities to ask not only "how" questions but also "why" questions. We hope that this discussion paper informed by our experience helps to clarify the theoretical, methodological, and practical approaches necessary to successfully adopt and employ living labs in ethics., (© 2023 The Authors. Bioethics published by John Wiley & Sons Ltd.)

Nonunion and segmental bone defects are complex issues in orthopedic trauma. The use of endothelial progenitor cells (EPCs), as part of a cell-based therapy for bone healing is a promising approach. In preclinical studies, culture medium (CM) is commonly used to deliver EPCs to the defect site, which has the potential for immunogenicity in humans. The goal of this study was to find an effective and clinically translatable delivery medium for EPCs. Accordingly, this study compared EPCs delivered in CM, phosphate-buffered saline (PBS), platelet-poor plasma (PPP), and platelet-rich plasma (PRP) in a rat model of femoral critical-size defects. Fischer 344 rats (n = 35) were divided into six groups: EPC+CM, EPC+PBS, EPC+PPP, EPC+PRP, PPP alone, and PRP alone. A 5 mm mid-diaphyseal defect was created in the right femur and stabilized with a miniplate. The defect was filled with a gelatin scaffold impregnated with the corresponding treatment. Radiographic, microcomputed tomography and biomechanical analyses were performed. Overall, regardless of the delivery medium, groups that received EPCs had higher radiographic scores and union rates, higher bone volume, and superior biomechanical properties compared to groups treated with PPP or PRP alone. There were no significant differences in any outcomes between EPC subgroups or between PPP and PRP alone. These results suggest that EPCs are effective in treating segmental defects in a rat model of critical-size defects regardless of the delivery medium used. Consequently, PBS could be the optimal medium for delivering EPCs, given its low cost, ease of preparation, accessibility, noninvasiveness, and nonimmunogenic properties., (© 2023 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Background: Medical assistance in dying (MAiD) sparks debate in several countries, some of which allow or plan to allow MAiD where a mental disorder is the sole underlying medical condition (MAiD-MD). Since MAiD-MD is becoming permissible in a growing number of jurisdictions, there is a need to better understand the moral concerns related to this option. Gaining a better understanding of the moral concerns at stake is a first step towards identifying ways of addressing them so that MAiD-MD can be successfully introduced and implemented, where legislations allow it., Methods: Thus, this article aims (1) to better understand the moral concerns regarding MAiD-MD, and (2) to identify potential solutions to promote stakeholders' well-being. A qualitative thematic review was undertaken, which used systematic keyword-driven search and thematic analysis of content. Seventy-four publications met the inclusion criteria., Results: Various moral concerns and proposed solutions were identified and are related to how MAiD-MD is introduced in 5 contexts: (1) Societal context, (2) Healthcare system, (3) Continuum of care, (4) Discussions on the option of MAiD-MD, (5) MAiD-MD practices. We propose this classification of the identified moral concerns because it helps to better understand the various facets of discomfort experienced with MAiD-MD. In so doing, it also directs the various actions to be taken to alleviate these discomforts and promote the well-being of stakeholders., Conclusion: The assessment of MAiD-MD applications, which is part of the context of MAiD-MD practices, emerges as the most widespread source of concern. Addressing the moral concerns arising in the five contexts identified could help ease concerns regarding the assessment of MAiD-MD., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Problem Addressed: Chronic noncancer pain is often excessively managed with medications (most notably opioids) instead of nonpharmacologic options or multidisciplinary care-the gold standards., Objective of Program: To offer an effective alternative to pharmacologic management of chronic noncancer pain in primary care., Program Description: Patients 18 years of age or older with chronic noncancer pain were referred by family physicians or nurse practitioners in a family health team (outpatient, multidisciplinary clinic) in Ottawa, Ont. A registered nurse used the Pain Explanation and Treatment Diagram with patients, taught self-management skills (related to habits [smoking, consumption of alcohol, diet], exercise, sleep, ergonomics, and psychosocial factors), and referred patients to relevant resources., Conclusion: A nurse-led chronic pain program, initiated without extra funding, was successfully integrated into a primary care setting. Among the participating patients in the pilot project, outcomes related to pain intensity, pain interference with daily living, and opioid use were encouraging. This program could serve as a model for improving chronic noncancer pain management in primary care., (Copyright © 2023 the College of Family Physicians of Canada.)