Dried Volumetric Microsampling Approaches for the Therapeutic Drug Monitoring of Psychiatric Patients Undergoing Clozapine Treatment

Clozapine is one of the most widely used second-generation antipsychotic drugs (SGAs) for the treatment of schizophrenia. Despite advantages over first-generation drugs, clozapine still shows significant side effects and interindividual variations in efficacy. In order to ensure frequent therapeutic drug monitoring (TDM) and improve the compliance of psychiatric patients undergoing clozapine treatment, two novel dried microsampling approaches based on whole blood and plasma volumetric absorptive microsampling (b-VAMS and p-VAMS) and microfluidic generated-dried blood spot technology (mfDBS) were developed and coupled to HPLC with electrochemical detection (ED). The proposed miniaturized strategies by means of VAMS and microfluidic channel-based devices provide several advantages in terms of collection, storage, and handling compared to classical blood and plasma processing. Satisfactory validation results were obtained for all microsampling platforms, with mean extraction yields >85.1%, precision as relative standard deviation (RSD) < 5.1%, and stability < 4.5% analyte loss after 30 days for p-VAMS; mean extraction yields > 83.4%, precision RSD < 5.4%, and stability < 4.6% analyte loss after 30 days for b-VAMS, and mean extraction yields > 74.0%, precision RSD < 5.6%, and stability < 4.9% analyte loss after 30 days for mfDBS. The original microsampling methodologies have been successfully applied to the blood and plasma collected from five psychiatric patients for the monitoring of the levels of clozapine and its main metabolites, providing robust and reliable quali-quantitative results. Comparisons between results of the two dried microsampling technologies with those obtained by classic fluid plasma analysis were in good agreement and have demonstrated that the proposed miniaturized approaches could be suitable for TDM purposes

Oxygen consumption is depressed in patients with lactic acidosis due to biguanide intoxication

INTRODUCTION: Lactic acidosis can develop during biguanide (metformin and phenformin) intoxication, possibly as a consequence of mitochondrial dysfunction. To verify this hypothesis, we investigated whether body oxygen consumption (VO2), that primarily depends on mitochondrial respiration, is depressed in patients with biguanide intoxication. METHODS: Multicentre retrospective analysis of data collected from 24 patients with lactic acidosis (pH 6.93 +/- 0.20; lactate 18 +/- 6 mM at hospital admission) due to metformin (n = 23) or phenformin (n = 1) intoxication. In 11 patients, VO2 was computed as the product of simultaneously recorded arterio-venous difference in O2 content [C(a-v)O2] and cardiac index (CI). In 13 additional cases, C(a-v)O2, but not CI, was available. RESULTS: On day 1, VO2 was markedly depressed (67 +/- 28 ml/min/m2) despite a normal CI (3.4 +/- 1.2 L/min/m2). C(a-v)O2 was abnormally low in both patients either with (2.0 +/- 1.0 ml O2/100 ml) or without (2.5 +/- 1.1 ml O2/100 ml) CI (and VO2) monitoring. Clearance of the accumulated drug was associated with the resolution of lactic acidosis and a parallel increase in VO2 (P < 0.001) and C(a-v)O2 (P < 0.05). Plasma lactate and VO2 were inversely correlated (R2 0.43; P < 0.001, n = 32). CONCLUSIONS: VO2 is abnormally low in patients with lactic acidosis due to biguanide intoxication. This finding is in line with the hypothesis of inhibited mitochondrial respiration and consequent hyperlactatemia

Lung anatomy, energy load, and ventilator-induced lung injury

High tidal volume can cause ventilator-induced lung injury (VILI), but positive end-expiratory pressure (PEEP) is thought to be protective. We aimed to find the volumetric VILI threshold and see whether PEEP is protective per se or indirectly

Stima della prevalenza di broncopneumopatia cronico-ostruttiva basata su dati sanitari correnti, mediante l\u27uso di un algoritmo comune, in differenti aree italiane

Aim: to estimate the prevalence of chronic obstructive pulmonary disease (COPD) by integrating various administrative health information systems. Methods: prevalent COPD cases were defined as those reported in the hospital discharge registry (HDR) and cause of mortality registry (CMR) with codes 490*, 491*, 492*, 494* e 496* of the International diseases classification 9th revision. Annual prevalence was estimated in 35+ year-old residents in six Italian areas of different sizes, in the period 2002-2004. We in- Annunziata Faustini,1 Silvia Cascini,1 Massimo Arc?,1 Daniela Balzi,2 Alessandro Barchielli,2 Cristina Canova,3 Claudia Galassi,4 Enrica Migliore,4,5 Sante Minerba,6 Maria Angela Protti,7 Anna Romanelli,7 Roberta Tessari,3,8 Maria Angela Vigotti,9 Lorenzo Simonato3 1Dipartimento di epidemiologia, ASL RME, Roma 2Unit? operativa di epidemiologia, Azienda sanitaria 10, Firenze 3Dipartimento di medicina ambientale e sanit? pubblica, Universit? di Padova 4Servizio di epidemiologia dei tumori, ASO S. Giovanni Battista, CPO Piemonte e Universit? di Torino 5Unit? di pneumologia, CPA-ASL TO2, Torino 6Unit? di statistica ed epidemiologia, ASL 1 Taranto 7Sezione di epidemiologia e ricerca sui servizi sanitari, IFC-CNR, Pisa 8Unit? di epidemiologia, Dipartimento di prevenzione, Azienda ULSS 12 Veneziana 9Dipartimento di biologia, Universit? di Pisa Corrispondenza: Annunziata Faustini, Dipartimento di epidemiologia, ASL RME, via Santa Costanza 53, 00198 Roma; tel. 06 86060486; fax 06 86060463; e-mail [email protected] cluded cases observed in the previous four years who were alive at the beginning of each year. Results: in 2003, age-standardized prevalence rates varied from 1.6% in Venice to 5% in Taranto. Prevalence was higher in males and increased with age. The highest rates were observed in central (Rome) and southern (Taranto) cities, especially in the 35-64 age group. HDR contributed 91% of cases. Healthtax exemption registry would increase the prevalence estimate by 0.2% if used as a third data source. Conclusions: with respect to the National Health Status suraldelvey, COPD prevalence is underestimated by 1%-3%; this can partly be due to the selection of severe and exacerbated COPD by the algorithm used. However, age, gender and geographical characteristics of prevalent cases were comparable to national estimates. Including cases observed in previous years (longitudinal estimates) increased the point estimate (yearly) of prevalence two or three times in each area.Obiettivi: stimare la prevalenza della broncopneumopatia cronico-ostruttiva (BPCO) mediante l\u27utilizzo integrato di dati sanitari correnti. Metodi: la prevalenza ? stata stimata nella popolazione residente di et? superiore ai 34 anni, in sei aree geografiche, per gli anni 2002-2004. I casi prevalenti sono stati individuati dai registri delle schede di dimissione ospedaliera (SDO) e delle cause di morte (RCM), mediante i codici ICD9-CM 490*, 491*, 492*, 494* e 496* della Classificazione internazionale delle malattie 9? revisione (ICD9-CM). Ai casi osservati in ciascun anno sono stati aggiunti i pazienti ricoverati nei quattro anni precedenti e vivi all\u27inizio dell\u27anno di stima. Risultati: la prevalenza della BPCO, stimata mediante tassi standardizzati per et?, varia per il 2003 dall\u271,6% di Venezia sural 5% di Taranto. La prevalenza ? pi? alta negli uomini e aumenta con l\u27et?; Taranto e Roma presentano i valori pi? elevati, specialmente nelle classi d\u27et? dai 35 ai 64 anni. Fonte principale dei casi sono i ricoveri ospedalieri, con un contributo di almeno il 91%. L\u27uso delle esenzioni ticket come terza fonte incrementa la stima di prevalenza dello 0,2%. Conclusioni: la prevalenza della BPCO ? sottostimata dell\u271%-3% rispetto ai dati dell\u27indagine Istat sullo stato di salute; questo ? in parte attribuibile alla selezione dei casi medio- gravi da parte dell\u27algoritmo utilizzato. Tuttavia le stime mantengono le caratteristiche attese nella distribuzione per genere, et? e area geografica. Inoltre, l\u27uso longitudinale dei dati ospedalieri aumenta di 2-3 volte la stima di prevalenza basata sui dati dei singoli anni

Association of COVID-19 Vaccinations With Intensive Care Unit Admissions and Outcome of Critically Ill Patients With COVID-19 Pneumonia in Lombardy, Italy

IMPORTANCE Data on the association of COVID-19 vaccination with intensive care unit (ICU) admission and outcomes of patients with SARS-CoV-2-related pneumonia are scarce. OBJECTIVE To evaluate whether COVID-19 vaccination is associated with preventing ICU admission for COVID-19 pneumonia and to compare baseline characteristics and outcomes of vaccinated and unvaccinated patients admitted to an ICU. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study on regional data sets reports: (1) daily number of administered vaccines and (2) data of all consecutive patients admitted to an ICU in Lombardy, Italy, from August 1 to December 15, 2021 (Delta variant predominant). Vaccinated patients received either mRNA vaccines (BNT162b2 or mRNA-1273) or adenoviral vector vaccines (ChAdOx1-S or Ad26.COV2). Incident rate ratios (IRRs) were computed from August 1, 2021, to January 31, 2022; ICU and baseline characteristics and outcomes of vaccinated and unvaccinated patients admitted to an ICU were analyzed from August 1 to December 15, 2021. EXPOSURES COVID-19 vaccination status (no vaccination, mRNA vaccine, adenoviral vector vaccine). MAIN OUTCOMES AND MEASURES The incidence IRR of ICU admission was evaluated, comparing vaccinated people with unvaccinated, adjusted for age and sex. The baseline characteristics at ICU admission of vaccinated and unvaccinated patients were investigated. The association between vaccination status at ICU admission and mortality at ICU and hospital discharge were also studied, adjusting for possible confounders. RESULTS Among the 10 107 674 inhabitants of Lombardy, Italy, at the time of this study, the median [IQR] agewas 48 [28-64] years and 5 154 914 (51.0%) were female. Of the 7 863 417 individuals who were vaccinated (median [IQR] age: 53 [33-68] years; 4 010 343 [51.4%] female), 6 251 417 (79.5%) received an mRNA vaccine, 550 439 (7.0%) received an adenoviral vector vaccine, and 1 061 561 (13.5%) received a mix of vaccines and 4 497 875 (57.2%) were boosted. Compared with unvaccinated people, IRR of individuals who received an mRNA vaccine within 120 days from the last dosewas 0.03 (95% CI, 0.03-0.04; P &lt;.001), whereas IRR of individuals who received an adenoviral vector vaccine after 120 days was 0.21 (95% CI, 0.19-0.24; P &lt;.001). There were 553 patients admitted to an ICU for COVID-19 pneumonia during the study period: 139 patients (25.1%) were vaccinated and 414 (74.9%) were unvaccinated. Compared with unvaccinated patients, vaccinated patients were older (median [IQR]: 72 [66-76] vs 60 [51-69] years; P &lt;.001), primarily male individuals (110 patients [ 79.1%] vs 252 patients [60.9%]; P &lt;.001), with more comorbidities (median [IQR]: 2 [1-3] vs 0 [0-1] comorbidities; P &lt;.001) and had higher ratio of arterial partial pressure of oxygen (PaO2) and fraction of inspiratory oxygen (FiO(2)) at ICU admission (median [IQR]: 138 [100-180] vs 120 [90-158] mm Hg; P =.007). Factors associated with ICU and hospital mortality were higher age, premorbid heart disease, lower PaO2/FiO(2) at ICU admission, and female sex (this factor only for ICU mortality). ICU and hospital mortality were similar between vaccinated and unvaccinated patients. CONCLUSIONS AND RELEVANCE In this cohort study, mRNA and adenoviral vector vaccines were associated with significantly lower risk of ICU admission for COVID-19 pneumonia. ICU and hospital mortality were not associated with vaccinated status.These findings suggest a substantial reduction of the risk of developing COVID-19-related severe acute respiratory failure requiring ICU admission among vaccinated people

Time course of risk factors associated with mortality of 1260 critically ill patients with COVID-19 admitted to 24 Italian intensive care units

Purpose: To evaluate the daily values and trends over time of relevant clinical, ventilatory and laboratory parameters during the intensive care unit (ICU) stay and their association with outcome in critically ill patients with coronavirus disease 19 (COVID-19). Methods: In this retrospective–prospective multicentric study, we enrolled COVID-19 patients admitted to Italian ICUs from February 22 to May 31, 2020. Clinical data were daily recorded. The time course of 18 clinical parameters was evaluated by a polynomial maximum likelihood multilevel linear regression model, while a full joint modeling was fit to study the association with ICU outcome. Results: 1260 consecutive critically ill patients with COVID-19 admitted in 24 ICUs were enrolled. 78% were male with a median age of 63 [55–69] years. At ICU admission, the median ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) was 122 [89–175] mmHg. 79% of patients underwent invasive mechanical ventilation. The overall mortality was 34%. Both the daily values and trends of respiratory system compliance, PaO2/FiO2, driving pressure, arterial carbon dioxide partial pressure, creatinine, C-reactive protein, ferritin, neutrophil, neutrophil–lymphocyte ratio, and platelets were associated with survival, while for lactate, pH, bilirubin, lymphocyte, and urea only the daily values were associated with survival. The trends of PaO2/FiO2, respiratory system compliance, driving pressure, creatinine, ferritin, and C-reactive protein showed a higher association with survival compared to the daily values. Conclusion: Daily values or trends over time of parameters associated with acute organ dysfunction, acid–base derangement, coagulation impairment, or systemic inflammation were associated with patient survival

COVID-19 Severity in Multiple Sclerosis: Putting Data Into Context

Background and objectives: It is unclear how multiple sclerosis (MS) affects the severity of COVID-19. The aim of this study is to compare COVID-19-related outcomes collected in an Italian cohort of patients with MS with the outcomes expected in the age- and sex-matched Italian population. Methods: Hospitalization, intensive care unit (ICU) admission, and death after COVID-19 diagnosis of 1,362 patients with MS were compared with the age- and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher risk: Expanded Disability Status Scale [EDSS] score &gt; 3 or at least 1 comorbidity, lower risk: EDSS score ≤ 3 and no comorbidities) by the χ2 test, and the risk excess was quantified by risk ratios (RRs). Results: The risk of severe events was about twice the risk in the age- and sex-matched Italian population: RR = 2.12 for hospitalization (p &lt; 0.001), RR = 2.19 for ICU admission (p &lt; 0.001), and RR = 2.43 for death (p &lt; 0.001). The excess of risk was confined to the higher-risk group (n = 553). In lower-risk patients (n = 809), the rate of events was close to that of the Italian age- and sex-matched population (RR = 1.12 for hospitalization, RR = 1.52 for ICU admission, and RR = 1.19 for death). In the lower-risk group, an increased hospitalization risk was detected in patients on anti-CD20 (RR = 3.03, p = 0.005), whereas a decrease was detected in patients on interferon (0 observed vs 4 expected events, p = 0.04). Discussion: Overall, the MS cohort had a risk of severe events that is twice the risk than the age- and sex-matched Italian population. This excess of risk is mainly explained by the EDSS score and comorbidities, whereas a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon