In vivo articular cartilage deformation: noninvasive quantification of intratissue strain during joint contact in the human knee

The in vivo measurement of articular cartilage deformation is essential to understand how mechanical forces distribute throughout the healthy tissue and change over time in the pathologic joint. Displacements or strain may serve as a functional imaging biomarker for healthy, diseased, and repaired tissues, but unfortunately intratissue cartilage deformation in vivo is largely unknown. Here, we directly quantified for the first time deformation patterns through the thickness of tibiofemoral articular cartilage in healthy human volunteers. Magnetic resonance imaging acquisitions were synchronized with physiologically relevant compressive loading and used to visualize and measure regional displacement and strain of tibiofemoral articular cartilage in a sagittal plane. We found that compression (of 1/2 body weight) applied at the foot produced a sliding, rigid-body displacement at the tibiofemoral cartilage interface, that loading generated subject- and gender-specific and regionally complex patterns of intratissue strains, and that dominant cartilage strains (approaching 12%) were in shear. Maximum principle and shear strain measures in the tibia were correlated with body mass index. Our MRI-based approach may accelerate the development of regenerative therapies for diseased or damaged cartilage, which is currently limited by the lack of reliable in vivo methods for noninvasive assessment of functional changes following treatment

Intervertebral Disc Internal Deformation Measured by Displacements Under Applied Loading with MRI at 3T

Purpose: Noninvasive assessment of tissue mechanical behavior could enable insights into tissue function in healthy and diseased conditions and permit the development of effective tissue repair treatments. Measurement of displacements under applied loading with MRI (dualMRI) has the potential for such biomechanical characterization on a clinical MRI system. Methods: dualMRI was translated from high-field research systems to a 3T clinical system. Precision was calculated using repeated tests of a silicone phantom. dualMRI was demonstrated by visualizing displacements and strains in an intervertebral disc and compared to T 2 measured during cyclic loading. Results: The displacement and strain precisions were 24 mm and 0.3% strain, respectively, under the imaging parameters used in this study. Displacements and strains were measured within the intervertebral disc, but no correlations were found with the T 2 values. Conclusion: The translation of dualMRI to a 3T system unveils the potential for in vivo studies in a myriad of tissue and organ systems. Because of the importance of mechanical behavior to the function of a variety of tissues, it's expected that dual-MRI implemented on a clinical system will be a powerful tool in assessing the interlinked roles of structure, mechanics, and function in both healthy and diseased tissues. Key words: displacement; strain; intervertebral disc; elastography; clinical magnetic resonance imaging The mechanical behavior of a biomaterial is intimately linked to its function, both within natural tissues and biocompatible materials. The material properties and also the loading environment affect the mechanical behavior of tissues, particularly as they relate to healthy and pathological conditions within the body. Noninvasive methods to quantify the mechanical behavior of biomaterials and tissues would permit the measurement of material properties while both preserving the native loading environment and accounting for its influence. Such methods would improve longitudinal studies in animals or humans, greatly reducing the number of animals or human subjects needed for clinical trials, among other benefits. Additionally, these methods could also be implemented to assess tissue quality in patients and monitor the long-term effectiveness of pharmacological or tissue engineering treatments. Some studies have attempted to correlate various relaxometry measures, such as T 2 and T 1r , to mechanical properties in a number of tissues (1,2), motivated by the idea that relaxometry measures correspond to biochemistry and, in turn, are related to mechanical behavior. However, these correlations are based on mechanical tests performed on explanted tissue and do not take advantage of the noninvasive nature of MRI to fully assess tissues within their native environment. Because techniques like displacementencoded MRI can measure displacements