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Mid Regional pro-ADM (MR-proADM) is a promising novel biomarker in the evaluation of deteriorating patients and an emergent prognosis factor in patients with sepsis, septic shock and organ failure. It can be induced by bacteria, fungi or viruses. We hypothesized that the assessment of MR-proADM, with or without other inflammatory cytokines, as part of a clinical assessment of COVID-19 patients at hospital admission, may assist in identifying those likely to develop severe disease. A pragmatic retrospective analysis was performed on a complete data set from 111 patients admitted to Udine University Hospital, in northern Italy, from 25th March to 15th May 2020, affected by SARS-CoV-2 pneumonia. Clinical scoring systems (SOFA score, WHO disease severity class, SIMEU clinical phenotype), cytokines (IL-6, IL-1b, IL-8, TNF-α), and MR-proADM were measured. Demographic, clinical and outcome data were collected for analysis. At multivariate analysis, high MR-proADM levels were significantly associated with negative outcome (death or orotracheal intubation, IOT), with an odds ratio of 4.284 [1.893–11.413], together with increased neutrophil count (OR = 1.029 [1.011–1.049]) and WHO disease severity class (OR = 7.632 [5.871–19.496]). AUROC analysis showed a good discriminative performance of MR-proADM (AUROC: 0.849 [95% Cl 0.771–0.730]; p  < 0.0001). The optimal value of MR-proADM to discriminate combined event of death or IOT is 0.895 nmol/l, with a sensitivity of 0.857 [95% Cl 0.728–0.987] and a specificity of 0.687 [95% Cl 0.587–0.787]. This study shows an association between MR-proADM levels and the severity of COVID-19. The assessment of MR-proADM combined with clinical scoring systems could be of great value in triaging, evaluating possible escalation of therapies, and admission avoidance or inclusion into trials. Larger prospective and controlled studies are needed to confirm these findings.

Background Mid-Regional pro-Adrenomedullin (MR-proADM) is an inflammatory biomarker that improves the prognostic assessment of patients with sepsis, septic shock and organ failure. Previous studies of MR-proADM have primarily focussed on bacterial infections. A limited number of small and monocentric studies have examined MR-proADM as a prognostic factor in patients infected with SARS-CoV-2, however there is need for multicenter validation. An evaluation of its utility in predicting need for hospitalisation in viral infections was also performed. Methods An observational retrospective analysis of 1861 patients, with SARS-CoV-2 confirmed by RT-qPCR, from 10 hospitals across Europe was performed. Biomarkers, taken upon presentation to Emergency Departments (ED), clinical scores, patient demographics and outcomes were collected. Multiclass random forest classifier models were generated as well as calculation of area under the curve analysis. The primary endpoint was hospital admission with and without death. Results Patients suitable for safe discharge from Emergency Departments could be identified through an MR-proADM value of ≤ 1.02 nmol/L in combination with a CRP (C-Reactive Protein) of ≤ 20.2 mg/L and age ≤ 64, or in combination with a SOFA (Sequential Organ Failure Assessment) score < 2 if MR-proADM was ≤ 0.83 nmol/L regardless of age. Those at an increased risk of mortality could be identified upon presentation to secondary care with an MR-proADM value of > 0.85 nmol/L, in combination with a SOFA score ≥ 2 and LDH > 720 U/L, or in combination with a CRP > 29.26 mg/L and age ≤ 64, when MR-proADM was > 1.02 nmol/L. Conclusions This international study suggests that for patients presenting to the ED with confirmed SARS-CoV-2 infection, MR-proADM in combination with age and CRP or with the patient’s SOFA score could identify patients at low risk where outpatient treatment may be safe.

