Development and validation of LC-MS/MS methods for the simultaneous quantification of sofosbuvir and its major metabolite (GS-331007) in blood plasma and cerebrospinal and seminal fluid: Application to a pilot clinical trial with a focus on Zika.

Zika still poses a threat to global health owing to its association with serious neurological conditions and the absence of a vaccine and treatment. Sofosbuvir, an anti-hepatitis C drug, has shown anti-Zika effects in animal and cell models. Thus, this study aimed to develop and validate novel LC-MS/MS methods for the quantification of sofosbuvir and its major metabolite (GS-331007) in human plasma and cerebrospinal (CSF) and seminal fluid (SF), and apply the methods to a pilot clinical trial. The samples were prepared by liquid-liquid extraction and separated using isocratic mode on Gemini C18 columns. Analytical detection was performed using a triple quadrupole mass spectrometer equipped with an electrospray ionization source. The validated ranges for sofosbuvir were 0.5-2,000 ng/mL (plasma) and 0.5-100 ng/mL (CSF and SF), while for the metabolite they were 2.0-2,000 ng/mL (plasma), 5.0-200 ng/mL (CSF) and 10-1,500 ng/mL (SF). The intra-day and inter-day accuracies (90.8-113.8%) and precisions (1.4-14.8%) were within the acceptance range. The developed methods fulfilled all validation parameters concerning selectivity, matrix effect, carryover, linearity, dilution integrity, precision, accuracy and stability, confirming the suitability of the method for the analysis of clinical samples.

Childhood poverty and mental health disorders in early adulthood: evidence from a Brazilian cohort study.

BACKGROUND: We examined the association between childhood poverty and mental health disorders (MHD) in childhood and early adulthood. We also investigated whether the association between poverty in childhood and MHD is mediated by exposure to stressful life events (SLE). METHODS: We used data from a prospective community cohort of young people assessed at baseline (M = 9.7 years, SD = 1.9), first (M = 13.5 years, SD = 1.9), and second (M = 18.2 years, SD = 2.0) follow-ups (N = 1,590) in Brazil. Poverty was assessed using a standardized classification. Exposure to 20 different SLE was measured using the Life History instrument. Psychiatric diagnoses were evaluated using the Development and Well-Being Assessment. Latent growth models investigated the association between poverty at baseline and the growth of any MHD, externalizing, and internalizing disorders. Mediation models evaluated whether the association between childhood poverty and MHD in early adulthood was mediated by exposure to SLE. RESULTS: Poverty affected 11.4% of the sample at baseline and was associated with an increased propensity for presenting externalizing disorders in adolescence or early adulthood (standardized estimate = 0.27, p = 0.016). This association was not significant for any disorder or internalizing disorders. Childhood poverty increased the likelihood of externalizing disorders in early adulthood through higher exposure to SLE (OR = 1.07, 95 CI% 1.01-1.14). Results were only replicated among females in stratified analyses. CONCLUSIONS: Childhood poverty had detrimental consequences on externalizing MHD in adolescence, especially among females. Poverty and SLE are preventable risk factors that need to be tackled to reduce the burden of externalizing disorders in young people.

Pharmacokinetics of chloroquine and primaquine in healthy volunteers.