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and fibromyalgia (FM) are two chronic complex diseases with overlapping symptoms affecting multiple systems and organs over time. Due to the absence of validated biomarkers and similarity in symptoms, both disorders are misdiagnosed, and the comorbidity of the two is often unrecognized. Our study aimed to investigate the expression profiles of 11 circulating miRNAs previously associated with ME/CFS pathogenesis in FM patients and individuals with a comorbid diagnosis of FM associated with ME/CFS (ME/CFS + FM), and matched sedentary healthy controls. Whether these 11 circulating miRNAs expression can differentiate between the two disorders was also examined. Our results highlight differential circulating miRNAs expression signatures between ME/CFS, FM and ME/CFS + FM, which also correlate to symptom severity between ME/CFS and ME/CFS + FM groups. We provided a prediction model, by using a machine-learning approach based on 11 circulating miRNAs levels, which can be used to discriminate between patients suffering from ME/CFS, FM and ME/CFS + FM. These 11 miRNAs are proposed as potential biomarkers for discriminating ME/CFS from FM. The results of this study demonstrate that ME/CFS and FM are two distinct illnesses, and we highlight the comorbidity between the two conditions. Proper diagnosis of patients suffering from ME/CFS, FM or ME/CFS + FM is crucial to elucidate the pathophysiology of both diseases, determine preventive measures, and establish more effective treatments., (© 2023. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that leads some people with the disease to consider medical assistance in dying (MAiD). In this article, we describe how a variety of moral problems can emerge from this particular context and affect the well-being of people with ALS, their loved ones, and their caregivers. As MAiD is framed by specific eligibility criteria, broadening its eligibility is often proposed to address these issues. This critical review of the literature aims to identify moral issues relating to ALS that may persist or arise in the event of such widening. The MEDLINE, EMBASE CINAHL and Web of Science databases were searched using 4 search combinations to capture insights from existing literature on ethics, MAiD and ALS (N=41). A thematic content analysis highlighted 3 contextual categories where moral issues emerge (the experience of the disease, the choice of how to die, and the implementation of MAiD). Two important observations are discussed: 1) there are differences in perspective between stakeholders, which can lead to disagreement, but some similarities of perspective also exist; 2) the widening of MAiD eligibility mainly concerns moral issues related to the choice of how to die, and thus constitutes a partial solution to the problems identified.

DNA polymerase theta (Polθ) is an attractive synthetic lethal target for drug discovery, predicted to be efficacious against breast and ovarian cancers harboring BRCA-mutant alleles. Here, we describe our hit-to-lead efforts in search of a selective inhibitor of human Polθ (encoded by POLQ). A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods. Structure-based drug design efforts along with optimization of cellular potency and ADME ultimately led to the identification of RP-6685 : a potent, selective, and orally bioavailable Polθ inhibitor that showed in vivo efficacy in an HCT116 BRCA2 -/- mouse tumor xenograft model.

PKMYT1 is a regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal relationship with CCNE1 amplification. To date, no selective inhibitors have been reported for this kinase that would allow for investigation of the pharmacological role of PKMYT1. To address this need compound 1 was identified as a weak PKMYT1 inhibitor. Introduction of a dimethylphenol increased potency on PKMYT1. These dimethylphenol analogs were found to exist as atropisomers that could be separated and profiled as single enantiomers. Structure-based drug design enabled optimization of cell-based potency. Parallel optimization of ADME properties led to the identification of potent and selective inhibitors of PKMYT1. RP-6306 inhibits CCNE1 -amplified tumor cell growth in several preclinical xenograft models. The first-in-class clinical candidate RP-6306 is currently being evaluated in Phase 1 clinical trials for treatment of various solid tumors.

