Long-term evaluation of infliximab in the treatment of persistently active juvenile idiopathic arthritis refractory to conventional therapy

Objectives: To evaluate, in long-term open label prospective study, infliximab as therapeutic choice for Juvenile Idiopathic Arthritis (JIA) non responsive to conventional therapy. Methods: We enrolled to treat with infliximab 78 JIA patients (66 females, 12 males): the mean age was 20.7±7.1 years (median 20.9, range 5.4-34.9); mean JIA duration was 13.6±7.6 years (median 13.5, range 0.4-31.4). Infliximab, at dose of 3-10 mg/kg/infusion added to weekly subcutaneous Methotrexate or other previous DMARDs, was administered by intravenous infusions at weeks 0, 2, 6 and every 8 weeks thereafter. Chest X-ray, Mantoux's test, electrocardiogram were performed at baseline; laboratory tests and clinical evaluation were performed at each infusion. Response was evaluated according to ACR improvement criteria. Results: Mean treatment period was 21.6 months±18.8 (median 14.7, range 1.4-72.4). Just after first infusion most of patients reported significant improvement in pain, fatigue, morning stiffness. Infliximab is still successfully administered to 23 patients (29.5%); 55 (70.5%) patients suspended because of: inefficacy (7), infusion reactions (17), adverse events (9), disease flare-up after a period of effectiveness on synovitis, pain, and morning stiffness (19), remission (2), lack of compliance to treatment (1). Infusion reactions, like dyspnea, flushing, chills, headache, hypotension, anxiety, throat oedema, were observed in 29 patients (34.5%). Anti-DNA antibodies were present in 7 patients (none developed Systemic Lupus Eritematous). Conclusions: Infliximab showed impressive effectiveness treating refractory JIA, although most of patients had to discontinue treatment because of disease flare-up or adverse events. Infliximab may represent a good therapeutic choice in patients non-responders to Methotrexate

Side effects of anti-TNFa therapy in juvenile idiopathic arthritis

Aim of the study: To report adverse events registered in our population affected by JIA and treated with anti-TNFαblockers. Methods: Ninety-five patients were enrolled to be treated with Etanercept, median age 14 years (range 4-34); median duration of therapy 12 months (range 1-40). 19 patients were als treated with MTX (median dose 12.5 mg/week).Fifty-six patients were enrolled to be treated with Infliximab associated with MTX (median dose of MTX 8.8mg/week),median age 23.2 years (range 7.8-34.9); median duration of therapy 20.1 months (range 1.4-60.4). All adverse events were divided in definitely, probably and possibly related to the biologic agent. Results: Side effects definitely related to Infliximab were the reactions to infusions and the Anti-dsDNA positivity. Side effects definitely related to Etanercept were severe headache and thrombocytopenia. Side effects probably correlated to both the biological agents were behavioural modifications and pain amplification syndrome. Probably correlated to the treatment with Etanercept was the onset of Crohn’s disease in 3 patients. Possibly correlated to the biological agents were the new onset or flare-up of Chronic Iridocyclitis and single cases of thyroideal cancer, hypoglossal nerve paralysis and a severe Cytomegalovirus pulmonary infection. No case of tuberculosis infection was registered during this study. Conclusions: Treatment with a TNFαantagonist seems to be associated with various adverse events. Some of them,like onset of Crohn’s disease, behavioural modifications are unusual and others, like pain amplification syndrome were never described before. Children and young adults affected by JIA should be monitored very carefully so as to limit as much as possible the risk of serious side effects on anti-TNFα therapy

Paroxysmal Nocturnal Hemoglobinuria (Pnh) : Brain Mri Ischemic Lesions in Neurologically Asymtomatic Patients

This study investigated for the first time brain ischemic involvement in 19 consecutive neurologically asymptomatic PNH patients by non-enhanced cerebral MRI, and by intracranial arterial and venous angio-MRI. Eleven cases (58%, 7 aged 5 mm, and 5 cases a score >4 by the age-related white matter changes (ARWMC) scale. Compared with age and sex-matched controls (1:2 ratio), patients showed an increased frequency of periventricular WM vascular degeneration (32% versus 5.2%, p = 0.04) and of severe lesions (ARWMC scale score >4) (26% versus 2.6%, p = 0.05), and a higher overall ARWMC scale score (3.5 \uc2\ub1 1.07 versus 2.0 \uc2\ub1 0.8, mean \uc2\ub1 SD, p < 0.0001). Notably, vascular abnormalities suspected for prior partial venous thrombosis, were observed in PNH cases only. MRI lesions were not related to blood counts, hemolytic markers, clone size, disease duration, and therapy with eculizumab. Neurological examination was unremarkable in all patients but one (Parkinson disease). Psychiatric assessment revealed a case of generalized anxiety disorder, 1 bipolar disorder type 2, and 1 adjustment disorder. In conclusion, brain MRI may be useful at diagnosis and during the course of the disease to explore subclinical neurological involvement

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Hereditary hemorrhagic telangiectasia associated with cortical development malformation due to a start loss mutation in ENG

Background: Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is a rare disorder characterized by recurrent epistaxis, telangiectasias and systemic arteriovenous malformations (AVMs). HHT is associated with mutations in genes encoding for proteins involved in endothelial homeostasis such as ENG (endoglin) and ACVRL1 (activin receptor-like kinase-1). Case presentation: Here we describe a 22-year-old male presenting with a transient episode of slurred speech and left arm paresis. Brain MRI displayed polymicrogyria. A right-to-left shunt in absence of an atrial septum defect was noted. Chest CT revealed multiple pulmonary AVMs, likely causing paradoxical embolism manifesting as a transient ischemic attack. The heterozygous ENG variant, c.3G &gt; A (p.Met1lle), was detected in the patient. This variant was also found in patient's mother and in his younger brother who displayed cortical dysplasia type 2. Conclusions: The detection of cortical development malformations in multiple subjects from the same pedigree may expand the phenotypic features of ENG-related HHT patients. We suggest considering HHT in young patients presenting with acute cerebral ischemic events of unknown origin

Brain MRI Findings and Neuro-Psychiatric Involvement in Paroxysmal Nocturnal Hemoglobinuria (PNH)

PNH is a rare disorder characterized by hemolytic anemia, marrow failure and thrombosis, due to a deficiency in GPI-anchored proteins. Thrombotic events in PNH are commonly described in hepatic, portal, mesenteric, splenic, and renal veins, along with anecdotic case reports of cerebral venous sinus thrombosis and arterial ischemic strokes. This study was aimed at investigate brain involvement in 19 asymptomatic PNH patients by non-enhanced cerebral magnetic resonance imaging (MRI), and by intracranial arterial and venous angio-MRI. Neuroradiological findings were completed with a neuro-psychiatric evaluation, and correlated with clinical/hematologic features and therapy. Seventeen out of 19 patients were classical hemolytic (63% transfusion dependent before treatment with eculizumab and 1 patient also after), and 2 PNH in the context of aplastic anemia (all transfusion-dependent until treatment with ATG-CyA). Median age at diagnosis was 44 years (range 17-80); asthenia and dyspnea on exertion were present in all patients, abdominal pain in 8, and a thrombotic event in 4. Median Hb was 9.6 g/dL (range 6.7-12.9), LDH 3.7-fold (range 1.2-16.3) over upper limit of normal (ULN), and 73% of patients displayed a clone size greater than 50% GPI negative cells; 10/19 of patients were on eculizumab at the moment of the study. On MRI, 11 subjects showed pathological findings: 9 cases displayed white matter (WM) abnormalities related to chronic ischemic small vessel disease, of whom 6 periventricular WM vascular degeneration, and 8 deep WM focal chronic ischemic lesions (5 cases have both sites involved). Moreover, 1 subject showed a focal abnormality &gt;5 mm and 5 subjects a score &gt; 4 as evaluated in WM and basal ganglia by the age related white matter changes (ARWMC) scale. No subject displayed active or previous bleeding, nor were focal alterations of the basal nuclei by the ARWMC scale found. Two patients (80 and 81 yrs) showed atrophy of the cerebral hemispheres. Regarding vascular abnormalities, one subject had hypoplastic left transverse sinus with irregularities in the sinus wall, suspected for prior partial venous thrombosis. Three further cases displayed hypoplastic transverse sinus associated with collateral draining cortical veins, indistinguishable from anatomical variants. Intracranial artery stenosis or aneurysm, and Moya-Moya like alterations were not observed. Finally, cerebral MRI was unremarkable in 8/19 subjects. By comparing patients with or without any MRI abnormality (WM and vascular alterations), mean age was significantly higher in the former (60+17 vs 43+8 yrs, mean+SD, p&lt;0.05), whereas blood counts, hemolytic markers and clone size showed no remarkable differences. Hemoglobin at diagnosis was slightly lower (9.5+1.5 vs 9.9+1.6 g/dL, mean+SD), and LDH greater (5.8+4.4 vs 4.1+2.9 over ULN, mean+SD) in subjects who displayed MRI abnormalities. Moreover, individual hemoglobin levels negatively correlated with the ARWMC score (r=-0.45, p&lt;0.05). No relationship was found between history of abdominal pain/thrombosis and MRI pathological findings. Likewise, MRI abnormalities were not correlated with disease duration. As regards therapy with eculizumab, a pathological MRI was found in 6/10 subjects under treatment and in 5/9 without; the sole significant vascular alteration was detected in a patient under treatment. Neurological examination was unremarkable in all patients but one, who complained of progressive rest tremor in his left arm and leg (twelve years after PNH diagnosis), and was diagnosed with possible Parkinson disease. Previous history of neurological disorders was observed in 3 patients: one typical transient global amnesia (at the age of 60), one seizures (at 5 years), and one headache before the diagnosis of PNH. Regarding psychiatric evaluation, 3/18 patients had a psychiatric disorder according to structured clinical interview for axis I DSM-IV-TR disorders (1 generalized anxiety disorder, 1 bipolar disorder type 2, and 1 adjustment disorder as a consequence of PNH diagnosis). No relationship was observed between MRI findings and neuro-psychiatric assessment. In conclusion, brain MRI revealed chronic ischemic and vascular lesions in 58% of asymptomatic PNH patients. Brain MRI is advisable at diagnosis and during the course of the disease, and WM lesion burden may be useful in the decision to start therapy

New “CAPE” solutions for olefins plants. Detailed dynamic simulation and dynamic real-time optimization

This paper deals with certain novel and appealing computer-aided process engineering (CAPE) solutions to improve flexibility, controllability, and operability of olefins plants. It shows the use of detailed kinetic schemes, developed and validated by Professor Sauro Pierucci and his colleagues at the Chemical Engineering group at Politecnico di Milano, to produce new effective tools for reliable and accurate dynamic simulation and dynamic real-time optimization methodologies. Preliminary results and tangible benefits are explained for a steam cracking furnace