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ID PMID Title PublicationDate abstract
32670950 Effect of depression on attentional network system among rheumatoid arthritis patients-A c 2020 Apr Rheumatoid arthritis (RA) is a chronic, painful and debilitating musculoskeletal condition with depression being its common co-morbidity. It is associated with symptoms of fatigue, pain, and sleep disturbances that can overlap with or mimic symptoms of depression. It may occur with at least mild severity is up to 42% of RA patients. Basically, depression refers to a constellation of experience including not only mood but also physical, mental and behavioral experiences. The fact that rates of depression are higher in samples of patients with RA than in the normal population is well documented. The present study was conducted in order to examine the effect of depression on attentional functioning with diagnosed RA patients. Twenty RA patients out of which 10 patients with depression and 10 patients without depression participated in the study. The Beck Depression Inventory was administered for the assessment of depression and the attentional network task was used to measure the attentional performance of the RA patients. Results revealed that there was a significant difference in depressive symptoms among RA patients on accuracy and reaction time (P < 0.01) and orienting effect (P < 0.05). The findings would also imply intervention and rehabilitation of depression among RA patients.
32548022 Rare Presentation of Subacromial Bursitis Mimics Neoplasm in a Case of Rheumatoid Arthriti 2020 INTRODUCTION: We report a rare case of massive subacromial bursitis in Rheumatoid Arthritis (RA) patient. A solid tumor was initially suspected because it was very large with no apparent local sign of inflammation or infection in a 69-year-old patient. Isolated subacromial bursa is an uncommon and it is usually small in size. This bursa usually does not enlarge enough to mimic a neoplastic lesion. The presence of huge swelling around shoulder usually raises the suspicion of neoplastic lesion. However, even in the presence of huge swelling, a benign lesion such as infection, cyst, or bursitis should be considered. This case report presents that even if swelling is huge, the benign lesion must be considered as a differential diagnosis of swelling around shoulder joint. CASE REPORT: We describe the clinical presentation, radiological investigations, and strategies for the management of a 69-year-old patient who was a known case of RA, and he was non-diabetic. Patient presented with massive swelling around shoulder for the past 6 years. We performed radiograms, a plain computed tomography, magnetic resonance imaging, a 99m Tc-MDP bone scintigram, and a 67Ga-citrate scintigram, which all indicated no evidence of tumor. It was treated by excision and no recurrence observed after 5 years. CONCLUSION: Massive subacromial bursitis is rarely reported in medical literature. Even if swelling is massive, the benign lesion must be considered as a differential diagnosis of swelling around shoulder joint.
33520539 An Analysis of Rheumatoid Arthritis Hospitalizations. 2020 Dec 28 Background We used a large United States (US) population-based database to analyze the reasons for hospitalization of rheumatoid arthritis (RA) patients. Methods The International Classification of Diseases, Tenth Revision (ICD-10) code was used to search for hospitalizations in 2017 in the National Inpatient Sample (NIS) database with RA as the principal or secondary diagnosis. The reasons for hospitalization were divided into 19 categories based on their principal discharge ICD-10 diagnosis code. We also ranked the five most common specific reasons for hospitalization. Results There were over 35 million discharges included in the 2017 NIS database; 565,440 hospitalizations had either a principal or secondary ICD-10 code for RA. The top five reasons for RA hospitalization by ICD-10 code categories were as follows: cardiovascular (CV): 93,825 (16.59%), rheumatologic: 82,785 (14.64%), respiratory: 66,895 (11.83%), infection: 62,660 (11.09%), and injury/poisoning: 56,460 (9.96%). Sepsis was the most common principal diagnosis for RA hospitalizations. Conclusion CV diseases were the most common ICD category, and sepsis was the most common principal diagnosis for RA hospitalizations. Management of medical comorbidities (such as CV) and prevention of infection is essential for reducing the rates of RA hospitalizations.
33758819 Spontaneous Spinal Epidural Hematoma During Simultaneous Tocilizumab and Warfarin Use in a 2020 Dec Interleukin 6 (IL-6) plays a main role in the immunopathogenesis of rheumatoid arthritis (RA). Tocilizumab (TCZ) is a humanized immunoglobulin G1 monoclonal antibody against the human IL-6. Warfarin sodium is an oral anticoagulant that is primarily metabolized by cytochrome P450 2C9 (CYP2C9). Impaired metabolism of this low therapeutic index drug is important as it may result in serious bleeding. In this article, we present a 56-year-old female patient with RA, treated with TCZ and warfarin sodium and presented spontaneous spinal epidural hematoma (SSEH) of thoracic spine although international normalized ratio levels were in normal ranges. One week after decompressive surgery for hematoma, a cervical spine abscess developed which resulted in her death. To the best of our knowledge, this is the first case of RA developing SSEH while taking TCZ and warfarin sodium together. Although it is difficult to attribute the severe bleeding to TCZ treatment, clinicians should be aware that concomitant use of oral anticoagulants and TCZ might result in potentially fatal complications in patients with RA.
33643941 Construction of Exercise Behavior Model in Patients with Rheumatoid Arthritis. 2020 Sep BACKGROUND: Despite the awareness that regular exercise has a positive impact on maintaining health, patients with rheumatoid arthritis (RA) engage in markedly less exercise than do the general population. Weaimed to construct and test a structural equation model of exercise behavior in patients with RA based on self-determination theory and self-efficacy theory. METHODS: Participants were 214 outpatients with RA at Chonnam National University Hospital located in the Gwangju City, South Korea from Mar to Apr 2018. A structured self-report questionnaire was used to assess autonomy support, autonomy, competence, relatedness, autonomous motivation, self-efficacy, and exercise behavior. Collected data were analyzed using SPSS 22.0 and AMOS 22.0 program. RESULTS: The structural model showed a good fitness with the data (χ(2)= 727.27, df = 392, P<0.001, TLI = 0.92, CFI = 0.93, RMSEA = 0.07, SRMR = 0.07). Autonomous motivation and self-efficacy had a significant effect on exercise behavior in patients with RA. This model explained 21.2% of the variance of exercise behavior in patients with RA. CONCLUSION: Self-efficiency and autonomous motivation should be promoted in order to strengthen the exercise behavior of patients with RA.
33092162 Bone Loss, Osteoporosis, and Fractures in Patients with Rheumatoid Arthritis: A Review. 2020 Oct 20 Rheumatoid arthritis (RA) is often characterized by bone loss and fragility fractures and is a frequent comorbidity. Compared with a matched population, RA patients with fractures have more common risk factors of osteoporosis and fragility fractures but also risk factors resulting from the disease itself such as duration, intensity of the inflammation and disability, and cachexia. The inflammatory reaction in the synovium results in the production of numerous cytokines (interleukin-1, interleukin-6, tumor necrosis factor) that activate osteoclasts and mediate cartilage and bone destruction of the joints, but also have a systemic effect leading to generalized bone loss. Regular bone mineral density (BMD) measurement, fracture risk assessment using tools such as the FRAX algorithm, and vertebral fracture assessment (VFA) should be performed for early detection of osteoporosis and accurate treatment in RA patients.
32571731 Remission of Rheumatoid Arthritis and Primary Biliary Cholangitis After Treatment With Toc 2021 Jun Rheumatoid arthritis (RA) is characterized by synovitis of multiple joints which if untreated progresses to joint destruction. Primary biliary cholangitis (PBC) is an autoimmune and progressive disease of the liver of unknown origin. About 1.8-5.6% of individuals with PBC have RA and patients with RA are at higher risk of developing PBC compared to the general population. We report a case of a 76-year-old man, with a history of PBC, and a recent RA diagnosis, in which tocilizumab therapy was effective in the control of RA and PBC, and a literature review was performed. This case, along with only one case published in literature in which tocilizumab was used in the treatment of RA and PBC, suggests that tocilizumab may be effective and safe in the treatment of RA in patients with PBC. Inhibition of IL-6 may also be effective in PBC treatment.
