MicroRNA-19b exacerbates systemic sclerosis through promoting Th9 cells.

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis of the skin and multiple vital organs, but the immunological pathogenesis of SSc remains unclear. We show here that miR-19b promotes Th9 cells that exacerbate SSc. Specifically, miR-19b and interleukin (IL)-9 increase in CD4 T cells in experimental SSc in mice induced with bleomycin.

Educational needs of patients, families, and healthcare professionals to support the patient journey in haemophilia gene therapy in the UK.

With the first gene therapies for haemophilia approved by the European Commission, the US Food and Drug Administration, and the Medicines and Healthcare products Regulatory Agency, it is important to consider the remaining unmet needs and challenges that may arise throughout patients' treatment journeys. We discuss existing unmet needs and important considerations prior to, during, and following haemophilia gene therapy treatment in the UK, and propose potential next steps. Key areas for attention are education, psychological support, and guidance on implementation.

Health-related quality of life following valoctocogene roxaparvovec gene therapy for severe hemophilia A in the phase 3 trial GENEr8-1.

Background: Severe hemophilia A (HA) negatively impacts health-related quality of life (HRQOL).

Objectives: We aimed to analyze HRQOL in adult men with severe HA without inhibitors after valoctocogene roxaparvovec gene transfer in the phase 3 trial GENEr8-1.

Methods: Participant-reported outcomes were the hemophilia-specific quality of life questionnaire for adults (Haemo-QOL-A), the EQ-5D-5L instrument, the Hemophilia Activities List (HAL), and the Work Productivity and Activity Impairment Questionnaire: Hemophilia Specific (WPAI+CIQ:HS).

TGF-β uncouples glycolysis and inflammation in macrophages and controls survival during sepsis.

Changes in metabolism of macrophages are required to sustain macrophage activation in response to different stimuli. We showed that the cytokine TGF-β (transforming growth factor-β) regulates glycolysis in macrophages independently of inflammatory cytokine production and affects survival in mouse models of sepsis. During macrophage activation, TGF-β increased the expression and activity of the glycolytic enzyme PFKL (phosphofructokinase-1 liver type) and promoted glycolysis but suppressed the production of proinflammatory cytokines.

TGF-β controls development of TCRγδCD8αα intestinal intraepithelial lymphocytes.

γδ intestinal intraepithelial lymphocytes (IELs) constitute the majority of IELs with unique CD8αα homodimers that are distinct from γδT cells in other tissues. However, it remains largely unclear how those cells develop. Here we show that transforming growth factor beta (TGF-β) signaling controls the development of TCRγδCD8αα IELs.

Urinothorax, a rare complication of rupture renal calyx.

Urinothorax is one of the rare causes of pleural effusion of extra-vascular origin, commonly presents with a transudative pleural effusion due to obstruction, injury or trauma to the genitourinary tract. It is not a common cause which increases the likelihood of underdiagnosis or misdiagnosis. Herein, we are presenting a 65-year-old gentleman who presented with urinary symptoms found to have urinothorax secondary to urinary tract obstruction by benign prostatic hypertrophy.

Diabetic Ketoacidosis-Induced Cardiomyopathy and Reversible Dialysis-Dependent Renal Failure With Successful Outcome: A Report of a Rare Case.

Stress-induced or Takotsubo cardiomyopathy (TCM) is a phenomenon that typically occurs in postmenopausal women in the setting of acute emotional or medical stressors. It typically causes reversible akinesis of the heart apex with opposite hyperdynamic basal segments. An electrocardiogram (ECG) would show ischemic ST elevation in anterior leads in >90% of cases with elevated troponin, yet coronary angiography rules out occlusive disease.

Hyperhemolytic Crisis Following Transfusion in Sickle Cell Disease With Acute Hepatic Crisis: A Case Report.

Hyperhemolysis syndrome (HHS) is a catastrophic unpredictable consequence of blood transfusion in sickle cell disease. It leads to further drop in hemoglobin via immune mechanisms complicating a hospital course and prolonging length of stay. Although sickle cell patients receive multiple transfusions throughout their disease course, this condition remains underreported by health care professionals or misinterpreted for other sickle cell crises.

Living bioethics, clinical ethics committees and children's consent to heart surgery.

This discussion paper considers how seldom recognised theories influence clinical ethics committees. A companion paper examined four major theories in social science: positivism, interpretivism, critical theory and functionalism, which can encourage legalistic ethics theories or practical living bioethics, which aims for theory-practice congruence. This paper develops the legalistic or living bioethics themes by relating the four theories to clinical ethics committee members' reported aims and practices and approaches towards efficiency, power, intimidation, justice, equality and children's interests and rights.

Children's informed signified and voluntary consent to heart surgery: Professionals' practical perspectives.

