Dose escalation using carbamylated monomeric tree pollen drops is well tolerated in patients with allergic rhinoconjunctivitis and points towards clinical effects.

Pulmonary Aspergillosis in Critically Ill Coronavirus Disease 2019 Patients– A Multinational Observational Study by the European Confederation of Medical Mycology

Inhaled Treprostinil and FVC Change in Patients With Interstitial Lung Disease and Associated Pulmonary Hypertension

Safety of biweekly α1-antitrypsin treatment in the RAPID programme

Outcomes for Patients with <i>IDH</i>-Mutated Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

Background: Atrial fibrillation (AF) is the most common sustained heart arrhythmia. Difficulties in diagnosing AF - particularly when paroxysmal and asymptomatic - and lack of routine screening contribute to underdiagnoses. Efficient, cost-effective detection of the undiagnosed may be supported by risk-prediction models relating patient factors to AF risk. However, there exists a need for an implementable risk model that is contemporaneous and informed by routinely collected patient data, reflecting the real-world pathology of AF. Methods: Machine learning and conventional statistical models were evaluated using patients identified from UK healthcare records, aged ≥30 years, without a history of AF, from January-2006 to December-2016. A matched case-control study evaluated published risk models (Framingham, ARIC, CHARGE-AF), machine learning models using baseline and time-updated information (neural network, LASSO, random forests, support vector machines) and Cox regression. Models were ranked with maximal discrimination between AF and non-AF cases (area under the receiver operating characteristic curve, AUROC) and potential number-needed-to-screen (NNS) to detect a case of AF. Findings: Analysis of 2,994,837 patients (3.2% AF) identified time-varying neural networks as the optimal model. Compared to the best existing model CHARGE-AF, the optimal model achieved an AUROC of 0.827 vs. 0.725, with NNS of 9 vs. 13 patients at 75% sensitivity. The optimal model confirmed known baseline risk factors (age, previous cardiovascular disease, antihypertensive medication usage) and identified additional time-varying predictors previously unknown (recency of cardiovascular events, body mass index (both levels and changes), pulse pressure, and the frequency of blood pressure measurements). Interpretation: The optimal time-varying machine learning model exhibited greater predictive performance than existing AF risk models and reflected known and new relationships between patient risk factors for AF. If utilised, the model may help improve the precision of AF screening, leading to better patient outcomes and cost-effective use of healthcare resources. Funding: Bristol-Myers Squibb and Pfizer. Declaration of Interest: NR Hill, U Farooqui, & S Lister are employees of Bristol-Myers Squibb Company. M Lumley is an employee of Pfizer Inc. D Ayoubkhani, P McEwan, D M Sugrue, J Gordon are employed by HEOR ltd., which provides consulting and other research services to pharmaceutical, medical device, and related organizations. In their salaried positions, they work with a variety of companies and organizations, and are precluded from receiving payments or honoraria directly from these organizations for services rendered. AT Cohen reports grants and personal fees from Bristol-Myers Squibb Company and Pfizer Inc. during the conduct of the study; personal fees from Boehringer Ingelheim, grants and personal fees from Bristol-Myers Squibb Company, grants and personal fees from Daiichi-Sankyo Europe, personal fees from Johnson & Johnson, grants and personal fees from Pfizer, Inc., personal fees from Portola, personal fees from Sanofi, personal fees from XO1, personal fees from Janssen, personal fees from ONO Pharmaceuticals, and grants and personal fees from Bayer AG, outside the submitted work. A Bakhai reports personal fees from Bristol-Myers Squibb Company and Pfizer Inc. during the conduct of the study; personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers Squibb Company, personal fees from Daiichi-Sankyo Europe, personal fees from Johnson & Johnson, personal fees from Pfizer, Inc., personal fees from Novartis, personal fees from Sanofi, personal fees from MSD, personal fees from Janssen, personal fees from Roche, and personal fees from Bayer AG, outside the submitted work. DA Clifton reports personal fees from Bristol-Myers Squibb Company during the conduct of the study; and outside the submitted work, personal fees from Drayson Health (now Sensyne Health), personal fees from Ferrovial plc., personal fees from Quanta Dialysis, and personal fees from BioBeats Ltd. M O’Neill reports personal fees from Bristol-Myers Squibb Company and Pfizer Inc. during the conduct of the study; grants and personal fees from Biosense Webster, grants and personal fees from Abbott, personal fees from Siemens, personal fees from Vytronus, personal fees from Medtronic outside the submitted work. Ethical Approval: The study protocol was reviewed and approved by the Independent Scientific Advisory Committee for MHRA database research (ISAC, reference number 17_151).

Increasing bronchiectasis prevalence in Germany, 2009-2017: a population-based cohort study.

Directing Therapy with Circulating Tumor DNA Analysis in Advanced Breast Cancer: The PlasmaMATCH Trial

Phase II Trial of Cediranib in Combination with Cisplatin and Pemetrexed in Chemo Naive Patients with Unresectable Malignant Pleural Mesothelioma (SWOG S0905, NCT01064648)

Artificial Intelligence Uncovered Clinical Factors for Cardiovascular Events in Myocardial Infarction Patients with Glucose Intolerance in the Cohort of Two Large-Scale ABC and PPAR Clinical Trials

Dear Editor, We congratulate Ojeda-Fernández et al1 on their study of the association between metformin use and lower risks of hospitalization and mortality in COVID-19 patients with diabetes. The study, one of the largest yet published, emphasizes the consistency of the association between metformin use and improved COVID-19 outcomes after hospital admission and in the medium term. However, we believe the published data on this topic should be interpreted with caution. In Table 1, we present an up-to-date summary of studies on the relationship between metformin use and COVID-19 that (i) were published in peer-reviewed medical journals and (ii) included more than 100 patients overall and more than 50 metformin users in particular. Duplicate studies and studies published in languages other than English, French or Italian were excluded. Overall, almost all the studies found that the short- and/or medium-term survival outcomes for metformin users were generally favourable. Ojeda-Fernández et al attributed the favourable association between metformin use and survival to a confounding effect of the indication; metformin is used early in the care trajectory for type 2 diabetes and is discontinued in long-term diabetes with cardiorenal comorbidities, whereas insulin is usually started later—typically when metformin is no longer indicated. Only few studies reported on the duration of diabetes in metformin users and non-users; this lack of data prevents meaningful conclusions from being drawn. However, 15 studies reported the proportion of participants who were being treated with insulin. Of these, 14 estimated the relative risk in the metformin group versus the non-metformin group. We performed a meta-regression analysis of the 14 datasets in order to determine whether or not the proportion of insulin-treated patients could account for the observed between-study heterogeneity. The analysis revealed a significant, inverse association between relative risk reduction and the proportion of insulin-treated patients (P = 0.0247). However, inclusion of the proportion of insulin-treated patients only reduced the I2 value very slightly (from 69.3% to 68.83%)—meaning there was still a substantial amount of residual between-study variance. In conclusion, although the findings by Ojeda-Fernández et al reinforce the conclusion that metformin is associated with a lower rate of mortality in type 2 diabetes patients with COVID-19, the assessment of this association is still strewn with pitfalls. Therefore, more studies are needed. Design and data collection: Abdallah Al-Salameh and Jean-Daniel Lalau. Analysis: Abdallah Al-Salameh, Nicolas Wiernsperger, Bertrand Cariou and Jean-Daniel Lalau. Writing manuscript: Abdallah Al-Salameh, Nicolas Wiernsperger, Bertrand Cariou and Jean-Daniel Lalau. This study did not receive any specific funding from agencies or organizations in the public, commercial, or not-for-profit sectors. Abdallah Al-Salameh reports personal fees from AstraZeneca, Lilly, and Novo Nordisk, none of which related to the subject discussed in this manuscript. Nicolas Wiernsperger declares no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported. Bertrand Cariou reports grants and personal fees from Amgen, personal fees from AstraZeneca, personal fees from Akcea, personal fees from Genfit, personal fees from Gilead, personal fees from Eli Lilly, personal fees from Novo Nordisk, personal fees from MSD, grants and personal fees from Sanofi, and grants and personal fees from Regeneron. Jean-Daniel Lalau reports personal fees from AstraZeneca, Brothier, Lilly, MSD, Novo Nordisk, Pfizer, and Sanofi. The peer review history for this article is available at https://publons.com/publon/10.1111/dom.14746. Data sharing not applicable to this article as no datasets were generated The peer review history for this article is available at https://publons.com/publon/10.1111/dom.14746. Data sharing not applicable to this article as no datasets were generated

Effects of Two-Drug Regimens of Antiretroviral Therapy on Inflammatory Biomarkers in CoRIS: A Prospective Nested Cohort Study

Title Eyelid myotonia and face stiffness in skeletal muscle sodium channelopathy Video Legend Video 1. Notice the delayed relaxation of the eyelids after forced eye closure (eyelid myotonia). Also, notice the full facial hair to prevent facial muscle stiffening exacerbation with cold weather. AuthorsSrijan Adhikari, MBBS, Jeffrey Statland, MD, Constantine Farmakidis, MD Authors information: Srijan Adhikari, MBBS, ORCID ID: 0000-0001-9653-3079, University of Kansas Medical Center, Department of Neurology, Kansas City, Kansas, USAJeffrey Statland, MD, ORCID ID: 0000-0003-0790-5315 University of Kansas Medical Center, Department of Neurology, Kansas City, Kansas, USAConstantine Farmakidis, MD, ORCID ID: 0000-0002-4688-9224, University of Kansas Medical Center, Department of Neurology, Kansas City, Kansas, USA Corresponding Author Srijan Adhikari, MBBS,Department of Neurology,University of Kansas Medical Center,3901 Rainbow Boulevard., MS 2012,Kansas City, KS 66160sadhikari@kumc.edu Author Conflict of Interests Dr Adhikari has nothing to disclose.Dr. Statland reports grants from NIH, grants from MDA, grants from FSHD Society, grants from Friends of FSH Research, personal fees from Dyne, personal fees from Fulcrum, personal fees from Avidity, personal fees from MT Pharma, personal fees from Acceleron, personal fees from Sarepta, personal fees from Strongbridge, outside the submitted work. Dr. Farmakidis reports personal fees from Argnex, personal fees from Momenta, personal fees from Terumo BCT, outside the submitted work.

Background: Autoimmunity may play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear if this is causative, or as a bystander of disease and if it carries any prognostic or treatment significance. Methods: Comprehensive immune phenotyping was performed in IPAH patients, utilising patient samples from the UK National cohort study of Idiopathic and Heritable PAH. Standardised flow cytometric analysis of peripheral blood mononuclear cell types was assessed in IPAH patients and healthy controls. Serum autoantibody biomarkers were assayed using a Protoplex™ autoimmune panel in 473 type I PAH patients and 946 matched controls. Finally, a GST-fusion human proteomic screen was undertaken to identify novel circulating autoantibodies in PAH, and 350 PAH sera samples ELISA assayed for a putative antibody to BMPR2. Findings: Flow cytometric immune profiling demonstrates IPAH is associated with a signature consistent with altered humoral immune response. Increased autoantibody positivity was detected in PAH and patient subgroups associated with worse haemodynamic parameters but better overall survival. We identify a small subset of PAH patients who demonstrate immunoglobulin reactivity to the extracellular domain of the TGFbeta superfamily receptor, BMPR2, a protein which is strongly associated with hereditary causes of the disease. Interpretation: This evidence strongly suggests a proportion of patients with IPAH have an autoimmune component to the disease and that the BMPR2 pathway may be a target. Future trials targeting inflammation need to consider biomarker stratification. Funding Information: NIHR BRC, The Dinosaur Trust, MRC (MC_UU_00002/4) and the Wellcome Trust [WT107881]. Declarations of Interest: Gerry Coghlan reports grants and personal fees for conference attendance from Johnson & Johnson, personal fees for lectures from GlaxoSmithKline, Bayer and MSD, outside the submitted work. Paul Corris reports grants and personal fees for lectures and consultations from Actelion and Bayer, and personal fees for lectures and consultations from MSD, outside the submitted work. Luke Howard reports grants, personal fees for lectures, steering committee and advisory board work, and non-financial support for meeting attendance from Actelion, personal fees for lectures and advisory board work from Bayer and MSD, personal fees for advisory board work from GSK, outside the submitted work. Martin Johnson reports grants and personal fees for meeting attendance, lectures, and advisory board work from Actelion and MSD, outside the submitted work. David Kiely reports grants, personal fees, and other support from Actelion, Bayer and GSK, and personal fees and other support from MSD, outside the submitted work. Allan Lawrie reports grants from British Heart Foundation and Medical Research Council, grants, personal fees, and travel support from Actelion Pharmaceuticals Ltd, grants and personal fees from GlaxoSmithKline, outside the submitted work. James Lordan has received modest honoraria from Actelion and modest support to attend conference from Merck Sharp & Dohme, outside the submitted work. Joanna Pepke Zaba received fees for research grant, support to travel to meetings and honoraria from Actelion, Bayer, GlaxoSmithKline and Merck Sharp & Dohme, outside the submitted work. S.John Wort has received modest honoraria from GlaxoSmithKline, Actelion and Bayer and has received significant research grants from Actelion and Bayer, outside the submitted work. Nicholas Morrell reports personal fees from GSK and Johnson & Johnson/Actelion, outside the submitted work. Mark Toshner reports personal fees from GSK, grants and personal fees from J&J/Actelion, grants from Merck and Bayer, outside the submitted work. All other authors have nothing to disclose Ethics Approval Statement: Ethical approval was obtained, and informed written consent was given. For collection and processing of samples for autoantibody analysis, including controls ethical approval was obtained (An integrated approach to dissect the determinants, risk factors and pathways of ageing in the immune system 15/EE/0327, IRAS # 188383 and Genetics and epidemiology of aging-associated conditions in the Sardinian population, ProgeNIA PROT 2171/CE).

Freezing All Embryos Versus Fresh Embryo Transfer in In-Vitro Fertilisation – a Multicentre Randomised Controlled Trial in the UK (E-Freeze)

Infectious Titres of Human Papillomaviruses (HPVs) in Patient Lesions, Methodological Considerations in Evaluating HPV Infectivity and Implications for the Efficacy of High-Level Disinfectants