BACKGROUND: Vivax malaria is a neglected disease. There is an irrefutable need for better treatments with higher acceptability and efficacy. The treatment efficacy is influenced by many factors, including bioavailability. Hence, a straightforward strategy to improve vivax malaria treatment efficacy is the deployment of good quality formulations of primaquine and chloroquine. As these treatments were developed more than 70 years ago, many of the available data on blood levels of both drugs are based on obsolete analytical methodologies or pharmaceutical formulations, which are not available anymore. Herein, the results of three bioequivalence studies are presented, providing individual pharmacokinetic data on chloroquine and primaquine of more than a hundred healthy volunteers and using up-to-date analytical methods. METHODS: Three trials were designed as a single centre, randomized, single dose, open label, fasting, crossover bioequivalence studies comparing a new coated chloroquine tablet to the uncoated tablet, and 5 and 15 mg primaquine formulations to either an international reference product or the currently distributed tablets. Plasma concentrations of chloroquine and primaquine were measured using a validated HPLC-MS/MS method in accordance with current international regulatory requirements for bio-analytical methods. RESULTS: In total, a hundred eleven healthy volunteers of both genders were included in the three studies (n = 32; 30 and 56 respectively). No serious adverse events occurred. Drugs levels were measured in 5,520 blood samples. The estimated ratio of the geometric means of Cmax, AUC0-t and AUC0-inf of test and reference drugs and their 90% CI for chloroquine 150 mg, primaquine 15 mg and primaquine 5 mg were: 95.33% (89.18; 101.90), 86. 85% (82.61; 91.31), and 84.45% (76.95; 92.67); 93.28% (81.76; 106.41), 94.52% (86.13; 103.73) and 93.93% (85.83; 102.79); 97.44% (90.60; 104.78), 93.70% (87.04; 100.87) and 91.36% (85.27; 97.89), respectively. As Cmax and AUC0-t 90% CI were within the acceptance interval of 80-125% in all cases, the formulations tested were bioequivalent. CONCLUSIONS: In conclusion, the three studies provided detailed chloroquine and primaquine pharmacokinetic data in accordance with current regulatory standards. Together with other open data initiatives, this individual data may increase the accuracy of pharmacokinetic models guiding best dose, new combinations, regimens and formulations to optimize the current chloroquine and primaquine treatments for vivax malaria. The data presented here may support the deployment of high-quality drugs and evidence-based public health policies.

Investigation of Chloroquine Resinate Feasibility and In Vitro Taste Masking Evaluation for Pediatric Formulations.

In this study, chloroquine resinates were prepared at a 1:1 (w:w) drug-to-resin ratio using the batch method with polacrilex (PC), sodium polystyrene sulfonate (SPS), and polacrilin potassium (PP) ion exchange resins (IER). The influence of drug/resin ratio and pH of the medium on drug loading efficiency was explored. UV-VIS spectrophotometric analysis showed that SPS resin had high loading efficiency for chloroquine diphosphate (CLP), above 89%, regardless of the pH. PP resin was more effective at pH 5.0 (90.68%) than at pH 1.0 (2.09%), and PC resin had only 27.63% of CLP loading efficiency. CLP complexation with IER yielded amorphous mixtures according to results from differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD), thus indicating drug-resin interaction. The taste masking efficiency was evaluated with in vitro methods using an adapted dissolution test and an electronic tongue system. During dissolution tests, SPS released only 1.0% of CLP after 300 s, while PP released over 10% after 90 s in simulated saliva solution. The electronic tongue distinguished the samples containing CLP, resins, and resinates by using multidimensional projection techniques that indicated an effective drug taste masking. In an accelerated stability study, the drug contents did not decrease in chloroquine resinates, and there was no physical degradation of the resinates after 60 days. Using chloroquine resinates therefore represents a novel way to evaluate taste masking in vitro which is relevant for the early formulation development process.

In Vivo and In Vitro Taste Assessment of Artesunate-Mefloquine, Praziquantel, and Benznidazole Drugs for Neglected Tropical Diseases and Pediatric Patients.

The assessment of drug taste is crucial for pediatric treatments so that formulations can be developed to enhance their effectiveness. In this study, in vivo and in vitro methods were applied to evaluate the taste of tablets of three drugs administered to children without taste-masking excipients to treat tropical diseases, namely artesunate-mefloquine (ASMQ), praziquantel (PZQ), and benznidazole (BNZ). In the first method, a model of rat palatability was adapted with recirculation to ensure sample dispersion, and the data were analyzed using ANOVA (single factor, 95%). The taste assessment results (in vivo) indicated an aversion to the three medicines, denoted by the animals retracting themselves to the bottom of the box after the first contact with the drugs. For the placebo samples, the animals behaved normally, indicating that taste perception was acceptable. The second method was based on the in vitro analysis of capacitance data from a homemade impedimetric electronic tongue. Consistent with the in vivo taste assessment results, the data points obtained with PZQ, ASMQ, and BNZ were far away from those of their placebos in a map built with the multidimensional projection technique referred to as Interactive Document Mapping (IDMAP). A combined analysis of the results with the two methods allowed us to confirm the bitterness of the three drugs, also pointing to electronic tongues as a promising tool to replace in vivo palatability tests.

Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin-based combination therapy with primaquine.

BACKGROUND: Activation of hypnozoites of vivax malaria causes multiple clinical relapses, which contribute to the Plasmodium vivax burden and continuing transmission. Artemisinin-based combination therapy (ACT) is effective against blood-stage P. vivax but requires co-administration with primaquine to achieve radical cure. The therapeutic efficacy of primaquine depends on the generation of a therapeutically active metabolite via cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 metabolism has been associated with primaquine treatment failure. This study investigated the association between impaired CYP2D6 genotypes, drug-exposure to the long-acting ACT component (schizonticidal drugs) and tolerance and efficacy. METHODS: Adult patients with acute vivax malaria were enrolled in a recently completed trial and treated with artesunate-mefloquine, chloroquine or artemether-lumefantrine. All received concomitant primaquine (0.5 mg/kg/day for 7-9 days). The association between efficacy and safety and drug exposure was explored using area-under-the-curve (AUC) and half-life (t1/2) estimates obtained by non-compartmental analysis of the long half-life drugs. Parasite recurrences by day 63 were categorized as related relapses or re-infections/unrelated hypnozoite activation by genotyping three microsatellite loci and two polymorphic loci of merozoite surface antigen-1. The CYP2D6 genotype was identified with Taqman assays by real-time PCR to 9 polymorphisms (8 SNPs and one deletion). Impaired CYP2D6 activity was inferred using the Activity Score System. RESULTS: Most recurrences in the ASMQ (67%), CQ (80%) and AL (85%) groups were considered related relapses. Eight of nine (88.9%) of the patients with impaired CYP2D6 activity relapsed with related parasite compared to 18/25 (72%) with normal activity (RR = 1.23, 0.88; 1.72, p = 0.40). There were no associations between the measured PK parameters and recurrence. Patients with longer chloroquine half-lives had more pruritus (RR = 1.09, 1.03; 1.14, p = 0.001). Higher CQ AUCs were associated with reduced falls in haemoglobin by day 14 (Coef - 0.02, - 0.005; - 0.03, p = 0.01). All regimens were well tolerated. CONCLUSION: Genotyping of P. vivax showed that activation of related (homologous) hypnozoites was the most frequent cause of recurrence. The high proportion of the impaired CYP2D6 activity among patients with recurrent infections suggests that slow primaquine metabolism might influence related relapse rates in Brazil among patients receiving primaquine for radical cure, although confirmatory studies are needed. There was no association between drug exposure of the long-acting ACT component (schizonticidal drugs) and risk of related relapse. ACT was well tolerated. These results provide further re-assurance about the safety and efficacy of ACT when combined with short course primaquine to treat uncomplicated malaria vivax in Brazil. Trial registration RBR-79s56s ( http://www.ensaiosclinicos.gov.br/rg/RBR-79s56s/ ).

Safety, efficacy and pharmacokinetic evaluations of a new coated chloroquine tablet in a single-arm open-label non-comparative trial in Brazil: a step towards a user-friendly malaria vivax treatment.

BACKGROUND: Malaria remains a major public health problem, with half the world population at risk of contracting malaria. The effects of Plasmodium vivax on prosperity and longevity have been highlighted in several recent clinical case reports. The first line of vivax treatment drugs has seen no radical innovation for more than 60 years. This study introduces a subtle incremental innovation to vivax treatment: a chloroquine and primaquine co-blister. The co-blister includes a new chloroquine formulation incorporating coated tablets to mask the drug's bitter taste and user-friendly packaging containing tablets of each drug, which may improve patient adherence and facilitate the appropriate use of the drugs. This new formulation will replace the non-coated chloroquine distributed in Brazil. METHODS: Patients were orally treated with 150 mg coated chloroquine tablets for 3 days: an initial 450 mg dose, followed by two 300 mg doses. The patients were treated concomitantly with two 15 mg primaquine tablets for 7-9 days, according to their weight. The primary objective of this study was to prove parasitological and clinical cure rates above 90 % by day 28. RESULTS: This single-arm open-label non-comparative trial was conducted according to the WHO recommended methodology for the surveillance of anti-malarial drug efficacy in the Brazilian Amazon. On day 28, the parasitological and clinical response was adequate in 98.8 % of patients (CI 95 % 93.4-100 %). The success rate on day 3 was 100 %, and the cumulative success rate by day 28 was 98.8 % (CI 95 % 91.7-99.8 %). There were no serious adverse events, with most adverse events classified as mild. The pharmacokinetic parameters of chloroquine analysed in whole blood dry spot samples showed mean (coefficient of variation) Cmax and AUC0-t values of 374.44 (0.35) and 3700.43 (0.36) ng/mL, respectively. DISCUSSION: This study reports an appropriate safety and efficacy profile of a new formulation of coated chloroquine tablets for vivax malaria treatment in the Brazilian Amazon. The cure rates meet the WHO efficacy criteria, supporting current Brazilian guidelines and the use of the formulation for vivax malaria treatment. Nevertheless, further studies should be conducted to address adherence and the effectiveness of the formulation. Trial registration RBR-77q7t3-UTN: U1111-1121-2982. Registered 10th May 2011.

Nifedipine in semi-solid formulations for topical use in peripheral vascular disease: preparation, characterization, and permeation assay.

Nifedipine (NFD) has been used for the treatment of cutaneous lesions caused by peripheral vascular disease and diabetic ulcers. NFD was formulated at 8% in three semi-solid formulations: Polaxamer 407 Lecithin Organogel (PLO), PLO plus Transcutol(®), and an oil-in-water (o/w) emulsion. In vitro release and permeation tests were carried out using a synthetic (cellulose acetate) or natural membrane (pig ear skin), respectively, mounted in a Franz-type diffusion cell at 37°C in a constant water bath. As a receptor solution, isotonic phosphate buffer at pH 7.4 was used. All samples were analyzed by high-performance liquid chromatography by employing a previously validated method. The drug flow values were 6.126 ± 0.288, 4.030 ± 0.081, and 6.660 ± 0.254 µg/cm(2)/h for PLO, PLO plus Transcutol(®), and o/w emulsion, respectively. The three formulations did not show significant differences in drug flow, considering p > 0.05. Furthermore, their penetration profiles in both the epidermis and dermis were statistically different. Thus, the incorporation of NFD in PLO, PLO plus Transcutol(®), and o/w emulsion changed the drug thermodynamic activity, as expected. In addition, Transcutol(®) increased the solubility of NFD in the formulation and promoted its penetration in both the epidermis and dermis.

Treatment resistance in schizophrenia: a meta-analysis of prevalence and correlates.

OBJECTIVES: To determine the prevalence and correlates of treatment-resistant schizophrenia (TRS) through a systematic review and meta-analysis. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, an electronic search was performed in PubMed and Embase through May 17, 2022. All study designs that assessed a minimum of 20 schizophrenia-spectrum patients and provided data on TRS prevalence or allowed its calculation were included. Estimates were produced using a random-effects model meta-analysis. RESULTS: The TRS prevalence across 50 studies (n = 29,390) was 36.7% (95%CI 33.1-40.5, p < 0.0001). The prevalence ranged from 22% (95%CI 18.4-25.8) in first-episode to 39.5% (95%CI 32.2-47.0) in multiple-episode samples (Q = 18.27, p < 0.0001). Primary treatment resistance, defined as no response from the first episode, was 23.6% (95%CI 20.5-26.8) vs. 9.3% (95%CI 6.8-12.2) for later-onset/secondary (≥ 6 months after initial treatment response). Longer illness duration and recruitment from long-term hospitals or clozapine clinics were associated with higher prevalence estimates. In meta-regression analyses, older age and poor functioning predicted greater TRS. When including only studies with lower bias risk, the TRS prevalence was 28.4%. CONCLUSION: Different study designs and recruitment strategies accounted for most of the observed heterogeneity in TRS prevalence rates. The results point to early-onset and later-onset TRS as two separate disease pathways requiring clinical attention.

Longitudinal invariance of psychotic experiences in children and adolescents: What do the data tell us?

BACKGROUND: Psychotic experiences are common in adults, adolescents, and children. While usually self-limited, they can indicate psychosis proneness when persistent. The Community Assessment of Psychic Experiences (CAPE) measures lifetime psychotic experiences in three dimensions. The 20-item subscale addressing positive symptoms (CAPE-positive) is the most widely used. No study investigated its measurement invariance across timepoints during childhood and adolescence. This step is required to conduct reliable comparisons in longitudinal studies with different age groups. METHODS: We used data from the Brazilian High-Risk Cohort, which enrolled 2511 individuals aged 6-12 years from public schools for the baseline evaluation. A 3-year follow-up assessment evaluated 1880 participants. Subjects were rated with the CAPE-positive and we performed, at each wave, a Multigroup Confirmatory Factor Analysis testing Exploratory and Confirmatory Factor Analysis models identified in a previous systematic review, to assess longitudinal invariance. RESULTS: A three-factor solution was the best fitting model, comprising Persecutory Ideation, Bizarre Experiences and Perceptual Abnormalities. The longitudinal invariance analysis of the best-fit model was unsatisfactory, achieving only the metric level of invariance. CONCLUSIONS: Our findings suggest that the CAPE-positive scale has good model fit indices for each evaluated time point individually (children and adolescents), but it is not invariant over time. Identifying which factors affect CAPE latent structure at different time points can improve our understanding of psychosis proneness and how to measure it.

Identifying strategies to improve PANSS based dimensional models in schizophrenia: Accounting for multilevel structure, Bayesian model and clinical staging.

BACKGROUND: Dimensional approaches can decompose a construct in a set of continuous variables, improving the characterization of complex phenotypes, such as schizophrenia. However, the five-factor model of the Positive and Negative Syndrome Scale (PANSS), the most used instrument in schizophrenia research, yielded poor fits in most confirmatory factor analysis (CFA) studies, raising concerns about its applications. Thus, we aimed to identify dimensional PANSS CFA models with good psychometric properties by comparing the traditional CFA with three methodological approaches: Bayesian CFA, multilevel modeling, and Multiple Indicators Multiple Causes (MIMIC) modeling. METHODS: Clinical data of 700 schizophrenia patients from four centers were analyzed. We first performed a traditional CFA. Next, we tested the three techniques: 1) a Bayesian CFA; 2) a multilevel analysis using the centers as level; and 3) a MIMIC modeling to evaluate the impact of clinical staging on PANSS factors and items. RESULTS: CFA and Bayesian CFA produced poor fit models. However, when adding a multilevel structure to the CFA model, a good fit model emerged. MIMIC modeling yielded significant differences in the factor structure between the clinical stages of schizophrenia. Sex, age, age of onset, and duration of illness did not significantly affect the model fit. CONCLUSION: Our comparison of different CFA methods highlights the need for multilevel structure to achieve a good fit model and the potential utility of staging models (rather than the duration of illness) to deal with clinical heterogeneity in schizophrenia. Large prospective samples with biological data should help to understand the interplay between psychometrics concerns and neurobiology research.

Childhood individual and family modifiable risk factors for criminal conviction: a 7-year cohort study from Brazil.

Crime is a major public problem in low- and middle-income countries (LMICs) and its preventive measures could have great social impact. The extent to which multiple modifiable risk factors among children and families influence juvenile criminal conviction in an LMIC remains unexplored; however, it is necessary to identify prevention targets. This study examined the association between 22 modifiable individual and family exposures assessed in childhood (5-14 years, n = 2511) and criminal conviction at a 7-year follow-up (13-21 years, n = 1905, 76% retention rate) in a cohort of young people in Brazil. Population attributable risk fraction (PARF) was computed for significant risk factors. Criminal convictions were reported for 81 (4.3%) youths. Although most children living in poverty did not present criminal conviction (89%), poverty at baseline was the only modifiable risk factor significantly associated with crime (OR 4.14, 99.8% CI 1.38-12.46) with a PARF of 22.5% (95% CI 5.9-36.1%). It suggests that preventing children's exposure to poverty would reduce nearly a quarter of subsequent criminal convictions. These findings highlight the importance of poverty in criminal conviction, as it includes several deprivations and suggest that poverty eradication interventions during childhood may be crucial for reducing crime among Brazilian youth.

The enduring gap in educational attainment in schizophrenia according to the past 50 years of published research: a systematic review and meta-analysis.

BACKGROUND: Educational attainment is associated with wellbeing and health, but patients with schizophrenia achieve lower levels of education than people without. Several effective interventions can ameliorate this situation. However, the magnitude of the education gap in schizophrenia and its change over time are unclear. We aimed to reconstruct the trajectories of educational attainment in patients with schizophrenia and, if reported, their healthy comparator controls. METHODS: We did a systematic review and meta-analysis including all studies reporting on patients with schizophrenia (of mean age ≥18 years) and describing the number of years of education of the participants, with or without healthy controls. There were no other design constraints on studies. We excluded studies that included only patients with other schizophrenia spectrum disorders and studies that did not specify the number of years of education of the participants. 22 reviewers participated in retrieving data from a search in PubMed and PsycINFO (Jan 1, 1970, to Nov 24, 2020). We estimated the birth date of participants from their mean age and publication date, and meta-analysed these data using random-effects models, focusing on educational attainment, the education gap, and changes over time. The primary outcome was years of education. The protocol was registered on PROSPERO (CRD42020220546). FINDINGS: From 32 593 initial references, we included 3321 studies reporting on 318 632 patients alongside 138 675 healthy controls (170 941 women and 275 821 men from studies describing sex or gender; data on ethnicity were not collected). Patients' educational attainment increased over time, mirroring that of controls. However, patients with schizophrenia in high-income countries had 19 months less education than controls (-1·59 years, 95% CI -1·66 to -1·53; p<0·0001), which is equivalent to a Cohen's d of -0·56 (95% CI -0·58 to -0·54) and implies an odds ratio of 2·58 for not completing 12 years of education (ie, not completing secondary education) for patients compared with controls. This gap remained stable throughout the decades; the rate of change in number of total years of education in time was not significant (annual change: 0·0047 years, 95% CI -0·0005 to 0·0099; p=0·078). For patients in low-income and middle-income countries, the education gap was significantly smaller than in high-income countries (smaller by 0·72 years, 0·85 to 0·59; p<0·0001), yet there was evidence that this gap was widening over the years, approaching that of high-income countries (annual change: -0·024 years, -0·037 to -0·011; p=0·0002). INTERPRETATION: Patients with schizophrenia have faced persistent inequality in educational attainment in the last century, despite advances in psychosocial and pharmacological treatment. Reducing this gap should become a priority to improve their functional outcomes. FUNDING: Ciencia y Tecnología para el Desarrollo (CYTED) to the Latin American Network for the Study of Early Psychosis (ANDES).

Gender, age and geographical representation over the past 50 years of schizophrenia research.

Previous studies have suggested that subjects participating in schizophrenia research are not representative of the demographics of the global population of people with schizophrenia, particularly in terms of gender and geographical location. We here explored if this has evolved throughout the decades, examining changes in geographical location, gender and age of participants in studies of schizophrenia published in the last 50 years. We examined this using a meta-analytical approach on an existing database including over 3,000 studies collated for another project. We found that the proportion of studies and participants from low-and-middle income countries has significantly increased over time, with considerable input from studies from China. However, it is still low when compared to the global population they represent. Women have been historically under-represented in studies, and still are in high-income countries. However, a significantly higher proportion of female participants have been included in studies over time. The age of participants included has not changed significantly over time. Overall, there have been improvements in the geographical and gender representation of people with schizophrenia. However, there is still a long way to go so research can be representative of the global population of people with schizophrenia, particularly in geographical terms.

What is the Best Latent Structure of Negative Symptoms in Schizophrenia? A Systematic Review.

BACKGROUND: Determining the best latent structure of negative symptoms in schizophrenia could benefit assessment tools, neurobiological research, and targeted interventions. However, no review systematically evaluated studies that assessed and validated latent models of negative symptoms. OBJECTIVE: To identify and evaluate existing latent structure models in the literature of negative symptoms and to determine the best model. METHOD: Systematic search of MEDLINE, EMBASE, and Scopus on July 19, 2020, for confirmatory factor analysis models of negative symptoms in patients with schizophrenia. The available evidence was assessed through 2 sets of criteria: (1) study design quality-based on negative symptoms assessment and modeling strategy and (2) psychometric quality and model fit-based on fit indices and factor definition quality. RESULTS: In total, 22 studies (n = 17 086) from 9 countries were included. Studies differed greatly regarding symptom scales, setting, and sample size (range = 86-6889). Dimensional models included 2-6 factors (median = 4). Twelve studies evaluated competing models and adopted appropriate instruments to assess the latent structure of negative symptoms. The 5-factor and hierarchical models outperformed unitary, 2-factor, and 3-factor models on all direct comparisons, and most of the analyses derived from the Brief Negative Symptom Scale. Considering the quality criteria proposed, 5-factor and hierarchical models achieved excellent fit in just one study. CONCLUSIONS: Our review points out that the 5-factor and hierarchical models represent the best latent structure of negative symptoms, but the immaturity of the relevant current literature may affect the robustness of this conclusion. Future studies should address current limitations regarding psychometric properties and also address biological and clinical validity to refine available models.

Direct Powder Extrusion 3D Printing of Praziquantel to Overcome Neglected Disease Formulation Challenges in Paediatric Populations.

For the last 40 years, praziquantel has been the standard treatment for schistosomiasis, a neglected parasitic disease affecting more than 250 million people worldwide. However, there is no suitable paediatric formulation on the market, leading to off-label use and the splitting of commercial tablets for adults. In this study, we use a recently available technology, direct powder extrusion (DPE) three-dimensional printing (3DP), to prepare paediatric Printlets™ (3D printed tablets) of amorphous solid dispersions of praziquantel with Kollidon® VA 64 and surfactants (Span™ 20 or Kolliphor® SLS). Printlets were successfully printed from both pellets and powders obtained from extrudates by hot melt extrusion (HME). In vitro dissolution studies showed a greater than four-fold increase in praziquantel release, due to the formation of amorphous solid dispersions. In vitro palatability data indicated that the printlets were in the range of praziquantel tolerability, highlighting the taste masking capabilities of this technology without the need for additional taste masking excipients. This work has demonstrated the possibility of 3D printing tablets using pellets or powder forms obtained by HME, avoiding the use of filaments in fused deposition modelling 3DP. Moreover, the main formulation hurdles of praziquantel, such as low drug solubility, inadequate taste, and high and variable dose requirements, can be overcome using this technology.

AGEs accumulation is related to muscle degeneration and vascular calcification in peritoneal dialysis patients.

BACKGROUND: Patients with chronic kidney disease (CKD) are affected by dynapenia, sarcopenia, and vascular calcification. Advanced glycation end products (AGEs) may accumulate in peritoneal dialysis (PD) patients and favor sarcopenia via changes in collagen cross-linking, muscle protein breakdown, and the calcification of arterial smooth muscle cells via p38-MAPK activation. The aim of this study is to explore the relationships between AGEs, muscle degeneration, and coronary artery calcification. METHODS: This was a clinical observational study in patients with CKD undergoing PD, in which serum and skin AGEs (AGEs-sAF), cumulative glucose load, muscle strength and functional tests, muscle ultrasounds with elastography, coronary artery calcium (CAC) quantification, and muscle density by multislice computed tomography were measured. RESULTS: 27 patients aged 48±16 years, dialysis vintage of 27±17 months, had AGEs-sAF levels of 3.09±0.65 AU (elevated in 13 [87%] patients), grip strength levels of 26.2±9.2 kg (11 [42%] patients with dynapenia), gait speed of 1.04±0.3 m/s (abnormal in 14 [58%] patients) and "timed-up-and-go test" (TUG) of 10.5±2.2s (abnormal in 7 [26%] patients). Correlations between AGEs-sAF levels and femoral rectus elastography (R=-0.74; p=0.02), anterior-tibialis elastography (R= -0.68; p=0.04) and CAC (R=0.64; p=0.04) were detected. Cumulative glucose load correlated with femoral rectal elastography (R=-0.6; p=0.02), and serum glycated hemoglobin concentrations correlated with psoas muscle density (R= -0.58; p=0.04) and CAC correlated with psoas muscle density (R=0.57; p=0.01) and lumbar square muscle density (R=-0.63; p=0.005). CONCLUSIONS: The study revealed associations between AGEs accumulation and lower muscle stiffness/density. Associations that linked muscle degeneration parameters with vascular calcification were observed.

Diversity matters: opportunities in the study of the genetics of psychotic disorders in low- and middle-income countries in Latin America.

Lack of diversity regarding genetic and environmental backgrounds weakens the generalization and clinical applicability of research findings on psychotic disorders. Notably, Latin Americans have been generally neglected in genetic studies, comprising less than 2% of genome-wide association study samples. But Latin American populations represent a unique opportunity for research, given the exceptionally high ethnic admixture of this group. Increasing genetic diversity is essential to improve the fine mapping of known regions associated with psychotic disorders, discover novel genetic associations, and replicate studies. Additionally, Latin America is characterized by massive social, political, and economic inequalities, all known risk factors for mental health issues, including psychotic disorders. This article aims to 1) discuss the challenges and advantages of studying Latin America's particular genetic makeup and environmental context; 2) review previous studies conducted in the region; and 3) describe three Latin American research initiatives in progress: the Neuropsychiatric Genetics of Psychosis in Mexican Populations (NeuroMEX), the Paisa, and the Latin American Network for the Study of Early Psychosis (ANDES) studies.

Predictors of gaming disorder in children and adolescents: a school-based study.

OBJECTIVE: To determine whether psychiatric and gaming pattern variables are associated with gaming disorder in a school-based sample. METHODS: We analyzed data from the Brazilian High-Risk Cohort for Psychiatric Disorders, a community sample aged 10 to 18, using questionnaires on gaming use patterns. We applied the Gaming Addiction Scale to diagnose gaming disorder and the Development and Well-Being Behavior Assessment for other diagnoses. RESULTS: Out of 407 subjects, 83 (20.4%) fulfilled the criteria for gaming disorder. More role-playing game players were diagnosed with gaming disorder that any other genre. Gaming disorder rates increased proportionally to the number of genres played. Playing online, being diagnosed with a mental disorder, and more hours of non-stop gaming were associated with higher rates of gaming disorder. When all variables (including age and gender) were considered in a logistic regression model, the number of genres played, the number of non-stop hours, the proportion of online games, and having a diagnosed mental disorder emerged as significant predictors of gaming disorder. CONCLUSION: Each variable seems to add further risk of gaming disorder among children and adolescents. Monitoring the length of gaming sessions, the number and type of genres played, time spent gaming online, and behavior changes may help parents or guardians identify unhealthy patterns of gaming behavior.