Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency

One of the severe combined immunodeficiencies (SCIDs), which is caused by a genetic defect in the signal transduction pathways involved in T-cell activation, is the ZAP70 deficiency. Mutations in ZAP70 lead to both abnormal thymic development and defective T-cell receptor (TCR) signaling of peripheral T-cells. In contrast to the lymphopenia in most SCID patients, ZAP70-deficient patients have lymphocytosis, despite the selective absence of CD8+ T-cells. The clinical presentation is usually before 2 years of age with typical findings of SCID. Here, we present three new ZAP70-deficient patients who vary in their clinical presentation. One of the ZAP70-deficient patients presented as a classical SCID, the second patient presented as a healthy looking wheezy infant, whereas the third patient came to clinical attention for the eczematous skin lesions simulating atopic dermatitis with eosinophilia and elevated immunoglobulin E (IgE), similar to the Omenn syndrome. This study illustrates that awareness of the clinical heterogeneity of ZAP70 deficiency is of utmost importance for making a fast and accurate diagnosis, which will contribute to the improvement of the adequate treatment of this severe immunodeficiency

A search for spectral hysteresis and energy-dependent time lags from X-ray and TeV gamma-ray observations of Mrk 421

Blazars are variable emitters across all wavelengths over a wide range of timescales, from months down to minutes. It is therefore essential to observe blazars simultaneously at different wavelengths, especially in the X-ray and gamma-ray bands, where the broadband spectral energy distributions usually peak. In this work, we report on three "target-of-opportunity" (ToO) observations of Mrk 421, one of the brightest TeV blazars, triggered by a strong flaring event at TeV energies in 2014. These observations feature long, continuous, and simultaneous exposures with XMM-Newton (covering X-ray and optical/ultraviolet bands) and VERITAS (covering TeV gamma-ray band), along with contemporaneous observations from other gamma-ray facilities (MAGIC and Fermi-LAT) and a number of radio and optical facilities. Although neither rapid flares nor significant X-ray/TeV correlation are detected, these observations reveal subtle changes in the X-ray spectrum of the source over the course of a few days. We search the simultaneous X-ray and TeV data for spectral hysteresis patterns and time delays, which could provide insight into the emission mechanisms and the source properties (e.g. the radius of the emitting region, the strength of the magnetic field, and related timescales). The observed broadband spectra are consistent with a one-zone synchrotron self-Compton model. We find that the power spectral density distribution at $\gtrsim 4\times 10^{-4}$ Hz from the X-ray data can be described by a power-law model with an index value between 1.2 and 1.8, and do not find evidence for a steepening of the power spectral index (often associated with a characteristic length scale) compared to the previously reported values at lower frequencies.Comment: 45 pages, 15 figure

Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding: Sanofi and Regeneron Pharmaceuticals

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

New constraints on the mid-IR EBL from the HESS discovery of VHE gamma-rays from 1ES 0229+200

Aims.To investigate the very high energy (VHE: >100 GeV) γ-ray emission from the high-frequency peaked BL Lac 1ES 0229+200. Methods: Observations of 1ES 0229+200 at energies above 580 GeV were performed with the High Energy Stereoscopic System (HESS) in 2005 and 2006. Results: 1ES 0229+200 is discovered by HESS to be an emitter of VHE photons. A signal is detected at the 6.6σ level in the HESS observations (41.8 h live time). The integral flux above 580 GeV is (9.4±1.5_stat±1.9_syst) × 10-13 cm-2 s-1, corresponding to ~1.8% of the flux observed from the Crab Nebula. The data show no evidence for significant variability on any time scale. The observed spectrum is characterized by a hard power law (Γ = 2.50±0.19_stat±0.10_syst) from 500 GeV to ~15 TeV. Conclusions: The high-energy range and hardness of the observed spectrum, coupled with the object's relatively large redshift (z = 0.1396), enable the strongest constraints so far on the density of the Extragalactic Background Light (EBL) in the mid-infrared band. Assuming that the emitted spectrum is not harder than Γ_int ≈ 1.5, the HESS data support an EBL spectrum ∝λ-1 and density close to the lower limit from source counts measured by Spitzer, confirming the previous indications from the HEGRA data of 1ES 1426+428 (z=0.129). Irrespective of the EBL models used, the intrinsic spectrum of 1ES 0229+200 is hard, thus locating the high-energy peak of its spectral energy distribution above a few TeV.Aharonian, F.; Akhperjanian, A. G.; Barres de Almeida, U.; Bazer-Bachi, A. R.; Behera, B.; Beilicke, M.; Benbow, W.; Bernlöhr, K.; Boisson, C.; Bolz, O.; Borrel, V.; Braun, I.; Brion, E.; Brown, A. M.; Bühler, R.; Bulik, T.; Büsching, I.; Boutelier, T.; Carrigan, S.; Chadwick, P. M.; Chounet, L.-M.; Clapson, A. C.; Coignet, G.; Cornils, R.; Costamante, L.; Dalton, M.; Degrange, B.; Dickinson, H. J.; Djannati-Ataï, A.; Domainko, W.; O'C. Drury, L.; Dubois, F.; Dubus, G.; Dyks, J.; Egberts, K.; Emmanoulopoulos, D.; Espigat, P.; Farnier, C.; Feinstein, F.; Fiasson, A.; Förster, A.; Fontaine, G.; Funk, Seb.; Füßling, M.; Gallant, Y. A.; Giebels, B.; Glicenstein, J. F.; Glück, B.; Goret, P.; Hadjichristidis, C.; Hauser, D.; Hauser, M.; Heinzelmann, G.; Henri, G.; Hermann, G.; Hinton, J. A.; Hoffmann, A.; Hofmann, W.; Holleran, M.; Hoppe, S.; Horns, D.; Jacholkowska, A.; de Jager, O. C.; Jung, I.; Katarzyński, K.; Kendziorra, E.; Kerschhaggl, M.; Khélifi, B.; Keogh, D.; Komin, Nu.; Kosack, K.; Lamanna, G.; Latham, I. J.; Lemière, A.; Lemoine-Goumard, M.; Lenain, J.-P.; Lohse, T.; Martin, J. M.; Martineau-Huynh, O.; Marcowith, A.; Masterson, C.; Maurin, D.; Maurin, G.; McComb, T. J. L.; Moderski, R.; Moulin, E.; de Naurois, M.; Nedbal, D.; Nolan, S. J.; Ohm, S.; Olive, J.-P.; de Oña Wilhelmi, E.; Orford, K. J.; Osborne, J. L.; Ostrowski, M.; Panter, M.; Pedaletti, G.; Pelletier, G.; Petrucci, P.-O.; Pita, S.; Pühlhofer, G.; Punch, M.; Ranchon, S.; Raubenheimer, B. C.; Raue, M.; Rayner, S. M.; Renaud, M.; Ripken, J.; Rob, L.; Rolland, L.; Rosier-Lees, S.; Rowell, G.; Rudak, B.; Ruppel, J.; Sahakian, V.; Santangelo, A.; Schlickeiser, R.; Schöck, F.; Schröder, R.; Schwanke, U.; Schwarzburg, S.; Schwemmer, S.; Shalchi, A.; Sol, H.; Spangler, D.; Stawarz, Ł.; Steenkamp, R.; Stegmann, C.; Superina, G.; Tam, P. H.; Tavernet, J.-P.; Terrier, R.; van Eldik, C.; Vasileiadis, G.; Venter, C.; Vialle, J. P.; Vincent, P.; Vivier, M.; Völk, H. J.; Volpe, F.; Wagner, S. J.; Ward, M.; Zdziarski, A. A.; Zech,

Alcohol, tobacco and breast cancer – collaborative reanalysis of individual data from 53 epidemiological studies, including 58 515 women with breast cancer and 95 067 women without the disease

Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58 515 women with invasive breast cancer and 95 067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, women's age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19–1.45, P<0.00001) for an intake of 35–44 g per day alcohol, and 1.46 (1.33–1.61, P<0.00001) for ⩾45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5–8.7%; P<0.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1% per 10 g per day, P<0.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers=1.03, 95% CI 0.98–1.07, and for current smokers=0.99, 0.92–1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver