UMG1/CD3ε-bispecific T-cell engager redirects T-cell cytotoxicity against diffuse large B-cell lymphoma.

UMG1 is a unique epitope of CD43, not expressed by normal cells and tissues of haematopoietic and non-haematopoietic origin, except thymocytes and a minority (<5%) of peripheral blood T lymphocytes. By immunohistochemistry analysis of tissue microarray and pathology slides, we found high UMG1 expression in 20%-24% of diffuse large B-cell lymphomas (DLBCLs), including highly aggressive BCL2high and CD20low cases. UMG1 membrane expression was also found in DLBCL bone marrow-infiltrating cells and established cell lines. Targeting UMG1 with a novel asymmetric UMG1/CD3ε-bispecific T-cell engager (BTCE) induced redirected cytotoxicity against DLBCL cells and was synergistic with lenalidomide. We conclude that UMG1/CD3ε-BTCE is a promising therapeutic for DLBCLs.

The role of psychotic-like experiences in the association between aberrant salience and anxiety: A psychopathological proposal based on a case-control study.

AIM: Aberrant salience (AS) and psychotic-like experiences (PLEs) have been proven to be linked. Moreover, anxiety is a key symptom in psychosis-prone subjects and most psychotic patients. We propose a model that attempts to interpret the role of PLEs in the association between AS and anxiety among healthy controls and psychotic patients. METHODS: Demographic and psychometric data (Aberrant Salience Inventory, Community Assessment of Psychic Experiences, Symptom Check List-90-revised) from 163 controls and 44 psychotic patients was collected. Descriptive statistics, correlations, a linear regression model and a mediation analysis with covariates were subsequently performed. RESULTS: AS correlated with more frequent positive PLEs and higher anxiety levels in both patients and controls. However, positive PLEs' frequency mediated the relationship between AS and anxiety only among controls. CONCLUSIONS: PLEs linked to AS appear to induce anxiety among the control group but not among psychotic patients. The progressive loss of both novelty and insight, which may, respectively, impair the somatic emotional reactivity to PLEs and the ability to recognize some bodily phenomena as the embodied correlates of anxiety, is seen as the most probable theoretical explanation.

Aberrant Salience Inventory: A meta-analysis to investigate its psychometric properties and identify screening cutoff scores.

INTRODUCTION: The Aberrant Salience Inventory (ASI) is a useful tool to measure salience abnormalities among the general population. There is strong clinical and scientific evidence that salience alteration is linked to psychosis. To the present day, no meta-analysis evaluating ASI's psychometric properties and screening potential has been published. MATERIALS AND METHODS: PubMed, Google Scholar, Scopus, and Embase were searched using terms including "psychosis," "schizophrenia," and "Aberrant Salience Inventory." Observational and experimental studies employing ASI on populations of non-psychotic controls and patients with psychosis were included. ASI scores and other demographic measures (age, gender, ethnicity) were extracted as outcomes. Individual patients' data (IPD) were collected. Exploratory factor analysis (EFA) was performed on the IPD. RESULTS: Eight articles were finally included in the meta-analysis. ASI scores differ significantly between psychotic and non-psychotic populations; a novel three-factor model is proposed regarding subscales structure. Theoretical positive predictive values (PPVs) and negative predictive values (NPVs) were calculated and presented together with different cutoff points depending on preselected specific populations of interest. DISCUSSION: PPV and NPV values reached levels adequate for ASI to be considered a viable screening tool for psychosis. The factor analysis highlights the presence of a novel subscale that was named "Unveiling experiences." Implications regarding the meaning of the new factor structure are discussed, as well as ASI's potential as a screening tool.

Treatment persistence with aripiprazole once monthly: a 4-year follow-up.

OBJECTIVES: Treatment persistence refers to the act of continuing a treatment as prescribed and reflects the patient's or doctor's judgment about efficacy, tolerability, and acceptability. In patients with schizophrenia, antipsychotic persistence is often poor, because of issues such as lack or loss of efficacy, side effects, and poor adherence, which is often related to the degree to which patients find the medication and overall intervention to be helpful, tolerable, fair, reasonable, appropriate, and consistent with expectations of treatment. Despite the poor antipsychotic persistence that has been reported to date in patients with schizophrenia, we previously observed a relatively high (86%) 6 months persistence with aripiprazole once-monthly (AOM) in a group of patients with schizophrenia, treated in the real world Italian clinical practice. The present study explores the longer term persistence with AOM, over a mean follow-up period of 48 months. METHODS: This was a multicenter, retrospective, non-interventional follow-up study, aimed at evaluating the longer term persistence with AOM in a group of patients with schizophrenia who had already shown persistence over a period of at least 6 months. The study included 161 individuals who had participated in our previous study, where 86% of participating individuals had shown persistence with AOM for at least 6 months. Non-persistence was defined as discontinuing the medication for any reason. Baseline demographic and clinical characteristics of patients who continued AOM were then compared to those of patients who discontinued the medication. RESULTS: Study subjects were predominantly male (64.4%) and their mean age was 39.7 (SD: 12.24). Treatment persistence with AOM was 69.6% and 112 out of 161 patients were still receiving AOM treatment at the last follow-up visit. The mean duration of AOM treatment until the last recorded observation was 55.87 months (median 56.17, SD6.23) for the 112 persistent patients and 32.23 (median 28.68.SD 15.09) months for the 49 non-persistent individuals. The mean observation period for all patients (persistent and non-persistent) was 48.78 months (median 52.54, SD 14.64). For non-persistent subjects, the observation period ended with the discontinuation of AOM. Subjects treated with AOM at 400 mg presented a 69.6% lower risk of all-cause treatment discontinuation when compared with patients treated with 300 mg (HR: 0.314; 95% confidence interval [CI] 0.162-0.608; P = 0.001). The main reasons for discontinuation were lack of efficacy (30.6%), patient/caregiver choice (18.4%), physician's choice (16.3%), non-adherence (12.2%) and inconvenience (6.1%). Only 3 patients (6.1%) discontinued AOM for tolerability issues. CONCLUSIONS: In subjects with schizophrenia, who had already shown a 6 months persistence with AOM, a high number of patients (69.6%) continued to be persistent over a 4-year follow-up period. This may reflect a favourable profile of efficacy, tolerability, and acceptability. Larger and prospective studies are warranted to confirm our observations.

A Novel Bispecific T-Cell Engager (CD1a x CD3ε) BTCE Is Effective against Cortical-Derived T Cell Acute Lymphoblastic Leukemia (T-ALL) Cells.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy burdened by poor prognosis. While huge progress of immunotherapy has recently improved the outcome of B-cell malignancies, the lack of tumor-restricted T-cell antigens still hampers its progress in T-ALL. Therefore, innovative immunotherapeutic agents are eagerly awaited. To this end, we generated a novel asymmetric (2 + 1) bispecific T-cell engager (BTCE) targeting CD1a and CD3ε (CD1a x CD3ε) starting from the development of a novel mAb named UMG2. UMG2 mAb reacts against CD1a, a glycoprotein highly expressed by cortical T-ALL cells. Importantly, no UMG2 binding was found on normal T-cells. CD1a x CD3ε induced high T-cell mediated cytotoxicity against CD1a+ T-ALL cells in vitro, as demonstrated by the concentration-dependent increase of T-cell proliferation, degranulation, induction of cell surface activation markers, and secretion of pro-inflammatory cytokines. Most importantly, in a PBMC-reconstituted NGS mouse model bearing human T-ALL, CD1a x CD3ε significantly inhibited the growth of human T-ALL xenografts, translating into a significant survival advantage of treated animals. In conclusion, CD1a x CD3ε is a novel BTCE highly active against CD1a-expressing cortical-derived T-ALL cells suitable for clinical development as an effective therapeutic option for this rare and aggressive disease.

Therapeutic Drug Monitoring of Long-Acting Injectable Antipsychotics as a Predictor of Relapse in Schizophrenia Spectrum Disorders: A 1-Year Pilot Study.

BACKGROUND: Long-acting injectable antipsychotics (LAIs) have been shown to reduce acute episodes of schizophrenia spectrum disorders (SSDs). However, breakthrough relapses are frequent, possibly because of underdosing in clinical practice. In this framework, the advantages of therapeutic drug monitoring (TDM) may be overlooked. This study explored the association of low steady-state LAI levels with a higher risk of relapse in SSDs, despite the use of a licensed posology. METHODS: Forty-eight clinically stable outpatients with SSD underwent LAI-TDM using liquid chromatography-mass spectrometry for routine observational purposes. Baseline anamnestic, pharmacological, and psychometric evaluations compared subjects with "under-range" versus "in-range" LAI serum levels; between-group comparisons for different LAI treatments were also performed. A binary logistic regression explored which baseline factors (age, sex, previous hospitalizations, psychopathology, specific LAI treatment, and underrange serum levels) predicted relapse during the next 12 months. RESULTS: Baseline comparisons did not show significant between-group differences, except for a higher percentage of underrange values in individuals receiving olanzapine pamoate. A total of 10 patients (20.8%) relapsed during the follow-up; only underrange LAI levels predicted the event (odds ratio 0.03, 95% confidence interval 0.01-0.36; P = 0.005). CONCLUSIONS: Even if relapse remains as a multifactorial event, LAI-TDM may identify subjects at risk for this negative outcome, thus optimizing antipsychotic maintenance treatment in the context of precision medicine. The finding of underrange LAI plasma levels in real-world practice should prompt adequate monitoring of clinically stable outpatients to identify the early signs of psychopathological deterioration.

Aberrant salience relationship with first rank symptoms.

BACKGROUND: Aberrant salience is the incorrect assignment of salience, significance, or value to different innocuous stimuli that might precede the onset of psychotic symptoms. The present study aimed to perform a preliminary evaluation of potentially different correlations between the Aberrant Salience Inventory (ASI) score and dimensional or categorical diagnostic approaches. METHODS: 168 adult outpatients with a current psychiatric diagnosis were consecutively enrolled. Patients were evaluated using different psychometric scales. ASI was used to evaluate aberrant salience, and to evaluate the association between ASI scores and first rank symptoms (FRS), and/or with a psychiatric diagnosis. Principal dichotomic clusters of ASI were identified using the Chi-square automatic interaction detection (CHAID) method. RESULTS: Current (16.76 ± 6.02 vs 13.37 ± 5.76; p = 0.001), lifetime (15.74 ± 6.08 vs 13.16 ± 5.74; p = 0.005) and past (15.75 ± 6.01 vs 13.33 ± 5.80; p = 0.009) FRS were the main clusters dichotomizing ASI. The average ASI score did not significantly differ among patients with different diagnoses. CONCLUSIONS: ASI could be used as a tool to identify psychopathological dimensions, rather than the categorical diagnoses, in the schizophrenic spectrum.

Aberrant Salience among Young Healthy Postgraduate University Students: The Role of Cannabis Use, Psychotic-Like Experiences, and Personality.

Aberrant salience (AS) is an anomalous world experience which plays a major role in psychotic proneness. In the general population, a deployment of this construct - encompassing personality traits, psychotic-like symptoms, and cannabis use - could prove useful to outline the relative importance of these factors. For this purpose, 106 postgraduate university students filled the AS Inventory (ASI), the Community Assessment of Psychic Experiences (CAPE), the Temperament and Character Inventory (TCI), and the Symptom Checklist 90-Revised (SCL-90-R). Lifetime cannabis users (n = 56) and individuals who did not use cannabis (n = 50) were compared. The role of cannabis use and psychometric indexes on ASI total scores was tested in different subgroups (overall sample, cannabis users, and nonusers). The present study confirmed that cannabis users presented higher ASI scores. The deployment of AS proved to involve positive symptom frequency (assessed through CAPE), character dimensions of self-directedness and self-transcendence (TCI subscales), and cannabis use. Among nonusers, the role of personality traits (assessed through the TCI) was preeminent, whereas positive psychotic-like experiences (measured by means of CAPE) had a major weight among cannabis users. The present study suggests that pre-reflexive anomalous world experiences such as AS are intertwined with reflexive self-consciousness, personality traits, current subclinical psychotic symptoms, and cannabis use. In the present study, subthreshold psychotic experiences proved to play a major role among cannabis users, whereas personality appeared to be more relevant among nonusers.

Psychometric Properties of the Italian Version of the Embodied Sense-of-Self Scale.

(1) Background: The Embodied Sense-of-Self Scale (ESSS) is the only validated measure for self-assessing embodiment abnormalities, which differentiate people with anomalous embodied self-representations such as schizophrenic patients from controls. The aim of the current study was to translate the ESSS from English to Italian and to examine its factor structure, reliability, and validity in the Italian context. (2) Methods: We tested the fit of the original three-factor structure (agency, ownership, and narrative identity) across a community sample (N = 269) and the reliability as well as the convergent and divergent validity of the ESSS. (3) Results: The three-factor structure of the ESSS was confirmed. However, three different factors have emerged from our analysis (self-recognition, self-consistence, and self-awareness). Higher internal consistency of the ESSS was obtained by removing six items that seemed problematic. The three ESSS scales show highly intercorrelated constructs. The measure was reliable and positively correlated with schizotypy (via the Perceptual Aberration Scale) and aberrant salience (via the Aberrant Salience Inventory), and negatively correlated with empathy (via the Italian Short Empathy Quotient scale), generalized self-efficacy (via the Generalized Self-Efficacy Scale), and social self-efficacy (via the Perceived Social Self-Efficacy Scale). (4) Conclusions: The 19-item Italian version of the ESSS is a suitable measure with which to assess embodiment abnormalities in Italian samples.

A randomised, double-blind, sham-controlled study of left prefrontal cortex 15 Hz repetitive transcranial magnetic stimulation in cocaine consumption and craving.

BACKGROUND: Cocaine use disorder (CUD) is a global health issue with no effective treatment. Repetitive Transcranial Magnetic Stimulation (rTMS) is a recently proposed therapy for CUD. METHODS: We conducted a single-center, randomised, sham-controlled, blinded, parallel-group research with patients randomly allocated to rTMS (15 Hz) or Sham group (1:1) using a computerised block randomisation process. We enrolled 62 of 81 CUD patients in two years. Patients were followed for eight weeks after receiving 15 15 Hz rTMS/sham sessions over the left dorsolateral prefrontal cortex (DLPFC) during the first three weeks of the study. We targeted the DLFPC following the 5 cm method. Cocaine lapses in twice a week urine tests were the primary outcome. The secondary outcomes were craving severity, cocaine use pattern, and psychometric assessments. FINDINGS: We randomly allocated patients to either an active rTMS group (32 subjects) or a sham treatment group (30 subjects). Thirteen (42%) and twelve (43.3%) of the subjects in rTMS and sham groups, respectively, completed the full trial regimen, displaying a high dropout rate. Ten/30 (33%) of rTMS-treated patients tested negative for cocaine in urine, in contrast to 4/27 of placebo controls (p = 0.18, odd ratio 2.88, CI 0.9-10). The Kaplan-Meier survival curve did not state a significant change between the treated and sham groups in the time of cocaine urine negativisation (p = 0.20). However, the severity of cocaine-related cues mediated craving (VAS peak) was substantially decreased in the rTMS treated group (p<0.03) after treatment at T1, corresponding to the end of rTMS treatment. Furthermore, in the rTMS and sham groups, self-reported days of cocaine use decreased significantly (p<0.03). Finally, psychometric impulsivity parameters improved in rTMS-treated patients, while depression scales improved in both groups. CONCLUSIONS: In CUD, rTMS could be a useful tool for lowering cocaine craving and consumption. TRIAL REGISTRATION: The study number on clinicalTrials.gov is NCT03607591.

Self- and caregiver-perceived disability, subjective well-being, quality of life and psychopathology improvement in long-acting antipsychotic treatments: a 2-year follow-up study.

OBJECTIVE: Switching to long-acting injectable (LAI) antipsychotic maintenance treatment (AMT) represents a valuable strategy for schizophrenia. In a recovery-oriented approach, patient-reported outcomes (PROs) such as perceived disability, subjective well-being, and quality of life cannot be neglected. METHODS: Forty clinically stable outpatients with schizophrenia treated with oral second-generation antipsychotics were enrolled at the time of switching to the equivalent dose of LAI. 35 subjects completed this 2-year longitudinal, prospective, open-label, observational study. Patients were assessed at baseline, after 1 year, and after 2 years of LAI-AMT, using psychometric scales (Positive And Negative Syndrome Scale, PANSS; Young Mania Rating Scale, YMRS; Montgomery-Åsberg Depression Rating Scale, MADRS), PROs (Subjective Well-Being under Neuroleptics short form, SWN-K; Short Form-36 health survey, SF-36; 12-item World Health Organisation Disability Assessment Schedule, WHODAS 2.0), and caregiver-reported outcomes (12-item WHODAS 2.0). RESULTS: No psychotic relapses were observed. Psychopathology measures (PANSS total and subscales - excluding negative symptoms), mood symptoms (YMRS, MADRS), perceived disability (patient- and caregiver-administered WHODAS 2.0), subjective well-being (SWN-K), and quality of life (SF-36) showed a concomitant amelioration after 1 year, without further significant variations. DISCUSSION: Switching to LAI-AMT may decrease perceived impairment, and increase subjective well-being and quality of life in clinically stable outpatients with schizophrenia.HighlightsLAI treatment may improve outcomes by reducing psychopathology levels and relapses.In a recovery-oriented approach, patient-reported outcomes cannot be neglected.LAI antipsychotics may optimise the subjective experience of treatment.Switching to LAI therapy may result in a reduction in perceived disability.There is a significant correlation between proxy- and patient-reported disability.

Predictors of long-acting injectable antipsychotic treatment discontinuation in outpatients with schizophrenia: relevance of the Drug Attitude Inventory-10.

Given the importance of patients' subjective experience and attitudes in the management of severe mental illness, the present study evaluated their potential role as predictors of future continuation of long-acting injectable antipsychotic maintenance treatment (LAI-AMT) in clinically stable outpatients with schizophrenia switching from an oral therapy. Retrospective data from 59 subjects receiving LAI-AMT for at least 6 months were collected. Patients who continued LAI treatment (n = 32) were compared to those who discontinued it (n = 27), assessing baseline socio-demographic and clinical characteristics, psychopathological features (Positive And Negative Syndrome Scale, Montgomery-Åsberg Depression Rating Scale and Young Mania Rating Scale) and patient-reported experience of treatment through Drug Attitude Inventory 10-item (DAI-10) and Subjective Well-being under Neuroleptics short form. Binary logistic and Cox regression analyses explored the predictive role of the mentioned variables on treatment discontinuation. The Kaplan-Meier estimator compared dropout from LAI treatment in subsamples with different characteristics. Unemployment and lower baseline DAI-10 scores predicted LAI-AMT discontinuation. No major differences were detected in other socio-demographic, clinical or psychometric indexes. When switching from oral to LAI-AMT, the preliminary assessment of attitude towards drug might be clinically relevant, allowing the identification of patients at risk for treatment discontinuation.

Therapeutic afucosylated monoclonal antibody and bispecific T-cell engagers for T-cell acute lymphoblastic leukemia.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a poor cure rate for relapsed/resistant patients. Due to the lack of T-cell restricted targetable antigens, effective immune-therapeutics are not presently available and the treatment of chemo-refractory T-ALL is still an unmet clinical need. To develop novel immune-therapy for T-ALL, we generated an afucosylated monoclonal antibody (mAb) (ahuUMG1) and two different bispecific T-cell engagers (BTCEs) against UMG1, a unique CD43-epitope highly and selectively expressed by T-ALL cells from pediatric and adult patients. METHODS: UMG1 expression was assessed by immunohistochemistry (IHC) on a wide panel of normal tissue microarrays (TMAs), and by flow cytometry on healthy peripheral blood/bone marrow-derived cells, on 10 different T-ALL cell lines, and on 110 T-ALL primary patient-derived cells. CD43-UMG1 binding site was defined through a peptide microarray scanning. ahuUMG1 was generated by Genetic Glyco-Engineering technology from a novel humanized mAb directed against UMG1 (huUMG1). BTCEs were generated as IgG1-(scFv)2 constructs with bivalent (2+2) or monovalent (2+1) CD3ε arms. Antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP) and redirected T-cell cytotoxicity assays were analysed by flow cytometry. In vivo antitumor activity of ahUMG1 and UMG1-BTCEs was investigated in NSG mice against subcutaneous and orthotopic xenografts of human T-ALL. RESULTS: Among 110 T-ALL patient-derived samples, 53 (48.1%) stained positive (24% of TI/TII, 82% of TIII and 42.8% of TIV). Importantly, no expression of UMG1-epitope was found in normal tissues/cells, excluding cortical thymocytes and a minority (<5%) of peripheral blood T lymphocytes. ahUMG1 induced strong ADCC and ADCP on T-ALL cells in vitro, which translated in antitumor activity in vivo and significantly extended survival of treated mice. Both UMG1-BTCEs demonstrated highly effective killing activity against T-ALL cells in vitro. We demonstrated that this effect was specifically exerted by engaged activated T cells. Moreover, UMG1-BTCEs effectively antagonized tumor growth at concentrations >2 log lower as compared with ahuUMG1, with significant mice survival advantage in different T-ALL models in vivo. CONCLUSION: Altogether our findings, including the safe UMG1-epitope expression profile, provide a framework for the clinical development of these innovative immune-therapeutics for this still orphan disease.

Clinical guidance for the use of trazodone in major depressive disorder and concomitant conditions: pharmacology and clinical practice.

AIM: To provide a review of the clinically relevant evidence pertaining to the use of trazodone in major depressive disorder. METHODS: Medline and Cochrane Library searches were searched using the keywords 'trazodone' AND 'depression', to identify the most relevant literature pertinent to the pharmacological properties of trazodone and its use in clinical practice. Articles that were selected included basic pharmacology papers, clinical trials, clinical practice guidelines, and reviews. Related references were cross checked. European and United States prescribing information was reviewed as well. An effort was made to give weight to the information that was most relevant for daily clinical practice. RESULTS: Trazodone is an antidepressant with a mechanism of action that remains innovative and with a favorable profile for the treatment of depression. The appropriate antidepressant doses are usually 150-300 mg/day and are often higher than the doses that are used when trazodone is prescribed to augment the antidepressant effect of another medication, for instance when trazodone is prescribed to address insomnia in a patient treated with an SSRI. Trazodone is usually well tolerated and has a low risk of anticholinergic side effects, weight gain and sexual side effects. DISCUSSION: Trazodone is an established medication that is efficacious for the treatment of a broad array of depressive symptoms, including symptoms that are less likely to respond to other antidepressants (e.g. SSRI), such as insomnia. As an antidepressant, trazodone has proven as efficacious as the tricyclic and second-generation antidepressants and is tolerated relatively well. Trazodone may be helpful for patients with major depression and comorbid insomnia, anxiety or psychomotor agitation. CONCLUSIONS: Trazodone is efficacious antidepressants with a relatively low risks of side effects such as weight gain, sexual or anticholinergic effects (such as constipation, urinary retention, dry mouth). In addition to being able to control a wide range of depressive symptoms, trazodone may improve sleep and be particularly helpful for patients whose symptoms of depression include insomnia.

Advanced implantable drug delivery technologies: transforming the clinical landscape of therapeutics for chronic diseases.

Chronic diseases account for the majority of all deaths worldwide, and their prevalence is expected to escalate in the next 10 years. Because chronic disorders require long-term therapy, the healthcare system must address the needs of an increasing number of patients. The use of new drug administration routes, specifically implantable drug delivery devices, has the potential to reduce treatment-monitoring clinical visits and follow-ups with healthcare providers. Also, implantable drug delivery devices can be designed to maintain drug concentrations in the therapeutic window to achieve controlled, continuous release of therapeutics over extended periods, eliminating the risk of patient non-compliance to oral treatment. A higher local drug concentration can be achieved if the device is implanted in the affected tissue, reducing systemic adverse side effects and decreasing the challenges and discomfort of parenteral treatment. Although implantable drug delivery devices have existed for some time, interest in their therapeutic potential is growing, with a global market expected to reach over $12 billion USD by 2018. This review discusses implantable drug delivery technologies in an advanced stage of development or in clinical use and focuses on the state-of-the-art of reservoir-based implants including pumps, electromechanical systems, and polymers, sites of implantation and side effects, and deployment in developing countries.

The modern perspective for long-acting injectables antipsychotics in the patient-centered care of schizophrenia.

Schizophrenia is a chronic syndrome involving different clinical dimensions, and causes significant disability with a negative impact on the quality of life of patients and their caregivers. Current guidelines for the treatment of schizophrenia focus on maximizing a patient's adaptive functioning and quality of life in a recovery-oriented approach that encourages active collaboration among patients, caregivers, and mental health professionals to design and manage a customized and comprehensive care plan. In the present study, a panel of experts (psychiatrists, psychologists, nurse, and social worker) gathered to review and explore the need for contemporary use of second-generation antipsychotic long-acting injectables (SGA LAIs) in "recovery-oriented" and "patient-centered" care of schizophrenia. Starting from the available data and from sharing personal attitudes and experiences, the panel selected three clinical dimensions considered useful in characterizing each patient: phase of disease, adherence to treatment, and level of functioning. For each clinical dimension, perspectives of patients and caregivers with regard to needs, expectations, and personal experiences were reviewed and the role of SGA LAIs in achieving shared goals examined. The experts concluded that from today's modern perspectives, SGA-LAIs may play an important role in breaking the spiral of desocialization and functional decline in schizophrenia, thus favoring the recovery process.

Asparagine levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia treated with pegylated-asparaginase in the induction phase of the AIEOP-BFM ALL 2009 study.

Asparagine levels in cerebrospinal fluid and serum asparaginase activity were monitored in children with acute lymphoblastic leukemia treated with pegylated-asparaginase. The drug was given intravenously at a dose of 2,500 IU/m2 on days 12 and 26. Serum and cerebrospinal fluid samples obtained on days 33 and 45 were analyzed centrally. Since physiological levels of asparagine in the cerebrospinal fluid of children and adolescents are 4-10 µmol/L, in this study asparagine depletion was considered complete when the concentration of asparagine was ≤0.2 µmol/L, i.e. below the lower limit of quantification of the assay used. Over 24 months 736 patients (AIEOP n=245, BFM n=491) and 903 cerebrospinal fluid samples (n=686 on day 33 and n=217 on day 45) were available for analysis. Data were analyzed separately for the AIEOP and BFM cohorts and yielded superimposable results. Independently of serum asparaginase activity levels, cerebrospinal fluid asparagine levels were significantly reduced during the investigated study phase but only 28% of analyzed samples showed complete asparagine depletion while relevant levels, ≥1 µmol/L, were still detectable in around 23% of them. Complete cerebrospinal fluid asparagine depletion was found in around 5-6% and 33-37% of samples at serum asparaginase activity levels <100 and ≥ 1,500 IU/L, respectively. In this study cerebrospinal fluid asparagine levels were reduced during pegylated-asparaginase treatment, but complete depletion was only observed in a minority of patients. No clear threshold of serum pegylated-asparaginase activity level resulting in complete cerebrospinal fluid asparagine depletion was identified. The consistency of the results found in the two independent data sets strengthen the observations of this study. Details of the treatment are available in the European Clinical Trials Database at https://www.clin-icaltrialsregister.eu/ctr-search/trial/2007-004270-43/IT.

Nanofluidic microsystem for sustained intraocular delivery of therapeutics.

Globally, 145.2 million people suffer from moderate to severe vision impairment or blindness due to preventable or treatable causes. However, patient adherence to topical or intravitreal treatment is a leading cause of poor outcomes. To address this issue, we designed an intraocularly implantable device called the nanofluidic Vitreal System for Therapeutic Administration (nViSTA) for continuous and controlled drug release based on a nanochannel membrane that obviates the need for pumps or actuation. In vitro release analysis demonstrated that our device achieves sustained release of bimatoprost (BIM) and dexamethasone (DEX) at concentrations within clinically relevant therapeutic window. In this proof of concept study, we constructed an anatomically similar in silico human eye model to simulate DEX release from our implant and gain insight into intraocular pharmacokinetics profile. Overall, our drug-agnostic intraocular implant represents a potentially viable platform for long-term treatment of various chronic ophthalmologic diseases, including diabetic macular edema and uveitis.

Transcutaneously refillable nanofluidic implant achieves sustained level of tenofovir diphosphate for HIV pre-exposure prophylaxis.

Pre-exposure prophylaxis (PrEP) with antiretroviral (ARV) drugs are effective at preventing human immunodeficiency virus (HIV) transmission. However, implementation of PrEP presents significant challenges due to poor user adherence, low accessibility to ARVs and multiple routes of HIV exposure. To address these challenges, we developed the nanochannel delivery implant (NDI), a subcutaneously implantable device for sustained and constant delivery of tenofovir alafenamide (TAF) and emtricitabine (FTC) for HIV PrEP. Unlike existing drug delivery platforms with finite depots, the NDI incorporates ports allowing for transcutaneous refilling upon drug exhaustion. NDI-mediated drug delivery in rhesus macaques resulted in sustained release of both TAF and FTC for 83 days, as indicated by concentrations of TAF, FTC and their respectively metabolites in plasma, PBMCs, rectal mononuclear cells and tissues associated with HIV transmission. Notably, clinically relevant preventative levels of tenofovir diphosphate were achieved as early as 3 days after NDI implantation. We also demonstrated the feasibility of transcutaneous drug refilling to extend the duration of PrEP drug delivery in NHPs. Overall, the NDI represents an innovative strategy for long-term HIV PrEP administration in both developed and developing countries.