Explore the vast range of titles available.

Background There are very limited mitogenome data representing most animal groups, particularly among the insects, which are otherwise extremely diverse and fulfill important ecological, sanitary, forest and agroeconomic roles. Increasing taxonomic diversity with new additions to the pool of mitogenomes for unrepresented evolutionary lineages is an opportunity to increase the phylogenetic power of mitogenome data, as well as refining our understanding of mitogenome diversity. Here, we characterize the complete mitogenomes of three species in two subgenera of Taophila leaf beetles, members of the hyperdiverse Eumolpinae, currently very poorly represented by mitogenomes, and the first representing an enigmatic independent evolutionary branch of the Eumolpini tribe, originated in the Cretaceous-Paleogene transition and endemic to the South Pacific. Results These mitogenomes, assembled from genomic Illumina libraries, are relatively small (15,484–15,597 bp), retain the ancestral gene order of insect mitogenomes, except for a switch in the positions of trnA and trnR , a synapomorphic trait of the leaf beetle clade including Eumolpinae, Cryptocephalinae and Lamprosomatinae. Nucleotide composition, codon usage, relative synonymous codon usage and initiation and termination codons of protein-coding genes of these mitogenomes are all typical of insect mitogenomes, where nucleotide composition bias may be the result of mutation pressure, rather than natural selection. A mitogenome phylogeny of Eumolpinae, Cryptocephalinae and Lamprosomatinae revealed a strongly supported topology concordant with previous molecular systematic studies of these groups, including the identification of polytomies consistent with rapid early diversification of the Cryptocephalinae tribes and the separation of the main lineages within Eumolpini, one of them represented by Taophila . Conclusions New mitogenomes from previously undersampled taxa contribute to an important, collective effort to populate mitogenome databases with an increasingly dense representation of the Tree-of-Life. It is crucial that these efforts are driven and supported by consolidated taxonomic expertise to guarantee the quality of results derived from these data. The availability of South Pacific Eumolpinae in the public mitogenome pool increases the likelihood of finding their missing link, if any, with other Eumolpini.

Baricitinib is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently predicted, using artificial intelligence (AI) algorithms, to be useful for COVID‐19 infection via proposed anti‐cytokine effects and as an inhibitor of host cell viral propagation. We evaluated the in vitro pharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated in COVID‐19 infection. We validated the AI‐predicted biochemical inhibitory effects of baricitinib on human numb‐associated kinase (hNAK) members measuring nanomolar affinities for AAK1, BIKE, and GAK. Inhibition of NAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids. These effects occurred at exposure levels seen clinically. In a case series of patients with bilateral COVID‐19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS‐CoV‐2 viral load, inflammatory markers, and IL‐6 levels. Collectively, these data support further evaluation of the anti‐cytokine and anti‐viral activity of baricitinib and support its assessment in randomized trials in hospitalized COVID‐19 patients. Synopsis This study provides biochemical and cellular evidence confirming artificial intelligence (AI)‐predictions focused on anti‐cytokine signaling and potential anti‐viral effects for baricitinib, along with a case series, supporting its potential utility in hospitalized COVID‐19 patients. Baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor used to treat rheumatoid arthritis, was hypothesised using AI to be useful in COVID‐19. Baricitinib‐mediated inhibition of numb associated kinases utilized by SARS‐CoV‐2 for its propagation, led to reduced viral infectivity in primary liver spheroids. Baricitinib reduces levels of cytokines implicated in COVID‐19 and inhibits their signaling. In patients with bilateral COVID‐19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS‐CoV‐2 viral load, inflammatory markers, and IL‐6 levels. Graphical Abstract This study provides biochemical and cellular evidence confirming artificial intelligence (AI)‐predictions focused on anti‐cytokine signaling and potential anti‐viral effects for baricitinib, along with a case series, supporting its potential utility in hospitalized COVID‐19 patients.

In this work, we use a combined analysis of morphological and mtDNA sequence data to recognize and revise a group of species allied to the New Caledonian endemic leaf beetle genus Cazeresia Jolivet, Verma & Mille, 2005 of the Eumolpinae, considered monotypic before this work. We characterize and describe 20 new species allied to C. montana Jolivet, Verma & Mille, 2005 based on the recognition of morphological diagnostic traits and DNA-based species delimitation: C. australis sp. nov. , C. clipeata sp. nov. , C. corrugata sp. nov. , C. globosa sp. nov. , C. gracilis sp. nov. , C. holosericea sp. nov. , C. imperiosa sp. nov. , C. impressicornis sp. nov. , C. laevigata sp. nov. , C. laticollis sp. nov. , C. maquis sp. nov. , C. ovata sp. nov. , C. parentalis sp. nov. , C. petitpierrei sp. nov. , C. robusta sp. nov. , C. spadicea sp. nov. , C. subgeminata sp. nov. , C. tibialis sp. nov. , C. tricolor sp. nov. and C. wanati sp. nov. For C. globosa and C. spadicea we additionally describe the subspecies C. globosa altitudinalis ssp. nov. and C. spadicea bruna ssp. nov. We also propose transferring to this genus the species Thasycles humboldtiana Heller, 1916, Colaspis kanalensis Perroud, 1864, Dematochroma thyiana Jolivet, Verma & Mille, 2008 and Dumbea striata Jolivet, Verma & Mille, 2007, as C. humboldtiana (Heller) comb. nov. , C. kanalensis (Perroud) comb. nov. , C. thyiana (Jolivet, Verma & Mille) comb. nov. and C. striata (Jolivet, Verma & Mille) comb. nov. , respectively. At present, the genus Cazeresia includes 25 species, the vast majority distributed in the southern part of Grande Terre in areas characterized by ultramafic soils and we speculate that the adaptation to these environmental characteristics in lowland areas may be ancestral in this lineage. Two thirds of the species are only known from their type locality, thus treated as potential microendemics, and most other have reduced ranges generally spanning few tens of kilometres. Finally, the degree of species sympatry or parapatry exhibited by Cazeresia is noteworthy, which in the absence of marked morphological differences among species suggests the possibility of the interplay of ecological mechanisms to minimize competition and exclusion.

IntroductionMany rheumatoid arthritis (RA) patients do not achieve their treatment goals and experience symptoms that affect psychosocial outcomes and daily activities. This study aimed to identify and quantify the unmet needs perceived by US patients with RA currently taking a disease-modifying antirheumatic drug (DMARD).MethodsA cross-sectional, web-based survey was conducted with RA patients recruited through CreakyJoints, an online patient support community, and ArthritisPower®, an online patient research registry, from December 2017 to January 2018. Participant patients were aged ≥ 21 years, failed ≥ 1 DMARDs, and were receiving their current DMARD(s) for ≥ 6 months; they answered 50 questions about treatment history, RA symptoms, and flares and completed the Rheumatoid Arthritis Impact of Disease (RAID) questionnaire and the Treatment Satisfaction Questionnaire for Medication (TSQM). Treatment satisfaction was defined by a TSQM global satisfaction score ≥ 80.ResultsOf 415 patients screened, 258 (62%) were eligible and completed the survey; 87% were women, and 87% white, with mean (SD) age of 54.5 (11.4) years. A total of 232 patients (90%) had current or past biologic DMARD (bDMARD) use, with 67% currently on a bDMARD, 65% on ≥ 1 conventional synthetic DMARD, and 40% on methotrexate. Forty-three percent of patients reported daily/almost daily use of prescription pain medications, and 44% reported a current flare. Mean (SD) TSQM scores were 59 [20] for effectiveness, 59 [26] for side effects, 72 [18] for convenience, and 65 [21] for global satisfaction. The mean (SD) RAID overall score was 5.1 (2.0) on a 0–10 scale. Only 26% (67 patients) were satisfied with their RA treatment. Patients not satisfied with treatment reported higher RAID scores overall and by domain, and approximately half reported a current flare.ConclusionsResults from this real-world survey suggest that three-fourths of RA patients are not satisfied with treatments, which include bDMARDs. Patients continued to experience bothersome symptoms that impacted their daily activities and life. There remains a need for improved disease management among currently treated RA patients.FundingEli Lilly and Company (Indianapolis, IN, USA).

ObjectiveTo characterise changes in selected haematological parameters following once-daily oral baricitinib dosing.MethodsData were pooled from eight randomised clinical trials (four phase 3, three phase 2, one phase 1b) and one long-term extension. Changes in haematological parameters were evaluated up to 128 weeks (N=2387); overall safety of baricitinib was assessed up to 6 years (N=3492).ResultsMean absolute neutrophil counts decreased (−1.36×109/L) within 1 month, followed by stabilisation within the normal reference range through week 128. The incidence of serious infections was not elevated in patients with neutropenia during the 24-week placebo-controlled period. Mean lymphocyte counts increased (+0.30×109/L) within 1 month, then decreased to baseline (weeks 12–24). Mean platelet counts increased at week 2 (+51×109/L), then decreased towards baseline. Overall, mean haemoglobin concentrations decreased (−0.12 mmol/L), then returned to baseline; however, reduced baseline haemoglobin concentrations observed in the highest baseline high-sensitivity C reactive protein quartile increased over time. Permanent drug discontinuation occurred due to laboratory abnormalities related to neutrophil count in 8 (0.2%), lymphocyte counts in 6 (0.2%), platelet counts in 8 (0.2%), and haemoglobin levels in 16 (0.5%) of all baricitinib-treated patients (N=3492 with 7993 total person-years of exposure).ConclusionsModerate decreases in neutrophils were seen during baricitinib treatment; however, serious infection was uncommon in patients with neutropenia. Transient increases were observed in lymphocytes and platelets, which returned to baseline over time. Changes in haemoglobin concentration were generally small. Haematological abnormalities seldom led to drug discontinuation.

Objective Pain reduction with baricitinib was assessed in patients with rheumatoid arthritis (RA) who either used opioids or did not use opioids during three randomized, double‐blind phase 3 trials. Methods Analysis populations were as follows: i) baricitinib 4 mg once daily versus placebo groups integrated from RA‐BEAM (NCT01710358) for patients with inadequate response (IR) to methotrexate, RA‐BUILD (NCT01721057) with IR to conventional disease‐modifying antirheumatic drugs, and RA‐BEACON (NCT01721044) with IR to at least one tumor necrosis factor inhibitors; ii) baricitinib 2 mg versus placebo from RA‐BUILD and RA‐BEACON; and iii) adalimumab 40 mg every other week versus placebo from RA‐BEAM. Pain was measured by the Patient Assessment of Pain Visual Analog Scale. Analysis of covariance modeling assessed differences in pain reduction between treatments at each time point through Week 24, with an interaction term to test heterogeneous treatment effects across opioid users and nonusers. Results Baricitinib 4 mg had greater pain reduction versus placebo in opioid users and nonusers (P < 0.05) at all time points starting from Week 1; the pain reduction was similar between opioid users and nonusers. Baricitinib 2 mg had greater pain reduction versus placebo in opioid users and nonusers starting at Week 4. A significant difference in pain reduction was not observed for adalimumab versus placebo in the opioid users but was observed in nonusers at all time points. Conclusion Pain reduction was observed and was similar between opioid users and nonusers with baricitinib 2 mg and 4 mg but not adalimumab in this post hoc analysis.

In a trial involving 1033 patients hospitalized with Covid-19, the addition of baricitinib to remdesivir was associated with shorter recovery time, particularly among patients receiving high-flow oxygen, and with a 30% higher odds of improvement at day 15 than remdesivir alone. Adverse events were less frequent with the combination therapy.

Cataloging the very large number of undescribed species of insects could be greatly accelerated by automated DNA based approaches, but procedures for large-scale species discovery from sequence data are currently lacking. Here, we use mitochondrial DNA variation to delimit species in a poorly known beetle radiation in the genus Rivacindela from arid Australia. Among 468 individuals sampled from 65 sites and multiple morphologically distinguishable types, sequence variation in three mtDNA genes (cytochrome oxidase subunit 1, cytochrome b, 16S ribosomal RNA) was strongly partitioned between 46 or 47 putative species identified with quantitative methods of species recognition based on fixed unique (“diagnostic”) characters. The boundaries between groups were also recognizable from a striking increase in branching rate in clock-constrained calibrated trees. Models of stochastic lineage growth (Yule models) were combined with coalescence theory to develop a new likelihood method that determines the point of transition from species-level (speciation and extinction) to population-level (coalescence) evolutionary processes. Fitting the location of the switches from speciation to coalescent nodes on the ultrametric tree of Rivacindela produced a transition in branching rate occurring at 0.43 Mya, leading to an estimate of 48 putative species (confidence interval for the threshold ranging from 47 to 51 clusters within 2 logL units). Entities delimited in this way exhibited biological properties of traditionally defined species, showing coherence of geographic ranges, broad congruence with morphologically recognized species, and levels of sequence divergence typical for closely related species of insects. The finding of discontinuous evolutionary groupings that are readily apparent in patterns of sequence variation permits largely automated species delineation from DNA surveys of local communities as a scaffold for taxonomy in this poorly known insect group.