Idiopathic pulmonary fibrosis is a progressive lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. YAP (Yes-associated protein) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. We previously identified HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) as YAP inhibitors based on a high-throughput small-molecule screen in primary human lung fibroblasts. Here we report that several Aurora kinase inhibitors were also identified from the top hits of this screen. MK-5108, a highly selective inhibitor for AURKA (Aurora kinase A), induced YAP phosphorylation and cytoplasmic retention and significantly reduced profibrotic gene expression in human lung fibroblasts. The inhibitory effect on YAP nuclear translocation and profibrotic gene expression is specific to inhibition of AURKA, but not Aurora kinase B or C, and is independent of the Hippo pathway kinases LATS1 and LATS2 (Large Tumor Suppressor 1 and 2). Further characterization of the effects of MK-5108 demonstrate that it inhibits YAP nuclear localization indirectly via effects on actin polymerization and TGFβ (Transforming Growth Factor β) signaling. In addition, MK-5108 treatment reduced lung collagen deposition in the bleomycin mouse model of pulmonary fibrosis. Our results reveal a novel role for AURKA in YAP-mediated profibrotic activity in fibroblasts and highlight the potential of small-molecule screens for YAP inhibitors for identification of novel agents with antifibrotic activity.

Introduction: The induced membrane technique (IMT) is a two-stage surgical procedure used to treat fracture nonunion and bone defects. Although there is an increasing number of animal studies investigating the IMT, few have examined the outcomes of bone healing after a second stage grafting procedure. This study aimed at comparing two bone grafting procedures, as part of the IMT, in order to establish a rat model providing consistent healing outcomes., Methods: In male Fischer 344 rats, we created a 5 mm defect in the right femur, stabilized the bone with a plate and screws, and inserted a polymethylmethacrylate spacer into the defect. Four weeks later, the spacer was removed. Bone graft was harvested from a donor rat and placed into the defect, followed by membrane and wound closure. Experiments were conducted in two groups. In group 1 (n = 11), the bone graft contained a variable amount of cortical and cancellous bone, the time from donor euthanasia to grafting was up to 240 min, and one donor rat provided graft for 5-6 recipients. In group 2 (n = 12), we reduced the contribution of cortical bone to the graft, included bone marrow, and kept donor euthanasia to grafting time under 150 min. One donor was used per 3-4 recipients. The volume of graft per recipient and all other elements of the protocol were the same across groups. Bone healing at 12 weeks post grafting was compared radiographically by two orthopaedic surgeons in a blinded fashion, based on union status and a modified Lane & Sandhu score., Results: Healing rates improved from 36.4% in Group 1 to 91.6% in Group 2. There was a significant relationship between the methods and resulting union status (p = 0.004). The odds of achieving full union were significantly higher in group 2 compared to group 1 (odds ratio=19.25, 95% confidence interval [1.77-209.55]; p = 0.009). The average radiographic score was also significantly higher in group 2 (p = 0.005)., Conclusion: The revised bone grafting method significantly improved the healing outcomes and contributed to establishing a consistent rat model of the IMT. This model can benefit preclinical investigations by allowing for reliable and clinically-relevant comparisons., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Objectives: The induced membrane technique (IMT) is a 2-stage surgical approach that has become increasingly popular to manage bone defects. Preclinical investigations have been conducted to better understand and define several aspects of this technique. This review summarizes the literature regarding the IMT performed in animal models and identifies potential future directions., Data Sources: Biosis Citation Index, Ovid Embase, and Ovid MEDLINE databases were searched from inception up to June 23, 2021 for articles related to the IMT., Study Selection: Animal studies involving the use of the IMT for segmental defects in long bones were selected. Only full-length original research articles published in English or French were included., Data Extraction: Two authors extracted the data from the selected studies and a third author verified the accuracy of the information., Data Synthesis: Information concerning the animal model, the surgical procedures, and the outcome measures were recorded for each study and compiled., Conclusions: Forty-seven studies were included in this review. Twenty-nine studies (62%) performed both stages of the technique, but only 8 (17%) reported on radiographic union rates explicitly and 5 (11%) included biomechanical testing. A large proportion of the preclinical literature on the IMT has failed to report on radiographic union as an outcome. While studies reporting membrane properties are valuable, they may not provide information that translates into clinical practice or further clinical research if the ultimate outcome of bony healing is not considered. Future animal studies of the IMT should consider this in their study design., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Orthopaedic Trauma Association.)

Objectives: To investigate the feasibility of eye-tracking-based testing of the speed of visual orienting in malnourished young children at rural clinics in Sierra Leone., Design: Prospective dual cohort study nested in a cluster-randomised trial., Setting: 8 sites participating in a cluster-randomised trial of supplementary feeding for moderate acute malnutrition (MAM)., Participants: For the MAM cohort, all infants aged 7-11 months at the eight sites were enrolled, 138 altogether. For controls, a convenience sample of all non-malnourished infants aged 7-11 months at the same sites were eligible, 60 altogether. A sample of 30 adults at the sites also underwent eye-tracking tests as a further control., Interventions: Infants with MAM were provided with supplementary feeding., Outcome Measures: The primary outcomes were feasibility and reliability of eye-tracking-based testing of saccadic reaction time (SRT). Feasibility was assessed by the percent of successful tests in the infants. Reliability was measured with intraclass correlation coefficients (ICCs). Secondary outcomes were mean SRT based on nutritional state as well as and changes in mean SRT after supplementary feeding of MAM children., Results: Infants exhibited consistent orienting to targets on a computer screen (>95% of valid trials). Mean SRTs had moderate stability within visits (ICCs 0.60-0.69) and across the 4-week test-retest interval (0.53) in infants; the adult control group had greater SRT stability (within visit ICC=0.92). MAM infants had a trend toward higher adjusted SRT at baseline (difference=12.4 ms, 95% CI -2 to 26.9, p=0.09) and improvement in SRT 4 weeks thereafter (difference=-14 ms, 95% CI -26.2 to -1.7, p=0.025) compared with age-matched controls., Conclusions: The results demonstrate the feasibility of eye-tracking-based testing in a resource-poor field setting and suggest eye-tracking measures have utility in the detection of group level effects of supplementary feeding., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is a lack of consensus on what is the most appropriate treatment of moderate acute malnutrition (MAM)., Objectives: We aimed to determine if provision of ready-to-use-therapeutic food (RUTF) and antibiotics to "high-risk" MAM (HR-MAM) children in addition to nutritional counseling would result in higher recovery and less deterioration than nutrition counseling alone., Methods: At the 11 intervention clinics, HR-MAM children were given RUTF and amoxicillin along with standard nutrition counseling, for 2-12 wk. All others received 6 wk of nutrition counseling alone. HR-MAM was defined as midupper arm circumference (MUAC) <11.9 cm, weight-for-age z score (WAZ) <-3.5, mother not the main caregiver, or a child <2 y old not being breastfed. Outcomes were compared using intention-to-treat analysis., Results: Analysis included 573 children at the intervention sites and 714 children at the control sites. Of the intervention group, 317 (55%) were classified as HR-MAM. Short-term recovery was greater at the intervention sites [48% compared with 39% at week 12; risk difference (rd): 0.08; 95% CI: 0.03, 0.13]. The intervention group had lower risk of deteriorating to severe acute malnutrition (SAM) (18% compared with 24%; rd: -0.07; 95% CI: -0.11, -0.04), lower risk of dying (1.8% compared with 3.1%; rd: -0.02; 95% CI: -0.03, -0.00), and greater gains in MUAC and weight than did children at the control sites. However, by 24 wk, the risk of SAM was similar between the 2 arms (31% compared with 34%; rd: -0.03; 95% CI: -0.09, 0.02). Control group data identified recent illness, MUAC <12.0 cm, WAZ <-3, dropping anthropometry, age <12 mo, being a twin, and a history of previous SAM as risk factors for deterioration., Conclusions: Provision of RUTF and antibiotics to HR-MAM children improved short-term recovery and reduced short-term risk of deterioration. However, recovery rates were still suboptimal and differences were not sustained by 6 mo post enrollment.This trial was registered at clinicaltrials.gov as NCT03647150., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Introduction: The number of elderly patients undergoing major surgery is rapidly increasing. They are particularly at risk of developing postoperative neurocognitive disorders (NCD). Earlier studies suggested that processed electroencephalographic (EEG) monitors may reduce the incidence of postoperative NCD. However, none of these studies controlled for intraoperative nociception levels or personalized blood pressure targets. Their results remain unclear if the reduction in the incidence of postoperative NCD relates to avoidance of any electroencephalographic pattern suggesting excessive anesthesia depth., Objective: The objective of this trial is to investigate-in patients ≥ 70 years old undergoing major non-cardiac surgery-the effect of EEG-guided anesthesia on postoperative NCD while controlling for intraoperative nociception, personalized blood pressure targets, and using detailed information provided by the EEG monitor (including burst suppression ratio, density spectral array, and raw EEG waveform)., Material and Methods: This prospective, randomized, controlled trial will be conducted in a single Canadian university hospital. Patients ≥ 70 years old undergoing elective major non-cardiac surgery will be included in the trial. The administration of sevoflurane will be adjusted to maintain a BIS index value between 40 and 60, to keep a Suppression Ratio (SR) at 0%, to keep a direct EEG display without any suppression time and a spectrogram with most of the EEG wave frequency within the alpha, theta, and delta frequencies in the EEG-guided group. In the control group, sevoflurane will be administered to achieve an age-adjusted minimum alveolar concentration of [0.8-1.2]. In both groups, a nociception monitor will guide intraoperative opioid administration, individual blood pressure targets will be used, and cerebral oximetry used to tailor intraoperative hemodynamic management. The primary endpoint will be the incidence of NCD at postoperative day 1, as evaluated by the Montreal Cognitive Assessment (MoCA). Secondary endpoints will include the incidence of postoperative NCD at different time points and the evaluation of cognitive trajectories up to 90 days after surgery among EEG-guided and control groups., Study Registration: NCT04825847 on ClinicalTrials.gov., Competing Interests: The authors have declared that no competing interests exist.

Fracture healing is a complex process requiring mechanical stability, an osteoconductive matrix, and osteoinductive and osteogenic biology. This intricate process is easily disrupted by various patient factors such as chronic disease and lifestyle. As the medical complexity and age of patients with fractures continue to increase, the importance of developing relevant experimental models is becoming paramount in preclinical research. The objective of this review is to describe the most common small animal models of systemically impaired fracture healing used in the orthopedic literature including osteoporosis, diabetes mellitus, smoking, alcohol use, obesity, and ageing. This review will provide orthopedic researchers with a summary of current models of systemically impaired fracture healing used in small animals and present an overview of the methods of induction for each condition., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Objective: We hypothesised that an alternative RUTF (ready-to-use therapeutic food) made with oats (oat-RUTF) would be non-inferior to standard RUTF (s-RUTF)., Design: This was a randomised, triple-blind, controlled, clinical non-inferiority trial comparing oat-RUTF to s-RUTF in rural Sierra Leone. Children aged 6-59 months with severe acute malnutrition (SAM) were randomised to oat-RUTF or s-RUTF. s-RUTF was composed of milk powder, sugar, peanut paste and vegetable oil, with a hydrogenated vegetable oil additive. Oat-RUTF contained oats and no hydrogenated vegetable oil additives. The primary outcome was graduation, an increase in anthropometric measurements such that the child was not acutely malnourished. Secondary outcomes were rates of growth, time to graduation and presence of adverse events. Intention to treat analyses was used., Results: Of the 1406 children were enrolled, graduation was attained in 