OBJECTIVEBy correlating known diabetes duration with the prevalence of retinopathy, more than 10 years have been estimated to lapse between the onset and diagnosis of type 2 diabetes. Such calculations, however, assumed a linear model, included stages of retinopathy not specific to diabetes, and allowed 5 years for retinopathy to occur after the onset of diabetes. We calculated the duration of undiagnosed type 2 diabetes in outpatients screened for retinopathy in a hospital-based diabetes clinic after correcting these assumptions. RESEARCH DESIGN AND METHODSDiabetic patients (n = 12,074; 35,545 fundus examinations) were stratified into younger onset (YO; age at onset <30 years) or older onset (OO; age at onset ‡30 years), insulin treated (IT) or not IT (NIT), and with mild/more severe diabetic retinopathy (AnyDR) or moderate/more severe diabetic retinopathy (ModDR). The best-fitting equation correlating known duration among the OO-NIT group with the prevalence of ModDR was used to extrapolate time from appearance of retinopathy to diagnosis of type 2 diabetes. Time for retinopathy to develop after diabetes was calculated from the equation correlating the duration among the YO-IT group with appearance of ModDR. RESULTSThere were 1,719 patients in the OO-NIT group with AnyDR and 685 with ModDR and 756 in the YO-IT group with AnyDR and 385 with ModDR. A linear model showed ModDR appeared 2.66 years before diagnosis among those in the OO-NIT group. A quadratic model suggested that ModDR appeared 3.29 years after diagnosis among those in the YO-IT group. The resulting estimate was 6.05 years (2.66 + 3.29) between the onset and diagnosis of diabetes, compared with 13.36 years using standard criteria. CONCLUSIONSUsing best-fitting models and stratifying by glucose-lowering treatment and severity of retinopathy substantially lowers the estimated duration of undiagnosed type 2 diabetes.

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BackgroundChanges of volume status can be readily inferred from variations in diameter of the inferior vena cava (IVC) measured by ultrasound. However the effect of IVC changes following acute blood loss are not fully established. In this study, three different approaches to measuring IVC variables were compared in healthy blood donors, as a model of acute volume depletion, in order to establish their relative ability to detect acute blood loss.MethodsInspiratory and expiratory IVC diameters were measured before and after blood donation in hepatic long axis, hepatic short axis and renal short axis views using a 2–5 MHz curvilinear probe. All measurements were recorded and examined in real-time and post-processing sessions.ResultsAll windows performed satisfactorily but the renal window approach was feasible in only 30 out of 47 subjects. After blood donation, IVC diameters decreased in hepatic long axis, hepatic short axis and renal short axis (expiratory: −19.9, −18.0, −26.5 %; CI 95 %: 14.5–24.1; 13.1–22.9; 16.0–35.9, respectively) (inspiratory: −31.1, −31.6, −36.5 %; CI 95 %: 21.3–40.1; 18.8–45.2; 23.4–46.0, respectively), whereas the IVC collapsibility index increased by 21.6, 22.6 and 19.3 % (CI 95 %: 11.6–42.9; 18.5–39.5; 7.7–30.0). IVC diameters appeared to return to pre-donation values within 20 min but this was only detected by the hepatic long axis view.ConclusionsIVC diameter and collapsibility index variations, as measured in M mode, consistently detect volume changes after blood donation. The longitudinal mid-hepatic approach performed better by allowing a panoramic view, avoiding anatomical aberrancies at fixed points and permitting to identify the best possible perpendicular plane to the IVC. In addition, it was able to detect time-dependent physiological volume replacement. In contrast, in our hands, the renal window could not be visualized consistently well.