and strains noninvasively (3), such a technique for biomechanical characterization of tissue could complement other quantitative MRI techniques (4) for the overall assessment of soft tissue function. The goal of this study was to translate a noninvasive imaging technique that can measure displacements under applied loading with MRI (dualMRI) to a clinical 3T MRI system. Previous efforts in our lab have utilized dualMRI on a high-field MRI scanner, where displacements and strains were measured in explants of healthy cartilage (3) and in intact joints, including tibiofemoral cartilage (5) and degenerated intervertebral discs in animal models (6). Despite the advantages proffered by the higher magnetic field of research MRI systems, these systems are often limited to small volumes and are not approved for clinical use on human subjects. Translation of the dualMRI technique to a clinical scanner would allow for studies of live animals and human subjects, as well as larger tissues and biomaterials that would not be able to fit into the limited confines of a small-bore high-field MRI system. The technical challenge of implementing dualMRI on a living animal or human subject is twofold: (1) the translation of a load-synchronized, displacement-encoded MRI sequence and (2) the development of noninvasive, organ-or joint-specific loading systems capable of repeatable cyclic loading of the tissues of interest. In this article, to address the first of these challenges, we report the translation of dualMRI to a clinical MRI system at 3T, the determination of technique precision using imaging phantoms, and the demonstration of this technique within an intact human intervertebral disc section. We also demonstrate that the displacements and strains measured with dualMRI can be compared to the T 2 distribution of the disc measured under cyclic load. 1231 This research represents a critical step toward the noninvasive in vivo measurement of biomaterial mechanical properties, permitting future studies in clinical and animal research. METHODS Displacement-Encoded Imaging dualMRI was implemented on a 3T clinical MRI system (General Electric Signa HDx, Waukesha, WI) using an eight-channel knee volume coil and a custom pulse sequence After complementary phase-cycled scans were combined for CANSEL (8), a phase difference reconstruction across all channels (9) was used to isolate the overall phase difference between the reference and encoded scans. A sum of squares magnitude reconstruction across all channels was used to compute the signal-to-noise ratio (SNR) of a region-of-interest (ROI) with respect to a region of noise (i.e., air). The displacement in the encoding direction was then computed as a function of the phase difference, as previously described (3,10). Orthogonal in-plane displacements were then smoothed with a Gaussian 5 Â 5 kernel (11) prior to estimation of the Green-Lagrange strain tensor (12). Precision of dualMRI The precision of our dualMRI technique was evaluated across five repeated scan series of a silicone gel phantom (Sylgard 527, Dow Corning, Elizabethtown, KY) that was cyclically loaded with an MRI-compatible loading apparatus (4). Displacement encoding was accomplished with an encoding gradient area of 3.9145 mT ms/mm, equivalent to displacement encoding of 0.33 p/mm, based on pilot studies that showed no more than 63 mm of expected internal deformation. A mixing time (TM) of 600 ms, which included spoiler gradients immediately before acquisition, allowed for the onset of loading prior to data acquisition during the load plateau. TM is limited by the capabilities of the load apparatus (i.e., time required to reach desired load); therefore, the minimum TM allowable by the loading system was chosen to maximize the stimulated echo signal. SSFSE acquisition parameters were as follows: effective echo time (TE) ¼ 62 ms, matrix size ¼ 256 Â 256, spatial resolution ¼ 703 Â 703 mm 2 , and eight averages. The SSFSE sequence was limited by the system software to a field of view of 180 Â 180 mm 2 and slice thickness of 3 mm. Because the acquisition and the loading were synchronized, the effective repetition time was dictated by the 3-s duration loading cycles, during which a load of 18.5 N was applied for 1.5 s, based on previous studies (4,6). The experiment time for all scans within each repeated dualMRI experiment was 10 min. Image acquisition was completed before the load was released within each cycle. Imaging data was processed as described above to calculate in-plane displacements. Precision was computed as the