Efficacy, patient-reported outcomes, and safety of the anti-granulocyte macrophage colony-stimulating factor antibody otilimab (GSK3196165) in patients with rheumatoid arthritis: a randomised, phase 2b, dose-ranging study

The human monoclonal antibody otilimab inhibits granulocyte-macrophage colony-stimulating factor (GM-CSF), a key driver in immune-mediated inflammatory conditions. We aimed to evaluate the efficacy, safety, and key patient-reported outcomes related to pain in patients with active rheumatoid arthritis receiving otilimab. Methods. This phase 2b, dose-ranging, multicentre, placebo-controlled study was done at 64 sites across 14 countries. Patients aged 18 years or older with rheumatoid arthritis who were receiving stable methotrexate were randomly assigned (1:1:1:1:1:1) to subcutaneous placebo or otilimab 22·5 mg, 45 mg, 90 mg, 135 mg, or 180 mg, plus methotrexate, once weekly for 5 weeks, then every other week until week 50. The randomisation schedule was generated by the sponsor, and patients were assigned to treatment by interactive response technology. Randomisation was blocked (block size of six) but was not stratified. Investigators, patients, and the sponsor were blinded to treatment. An unblinded administrator prepared and administered the study drug. The primary endpoint was the proportion of patients who achieved disease activity score for 28 joints with C-reactive protein (DAS28-CRP) 3·2 (week 24) escaped to otilimab 180 mg. Patients who escaped were treated as non-responders in their original assigned group. Safety endpoints were incidence of adverse events and serious adverse events, infections, and pulmonary events. Efficacy and safety outcomes were assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02504671. Findings.Between July 23, 2015, and Dec 29, 2017, 222 patients were randomly assigned (37 to each group). 86 (49%) of 175 escaped to otilimab 180 mg at week 12 and 57 (69%) of 83 at week 24. At week 24, the proportion of patients with DAS28-CRP <2·6 was two (5%) of 37 in the otilimab 22·5 mg group, six (16%) of 37 in the 45 mg group, seven (19%) of 37 in the 90 mg group, five (14%) of 37 in the 135 mg group, five (14%) of 37 in the 180 mg, and one (3%) of 37 in the placebo group. The largest difference was achieved with otilimab 90 mg (16·2%; odds ratio [OR] 8·39, 95% CI 0·98–72·14; p=0·053). Adverse events were reported pre-escape in 19–24 (51–65%) patients and post escape in 10–17 (40–61%) patients across otilimab dose groups and in 18 (49%) of 37 and 22 (67%) of 33 in the placebo group. The most common adverse event was nasopharyngitis: 3–9 (8–24%) in otilimab groups and one (3%) in the placebo group pre-escape and 1–3 (4–10%) in otilimab groups and seven (21%) in the placebo group post escape. Pre-escape serious adverse events were foot fracture (otilimab 45 mg); arthralgia, myocardial infarction, dizziness (otilimab 90 mg); oesophageal spasm, acute pyelonephritis (otilimab 22·5 mg), and uterine leiomyoma (otilimab 135 mg). Post-escape serious adverse events were ankle fracture (placebo) and rheumatoid arthritis (otilimab 135 mg). There were no deaths or pulmonary events of clinical concern, and rates of serious infection were low. Interpretation. Otilimab plus methotrexate was well tolerated and, despite not achieving the primary endpoint of DAS28-CRP remission, there were improvements compared with placebo in disease activity scores. Of note, patients reported significant improvement in pain and physical function, supporting further clinical development of otilimab in rheumatoid arthritis

Seeking treatment for symptomatic malaria in Papua New Guinea

Background: Malaria places a significant burden on the limited resources of many low income countries. Knowing more about why and where people seek treatment will enable policy makers to better allocate the limited resources. This study aims to better understand what influences treatment-seeking behaviour for malaria in one such low-income country context, Papua New Guinea (PNG). Methods: Two culturally, linguistically and demographically different regions in PNG were selected as study sites. A cross sectional household survey was undertaken in both sites resulting in the collection of data on 928 individuals who reported suffering from malaria in the previous four weeks. A probit model was then used to identify the factors determining whether or not people sought treatment for presumptive malaria. Multinomial logit models also assisted in identifying the factors that determined where people sought treatments. Results: Results in this study build upon findings from other studies. For example, while distance in PNG has previously been seen as the primary factor in influencing whether any sort of treatment will be sought, in this study cultural influences and whether it was the first, second or even third treatment for a particular episode of malaria were also important. In addition, although formal health care facilities were the most popular treatment sources, it was also found that traditional healers were a common choice. In turn, the reasons why participants chose a particular type of treatment differed according to the whether they were seeking an initial or subsequent treatments. Conclusions: Simply bringing health services closer to where people live may not always result in a greater use of formal health care facilities. Policy makers in PNG need to consider within-country variation in treatment-seeking behaviour, the important role of traditional healers and also ensure that the community fully understands the potential implications of not seeking treatment for illnesses such as malaria at a formal health care facility.Carol P Davy, Elisa Sicuri, Maria Ome, Ellie Lawrence-Wood, Peter Siba, Gordon Warvi, Ivo Mueller and Lesong Conte

Impact of clinical phenotypes on management and outcomes in European atrial fibrillation patients: a report from the ESC-EHRA EURObservational Research Programme in AF (EORP-AF) General Long-Term Registry

Background: Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients\u2019 clinical phenotypes and analyse the differential clinical course. Methods: We performed a hierarchical cluster analysis based on Ward\u2019s Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. Results: A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients\u2019 prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5 months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P &lt;.001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27\u20133.62; HR 3.42, 95%CI 2.72\u20134.31; HR 2.79, 95%CI 2.32\u20133.35), and Cluster 1 (HR 1.88, 95%CI 1.48\u20132.38; HR 2.50, 95%CI 1.98\u20133.15; HR 2.09, 95%CI 1.74\u20132.51) reported a higher risk for the three outcomes respectively. Conclusions: In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century