Swift-BAT GUANO follow-up of gravitational-wave triggers in the Third LIGO–Virgo–KAGRA Observing Run

We present results from a search for X-ray/gamma-ray counterparts of gravitational-wave (GW) candidates from the third observing run (O3) of the LIGO–Virgo–KAGRA network using the Swift Burst Alert Telescope (Swift-BAT). The search includes 636 GW candidates received with low latency, 86 of which have been confirmed by the offline analysis and included in the third cumulative Gravitational-Wave Transient Catalogs (GWTC-3). Targeted searches were carried out on the entire GW sample using the maximum-likelihood Non-imaging Transient Reconstruction and Temporal Search pipeline on the BAT data made available via the GUANO infrastructure. We do not detect any significant electromagnetic emission that is temporally and spatially coincident with any of the GW candidates. We report flux upper limits in the 15–350 keV band as a function of sky position for all the catalog candidates. For GW candidates where the Swift-BAT false alarm rate is less than 10−3 Hz, we compute the GW–BAT joint false alarm rate. Finally, the derived Swift-BAT upper limits are used to infer constraints on the putative electromagnetic emission associated with binary black hole mergers

Clinical diversity and treatment results in Tegumentary Leishmaniasis: A European clinical report in 459 patients

Background Cutaneous leishmaniasis (CL) is frequent in travellers and can involve oro-nasal mucosae. Clinical presentation impacts therapeutic management. Methodology Demographic and clinical data from 459 travellers infected in 47 different countries were collected by members of the European LeishMan consortium. The infecting Leishmania species was identified in 198 patients. Principal findings Compared to Old World CL, New World CL was more frequently ulcerative (75% vs 47%), larger (3 vs 2cm), less frequently facial (17% vs 38%) and less frequently associated with mucosal involvement (2.7% vs 5.3%). Patients with mucosal lesions were older (58 vs 30 years) and more frequently immunocompromised (37% vs 3.5%) compared to patients with only skin lesions. Young adults infected in Latin America with L. braziliensis or L. guyanensis complex typically had an ulcer of the lower limbs with mucosal involvement in 5.8% of cases. Typically, infections with L. major and L. tropica acquired in Africa or the Middle East were not associated with mucosal lesions, while infections with L. infantum, acquired in Southern Europe resulted in slowly evolving facial lesions with mucosal involvement in 22% of cases. Local or systemic treatments were used in patients with different clinical presentations but resulted in similarly high cure rates (89% vs 86%). Conclusion/Significance CL acquired in L. infantum-endemic European and Mediterranean areas displays unexpected high rates of mucosal involvement comparable to those of CL acquired in Latin America, especially in immunocompromised patients. When used as per recommendations, local therapy is associated with high cure rates. </jats:sec

Exploring the Inflammatory Metabolomic Profile to Predict Response to TNF-α Inhibitors in Rheumatoid Arthritis

<div><p>In clinical practice, approximately one-third of patients with rheumatoid arthritis (RA) respond insufficiently to TNF-α inhibitors (TNFis). The aim of the study was to explore the use of a metabolomics to identify predictors for the outcome of TNFi therapy, and study the metabolomic fingerprint in active RA irrespective of patients’ response. In the metabolomic profiling, lipids, oxylipins, and amines were measured in serum samples of RA patients from the observational BiOCURA cohort, before start of biological treatment. Multivariable logistic regression models were established to identify predictors for good- and non-response in patients receiving TNFi (n = 124). The added value of metabolites over prediction using clinical parameters only was determined by comparing the area under receiver operating characteristic curve (AUC-ROC), sensitivity, specificity, positive- and negative predictive value and by the net reclassification index (NRI). The models were further validated by 10-fold cross validation and tested on the complete TNFi treatment cohort including moderate responders. Additionally, metabolites were identified that cross-sectionally associated with the RA disease activity score based on a 28-joint count (DAS28), erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). Out of 139 metabolites, the best-performing predictors were <i>sn1</i>-LPC(18:3-ω3/ω6), <i>sn1</i>-LPC(15:0), ethanolamine, and lysine. The model that combined the selected metabolites with clinical parameters showed a significant larger AUC-ROC than that of the model containing only clinical parameters (p = 0.01). The combined model was able to discriminate good- and non-responders with good accuracy and to reclassify non-responders with an improvement of 30% (total NRI = 0.23) and showed a prediction error of 0.27. For the complete TNFi cohort, the NRI was 0.22. In addition, 88 metabolites were associated with DAS28, ESR or CRP (p<0.05). Our study established an accurate prediction model for response to TNFi therapy, containing metabolites and clinical parameters. Associations between metabolites and disease activity may help elucidate additional pathologic mechanisms behind RA.</p></div

The genomic architecture of blood metabolites based on a decade of genome-wide analyses

AbstractMetabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes and lipid species. We performed a review of all genetic association studies, and identified &gt; 800 class-specific metabolite loci that influence metabolite levels. In a twin-family cohort (N= 5,117), these metabolite loci were leveraged to simultaneously estimate total heritability (h2total), and the proportion of heritability captured by known metabolite loci (h2Metabolite-hits) for 309 lipids and 52 organic acids. Our study revealed significant differences inh2Metabolite-hitsamong different classes of lipids and organic acids. Furthermore, phosphatidylcholines with a high degree of unsaturation had higherh2Metabolite-hitsestimates than phosphatidylcholines with a low degree of unsaturation. This study highlights the importance of common genetic variants for metabolite levels, and elucidates the genetic architecture of metabolite classes and lipid species.</jats:p

Prospective natural history study of <i>C9orf72</i> ALS clinical characteristics and biomarkers

ObjectiveTo define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patient population, develop disease biomarkers, and characterize patient pathologies.MethodsWe prospectively collected clinical and demographic data from 116 symptomatic C9ALS and 12 non–amyotrophic lateral sclerosis (ALS) full expansion carriers across 7 institutions in the United States and the Netherlands. In addition, we collected blood samples for DNA repeat size assessment, CSF samples for biomarker identification, and autopsy samples for dipeptide repeat protein (DPR) size determination. Finally, we collected retrospective clinical data via chart review from 208 individuals with C9ALS and 450 individuals with singleton ALS.ResultsThe mean age at onset in the symptomatic prospective cohort was 57.9 ± 8.3 years, and median duration of survival after onset was 36.9 months. The monthly change was −1.8 ± 1.7 for ALS Functional Rating Scale–Revised and −1.4% ± 3.24% of predicted for slow vital capacity. In blood DNA, we found that G4C2 repeat size correlates positively with age. In CSF, we observed that concentrations of poly(GP) negatively correlate with DNA expansion size but do not correlate with measures of disease progression. Finally, we found that size of poly(GP) dipeptides in the brain can reach large sizes similar to that of their DNA repeat derivatives.ConclusionsWe present a thorough investigation of C9ALS natural history, providing the basis for C9ALS clinical trial design. We found that clinical features of this genetic subset are less variant than in singleton ALS. In addition, we identified important correlations of C9ALS patient pathologies with clinical and demographic data.</jats:sec

Business travel-associated illness: a GeoSentinel analysis†

Abstract Background Analysis of a large cohort of business travelers will help clinicians focus on frequent and serious illnesses. We aimed to describe travel-related health problems in business travelers. Methods GeoSentinel Surveillance Network consists of 64 travel and tropical medicine clinics in 29 countries; descriptive analysis was performed on ill business travelers, defined as persons traveling for work, evaluated after international travel 1 January 1997 through 31 December 2014. Results Among 12 203 business travelers seen 1997–2014 (14 045 eligible diagnoses), the majority (97%) were adults aged 20–64 years; most (74%) reported from Western Europe or North America; two-thirds were male. Most (86%) were outpatients. Fewer than half (45%) reported a pre-travel healthcare encounter. Frequent regions of exposure were sub-Saharan Africa (37%), Southeast Asia (15%) and South Central Asia (14%). The most frequent diagnoses were malaria (9%), acute unspecified diarrhea (8%), viral syndrome (6%), acute bacterial diarrhea (5%) and chronic diarrhea (4%). Species was reported for 973 (90%) of 1079 patients with malaria, predominantly Plasmodium falciparum acquired in sub-Saharan Africa. Of 584 (54%) with malaria chemoprophylaxis information, 92% took none or incomplete courses. Thirteen deaths were reported, over half of which were due to malaria; others succumbed to pneumonia, typhoid fever, rabies, melioidosis and pyogenic abscess. Conclusions Diarrheal illness was a major cause of morbidity. Malaria contributed substantial morbidity and mortality, particularly among business travelers to sub-Saharan Africa. Underuse or non-use of chemoprophylaxis contributed to malaria cases. Deaths in business travelers could be reduced by improving adherence to malaria chemoprophylaxis and targeted vaccination for vaccine-preventable diseases. Pre-travel advice is indicated for business travelers and is currently under-utilized and needs improvement. </jats:sec

Author Correction: Heritability estimates for 361 blood metabolites across 40 genome-wide association studies

An amendment to this paper has been published and can be accessed via a link at the top of the paper.</jats:p