ObjectiveTo evaluate the performance of clinical criteria (CC) for diagnosis and initiation of empirical treatment with continuous positive airway pressure (CPAP) in patients with suspected obstructive sleep apnea (OSA) compared with the treatment decision based on sleep studies (polysomnography or respiratory polygraphy), guidelines, and experience of participating physicians.MethodsThis was a simulated intention-to-treat study in a retrospective (G1) and prospective (G2) cohort. Four observers (two per group) called CC1 and CC2 reviewed the sleep questionnaires and indicated CPAP if the patients presented snoring, frequent apneas (≥ 3–4/week), body mass index (BMI) > 25 kg/m2, sleepiness (Epworth > 11), or tiredness (at least 3–4 times per week) and some comorbidity (hypertension, coronary/cerebrovascular event, diabetes). Ten independent observers formed two groups of five (FD1 and FD2) and were blinded to each other’s opinion. These observers in FD1 and FD2 decided CPAP treatment based on guidelines of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) or guidelines of the American Academy of Sleep Medicine (AASM) and factored in their own opinion. Sensitivity (S), specificity (Sp), and positive/negative likelihood ratios (LR+/−) were calculated with the test method: CC1/2, and the reference method: majority decision of FD1/2.ResultsA total of 653 patients (264 women, 40%) were studied. Median age was 54 years, BMI 28 kg/m2, and apnea hypopnea index (AHI) 16.5 events/h. S ranged from 21 to 25% (p 0.60), Sp 96.1 to 97.6% (p 0.39), and LR+ of clinical criteria 6.4 to 8.9 (p 0.52).ConclusionCPAP indication without a previous sleep study showed a low sensitivity (≅ 22%) but a specificity greater than 95% in patients with high pretest probability for OSA (snoring, report of frequent apneas, BMI > 25 kg/m2 and sleepiness or tiredness plus comorbidity).

Reflex tests are widely used in clinical laboratories, for example, to diagnose thyroid disorders or in the follow-up of prostate cancer. Reflex tests for antinuclear antibodies (ANA) have recently gained attention as a way to improve appropriateness in the immunological diagnosis of autoimmune rheumatic diseases and avoid waste of resources. However, the ANA-reflex test is not as simple as other consolidated reflex tests (the TSH-reflex tests or the PSA-reflex tests) because of the intrinsic complexity of the ANA test performed by the indirect immunofluorescence method on cellular substrates. The wide heterogeneity of the ANA patterns, which need correct interpretation, and the subsequent choice of the most appropriate confirmatory test (ANA subserology), which depend on the pattern feature and on clinical information, hinder any informatics automation, and require the pathologist’s intervention. In this review, the Study Group on Autoimmune Diseases of the Italian Society of Clinical Pathology and Laboratory Medicine provides some indications on the configuration of the ANA-reflex test, using two different approaches depending on whether clinical information is available or not. We further give some suggestions on how to report results of the ANA-reflex test.

Background Adrenomedullin (ADM) is a potent hormone‐like peptide rapidly induced by hypoxia and inflammatory cytokines in the early stages of sepsis. For this reason, the dosage of its more stable precursor fragment called mid‐regional (MR)‐proADM is currently recommended to assist in triaging patients in the emergency department. Since MR‐proADM dosage is currently only approved for use in plasma, we validated its dosage in cerebrospinal fluid (CSF) samples to improve the diagnosis of central nervous system (CNS) diseases. Methods MR‐proADM concentrations were measured in samples using a fully automated platform (Brahms Kryptor Gold Analyzer, Thermo Scientific, Germany), applying the same analytical conditions in plasma and CSF samples, to finally set up an accurate laboratory protocol to validate its dosage in CSF. Results MR‐proADM is highly stable in CSF samples stored at room temperature for up to 48 h, allowing it to be measured with confidence also in CSF samples that may be left on the bench for several hours. In addition, the repeatability and within‐laboratory precision of the MR‐proADM assay using CSF samples appeared equal to or better than those obtained by the manufacturer using plasma samples, allowing the use of this assay, with high precision, also for CSF samples. Conclusion The reliable measure of MR‐proADM in CSF and the role of this molecule in CNS will allow its introduction in the diagnostic process of infectious, inflammatory, and degenerative neurological diseases. Numerous evidences suggest that Adrenomedullin represents an important regulator of endothelial homeostasis also in the central nervous system and may have a role in infectious, inflammatory, and degenerative neurological diseases. Mid‐regional proadrenomedullin (MR‐proADM) can be reliably measured in cerebrospinal fluid using commercially available methods. MR‐proADM is a promising biomarker to improve the diagnostic work‐up of neurological diseases.

COVID‐19 is heterogeneous; therefore, it is crucial to identify early biomarkers for adverse outcomes. Extracellular vesicles (EV) are involved in the pathophysiology of COVID‐19 and have both negative and positive effects. The objective of this study was to identify the potential role of EV in the prognostic stratification of COVID‐19 patients. A total of 146 patients with severe or critical COVID‐19 were enrolled. Demographic and comorbidity characteristics were collected, together with routine haematology, blood chemistry and lymphocyte subpopulation data. Flow cytometric characterization of the dimensional and antigenic properties of COVID‐19 patients' plasma EVs was conducted. Elastic net logistic regression with cross‐validation was employed to identify the best model for classifying critically ill patients. Features of smaller EVs (i.e. the fraction of EVs smaller than 200 nm expressing either cluster of differentiation [CD] 31, CD 140b or CD 42b), albuminemia and the percentage of monocytes expressing human leukocyte antigen DR (HLA‐DR) were associated with a better outcome. Conversely, the proportion of larger EVs expressing N‐cadherin, CD 34, CD 56, CD31 or CD 45, interleukin 6, red cell width distribution (RDW), N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), age, procalcitonin, Charlson Comorbidity Index and pro‐adrenomedullin were associated with disease severity. Therefore, the simultaneous assessment of EV dimensions and their antigenic properties complements laboratory workup and helps in patient stratification.

Rheumatoid arthritis (RA) is characterized by the presence of circulating rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPA), which are positive in about 70–80% of patients. APCA have a higher specificity and therefore a higher diagnostic power than RF, but are less informative than RF in monitoring the course of the disease in patients under treatment. Recently, it has been reported that the anticitrullinated vimentin (a-MCV) antibody test can identify a particular subgroup of APCA that may be negative for anticyclic citrullinated peptide (a-CCP) antibodies. Concerning RF, the RF IgA isotype has been described as a more specific marker of erosive joint damage than total RF. The aim of our study was to monitor the levels of a-CCP, a-MCV, total RF and RF IgA in the follow-up of patients with RA treated with B-lymphocytedepletive rituximab (RTX), to detect any differences or peculiarities in patterns of these autoantibodies, especially in relation to their potential use as predictive markers of therapeutic response. We studied 30 patients with RA treated with RTX. All patients were previously unresponsive to at least 6 months of therapy with disease-modifying antirheumatic drugs (DMARDs; methotrexate, leflunomide, cyclosporine, chloroquine) and/or at least 6 months of therapy with anti-TNF biologics. The evaluation of response to RTX was made at month +6 using the EULAR criteria (DAS28). a-CCP, a-MCV, total RF and RF IgA were determined at baseline (before the first infusion of RTX) and after 1, 3 and 6 months. In serum samples obtained before treatment two cytokines essential for Blymphocyte proliferation, interleukin 6 (IL-6) and B-lymphocyte stimulator (BLyS) were also determined. In all patients a significant and consistent reduction in all the tested antibodies was found during follow-up, with no differences in respect of the degree of response to RTX. Of note, at baseline, generally a higher titre of all autoantibodies was seen in patients who then showed a better response to RTX. Finally, there were no differences in serum concentrations of IL-6 and BLyS in patients in relation to the presence or absence of the autoantibodies investigated, nor was there any significant correlation between the serum concentrations of the cytokines and the titres of the autoantibodies. Thus, neither a-MCV compared to a- CCP, nor RF IgA compared to routine total RF, provided any additional predictive information in the follow-up of patients with RA treated with RTX.

Objectives Despite numerous pieces of evidence of its important role as a diagnostic and prognostic biomarker in infectious diseases and sepsis, adrenomedullin (ADM) was only poorly investigated in cerebrospinal fluid (CSF) in central nervous system (CNS) infections. In this multicentre retrospective study, we investigated ADM CSF concentrations in acute meningitis compared to other noninfectious neurological disorders. Methods Since ADM is rapidly metabolised in vivo, the available diagnostic methods are designed to measure its cognate metabolite called mid‐regional proADM (MR‐proADM). We collected detailed clinical and laboratory data about 293 patients in whom MR‐proADM was measured in CSF and plasma as part of the diagnostic workup. Results Patients were finally classified in CNS infection (n = 59), other CNS disorders (n = 190) and 14 disease controls, in which CNS infections and other definite disorders were excluded. Both cerebrospinal MR‐proADM levels and their CSF/blood ratio were significantly higher in CNS infections compared to the other two groups (p < 0.001 and p < 0.037 respectively). CSF MR‐proADM resulted informative for patients' classification, furnishing a volume under the ROC surface of 0.513 [0.414–0.613], overcoming the 1/6 threshold value for undecidability. Threshold values of < 0.807 and > 1.590 nmol/L can differentiate controls from neurological disorders and neurological disorders from CNS infections respectively. Conclusions We demonstrated significant upregulation of Adrenomedullin in CSF during infections compared to other neurological diseases and proposed preliminary thresholds of CSF MR‐proADM to be used in the diagnostic workup of acute CNS infections, to help with differential diagnosis and possibly guide targeted therapeutic interventions. MR‐ProADM levels reflect Adrenomedullin response to BBB damage. CSF levels are quite variable across different neurological syndromes, but they are particularly high in acute CNS infections, which makes MR‐ProADM a promising additional diagnostic and prognostic biomarker in this setting.

Diabetes mellitus is a common autoimmune endocrine disorder associated with organ-specific autoantibodies which are frequently detected at the time of diagnosis. Some of these antibodies are specific to the pancreas (GAD, IA2, ICA) while others are related to different autoimmune diseases. Aim of the study : To define the prevalence of thyroid autoimmune disease in Libyan patients with type 1 diabetes mellitus (T1DM) since no similar studies have been performed in Libya. Materials and methods : Blood samples were collected from 218 patients with T1DM who are followed by the Pediatric Department, Tripoli Medical Center, Libya. All sera were analyzed in Italy (Laboratory of Immunopathology and Allergy, Udine). The patients were composed of 123 females (56.4%) and 95 males (43.6%), mean age 12.2 ± 4.6 years (range 2.1–24.5 years), mean duration of diabetes 4.7 ± 4.0 years (range 0.1–17.5 years). Sera were tested for anti-thyroperoxidase (TPO) and anti-thyroglobulin antibodies (TG). TSH and FT4 concentrations were measured in all subjects. GAD, IA-2 was also measured. Results : Of the diabetic children, 23.4% were positive for anti-microsomal peroxidase antibodies (TPO-Ab) and 7.8% for antithyroglobulin antibodies (TG-Ab); whereas 6.9% of the patients were positive for both TPO-Ab and TG-Ab. Of the T1DM patients who were positive for TPO-Ab, 66.6% were females. The majority (57%) of the patients who were positive for TPO had diabetes for longer than 5 years. Five patients (2.3%) had evidence of subclinical hypothyroidism whereas two patients (0.9%) had overt hypothyroidism. Two patients had subclinical hyperthyroidism and two (0.9%) had overt hyperthyroidism. Interestingly, 16.2% of patients were positive for both thyroid and pancreatic antibodies. Conclusions : The prevalence of autoimmune thyroid disease in type 1 diabetic patients is higher than in the general population. A routine screening strategy should be implemented with the determination of anti-thyroid antibodies and TSH in type 1 diabetic patients, particularly in girls, and in patients with diabetes of more than 5 years duration. Patients who have positive TPO antibodies may need the assessment of thyroid function at shorter intervals.

Purpose Cholinesterase inhibitors are commonly prescribed to patients with Alzheimer’s disease (AD) to enhance cholinergic neurotransmission. Differential response to these treatments has been observed, and claims have been made that individual genetic variants may influence the pharmacokinetic and pharmacodynamic properties of these drugs. Here we assess the effects of genetic variation at two loci involved in the activity of cholinesterase inhibitors on longitudinal clinical change in AD patients being treated with donepezil, galantamine, and rivastigmine. Methods This was an open study in which 171 Italian AD patients treated with donepezil ( n  = 92), galantamine ( n  = 33), or rivastigmine ( n  = 46) were enrolled. Response to treatment was quantified by grading the patient’s cognitive state (Mini-Mental State Examination) and the patient’s ability to perform normal daily activities (Activities of Daily Living, Instrumental Activities of Daily Living) at baseline and after 6 and 12 months of treatment. Genetic variation was comprehensively characterized and analyzed at two loci: CYP2D6 , which is involved in donepezil and galantamine metabolism, and BCHE , which codes for an enzyme (butyrylcholinesterase) which is both target and metabolizer of rivastigmine. APOE (coding for apolipoprotein E), which is associated with the risk of AD and inefficacy of specific AD treatments, was genotyped to control for patient stratification. The influence of the CYP2D6 and BCHE genotype on clinical changes after 12 months was evaluated by several tests of association. Results After 1 year of treatment, 29, 12, and 12 of the patients receiving donepezil, galantamine, and rivastigmine, respectively, showed a cognitive decrement, while eight patients interrupted the therapy before 12 months of treatment. No significant differences between the three treatments were observed in terms of response and tolerability. Non-responders show a higher proportion of BCHE and CYP2D6 mutated alleles, but genetic variation at the two loci was not a reliable predictor of clinical changes in AD patients treated with cholinesterase inhibitors. Conclusions Individualized therapy based on CYP2D6 and BCHE genotypes is unlikely to be beneficial for treating Alzheimer’s disease patients in routine clinical practice.