404/721 (56%) children receiving oat-RUTF and 311/685 (45%) receiving s-RUTF (difference 10.6%, 95% CI 5.4% to 15.8%). Death, hospitalisation or remaining with SAM was seen in 87/721 (12%) receiving oat-RUTF and in 125/685 (18%) receiving s-RUTF (difference 6.2%, 95% CI 2.3 to 10.0, p=0.001). Time to graduation was less for children receiving oat RUTF; 3.9±1.8 versus 4.5±1.8 visits, respectively (p<0.001). Rates of weight in the oat-RUTF group were greater than in the s-RUTF group; 3.4±2.7 versus 2.5±2.3 g/kg/d, p<0.001., Conclusion: Oat-RUTF is superior to s-RUTF in the treatment of SAM in Sierra Leone. We speculate that might be because of beneficial bioactive components or the absence of hydrogenated vegetable oil in oat-RUTF., Trial Registration Number: NCT03407326., Competing Interests: Competing interests: DTH, MJM, CG, AL, DW, MC-G and MM report grants from Children’s Investment Fund Foundation paid to their university., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: The purpose of this study was to: review the efficacy of the induced membrane technique (IMT), also known as the Masquelet technique; and investigate the relationship between patient factors and technique variations on the outcomes of the IMT., Methods: A systematic search was performed in CINAHL, The Cochrane Library, Embase, Ovid MEDLINE, and PubMed. We included articles from 1 January 1980 to 30 September 2019. Studies with a minimum sample size of five cases, where the IMT was performed primarily in adult patients (≥ 18 years old), in a long bone were included. Multivariate regression models were performed on patient-level data to determine variables associated with nonunion, postoperative infection, and the need for additional procedures., Results: A total of 48 studies were included, with 1,386 cases treated with the IMT. Patients had a mean age of 40.7 years (4 to 88), and the mean defect size was 5.9 cm (0.5 to 26). In total, 82.3% of cases achieved union after the index second stage procedure. The mean time to union was 6.6 months (1.4 to 58.7) after the second stage. Our multivariate analysis of 450 individual patients showed that the odds of developing a nonunion were significantly increased in those with preoperative infection. Patients with tibial defects, and those with larger defects, were at significantly higher odds of developing a postoperative infection. Our analysis also demonstrated a trend towards the inclusion of antibiotics in the cement spacer having a protective effect against the need for additional procedures., Conclusion: The IMT is an effective management strategy for complex segmental bone defects. Standardized reporting of individual patient data or larger prospective trials is required to determine the optimal implementation of this technique. This is the most comprehensive review of the IMT, and the first to compile individual patient data and use regression models to determine predictors of outcomes. Cite this article: Bone Joint J 2020;102-B(12):1723-1734.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic disease, rooted in multi-system dysfunctions characterized by unexplained debilitating fatigue. Post-exertional malaise (PEM), defined as the exacerbation of the patient's symptoms following minimal physical or mental stress, is a hallmark of ME/CFS. While multiple case definitions exist, there is currently no well-established biomarkers or laboratory tests to diagnose ME/CFS. Our study aimed to investigate circulating microRNA expression in severely ill ME/CFS patients before and after an innovative stress challenge that stimulates PEM. Our findings highlight the differential expression of eleven microRNAs associated with a physiological response to PEM. The present study uncovers specific microRNA expression signatures associated with ME/CFS in response to PEM induction and reports microRNA expression patterns associated to specific symptom severities. The identification of distinctive microRNA expression signatures for ME/CFS through a provocation challenge is essential for the elucidation of the ME/CFS pathophysiology, and lead to accurate diagnoses, prevention measures, and effective treatment options.

The goals of all orthopaedic surgeons treating articular cartilage injuries have been anatomic reduction and stable fixation of the articular cartilage surface with restoration of limb alignment and/or reestablishment of the joint stability, all while minimizing the risk of surgical complications. Recent developments in the study of articular cartilage injury have shown that there is a robust cellular response to joint injury. This response has been shown to involve the synoviocytes, chondrocytes, and osteocytes in and around the injured joint and if these responses are left unchecked, they can lead to the development of posttraumatic osteoarthritis (PTOA). Therefore, to predictably and successfully treat articular cartilage injuries, it is not sufficient to just restore articular congruity, limb alignment, and joint stability, but we must also recognize and attempt to mitigate this associated cellular response. Understanding not only the mechanical aspects of these joint injuries but also the biological aspects is paramount to giving our patients the best opportunity to heal their injuries, recover full function, and avoid the potential devastating development of PTOA. Gone is the simplistic view that if one can achieve articular congruity after intraarticular fracture, as well as joint stability after ligamentous injury, that our patients will do just fine. This review sheds new light on the molecular response to cartilage injury, how residual joint incongruity and instability affect the joint's ability to recover from injury, and how chondrocyte apoptosis in response to injury can influence joint. This article then briefly reviews how cellular and growth factors may be beneficial to the treatment of articular cartilage injury and how ultimately cartilage regeneration may be used in the future to salvage the joints ravaged by PTOA in response to injury.

Background: Blood pressure measurement in severe obesity may be technically challenging as the cuff of the device may not fit adequately around the upper arm. The aim of the study was to assess the agreement between intra-arterial blood pressure values (gold standard) compared with forearm blood pressure measurements in severely obese patients in different arm positions., Methods: Thirty-three severely obese patients and 21 controls participated in the study. Pairs of intra-arterial blood pressures were compared with simultaneous forearm blood pressure measurement using an oscillometric device in 4 positions: (i) supine, (ii) semi-fowler with the forearm resting at heart level, (iii) semi-fowler with the arm downward, and (iv) semi-fowler with the arm raised overhead. Degree of agreement between measurements was assessed., Results: Overall, correlations of systolic and diastolic blood pressure measurements between the gold standard and forearm blood pressure were 0.95 (n = 722; P < 0.001) and 0.89 (n = 482; P < 0.001), respectively. Systolic blood pressure measured using the forearm approach in the supine and the semi-fowler positions with arm downward showed the best agreement when compared with the gold standard (-4 ± 11 (P < 0.001) and 2 ± 14 mm Hg (P = 0.19), respectively). In the control group, better agreement was found between the supine and semi-fowler positions with the arm resting at heart level (1 ± 9 mm Hg (P = 0.29) and -3 ± 10 mm Hg (P = 0.01), respectively)., Conclusions: Forearm systolic blood pressure consistently agreed with the gold standard in the supine position. This method can be of use in clinical settings when upper-arm measurement is challenging in severe obesity.

Background: The Radiographic Union Score for Tibial fractures (RUST) and the modified version of the system, mRUST, are popular standards for assessing fracture-healing progress with use of radiographs. To our knowledge, this is the first study to experimentally validate the ability of RUST and mRUST to accurately assess bone-healing progression with use of both micro-computed tomography (micro-CT) scanning and biomechanical testing., Methods: Adult male rats (n = 29) underwent osteotomy with a midshaft fracture gap repaired with use of a polyetheretherketone plate. Anteroposterior and lateral radiographs were made of the repaired femora prior to rat death at end points of 5, 6, 7, 8, 9, and 17 weeks, and 2 fellowship-trained orthopaedic trauma surgeons independently assigned RUST and mRUST scores to repaired femora. The repaired and intact contralateral femora were then dissected. Bones underwent dissection, micro-CT scanning, and biomechanical torsion testing at the end points., Results: RUST scores ranged from 5 to 12 and mRUST scores ranged from 5 to 16. Intraclass correlation coefficients (ICCs) were 0.89 (95% confidence interval [CI]: 0.78 to 0.94) for RUST and 0.86 (95% CI: 0.74 to 0.93) for mRUST, which fall within the "almost perfect agreement" category for ICCs. Spearman rank correlation coefficients (RS) showed correlation of RUST (RS range, 0.456 to 0.818) and mRUST (RS range, 0.519 to 0.862) with micro-CT measurements of mineralized callus volume (BV), total callus volume (TV), and BV/TV ratio, but less so with bone mineral density (BMD). Additionally, RUST (RS range, 0.524 to 0.863) and mRUST (RS range, 0.434 to 0.850) were correlated with some biomechanical properties. A RUST score of 10 or an mRUST score of 15 may be considered the threshold above which a plated bone is "healed" because, at these scores, 120% or 140% of failure torque, respectively, was achieved by the repaired femora as compared with the intact contralateral femora., Conclusions: RUST and mRUST both show strong statistical correlations with micro-CT and biomechanical parameters., Clinical Relevance: RUST and mRUST scoring systems provide clinicians with validated, reliable, and available tools to assess the progress of fracture-healing.

Objective: The purpose of this study was to review the rates of adverse healing outcomes following surgical fixation of lower extremity fractures in diabetic patients and matched controls., Materials and Methods: Searches of PubMed, MEDLINE, CINAHL and Embase were performed for studies published between the date of database inception and July 6, 2015. Patient characteristics and the incidence of adverse healing outcomes (nonunion, malunion, delayed union, infection and reoperation) were extracted from each study. The occurrence of each fracture healing complication was pooled and analyzed for comparisons between diabetic and non-diabetic patients. An odds ratio with a 95% confidence interval for each healing outcome was calculated between the diabetic and non-diabetic groups., Results: Diabetes was found to significantly increase rates of malunion, infection and reoperation in patients with surgically treated lower extremity fractures. In addition, when only peripheral lower extremity fractures (i.e. below the knee) were examined, diabetes significantly increased the rates of nonunion., Conclusion: Diabetes substantially alters bone metabolism and soft tissue healing, posing a risk of adverse fracture healing and other complications. This systematic review provides evidence that the presence of diabetes significantly increases the risks of infection, malunion, nonunion and re-operation across a wide variety of surgically treated lower extremity fractures. This study provides prognostic information for clinicians and may aid in guiding treatment for this population., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: Treating fracture nonunion with endothelial progenitor cells (EPCs) is a promising approach. Nevertheless, the effect of different EPC-related cell populations remains unclear. In this study, we compared the therapeutic potential of early (E-EPCs) and late EPCs (L-EPCs)., Methods: Male Fischer 344 rats were used for cell isolation and in vivo experiments. Bone marrow-derived E-EPCs and L-EPCs were kept in culture for seven to ten days and four weeks, respectively. For each treatment group, we seeded one million cells on a gelatin scaffold before implantation in a segmental defect created in a rat femur; control animals received a cell-free scaffold. Bone healing was monitored via radiographs for up to ten weeks after surgery. In vitro, secretion of vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP)-2 was quantified by ELISA for both cell populations. Tube formation assays were also performed., Results: Final radiographs showed complete (four out of five rats) or partial (one out of five rats) union with E-EPC treatment. In contrast, complete healing was achieved in only one of five animals after L-EPC implantation, while control treatment resulted in nonunion in all animals. In vitro, E-EPCs released more VEGF, but less BMP-2 than L-EPCs. In addition, L-EPCs formed longer and more mature tubules on basement membrane matrix than E-EPCs. However, co-culture with primary osteoblasts stimulated tubulogenesis of E-EPCs while inhibiting that of L-EPCs., Conclusions: We demonstrated that bone marrow-derived E-EPCs are a better alternative than L-EPCs for treatment of nonunion. We hypothesize that the expression profile of E-EPCs and their adaptation to the local environment contribute to superior bone healing.