Background: The law and literature about children's consent generally assume that patients aged under-18 cannot consent until around 12 years, and cannot refuse recommended surgery. Children deemed pre-competent do not have automatic rights to information or to protection from unwanted interventions. However, the observed practitioners tend to inform young children s, respect their consent or refusal, and help them to "want" to have the surgery.

Global Seroprevalence of Pre-existing Immunity Against AAV5 and Other AAV Serotypes in People with Hemophilia A.

Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA). However, pre-existing immunity against AAV may limit transduction efficiency and hence treatment success. Global data on the prevalence of AAV serotypes are limited.

Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in AIDS Patient.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening syndrome that is often underdiagnosed. There are limited treatments and clinical outcomes documented in adults, more so in the immunocompromised population. Here, we described the clinical features, diagnosis, treatment, and clinical outcome of an HLH secondary to histoplasmosis in an AIDS patient.

Acquired Bernard-Soulier syndrome and hypodysfibrinogenaemia because of multiple myeloma.

We describe a case of a patient with multiple myeloma with initial presentation simulating a bleeding disorder. Detailed coagulation work-up showed hypodysfibrinogenaemia along with a platelet function defect consistent with acquired Bernard-Soulier syndrome (BSS). Multiple plasma exchanges led to significant improvement in his bleeding symptoms.

Predictive Role of Haematological Determinants on Outcomes of Critically Ill COVID-19 Patients Admitted to Intensive Care Unit.

Background:  The mortality of patients admitted to the intensive care unit (ICU) with COVID-19 remains significantly high. Severe COVID-19 pneumonia is characterised by refractory hypoxemia with significant shunting due to a combination of alveolar damage, vascular vasoconstriction, and occlusion due to microthrombi. Similar pathological features are seen in extra-pulmonary organs.

Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19.

Thrombosis affecting the pulmonary and systemic vasculature is common during severe COVID-19 and causes adverse outcomes. Although thrombosis likely results from inflammatory activation of vascular cells, the mediators of thrombosis remain unconfirmed. In a cross-sectional cohort of 36 severe COVID-19 patients, we show that markedly increased plasma von Willebrand factor (VWF) levels were accompanied by a partial reduction in the VWF regulatory protease ADAMTS13.

Altered and Agitated due to Hypertension: A Case of Posterior Reversible Encephalopathy Syndrome.

The authors present a case of posterior reversible encephalopathy syndrome in a patient on nutritional supplements. The presentation and emergency management are discussed.

Metabolomic analysis of tomato seed germination.

Introduction: Seed germination is inherently related to seed metabolism, which changes throughout its maturation, desiccation and germination processes. The metabolite content of a seed and its ability to germinate are determined by underlying genetic architecture and environmental effects during development.

Objective: This study aimed to assess an integrative approach to explore genetics modulating seed metabolism in different developmental stages and the link between seed metabolic- and germination traits.

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.

Background: Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations.

Methods: In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies.

Short Term Donor Outcomes After Hepatectomy in Living Donor Liver Transplantation.

Objective: To determine the outcome of living-donor liver transplant (LDLT) donors from the first liver transplant program in Pakistan.

Study Design: Cohort study.

Place And Duration Of Study: Shifa International Hospital, Islamabad, from April 2012 to August 2014.

The Activation of Complement and Its Role in the Pathogenesis of Thromboembolism.

It is well established that inflammation and thrombosis are intricately linked processes, and there is increasing evidence of the importance of their roles in activated complement in the pathogenesis of thromboembolism. The two systems are activated by similar stimuli simultaneously and interact, either directly or through biochemical mediators, to protect the host from microbial invasion. Diseases characterized by complement hyperactivity such as paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome have high rates of thrombosis.

Homeostasis of Hemostasis: The Role of Endothelium.

Forming an interface with virtually every other organ, endothelium has a strategic role in modulating vascular homeostasis. While its miscellany of functions includes regulation of vasomotor tone, promotion, and prevention of vascular growth, and modulation of inflammatory and hemostatic processes, it functions critically in maintaining the balance of hemostasis in health. Whereas endothelium has been recognized to influence all stages of hemostasis, new evidence suggests it to have a primary role for thrombin generation.

Impaired fibrinolysis in angiographically documented coronary artery disease.

Impaired fibrinolysis may predispose to coronary artery disease (CAD). Hypofibrinolysis due to high levels of plasminogen activator inhibitor-1 (PAI-1) has been reported in CAD. A novel regulator of fibrinolytic activity, thrombin activatable fibrinolysis inhibitor (TAFI), has attracted attention in recent years.

Tissue factor and tissue factor pathway inhibitor in women with a past history of preeclampsia: implication for a hypercoagulable state postpregnancy.

Preeclampsia (P-EC) is a multisystem disorder of pregnancy whose cause and pathogenesis remain poorly understood. However, abnormal haemostasis and endothelial dysfunction are thought to be implicated. Women with a past medical history of P-EC have a baseline hypercoagulable state postpregnancy.