Paradoxical dominant negative activity of an immunodeficiency-associated activating variant.

encodes three regulatory subunits of class IA phosphoinositide 3-kinase (PI3K), each associating with any of three catalytic subunits, namely p110α, p110β, or p110δ. Constitutional mutations cause diseases with a genotype-phenotype relationship not yet fully explained: heterozygous loss-of-function mutations cause SHORT syndrome, featuring insulin resistance and short stature attributed to reduced p110α function, while heterozygous activating mutations cause immunodeficiency, attributed to p110δ activation and known as APDS2. Surprisingly, APDS2 patients do not show features of p110α hyperactivation, but do commonly have SHORT syndrome-like features, suggesting p110α hypofunction.

Long term health outcomes in people with diabetes 12 months after hospitalisation with COVID-19 in the UK: a prospective cohort study.

Background: People with diabetes are at increased risk of hospitalisation, morbidity, and mortality following SARS-CoV-2 infection. Long-term outcomes for people with diabetes previously hospitalised with COVID-19 are, however, unknown. This study aimed to determine the longer-term physical and mental health effects of COVID-19 in people with and without diabetes.

DISCOntinuation of disease-modifying therapies in MS: The DISCOMS extension trial.

Background: In the DISCOMS (DISCOntinuation of disease-modifying therapies (DMTs) in multiple sclerosis (MS)) randomized clinical trial, we could not demonstrate that discontinuing MS DMTs in older, stable adults was not inferior to continuing DMTs. Relapses were rare in both groups, and most new disease activity was one to two new brain magnetic resonance imaging (MRI) lesions unassociated with clinical changes.

Objective/aims: Describe results of the DISCOMS extension study.

CD36 enrichment in HER2-positive mesenchymal stem cells drives therapy refractoriness in breast cancer.

Background: Growing evidence shows that the reprogramming of fatty acid (FA) metabolism plays a key role in HER2-positive (HER2 +) breast cancer (BC) aggressiveness, therapy resistance and cancer stemness. In particular, HER2 + BC has been defined as a "lipogenic disease" due to the functional and bi-directional crosstalk occurring between HER2-mediated oncogenic signaling and FA biosynthesis via FA synthase activity. In this context, the functional role exerted by the reprogramming of CD36-mediated FA uptake in HER2 + BC poor prognosis and therapy resistance remains unclear.

Direct-acting oral anticoagulant removal by intraoperative hemoadsorption in CABG and/or single valve surgery: interim analysis of the International Safe and Timely Antithrombotic Removal (STAR) registry.

Objective: Patients on direct-acting oral anticoagulants (DOACs) are at high risk of perioperative bleeding complications. Intraoperative hemoadsorption is a novel strategy to reduce perioperative bleeding in patients on DOACs undergoing non-deferable cardiac surgery. The international STAR-registry reports real-world clinical outcomes associated with this application.

ARTN and CCL23 predicted chemosensitivity in acute myeloid leukemia: an Olink proteomics approach.

Background: The standard "7 + 3" induction results in 30% of de novo acute myeloid leukemia (AML) patients not achieving complete remission (CR). We aimed to utilize the Olink platform to compare the bone marrow plasma proteomic profiles of newly diagnosed de novo AML patients who did and did not achieve CR following "7 + 3" induction treatment.

Methods: This prospective study included 43 untreated AML patients, stratified into CR (n = 29) and non-CR (n = 14) groups based on their response to "7 + 3" induction therapy.

Features of intermediate and late dry age-related macular degeneration on adaptive optics ophthalmoscopy: Pinnacle Study Report 8.

Background/objectives: Adaptive optics ophthalmoscopy (AOO) has the potential to provide insights into AMD pathology and to assess the risk of progression. We aim to utilise AOO to describe detailed features of intermediate AMD and to characterise microscopic changes during atrophy development.

Subjects/methods: Patients with intermediate AMD were recruited into PINNACLE, a prospective observational cohort study.

Adaptive clinical trial of AZD7442 and SARS-CoV-2 vaccination in immunosuppressed patients highly vulnerable to infection with SARS-CoV-2 virus (RAPID-PROTECTION): protocol for a multicentre, interventional open-label, randomised controlled trial.

Introduction: Despite repeated vaccinations against SARS-CoV-2 virus, patients who are immunocompromised remain at very high risk of catching SARS-CoV-2 virus and becoming unwell. AZD7442 (Evusheld) is a long-acting monoclonal antibody treatment that has been shown in clinical trials to prevent SARS-CoV-2 infection for up to a year after a single dose. Vaccines require a healthy immune system to generate protective immunity.

Biologics as well as inhaled anti-asthmatic therapy achieve clinical remission: Evidence from the Severe Asthma Network in Italy (SANI).

Background: This study aimed to evaluate the impact of severe asthma (SA) treatments after 12 months in achieving clinical remission (CR) within the context of the Severe Asthma Network in Italy (SANI) using the recent SANI definition of CR on treatment.

Methods: CR has been defined by SANI as complete, partial, and no CR. Complete CR is defined by the absence of oral corticosteroids (OCS), no symptoms, no exacerbations, and stable lung function, and partial CR requires the absence of OCS and the fulfillment of 2 out of the other 3 criteria.

Immunosuppressive therapy to treat newly diagnosed primary heart involvement in patients with systemic sclerosis: An Italian cardiac magnetic resonance based study.

Background: Primary heart involvement (pHI) is frequent in systemic sclerosis (SSc), and is associated with a poor prognosis. Therapeutic strategies to treat SSc-pHI are not yet defined.

Objectives: To evaluate the efficacy of immunosuppressive therapy on cardiac magnetic resonance (CMR) features in patients with CMR-proven SSc-pHI.

Tucatinib and trastuzumab in HER2-mutated metastatic breast cancer: a phase 2 basket trial.

Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) signaling promotes cell growth and differentiation, and is overexpressed in several tumor types, including breast, gastric and colorectal cancer. HER2-targeted therapies have shown clinical activity against these tumor types, resulting in regulatory approvals. However, the efficacy of HER2 therapies in tumors with HER2 mutations has not been widely investigated.

Somatic CAG repeat expansion in blood associates with biomarkers of neurodegeneration in Huntington's disease decades before clinical motor diagnosis.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with the age at which characteristic symptoms manifest strongly influenced by inherited HTT CAG length. Somatic CAG expansion occurs throughout life and understanding the impact of somatic expansion on neurodegeneration is key to developing therapeutic targets. In 57 HD gene expanded (HDGE) individuals, ~23 years before their predicted clinical motor diagnosis, no significant decline in clinical, cognitive or neuropsychiatric function was observed over 4.

Diffuseness of coronary artery disease impacts on immediate hemodynamic and predicted clinical outcomes.

Diffuse coronary artery disease (CAD) impacts the immediate hemodynamic and clinical outcomes of percutaneous coronary intervention (PCI). We evaluated whether the diffuse pattern of CAD derived from angiographic Quantitative flow ratio (QFR) impacts the immediate hemodynamic outcome post-PCI and the medium term predicted vessel-oriented composite endpoint (VOCE). Paired pre-procedure QFRs were assessed in 503 patients and 1022 vessels in the Multivessel TALENT (MVT) trial.

Clinical characteristics affecting weight loss in an East Asian population receiving semaglutide: A STEP 6 subgroup analysis.

Objective: To explore the effects of semaglutide versus placebo on body weight (BW) by subgroups of baseline characteristics.

Methods: In STEP 6, Japanese and Korean adults with overweight or obesity were randomized to subcutaneous semaglutide 2.4 mg, semaglutide 1.

A constitutive interferon-high immunophenotype defines response to immunotherapy in colorectal cancer.

Fewer than 50% of metastatic deficient mismatch repair (dMMR) colorectal cancer (CRC) patients respond to immune checkpoint inhibition (ICI). Identifying and expanding this patient population remains a pressing clinical need. Here, we report that an interferon-high immunophenotype locally enriched in cytotoxic lymphocytes and antigen-presenting macrophages is required for response.

Conformational Antibodies to Proteolipid Protein-1 and Its Peripheral Isoform DM20 in Patients With CNS Autoimmune Demyelinating Disorders.

Background And Objectives: Antibodies to proteolipid protein-1 (PLP1-IgG), a major central myelin protein also expressed in the peripheral nervous system (PNS) as the isoform DM20, have been previously identified mostly in patients with multiple sclerosis (MS), with unclear clinical implications. However, most studies relied on nonconformational immunoassays and included few patients with non-MS CNS autoimmune demyelinating disorders (ADDs). We aimed to investigate conformational PLP1-IgG in the whole ADD spectrum.

Biologically relevant integration of transcriptomics profiles from cancer cell lines, patient-derived xenografts, and clinical tumors using deep learning.

Cell lines and patient-derived xenografts are essential to cancer research; however, the results derived from such models often lack clinical translatability, as they do not fully recapitulate the complex cancer biology. Identifying preclinical models that sufficiently resemble the biological characteristics of clinical tumors across different cancers is critically important. Here, we developed MOBER, Multi-Origin Batch Effect Remover method, to simultaneously extract biologically meaningful embeddings while removing confounder information.

Plasma biomarkers of amyloid, tau, astrogliosis, and axonal injury in a mixed memory clinic cohort.

Introduction: Studies have shown that blood biomarkers can differentiate dementia disorders. However, the diagnosis of dementia still relies primarily on cerebrospinal fluid and imaging modalities. The new disease-modifying treatments call for more widely applicable biomarkers.

Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial.

Aims/hypothesis: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications.

Methods: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions.

Efficacy and tolerability of neoadjuvant therapy with Talimogene laherparepvec in cutaneous basal cell carcinoma: a phase II trial (NeoBCC trial).

We present a single-arm, phase II, neoadjuvant trial with the oncolytic virus talimogene laherparepvec (T-VEC) in 18 patients with difficult-to-resect cutaneous basal cell carcinomas. The primary end point, defined as the proportion of patients, who after six cycles of T-VEC (13 weeks), become resectable without the need for plastic reconstructive surgery, was already achieved after stage I (9 of 18 patients; 50.0%); thus the study was discontinued for early success.

Prognostic models for depression and post-traumatic stress disorder symptoms following traumatic brain injury: a CENTER-TBI study.

Background: Traumatic brain injury (TBI) is associated with an increased risk of major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). We aimed to identify predictors and develop models for the prediction of depression and PTSD symptoms at 6 months post-TBI.

Methods: We analysed data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury study.

Ethnic Differences in Atrial Fibrillation in the United Kingdom.

Background: Within the United States, White individuals experience a higher risk of atrial fibrillation (AF) while exhibiting a lower AF-related stroke risk compared to other ethnic groups. It is possible that these observations stem from phenomena unique to the United States, such as differential health care access. The United Kingdom provides socialized medicine, which ostensibly promotes equitable health care access.