pooled standard deviation across the five repeated scan series of displacement and strain values across 16 points within the imaging phantom (3,5). Precision was calculated for raw displacements and displacements and strains after 10-100 cycles of smoothing (11). dualMRI in an Intact Intervertebral Disc Section To demonstrate the dualMRI technique in a biological specimen, cyclic compression and imaging of a cadaveric intervertebral disc section was synchronized. A cadaveric lumbar spine was obtained from a tissue bank (AlloSource, Centennial, CO) and kept frozen until specimen preparation. The donor was a 22-year-old male and weighed 111 kg, with no medical history of disc degeneration or other spine disease. A spine segment inclusive of the fourth lumbar vertebra (L4) to the fifth lumbar Timing of dualMRI on a 3T MRI system. This schematic shows the timing events for dualMRI in a clinical 3T MRI system (a). Cyclic loading was synchronized with radiofrequency (RF) pulses and gradient actions, including the gradient applied for displacement encoding (G de ). Gradient actions in the readout, phase-encode, and slice-select directions are typical for a singleshot fast spin echo (SSFSE) acquisition and, for brevity, are not shown here. RF transmission pulses are shown in the solid lines and receive action (i.e. acquisition) is shown in dashed lines. Standard MRI scans of an undeformed and deformed imaging phantom (b) are also shown to demonstrate the time points during which the key dualMRI actions were performed. The undeformed image was acquired during the equivalent time point when the phase-cycled RF pulses and displacement encoding gradient, with gradient strength k, were applied. After a mixing time (TM), dualMRI data was acquired using SSFSE during the deformed state. 1232 Chan and Neu vertebra (L5) was excised. The spinal processes and facet joints were removed by transecting the pedicles of the vertebral arch, retaining the vertebral bodies superior and inferior to the L4/L5 intervertebral disc. The L4 and L5 vertebral bodies were partially embedded in polymethylmethacrylate, permitting the full disc segment to be anchored into an MRI-compatible loading apparatus for cyclic compression. Prior to cyclic loading, standard MRI was performed to obtain morphological data. Compression of 450 N was then applied with the MRI-compatible cyclic loading apparatus for 1.5 s during a 3-s cycle. Preconditioning of more than 500 loading cycles (based on pilot studies) was applied prior to dualMRI to ensure that the specimen reached a quasi-steady state deformation response to the cyclic loading (13). Displacement-encoded images were acquired during the load plateau period under quasi-steady state. Parameters for dualMRI were same as for the precision studies above. Displacements within the L4/L5 disc were smoothed to 100 smoothing cycles, and strains were computed. During cyclic loading, standard MRI images were also acquired in the undeformed and deformed configurations for the measurement of nominal change in height and width under cyclic compression. The total experiment time for all dualMRI scans was 20 min, excluding the time necessary for the specimen to achieve quasi-steady state (less than 20 min under this experimental loading regime). T 2 Analysis In addition, to investigate whether any correspondence existed between the presence of mechanical loading and mechanical behavior and the measured T 2 , a known correlate to disc biochemistry (14) and stage of degeneration (15), we estimated T 2 prior to cyclic loading, during cyclic loading immediately after dualMRI, and immediately after the cessation of cyclic loading. T 2 was estimated using a set of fast spin echo acquisitions with variable TE (TEs ¼ 20, 60, 100, 140, 180, and 240 ms) of the same imaging plane as dualMRI. Repetition time was set to 3000 ms, which is approximately four to five times T 1 of human disc (16), to minimize T 1 -weighting. An electronic trigger was used to synchronize the acquisitions for T 2 mapping under cyclic loading. T 2 mapping experiments were performed within 10 min under each loading condition. A least squares fit of an exponential decay curve was used to estimate T 2 at each pixel within the disc ROI before, during and after cyclic loading. Histograms of the T 2 values in each ROI were generated using bins of 5 ms intervals for qualitative comparison. The ROIs were also divided into five regions along the width of the disc, and, separately, into five regions along the height of the disc. Average regional T 2 was computed and