33349438 Association Between the Anti-Aging Gene Klotho and Selected Rheumatologic Autoimmune Disea 2021 Feb Klotho long recognized for its role in anti-aging, is potentially implicated in the pathogenesis of rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis. Aging of the immune system coincides with the inability of the body to recognize self-antigens, which often leads to autoimmune responses. The role of Klotho in these autoimmune diseases should be of high interest; however, few articles have been published exploring the role of Klotho in the pathogenesis, organ involvement, or clinical manifestation of rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis. Herein, we discuss information gathered from peer-reviewed publications to describe the emerging role of Kl in these select rheumatologic autoimmune diseases.
32754578 Energy Conversion-Based Nanotherapy for Rheumatoid Arthritis Treatment. 2020 Rheumatoid arthritis (RA) is characterized by synovial hyperplasia and cartilage/bone destruction, which results in a high disability rate on human health and a huge burden on social economy. At present, traditional therapies based on drug therapy still cannot cure RA, in accompany with the potential serious side effects. Based on the development of nanobiotechnology and nanomedicine, energy conversion-based nanotherapy has demonstrated distinctive potential and performance in RA treatment. This strategy employs specific nanoparticles with intrinsic physiochemical properties to target lesions with the following activation by diverse external stimuli, such as light, ultrasound, microwave, and radiation. These nanoagents subsequently produce therapeutic effects or release therapeutic factors to promote necrotic apoptosis of RA inflammatory cells, reduce the concentration of related inflammatory factors, relieve the symptoms of RA, which are expected to ultimately improve the life quality of RA patients. This review highlights and discusses the versatile biomedical applications of energy conversion-based nanotherapy in efficient RA treatment, in together with the deep clarification of the facing challenges and further prospects on the final clinical translations of these energy conversion-based nanotherapies against RA.
32471260 Rheumatoid Meningitis a Rare Extra-Articular Manifestation of Rheumatoid Arthritis: Report 2020 May 27 OBJECTIVES: Central neurological manifestations of rheumatoid arthritis (RA) like rheumatoid meningitis (RM) are rare, little known and have a high rate of morbi-mortality. METHODS: We described six cases of RM that were directly related to RA activity after exhaustive assessment. RESULTS: They were mainly women, aged of 50 to 69. All were positive for anti-cyclic citrullinated peptide antibodies and half for rheumatoid factors. RA activity, duration, and treatments were heterogeneous including oral steroids, conventional synthetic disease modifying anti-rheumatic drugs (DMARDs) and biologic DMARDs. Symptoms were various, with acute or progressive beginning; main were: generalized or focal seizure (4/6), fever (3/6), headaches (3/6), and frontal syndrome (2/6). Imaging lesions were four leptomeningitis, one pachymeningitis, and one association of both. MRI usually showed hypersignal in various territories in T2-FLAIR (fluid attenuated inversion recovery) mode, and enhancement in T1-weighted mode after gadolinium injection. All patients had lumbar puncture that found sterile cerebrospinal fluid, no neoplasic cell, elevated cell count in 5/6 cases and elevated proteins concentration in 3/6 cases. Cerebral biopsy was possible for three patients, and definitively confirmed the diagnosis of aseptic lepto- or pachymenintis, excluding vasculitis and lymphoma. Different treatments were used like intravenous high dose steroids, immunoglobulins or biologic DMARDs, with variable clinical and imaging outcome: one death, one complete recovery, and four recoveries with sequelae. CONCLUSIONS: Clinical symptoms, imaging, lumbar puncture, and serological studies are often nonspecific, only histologic examination can confirm the diagnosis of RM. Any central neurological manifestation in RA patients, even in quiescent and ancient RA, should warn the physician.
33095144 A Training Tool to support the management and diagnosis of Sjögren's syndrome. 2020 Jul OBJECTIVES: The objective of this work is to present a Training Tool designed to support healthcare professionals involved in the diagnosis and management of Sjögren's syndrome. METHODS: The Training Tool aims to fulfil the gap of targeted education by providing a structured protocol of training including state of the art guidelines and practices. For the development of the Training Tool, latest relevant technologies have been used to assure efficiency and usability. Core functionalities include training by a series of multimedia courses, testing during the learning process, and profiling for monitoring the progress. An iterative requirement analysis process was established involving a large number of clinical experts, with the objective to identify user's training needs. RESULTS: Comprehensive usability evaluation was performed by applying, an Unmoderated Remote Usability Test resulting to 97.2% Success Rate; and the well-established System Usability Scale, reaching a score of 90.4 which classifies the Training Tool as "A" graded-excellent. CONCLUSIONS: The Training Tool offers open-online training of healthcare professionals involved in the diagnosis and management of Sjögren's syndrome, using a well-designed training protocol in highly usable manner. To our knowledge, this is the first such tool for Sjögren's syndrome.
33717783 Emphysematous cystitis in a patient using immunosuppressant agents. 2021 Mar A 72-year-old woman presented with a 3-day history of nausea, vomiting, and fever. She had rheumatoid arthritis and was taking prednisolone (10 mg), cyclosporine (150 mg), and actarit (200 mg) daily. Computed tomography revealed gases were detected in the bladder wall, and emphysematous cystitis was diagnosed. When an immunocompromised host is suspected of a severe urinary tract infection but lacks specific signs or symptoms such as costovertebral angle tapping pain, emphysematous cystitis should be considered.
33681846 Rheumatoid arthritis is associated with increased symptomatic acromial and scapular spine 2021 Mar BACKGROUND: The purpose of this study was to determine factors associated with early symptomatic acromial and scapular spine fractures in patients who underwent reverse total shoulder arthroplasty (RTSA). METHODS: We retrospectively evaluated all RTSAs performed by the senior author between 1/1/2013 and 6/1/2019. We evaluated patient demographics including gender, age, prevalence of comorbidities including osteoporosis, inflammatory arthritis, diabetes, and endocrine disorders such as hypothyroidism. We also evaluated preoperative and 2-week postoperative radiographs for center of rotation medialization (CORM) as distance between the center of the humeral head or glenosphere and the line of the deltoid, and distalization via the acromial-greater tuberosity distance (AGT). We evaluated inter- and intra-rater reliability via intraclass correlation coefficients. RESULTS: We included 335 RTSAs with a minimum of 3 months of follow-up in the analysis. Reliability was acceptable with all intraclass correlation coefficients> 0.75. Symptomatic acromial and scapular spine stress fractures were significantly more common in those with inflammatory arthritis than those without (18% vs. 5%, P = 0.016). The rate of fracture was highest in patients with rheumatoid arthritis (24% vs. 5.2%, P = 0.003). There was no statistically significant association between symptomatic fractures and preoperative CORM or AGT (P = 0.557, P = 0.528) or postoperative CORM or AGT (P = 0.56, P = 0.102). There also was no statistically significant correlation between symptomatic stress fracture and patient age, gender, BMI, smoking, osteoporosis, gout, medical comorbidity, or previous shoulder surgery. CONCLUSION: In this retrospective analysis of postoperative RTSA, symptomatic acromial and scapular stress fractures were significantly more common in patients with rheumatoid arthritis and thus precautions should be taken in these patients.
33379867 Treatment of Rheumatoid Arthritis by Serum Albumin Nanoparticles Coated with Mannose to Ta 2021 Jan 13 Rheumatoid arthritis (RA) is an angiogenic and chronic inflammatory disease. One of the most extensively used first-line drugs against RA is methotrexate (MTX), but it shows poor solubility, short in vivo circulation, and off-target binding, leading to strong toxicity. To overcome these shortcomings, the present study loaded MTX into nanoparticles of human serum albumin modified with mannose (MTX-M-NPs) to target the drug to neutrophils. MTX-M-NPs were prepared, and their uptake by neutrophils was studied using laser confocal microscopy and flow cytometry. A chick chorioallantoic membrane assay was used to assess their ability to inhibit angiogenesis. The pharmacokinetics and tissue distribution of MTX-M-NPs were investigated using fluorescence microscopy and high-performance liquid chromatography. Their pharmacodynamics was evaluated in a rat model with arthritis induced by collagen. Neutrophils took up MTX-M-NPs significantly better than the same nanoparticles (NPs) without mannose. MTX-M-NPs markedly suppressed angiogenesis in chick embryos, and the MTX circulation was significantly longer when it was delivered as MTX-M-NPs than as a free drug. MTX-M-NPs accumulated mainly in arthritic joints. The retention of NPs was promoted by mannose-derived coating in arthritic joints. Serum levels of inflammatory cytokines, joint swelling, and bone erosion were significantly decreased by MTX-M-NPs. In conclusion, these NPs can prolong the in vivo circulation of MTX and target it to the sites of inflammation in RA, reducing drug toxicity. MTX-M-NPs allow the drug to exert its intrinsic anti-inflammatory, antiangiogenic, and analgesic properties, making it a useful drug delivery system in RA.
32510034 Developing Smartphone-Based Objective Assessments of Physical Function in Rheumatoid Arthr 2020 Jan BACKGROUND: Digital biomarkers that measure physical activity and mobility are of great interest in the assessment of chronic diseases such as rheumatoid arthritis, as it provides insights on patients' quality of life that can be reliably compared across a whole population. OBJECTIVE: To investigate the feasibility of analyzing iPhone sensor data collected remotely by means of a mobile software application in order to derive meaningful information on functional ability in rheumatoid arthritis patients. METHODS: Two objective, active tasks were made available to the study participants: a wrist joint motion test and a walk test, both performed remotely and without any medical supervision. During these tasks, gyroscope and accelerometer time-series data were captured. Processing schemes were developed using machine learning techniques such as logistic regression as well as explicitly programmed algorithms to assess data quality in both tasks. Motion-specific features including wrist joint range of motion (ROM) in flexion-extension (for the wrist motion test) and gait parameters (for the walk test) were extracted from high quality data and compared with subjective pain and mobility parameters, separately captured via the application. RESULTS: Out of 646 wrist joint motion samples collected, 289 (45%) were high quality. Data collected for the walk test included 2,583 samples (through 867 executions of the test) from which 651 (25%) were high quality. Further analysis of high-quality data highlighted links between reduced mobility and increased symptom severity. ANOVA testing showed statistically significant differences in wrist joint ROM between groups with light-moderate (220 participants) versus severe (36 participants) wrist pain (p < 0.001) as well as in average step times between groups with slight versus moderate problems walking about (p < 0.03). CONCLUSION: These findings demonstrate the potential to capture and quantify meaningful objective clinical information remotely using iPhone sensors and represent an early step towards the development of patient-centric digital endpoints for clinical trials in rheumatoid arthritis.
32170487 Persistent chikungunya arthritis in Roraima, Brazil. 2020 Sep BACKGROUND: The Amazon region of Brazil experienced a large epidemic of East Central South African (ECSA) chikungunya virus (CHIKV) in 2017 and continuous transmission of CHIKV persists. The impact of chronic arthritis caused by ECSA CHIKV is unknown. OBJECTIVE: The study aim was to describe the duration, severity, and characteristics of CHIKV arthritis in Roraima, Brazil, in comparison with local controls to further understand the long-term rheumatologic impact of ECSA CHIKV infection. METHODS: We performed a cross-sectional analysis comparing clinical arthritis outcomes among 40 cases with chronic (> 3 months) arthritis attributed to their CHIKV disease (n = 40) with control participants who were exposed to CHIKV but did not develop chronic arthritis (n = 40), rheumatoid arthritis controls (n = 40), and healthy controls lacking CHIKV exposure and arthritis (n = 40). FINDINGS: Our primary finding is that over 2 years post-infection, patients report moderate arthritis disease severity comparable with rheumatoid arthritis with the most significant impact on decreased quality of life from pain. MAIN CONCLUSIONS: These findings suggest that chronic arthritis caused by ECSA CHIKV infection has had a moderate impact in the Americas. Key Points • Chikungunya infection is responsible for moderate arthritis disease severity. • The East Central South African (ECSA) strain of CHIKV is a cause of persistent arthritis in Roraima, Brazil.
32891004 Evaluation of anti rheumatic activity of Piper betle L. (Betelvine) extract using in silic 2020 Oct Rheumatoid Arthritis is a chronic, inflammatory, and systemic autoimmune disease, it affects elders worldwide. Herbal medicines have been used for the treatment of various ailments from ancient times. Betelvine (Piper betle L.) leaves have long been used in Asian countries as a medicine to relieve pain and some metabolic diseases. The present study of methanolic extract of phytochemical analysis confirms the presence of alkaloids, tannins, terpenoids, saponins, steroids, total flavonoids and total phenols. GC-MS analysis of MeOH extract of Piper betle (PBME) revealed the presence of 40 bioactive compounds. In vitro antioxidant and anti-inflammatory assays showed greater inhibitory effect. The anti-arthritic effects of PBME at 250 and 500 mg/kg concentration showed recovery from joint damage in in vivo rat model. Among the 40 GC-MS derived bioactives, 4-Allyl-1,2-Diacetoxybenzene exhibited the higher interactions with minimized binding energy to the RA targets of MMP 1 (-6.4 kcal/mol), TGF-β (-6.9 kcal/mol), IL-1β (-5.9 kcal/mol). Further, the effect of PBME extract against RA molecular disease targets (IL-1β, MMP1 and TGF- β) were studied using Real-time PCR. These results substantiate that P. betle leaves could be a source of therapeutics for the treatment of rheumatoid arthritis.
32455601 Interleukin-15 as a Biomarker Candidate of Rheumatoid Arthritis Development. 2020 May 21 There is a need for definite diagnosis of rheumatoid arthritis (RA) at its earliest stages of development in order to introduce early and effective treatment. Here we assessed whether serum interleukin-15 (IL-15) can serve as a new biomarker of RA development in patients with undifferentiated arthritis (UA). Interleukin-15, IgM-rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP Abs) were measured in UA patients at inclusion. Six months later, the diagnosis was re-evaluated, and statistical analysis was performed. We found that at the UA stage, IL-15 was more prevalent in patients who progressed to RA than RF or anti-CCP Abs (83.3% vs. 61.1% and 66.7%, respectively). Interleukin-15 showed higher sensitivity (77.8%) than both autoantibodies and higher specificity (80.9%) than anti-CCP Abs in identification of UA patients who developed RA. The diagnostic utility of IL-15 was comparable to that of RF (AUC: 0.814 vs. 0.750, p > 0.05), but higher than that of anti-CCP Abs (AUC: 0.814 vs. 0.684, p = 0.04). The combined use of IL-15, RF and anti-CCP Abs yielded higher diagnostic accuracy for RA than autoantibodies determination only. Our results indicate that IL-15 can be used as a biomarker of RA development in patients with UA.
33078092 Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives 2020 Oct 15 Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized. 2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structure-activity relationship (SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range. Further structure optimization revealed that an acrylamide with small hydrophobic groups (Me, Cl or Br) at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds 42 and 53‒55 with IC(50) values of 41, 44, 32, and 42 nmol/L, respectively. The most potent compound 54 also displayed favorable pharmacokinetic (PK) profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner.
32989436 Of mice and men: converging on a common molecular understanding of osteoarthritis. 2020 Oct Despite an increasing burden of osteoarthritis in developed societies, target discovery has been slow and there are currently no approved disease-modifying osteoarthritis drugs. This lack of progress is due in part to a series of misconceptions over the years: that osteoarthritis is an inevitable consequence of ageing, that damaged articular cartilage cannot heal itself, and that osteoarthritis is driven by synovial inflammation similar to that seen in rheumatoid arthritis. Molecular interrogation of disease through ex-vivo tissue analysis, in-vitro studies, and preclinical models have radically reshaped the knowledge landscape. Inflammation in osteoarthritis appears to be distinct from that seen in rheumatoid arthritis. Recent randomised controlled trials, using treatments repurposed from rheumatoid arthritis, have largely been unsuccessful. Genome-wide studies point to defects in repair pathways, which accords well with recent promise using growth factor therapies or Wnt pathway antagonism. Nerve growth factor has emerged as a robust target in osteoarthritis pain in phase 2-3 trials. These studies, both positive and negative, align well with those in preclinical surgical models of osteoarthritis, indicating that pathogenic mechanisms identified in mice can lead researchers to valid human targets. Several novel candidate pathways are emerging from preclinical studies that offer hope of future translational impact. Enhancing trust between industry, basic, and clinical scientists will optimise our collective chance of success.