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Systemic Lupus Erythematosus (SLE) is an autoimmune disease of unknown etiology that often affects women during childbearing age. Pregnant women with SLE are considered high-risk patients, with pregnancy outcomes being complicated by high maternal and fetal mortality and morbidity. Obstetric morbidity includes preterm birth, fetal growth restriction (FGR), and neonatal lupus syndromes. Active SLE during conception is a strong predictor of adverse pregnancy outcomes and exacerbations of disease can occur more frequently during gestation. Therefore, management of maternal SLE should include preventive strategies to minimize disease activity and to reduce adverse pregnancy outcomes. Patients with active disease at time of conception have increased risk of flares, like lupus nephritis, imposing a careful differential diagnosis of pre-eclampsia, keeping in mind that physiological changes of pregnancy may mimic a lupus flare. Major complications arise when anti-phospholipid antibodies are present, like recurrent pregnancy loss, stillbirth, FGR, and thrombosis in the mother. A multidisciplinary approach is hence crucial and should be initiated to all women with SLE at childbearing age with an adequate preconception counseling with assessment of risk factors for adverse maternal and fetal outcomes with a tight pregnancy monitoring plan. Although treatment choices are limited during pregnancy, prophylactic anti-aggregation and anticoagulation agents have proven beneficial in reducing thrombotic events and pre-eclampsia related morbidity. Pharmacological therapy should be tailored, allowing better outcomes for both the mother and the baby. Immunosuppressive and immunomodulators, must be effective in controlling disease activity and safe during pregnancy. Hydroxychloroquine is the main therapy for SLE due to its anti-inflammatory and immunomodulatory effects recommended before and during pregnancy and other immunosuppressive drugs (e.g. azathioprine and calcineurin inhibitors) are used to control disease activity in order to improve obstetrical outcomes. Managing a maternal SLE is a challenging task, but an early approach with multidisciplinary team with close monitoring is essential and can improve maternal and fetal outcomes.

In order to address the main challenges related to the rare diseases (RDs) the European Commission launched the European Reference Networks (ERNs), virtual networks involving healthcare providers (HCPs) across Europe. The mission of the ERNs is to tackle low prevalence and RDs that require highly specialised treatment and a concentration of knowledge and resources. In fact, ERNs offer the potential to give patients and healthcare professionals across the EU access to the best expertise and timely exchange of lifesaving knowledge, trying to make the knowledge travelling more than patients. For this reason, ERNs were established as concrete European infrastructures, and this is particularly crucial in the framework of rare and complex diseases in which no country alone has the whole knowledge and capacity to treat all types of patients. It has been five years since their kick-off launch in Vilnius in 2017. The 24 ERNs have been intensively working on different transversal areas, including patient management, education, clinical practice guidelines, patients' care pathways and many other fundamental topics. The present work is therefore aimed not only at reporting a summary of the main activities and milestones reached so far, but also at celebrating the first 5 years of the ERN on Rare and Complex Connective Tissue and Musculo-skeletal Diseases (ReCONNET), in which the members of the network built together one of the 24 infrastructures that are hopefully going to change the scenario of rare diseases across the EU.

Editor-in-Chief: A. Giustina ▶ Covers leading topics in endocrinology ▶ Includes Hormones of reproduction, metabolism, growth, and ion balance ▶ Offers the latest on insulin and diabetes ▶ Presents newly-emerging endocrine-related topics ▶ 94% of authors who answered a survey reported that they would definitely publish or probably publish in the journal againWell-established as a major journal in today's rapidly advancing experimental and clinical research, Endocrine publishes full-length original articles devoted to basic (including molecular, cellular and physiological studies), translational and clinical (including proof of concept studies and clinical trials) research in all the different fields of endocrinology and metabolism. Endocrine covers the following leading topics in Endocrinology such as: Neuroendocrinology, Pituitary and hypothalamic peptides, thyroid physiological and clinical aspects, bone and mineral metabolism and osteoporosis, obesity, lipid and energy metabolism and food intake control, insulin, type 1 and type 2 diabetes, hormones of male and female reproduction, and of HPA axis, pediatric and geriatric endocrinology, endocrine hypertension and endocrine oncology.

Key Clinical MessagePrimary immunodeficiency disorders are rarely diagnosed in adults but must be considered in the differential diagnosis of combined recurrent infections and autoimmune disease. We describe a patient with CTLA‐4 haploinsufficiency and an abnormal regulatory T‐cell phenotype. Unusually, infections were more severe than autoimmunity, illustrating therapeutic challenges in disease course.