compared for each of these sections between loading conditions. Average T 2 values are reported as mean 6 standard deviation. T 2 values were correlated pixel-by-pixel to displacements and strains using linear regression. Statistical significance was defined as P < 0.05. RESULTS dualMRI Precision Displacements measured by dualMRI, displacements after smoothing, and estimated strains were visualized in the silicone phantom FIG. 2. Displacement and strains in a silicone phantom used to evaluate precision. A cyclically loaded silicone phantom was used to validate displacements (a) and strains (b), and determine relationships between displacement and strain precision (c). Including raw displacements, and displacements and strains after 10 and 100 smoothing cycles, depict the influence of displacement smoothing on deformation patterns. Displacements and strains were measured with dualMRI under the same loading conditions that resulted in the undeformed and deformed images in Disc Displacements and Strains at 3T with DualMRI 1233 Intervertebral Disc Displacements and Strains dualMRI on a 3T MRI system permitted the visualization of displacements and strains within the L4/L5 intervertebral disc T 2 Values The average T 2 values across the full disc before, during, and after cyclic loading were 76.8 6 33.7, 80.8 6 33.8, and 80.5 6 34.7 ms, respectively DISCUSSION Translation of dualMRI from research (9.4 T/30 cm bore) to clinical (3.0 T/60 cm bore) MRI systems presented several technical challenges associated with the larger imaging volume and weaker magnetic field, including reduced spatial resolution and faster T 1 decay of the displacement-encoded signal. Despite a reduction in spatial resolution and increased slice thickness, the precision of raw displacement measurement, 95 mm, fell within the ranges of raw displacement precisions measured previously on a research MRI system (4,5). This is most likely because the precision of displacement is tied closely to the SNR (4), which is increased with larger voxel sizes. The displacement and strain fields and precision values after smoothing were also comparable to previous studies 1234 Chan and Neu note that increasing the amount of smoothing could increase bias between the smoothed value and the true value, previous studies with displacement smoothing showed that this bias is often smaller than the precision (11). This validation study therefore shows that, if larger voxel sizes are acceptable for the tissue of interest, displacement precisions of better than half the spatial resolution can be achieved without smoothing, and smoothing can improve displacement and strain precisions up to 24 mm and 0.3%, respectively. Although some spatial resolution may be lost in the translation from research to clinical scanner, the ability to measure displacements and strains noninvasively in larger volumes and potentially living subjects far outweigh the disadvantages of the clinical system. Several of the imaging parameters used in this study were limited by the imaging system, loading device, or image processing software. The effect on SNR by T 2 decay with TE (in fast spin echo acquisitions) and by T 1 decay with TM (in stimulated echo applications) are well known physical phenomena (3,4,10). Accordingly, image acquisition parameters were chosen to minimize TE and TM within the limitations of the chosen acquisition size and the timing of the load system, respectively. The displacement encoding of 0.33 p/mm was selected to avoid excessive phase wrapping and ease computational efforts in unwrapping the phase. Based on pilot studies, we expected internal deformations of no more than 3 mm in absolute value and therefore set the displacement encoding to encode 3 mm as p. Spatial resolution in this study was limited by the field of view and the choice in acquisition matrix size. In preliminary studies, we compared displacement precision for square matrix sizes of 256 Â 256, 384 Â 384, and 512 Â 512. The additional lines of acquisition resulted in longer effective TEs and required longer load plateaus to accommodate the longer total acquisition time, resulting in attenuation of signal and loss of precision. Although a smaller matrix size (i.e., 128 Â 128) could have been chosen for higher SNR and potentially improved FIG. 4. T 2 analysis of a cyclically loaded intervertebral disc. T 2 maps were estimated for an intervertebral disc (a), before (blue), during (red), and after (green) cyclic loading in the same imaging slice as was used for dualMRI. ROIs (mask for disc before loading shown) were divided into five regions along the width (b) and the height (c) and used to compare average regional T 2 and a histogram of T 2 values (binned in 5-ms intervals) across the full disc (d). Although no displacements and strains were significantly correlated to T 2 values (P > 0.05), the relationship with E xy after 100 cycles of smoothing for each pixel within the ROI is shown (e) because it had the highest R 2 of all linear regressions. Disc Displacements and Strains at 3T with DualMRI 1235 displacement precision, we desired a spatial resolution of at least 1 mm and therefore chose 256 Â 256 acquisition matrix. Although the aforementioned parameters are limited by the current system, a detailed, parameterized study of the effects of TE, TM, displacement encoding strength, spatial resolution, and other imaging parameters could be useful in further characterizing this technique. In this study, dualMRI was demonstrated on the clinical MRI system with a clinically relevant human intervertebral disc segment In previous studies, texture correlation has also been used with magnitude-based MRI to measure the internal strain of intervertebral discs (18). This previous study reported a displacement resolution of 1/20th of a pixel or 12 mm after interpolation and smoothing; however, the optimal subset of 61 pixels, equivalent to 5.2 mm in their study, reportedly resulted in loss of local strain detail. Compared to the cyclic loading conditions used in this study for dualMRI, the texture correlation study used a statically loaded disc. Although texture correlation can provide accurate strain measures in tissues that provide enough SNR and texture in magnitude images, phase-contrast techniques, including dualMRI, do not depend on image texture, which is especially an advantage in tissues that tend toward spatial homogeneity in MRI signal intensity. In this study, we also measured T 2 before, during, and after cyclic loading with the goal of directly comparing T 2 and displacements and strains during cyclic loading Although this study presents promising results for displacement and strain precision, there are a number of improvements that can expedite implementation in vivo. The use of surface array coils should be considered for tissues that would be inappropriate for a volume coil, with SNR as a key deciding factor. Although SSFSE is a fast sequence, it is limited in terms of spatial resolution and relies on the assumption of k-space symmetry to "fill" the remainder of k-space in post processing. A number of acquisition sequences could be substituted for SSFSE, although each acquisition technique presents its own advantages and disadvantages. Additionally, as a technique that synchronizes displacement-encoded MRI with externally applied loading, dualMRI requires an MRI-compatible loading system that can consistently load the tissue or tissues of interest in the confines of a clinical MRI system. The loading system should be able to bring the tissue of interest to a quasi-steady state load-deformation response (13) to achieve optimal image quality. Mechanically loading parts of a living animal or human volunteer, without inducing unwanted motion artifacts or causing undue discomfort, poses a strong technical challenge. Although there are a number of developments that remain to be surmounted, this study nonetheless demonstrates for the first time the use of dualMRI on a clinical MRI system, establishing the in vivo potential. CONCLUSIONS dualMRI was translated to a clinical 3T MRI system for the precise measurement of internal tissue deformation. The precision of displacement measurements was below half the spatial resolution of the image acquisition. Strain precisions were below 2% after just 10 smoothing cycles, and more smoothing (i.e., 100 smoothing cycles) permitted strain precisions of 0.3%. The sequence was demonstrated with a controlled loading system, permitting the visualization of displacement and strain fields in a cyclically compressed intervertebral disc. T 2 mapping during cyclic loading also provided an indication of the structural and biochemical characteristics of the disc. A combination of dualMRI and quantitative MRI could 1236 Chan and Neu be used in combination to gain insight into the structure and mechanical function of tissue noninvasively. ACKNOWLEDGMENTS The authors gratefully acknowledge the assistance of Kent Butz and Paull Gossett, in the specimen preparation and the design of the loading apparatus, Aaditya Chandramouli for his assistance in specimen preparation, Gregory Tamer for his technical assistance on the clinical MRI system, and Eric Nauman for advice and access to the cadaveric specimen. The purpose of this study was to compare displacement behavior of cyclically loaded cadaveric human intervertebral discs as measured noninvasively on a clinical 3.0 T and a research 9.4 T MRI system. Intervertebral discs were cyclically compressed at physiologically relevant levels with the same MRIcompatible loading device in the clinical and research systems. Displacement-encoded imaging was synchronized t

Transient and Microscale Deformations and Strains Measured under Exogenous Loading by Noninvasive Magnetic Resonance

Characterization of spatiotemporal deformation dynamics and material properties requires non-destructive methods to visualize mechanics of materials and biological tissues. Displacement-encoded magnetic resonance imaging (MRI) has emerged as a noninvasive and non-destructive technique used to quantify deformation and strains. However, the techniques are not yet applicable to a broad range of materials and load-bearing tissues. In this paper, we visualize transient and internal material deformation through the novel synchrony of external mechanical loading with rapid displacement-encoded MRI. We achieved deformation measurements in silicone gel materials with a spatial resolution of 100 µm and a temporal resolution (of 2.25 ms), set by the repetition time (TR) of the rapid MRI acquisition. Displacement and strain precisions after smoothing were 11 µm and 0.1%, respectively, approaching cellular length scales. Short (1/2 TR) echo times enabled visualization of in situ deformation in a human tibiofemoral joint, inclusive of multiple variable T2 biomaterials. Moreover, the MRI acquisitions achieved a fivefold improvement in imaging time over previous technology, setting the stage for mechanical imaging in vivo. Our results provide a general approach for noninvasive and non-destructive measurement, at high spatial and temporal resolution, of the dynamic mechanical response of a broad range of load-bearing materials and biological tissues

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

A Multicenter, Randomized, Placebo‐Controlled Trial of Atorvastatin for the Primary Prevention of Cardiovascular Events in Patients With Rheumatoid Arthritis

Objective: Rheumatoid arthritis (RA) is associated with increased cardiovascular event (CVE) risk. The impact of statins in RA is not established. We assessed whether atorvastatin is superior to placebo for the primary prevention of CVEs in RA patients. Methods: A randomized, double‐blind, placebo‐controlled trial was designed to detect a 32% CVE risk reduction based on an estimated 1.6% per annum event rate with 80% power at P 50 years or with a disease duration of >10 years who did not have clinical atherosclerosis, diabetes, or myopathy received atorvastatin 40 mg daily or matching placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, transient ischemic attack, or any arterial revascularization. Secondary and tertiary end points included plasma lipids and safety. Results: A total of 3,002 patients (mean age 61 years; 74% female) were followed up for a median of 2.51 years (interquartile range [IQR] 1.90, 3.49 years) (7,827 patient‐years). The study was terminated early due to a lower than expected event rate (0.70% per annum). Of the 1,504 patients receiving atorvastatin, 24 (1.6%) experienced a primary end point, compared with 36 (2.4%) of the 1,498 receiving placebo (hazard ratio [HR] 0.66 [95% confidence interval (95% CI) 0.39, 1.11]; P = 0.115 and adjusted HR 0.60 [95% CI 0.32, 1.15]; P = 0.127). At trial end, patients receiving atorvastatin had a mean ± SD low‐density lipoprotein (LDL) cholesterol level 0.77 ± 0.04 mmoles/liter lower than those receiving placebo (P < 0.0001). C‐reactive protein level was also significantly lower in the atorvastatin group than the placebo group (median 2.59 mg/liter [IQR 0.94, 6.08] versus 3.60 mg/liter [IQR 1.47, 7.49]; P < 0.0001). CVE risk reduction per mmole/liter reduction in LDL cholesterol was 42% (95% CI −14%, 70%). The rates of adverse events in the atorvastatin group (n = 298 [19.8%]) and placebo group (n = 292 [19.5%]) were similar. Conclusion: Atorvastatin 40 mg daily is safe and results in a significantly greater reduction of LDL cholesterol level than placebo in patients with RA. The 34% CVE risk reduction is consistent with the Cholesterol Treatment Trialists’ Collaboration meta‐analysis of statin effects in other populations

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570