Off-label long acting injectable antipsychotics in real-world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction Information on the off-label use of Long-Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on- vs off-label LAIs and predictors of off-label First- or Second-Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off- or on-label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off-label group. Results SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on- and off-label use. Approximately 1 in 4 patients received an off-label prescription. In the off-label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off-label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co-morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns

The Role of Attitudes Toward Medication and Treatment Adherence in the Clinical Response to LAIs: Findings From the STAR Network Depot Study

Background: Long-acting injectable (LAI) antipsychotics are efficacious in managing psychotic symptoms in people affected by severe mental disorders, such as schizophrenia and bipolar disorder. The present study aimed to investigate whether attitude toward treatment and treatment adherence represent predictors of symptoms changes over time. Methods: The STAR Network \u201cDepot Study\u201d was a naturalistic, multicenter, observational, prospective study that enrolled people initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centers were assessed at three time points: baseline, 6-month, and 12-month follow-up. Psychopathological symptoms, attitude toward medication and treatment adherence were measured using the Brief Psychiatric Rating Scale (BPRS), the Drug Attitude Inventory (DAI-10) and the Kemp's 7-point scale, respectively. Linear mixed-effects models were used to evaluate whether attitude toward medication and treatment adherence independently predicted symptoms changes over time. Analyses were conducted on the overall sample and then stratified according to the baseline severity (BPRS < 41 or BPRS 65 41). Results: We included 461 participants of which 276 were males. The majority of participants had received a primary diagnosis of a schizophrenia spectrum disorder (71.80%) and initiated a treatment with a second-generation LAI (69.63%). BPRS, DAI-10, and Kemp's scale scores improved over time. Six linear regressions\u2014conducted considering the outcome and predictors at baseline, 6-month, and 12-month follow-up independently\u2014showed that both DAI-10 and Kemp's scale negatively associated with BPRS scores at the three considered time points. Linear mixed-effects models conducted on the overall sample did not show any significant association between attitude toward medication or treatment adherence and changes in psychiatric symptoms over time. However, after stratification according to baseline severity, we found that both DAI-10 and Kemp's scale negatively predicted changes in BPRS scores at 12-month follow-up regardless of baseline severity. The association at 6-month follow-up was confirmed only in the group with moderate or severe symptoms at baseline. Conclusion: Our findings corroborate the importance of improving the quality of relationship between clinicians and patients. Shared decision making and thorough discussions about benefits and side effects may improve the outcome in patients with severe mental disorders

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Floppy Infant Syndrome: new approach to the study of neonatal hypotonia through the analysis of a rare case of X-Linked Myotubular Myopathy

The Floppy Infant Syndrome includes a variety of signs and symptoms: decrease in muscle tone (hypotonia), in muscle power (weakness) and ligamentous laxity and increased range of joint mobility. Strictly speaking, the term “floppy” should be used to describe a form of hypotonia. In our case the clinical and molecular study of a rare form (1:50.000) of X-Linked Myotubular Myopathy (X-Linked MM), with an early onset of peripheral hypotonia, led us to develop a general protocol for the differential diagnosis of neonatal hypotonia

Near-infrared spectroscopy in neonatal intensive care unit: do we make our life more difficult?

The question has been the following: can the regional oxygenation monitoring change our clinical practices in neonatal intensive care? Fifty newborns of gestational age ≤ 32 weeks were recruited for regional oxygenation continuous monitoring immediately after their admission. Of these newborns 44 showed a patent ductus arteriosus (PDA) with a left to right shunt. In these subjects, a progressive decrease of the renal oxygenation (rSO2) up to values of 59.6 ± 3.6% and an increase of the renal oxygen extraction fraction (rFTOE) to 50.9 ± 3 were observed during the first hours of monitoring. The cerebral oxygenation (cSO2) instead, remained relatively constant at 64.5(± 4.2%)-69.7(± 5.6%) with a cerebral oxygen extraction fraction (cFTOE) between 28.6 ± 4.7 and 24.6 ± 6.5. Renal oxygenation improved in almost all the subjects, except that in three, up to values of rSO2 of 75(± 1.0%)-82.2(± 4.9) with a rFTOE of 20.1(± 14.8)-13.4(± 3.5) after a three-six hours treatment with dopamine at 5-7.5 μg/kg/min. These data, together with echodoppler findings, have allowed us to modify our approach to the newborn with PDA and the left-right shunt. It now consists in using dopamine as soon as ductal shunt has been left to right and waiting until the hemodynamic stability persists or until the end of the first week of life prior to consider the closure of the duct by cyclooxygenase inhibitors. Besides, 42 newborns with a post-natal age ≥ 2 weeks were selected and submitted to a regional oxygenation monitoring once hematocrit had been less than 30%. Sixteen out of 42 newborns showed a decline of rSO2 to 50 ± 5% and a rFTOE of 45 ± 3, with a cSO2 of 69 ± 3% and a cFTOE of 23 ± 4. Of the 26 newborns with normal values of regional saturation, 10 showed a decrease of rSO2 to 50 ± 3 with a rFTOE of 45 ± 3 when the hematocrit fell to 20-22%. After a packed red cell transfusion, a progressive rise of the rSO2 to 83.8 ± 9.4 and a decline of the rFTOE to 8.1 ± 3.4 were observed. These changes started at the end of the transfusion and became stable in the following 12-24 hours. An increase of the cSO2 to 82.2 ± 2.9 and a decrease of the cFTOE to 12.2 ± 2.90 were observed after the transfusion and after the progressive normalization of the renal oxygenation as well. On the basis of these results, in our Unit only the newborns with a hematocrit ≤ 30 and clear sinking renal saturation values are transfused. In the light of the reported observations, we recognize to the regional oxygenation monitoring a precise role in the process of personalization of the newborn cares in intensive contexts. Despite the requirement for wider observations, the information drawn by the variations of the regional oxygenation in different pathophysiologic processes can substantially help in the prevention of the organ damage, particularly the brain, that upsets still today the results of the neonatal intensive cares. Proceedings of the 9th International Workshop on Neonatology · Cagliari (Italy) · October 23rd-26th, 2013 · Learned lessons, changing practice and cutting-edge researc

PDA management in preterm infants: keep your hands off the ductus!

The current management of a patent ductus arteriosus (PDA) in preterm infants is fundamentally aimed at the closure of ductus through the cyclooxygenase (Cox)-inhibitors or surgical ligation in case of failure. Although the role of surgical approach to morbidity and mortality remains unclear, measures avoiding it appear entirely justified. During the last two years, 8 newborns were admitted to our intensive care unit for surgical ligation of a hemodynamic significant PDA, after a two ineffective Cox-inhibitor courses. The mean gestational age was 26 5/7 weeks (24 6/7 - 28 3/7 w.), the mean birth weight 1,000 g (800-1,300 g) and the mean age at admission 20 days (9-29 d.) at a mean post-conceptional age (PCA) of 29 3/7 weeks (27 5/7 - 31 5/7 w.). We have submitted these newborns to an approach consisting in a continuous monitoring of cerebral and renal oxygenations, time-scheduled ultrasound controls, monitoring of blood pressure and of urine output and continuous aEEG registration. All were treated with dopamine infusion. Under dopamine, ranging from 5 to 10 μg/kg/min, the stabilization criteria (see text) were reached in 7/8 infants. Afterwards a new cycle of Cox-inhibitors has been tried with the result of closing the ductus in 4/8 and obtaining a flow closing pattern in other three. None of the seven infants has shown in the following weeks a reapparence of ductal reopening signs. In this way we avoided the surgical intervention in 7/8 newborns. An attempt with Cox-inhibitors (ibuprofen) has also been proved in the single newborn who didn’t reach the stabilization but resulted ineffective. This newborn has been submitted to surgical ligation immediately thereafter. Moreover, the clinical conditions observed in all the newborns at admission testify that the duration of the exposure to left-to-right shunt is a crucial factor of the organ damage. This aspect is often not considered, waiting for the Cox-inhibitor effects. The contribution of the aEEG recordings is, in this context, considerable, having shown a background pattern of burst suppression in four subjects and a discontinuous pattern not in line with reached PCA in other three. On the basis of these results we think that the therapy of PDA in preterm infants must be mainly aimed at the containment of the ductal shunt and of its effects on pulmonary and systemic flow. In this way the objective of the ductal closure stops to be primary, being possible, under conditions of hemodynamic stability, waiting during the first week of life for the physiologic events of closure or resorting in selected cases to the Cox-inhibitors or to the surgical intervention. This limited experience requires more consistent proofs of effectiveness, while the impact of this approach on the outcomes needs to be evaluated.   Proceedings of the 10th International Workshop on Neonatology · Cagliari (Italy) · October 22nd-25th, 2014 · The last ten years, the next ten years in Neonatology Guest Editors: Vassilios Fanos, Michele Mussap, Gavino Faa, Apostolos Papageorgio

Effectiveness of a training course on smoking cessation knowledge and behavior for health profession students: the SISMA project

INTRODUCTION: University students are at risk of starting smoking or continuing and increasing the consumption of tobacco products. The aim of the study was to evaluate the impact of the training course, Sisma Project, about smoking in healthcare degree courses, in terms of knowledge and behavior.METHODS: SISMA project is an intervention delivered to healthcare profession students about smoking, using a before-after design. It was an online optional course available on the eLearning platform Moodle 2 in a specific week during routine university lessons. The course was structured in four lessons of 60 minutes, with a final debate among experts and a test.RESULTS: The participants were 365 students (28.5% males and 71.5% females) that at the beginning of the trial filled out an online questionnaire. Current smokers were 161 (44.1%) before the course and 142 (38.9%) after the course (p<0.001). Students gave an evaluation about the course: 42.7% assigned a very high score, 33.2% expressed positive rating about material, 12.6% liked contents, and 15.6% appreciate the organization structure of the course.DISCUSSION: Given the central role health professionals play in patient care, students need to be trained in tobacco cessation techniques. Our results indicate that smoking behavior significantly changed after attending the course and students appreciated the contents and structure of the course