Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Towards a revised stratigraphy for the Middle to Upper Palaeolithic boundary at La Guelga (Narciandi, Asturias, Spain). Soil micromorphology and new radiocarbon data

The archaeological sequence of the Palaeolithic site of La Guelga apparently shows an interstratification of Aurignacian between the Mousterian and Chatelperronian layers, a sequence which disagrees with the stratigraphic model for the Middle to Upper Palaeolithic transition in SW-Europe. We analyzed the witness section of the interior sector in archaeological zone D using micromorphology and collected new radiocarbon dates for the Aurignacian and presumably Chatelperronian levels in order to provide detailed sediment descriptions of the site and scrutinize the presumed interstratification. Thin sections from Mousterian levels 8 and 9 show microstratification, signs of trampling and preferential sub-horizontal orientation of elongated particles. These features are less strongly developed in the Aurignacian deposit of levels 5 and 6 and are lacking in the presumably Chatelperronian ones of levels 1 and 2. The deposits of the latter show other features of reworked slope deposits such as a randomized distribution of limestone clasts. Radiocarbon dating on bone samples from level 2 places this layer to between similar to 41.5 and 45 ka cal BP, hence older than Aurignacian level 5, dated to between similar to 35.5 and 41.5 ka cal BP. Comparative dating of bones with and without ultrafiltration pretreatment conducted in two different laboratories yielded results in excellent agreement. Overall, the micromorphological observations and new radiocarbon ages strongly suggest that the few finds of presumably Chatelperronian affinity and sediments of levels 1 and 2 were transported by slope processes into the shelter

Retrospective natural history of thymidine kinase 2 deficiency

Background Thymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy. Objective To perform a retrospective natural history study of a large cohort of patients with TK2 deficiency. Methods The study was conducted by 42 investigators across 31 academic medical centres. Results We identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate-to-severe progression of generalised weakness and median POS at least 13 years; and (3) late-onset myopathy (17.4%) with mild limb weakness at onset and slow progression to respiratory insufficiency with median POS of 23 years. Ophthalmoparesis and facial weakness are frequent in adults. Muscle biopsies show multiple mtDNA deletions often with mtDNA depletion. Conclusions In TK2 deficiency, age at onset, rate of weakness progression and POS are important variables that define three clinical subtypes. Nervous system involvement often complicates the clinical course of the infantile-onset form while extraocular muscle and facial involvement are characteristic of the late-onset form. Our observations provide essential information for planning future clinical trials in this disorder.Peer reviewe

Efficacy and safety of FOLFIRI/Aflibercept (FA) in an elderly population with metastatic colorectal cancer (mCRC) after the failure of an oxaliplatin-based regimen

Introduction: Aflibercept (ziv-aflibercept) significantly improves progression-free (PFS) and overall survival (OS) when added to FOLFIRI, compared with FOLFIRI alone, in the overall population of patients pretreated with oxaliplatin-based therapy. A subset analysis of elderly patients included in the registration VELOUR trial suggested that elderly (> 65 years) patients have a consistent, albeit small benefit in OS in PFS and a higher percentage of grade 3-4 toxicity. Our hypothesis was that selected patients with good PS could benefit from FOLFIRI-aflibercept (FA), provided they underwent careful monitoring of toxicity, and rapid intervention. Methods: We conducted a retrospective, multicentre, observational study of elderly patients (> 70 years) with mCRC treated with FOLFIRI-aflibercept after progression on an oxaliplatin-based regimen as part of routine clinical practice at seven hospitals from the Galician Research Group on Digestive Tumours (GITuD). Results: Of 315 patients treated with FA between June 2013 to November 2018, 71 elderly patients were recorded in this study. Median age was 72.7 years (range 70-84 years) and 33.4% were over 75 years (compared with only 14% in the VELOUR study subanalysis), 66.2 % were male, 83.1 % ECOG PS0-1, 43.7 % left-sided location, 76.1 % low grade, 63.4% RASmt and 2.8% BRAFmt, 66.2 % synchronous presentation and 77.5 % primary tumor resection. Prior therapy included bevacizumab (57.7%) and anti-EGFR agents (22.5%). Median of FA cycles was 9 (range 1-35 cycles). Overall Response Rate (ORR) and disease control rate (DCR) were 31.0 % and 63.4 %, respectively. With a median follow up of 27.1 months, median PFS was 6.6 months (95% CI, 5.0-8.3 months) and median OS was 15.1 months (95% CI, 12.1-18.1 months). The most common grade 3-4 toxicities were asthenia (18.3%), neutropenia (15.5%), diarrhoea (11.3%) and mucositis (9.9%). Aflibercept most common grade 3-4 related toxicities were hypertension (5.6%), dysphonia (5.6%), proteinuria (2.8%). Two patients experienced grade 5 toxicity (1 cerebrovascular event and 1 bowel perforation). This toxicity was managed with dose reduction of aflibercept in 39.4 % of cases, dose reduction of FOLFIRI on 57.7% and led to the discontinuation of aflibercept in 39.4%. Conclusion: Older patients with mCRC are underrepresented in clinical trials. The VELOUR study included only 6.4% patients over 65 years of age and only 14% of those over 65 were 75 years or older. Elderly patients treated with FA in the VELOUR trial experienced a higher rate of G3-4 adverse events (89.3% versus 80.5%) but this increase in toxicity was even more evident in the control arm (67.4% versus 59.4%). Our series confirms that with careful dose adjustment based on toxicity, including dose interruption if necessary elderly patients can be treated with FA with a 49.3% of grade 3-4 toxicity a PFS of 6.6 months and OS of 15.1 months, results that are comparable to those of younger patients

Retrospective natural history of thymidine kinase 2 deficiency

Background Thymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy. Objective To perform a retrospective natural history study of a large cohort of patients with TK2 deficiency. Methods The study was conducted by 42 investigators across 31 academic medical centres. Results We identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate-to-severe progression of generalised weakness and median POS at least 13 years; and (3) late-onset myopathy (17.4%) with mild limb weakness at onset and slow progression to respiratory insufficiency with median POS of 23 years. Ophthalmoparesis and facial weakness are frequent in adults. Muscle biopsies show multiple mtDNA deletions often with mtDNA depletion. Conclusions In TK2 deficiency, age at onset, rate of weakness progression and POS are important variables that define three clinical subtypes. Nervous system involvement often complicates the clinical course of the infantile-onset form while extraocular muscle and facial involvement are characteristic of the late-onset form. Our observations provide essential information for planning future clinical trials in this disorder