Corrigendum: Initial adaptation of the OnTrack coordinated specialty care model in Chile: An application of the Dynamic Adaptation Process.

[This corrects the article DOI: 10.3389/frhs.2022.958743.].

Urban distance to mental healthcare units and public transport increases duration of untreated psychosis in first-episode patients.

BACKGROUND: There is a growing interest in environmental and social determinants of mental health. However, how distance to healthcare and public transportation affect illness is neglected in schizophrenia research. Here, we are interested in how the availability of mental healthcare and the ways to reach it may be associated with psychosis. AIMS: We aim to investigate the association between distances to healthcare units and subway stations and duration of untreated psychosis (DUP) and greater initial severity in an antipsychotic-naïve first episode of psychosis (FEP) sample. METHOD: Using 212 untreated FEP patients' data, we calculated the distances from their residences to the places of interest. Diagnoses comprehended schizophrenia spectrum disorders, depressive and bipolar affective disorders, and substance-induced disorders. Linear regressions were performed with distances as independent variables, DUP and Positive and Negative Syndrome Scale (PANSS) scores as dependent variables. RESULTS: Longer distance to emergency mental healthcare was related to longer DUP (95% CI: p = .034, B = 0.152) and higher total PANSS (95% CI: p = .007, B = 0.0189); longer distance to community mental healthcare units was related to longer DUP (95% CI: p = .004, B = 0.0204) and higher total PANSS (95% CI: p = .030, B = 0.152). Moreover, a longer distance to the closest subway station predicted longer DUP (95% CI: p = .019, B = 0.170). CONCLUSION: Our results indicate that poor healthcare access is related to longer DUP and higher initial PANSS scores. Future research should investigate how investments in mental health access and actions to improve public transport access could impact DUP and treatment outcomes in psychosis patients.

Molecular dynamics and free energy calculations of clozapine bound to D2 and H1 receptors reveal a cardiometabolic mitigated derivative.

Most atypical antipsychotics derive from a high dropout of drug treatments due to adverse cardiometabolic side effects. These side effects are caused, in part, by the H1 receptor blockade. The current work sought a clozapine derivative with a reduced affinity for the H1 receptor while maintaining its therapeutic effect linked to D2 receptor binding. Explicit molecular dynamics simulations and end-point free energy calculations of clozapine in complex with the D2 and H1 receptors embedded in cholesterol-rich lipid bilayers were performed to analyze the intermolecular interactions and address the relevance of clozapine-functional groups. Based on that, free energy perturbation calculations were performed to measure the change in free energy of clozapine structural modifications. Our results indicate the best clozapine derivative is the iodine atom substitution for chlorine. The latter is mainly due to electrostatic interaction loss for the H1 receptor, while the halogen orientation out of the D2 active site reduces the impact on the affinity.Communicated by Ramaswamy H. Sarma.

Auditory perceptual discomfort and low-hearing tolerance in the first episode psychosis.

Awareness of perceptual and sensory changes that might occur in visual, auditory, proprioception, and other senses, in the early stages towards the First Episode Psychosis (FEP), and their subsequent sensorial evolution as the disturb progresses deeper into an acute episode, might be a key element for interrupting the process. In the present study, we investigated hearing discomfort/tolerance to 16 given sound streams. Sixteen people diagnosed with FEP, participated in the experiment. Sixteen frequency sweeps varying in modulation envelopes (sawtooth, sine), order (ascending, descending), duration (4s, 8s), and range (50-8000 Hz, 2-8 kHz) were presented randomly, but always in the same sequence, to FEP and healthy controls (HC). The level of discomfort was estimated by the participant by making a mark across a continuous line whose extremes read "nothing bad" (left) and "too bad" (right). Results showed that ascending sine pure frequency sweeps (p < 0.01) and descending sine pure frequencies sweeps (p < 0.01) caused the maximum discomfort in FEP. Other variables also showed differences between FEP and HC, and FEP were always more intolerant to such pure frequency sweeps than HC. We conclude that this might be useful for very early assessment of people at risk, people with FEP, and people with schizophrenia.

Initial adaptation of the OnTrack coordinated specialty care model in Chile: An application of the Dynamic Adaptation Process.

Background: In 2005, Chile became the first country in Latin America to guarantee universal free access for the diagnosis and treatment of schizophrenia. A cluster randomized control trial utilizing the Dynamic Adaptation Process framework is underway to adapt and test the OnTrack coordinated specialty care model to provide recovery-oriented, person-centered care by a multidisciplinary team for individuals with first episode psychosis (FEP) in Chile. Methods: A qualitative formative research study was conducted to inform the initial adaptation of the OnTrack Chile (OTCH) program. We conducted key informant interviews (n = 17) with various stakeholders (policymakers; directors/managers of community mental health centers; mental health professionals) and focus group discussions (n = 6) with individuals with FEP and caregivers (n = 35 focus group participants total). Data was analyzed using thematic analysis, organized by participants' perspectives on the benefits, barriers, and recommendations for the key principles, multidisciplinary team, psychosocial components, and the training and supervision model of OnTrack. Results: Participants expressed enthusiasm and support for OnTrack's recovery-oriented and person-centered principles of care. While many participants lauded the emphasis on shared decision-making and family involvement, some reported reticence, citing that it is culturally normative for patients and families to adopt a passive role in treatment. Peer specialists, and the family psychoeducation and support and supported education and employment components were perceived as aspects that could encourage the promotion of personhood and autonomy development. However, implementation challenges, including the prevailing biomedical approach, professional hierarchy, and the lack of infrastructure, human, and financial resources necessitate some modifications to these aspects. Some mental health professionals further conveyed reservations regarding the perceived hierarchical structure of the supervision model. Conclusion: OnTrack represents a shift from a biomedical model to a valued, aspirational, person-centered and culturally responsive model that focuses on recovery, shared decision-making and psychosocial care. With the appropriate governmental and agency-level provision of resources and modifications to some of the program components, particularly regarding the shared decision-making framework, peer specialist, family engagement, and the training supervision model, OTCH could be a transformative program for a more comprehensive, evidence-based care for individuals with FEP in Chile.

Auditory perceptual discomfort and low-hearing tolerance in the first episode psychosis

Awareness of perceptual and sensory changes that might occur in visual, auditory, proprioception, and other senses, in the early stages towards the First Episode Psychosis (FEP), and their subsequent sensorial evolution as the disturb progresses deeper into an acute episode, might be a key element for interrupting the process. In the present study, we investigated hearing discomfort/tolerance to 16 given sound streams. Sixteen people diagnosed with FEP, participated in the experiment. Sixteen frequency sweeps varying in modulation envelopes (sawtooth, sine), order (ascending, descending), duration (4s, 8s), and range (50­8000 Hz, 2­8 kHz) were presented randomly, but always in the same sequence, to FEP and healthy controls (HC). The level of discomfort was estimated by the participant by making a mark across a continuous line whose extremes read "nothing bad" (left) and "too bad" (right). Results showed that ascending sine pure frequency sweeps (p < 0.01) and descending sine pure frequencies sweeps (p < 0.01) caused the maximum discomfort in FEP. Other variables also showed differences between FEP and HC, and FEP were always more intolerant to such pure frequency sweeps than HC. We conclude that this might be useful for very early assessment of people at risk, people with FEP, and people with schizophrenia. (AU)

Evaluación biológica de la exposición laboral al plomo / Biological assessment of the work-related exposure to lead

Introducción: El plomo, por su amplio uso causa una gran contaminación ambiental y problemas de salud en muchas partes del mundo. La Organización Mundial de la Salud incluyó el plomo dentro de una lista de diez productos químicos causantes de graves efectos sobre la salud. Objetivo: Evaluar los niveles de plomo en sangre y de protoporfirina libre eritrocitaria en un grupo de trabajadores expuestos a plomo inorgánico. Métodos: Estudio descriptivo de corte transversal donde se evaluaron 776 casos que acudieron a los laboratorios del Instituto Nacional de Salud de los Trabajadores en el año 2018, provenientes de diferentes sectores industriales. Se les realizó la determinación de plomo en sangre a 288 y la de protoporfirina a 488, según métodos establecidos en el laboratorio. Los datos obtenidos fueron procesados utilizando Microsoft Excel® y el paquete estadístico Statgraphics Centurion XVI.II. Resultados: El 92 por ciento de los pacientes fue del sexo masculino. La concentración de plomo en sangre osciló entre 5 µg/dL y 89 µg/dL para un promedio en hombres de 24 µg/dL ± 21 µg/dL y en las mujeres de 11 µg/dL ± 9 µg/dL. Para la protoporfirina, esta fluctuó entre 21 µg/dL y 274 µg/dL, con un promedio de 47 µg/dL ± 22 µg/dL en hombres y 66 µg/dL ± 32 µg/dL en las mujeres. El 8 por ciento de los casos evaluados tuvo valores de plomo en sangre mayores de 60 µg/dL y para la protoporfirina el 5 por ciento de los casos presentaron valores por encima de 85 μg/dL. Conclusiones: Algunos casos evaluados presentaron niveles elevados de plomo que superan los límites permitidos, lo que pone en evidencia la necesidad de reforzar las medidas de protección aplicadas a los trabajadores y la importancia de detectar precozmente el problema en el ámbito laboral, antes de que aparezcan repercusiones derivadas de una intoxicación por plomo(AU)

Introduction: Lead, due to its large use, causes a major environmental pollution and health problems in many places around the world. The World Health Organization included lead in a list of ten chemical products causing severe effects in health. Objective: To assess lead levels in blood and free-erythtocyte protoporphyrin (FEP) levels in groups of workers exposed to inorganic lead. Methods: Descriptive. cross-sectional study where 776 cases coming from different industrial sectors were assessed in the laboratories of the National Institute of Workers Health in the year 2018. It was conducted to 288 of the cases a test to determine if there was lead in blood and a test for FEP to 488 cases, according to the methods established in the laboratory. The data collected were processed using Microsoft Excel® and the statistical program called Statgraphics Centurion XVI.II. Results: 92 percent of the patients were males. Lead concentration in blood ranged from 5 µg/dL and 89 µg/dL, for an average in men of 24 µg/dL ± 21 µg/dL, and in women of 11 µg/dL ± µg/dL. FEP concentration swung from 21 µg/dL to 274 µg/dL, with an average of 47 µg/dL ± 22 µg/dL in men, and 66 µg/dL ± 32 µg/dL in women. 8 percent of the assessed cases presented values of lead in blood higher than 60 µg/dL and for FEP, 5 percent of the cases presented values higher than 85 µg/dL. Conclusions: Some of the assessed cases presented high levels of lead which exceed the permitted levels; so, this demonstrates the need of reinforzing the protection measures applied to the workers and the importance of early detecting this problem in work-related environments prior to the onset of repercutions derived from lead poisoning(AU)

A study in first-episode psychosis patients: does angiotensin I-converting enzyme (ACE) activity associated with genotype predict symptoms severity reductions after treatment with the atypical antipsychotic risperidone?

BACKGROUND: Our previous studies showed increased angiotensin I-converting enzyme (ACE) activity in chronic schizophrenia (SCZ) patients compared to healthy control (HC) volunteers, and the relevance of combining ACE genotype and activity for predicting SCZ was suggested. METHODS: ACE activity was measured in plasma of ACE insertion/deletion (I/D) genotyped HC volunteers (N = 53) and antipsychotic-naïve first-episode psychosis (FEP) patients (N = 45), assessed at baseline (FEB-B) and also after 2-months (FEP-2M) of treatment with the atypical antipsychotic risperidone. RESULTS: ACE activity measurements showed significant differences among HC, FEP-B and FEP-2M groups (F = 5.356, df = 2, p = 0.005), as well as between HC and FEP-2M (post-hoc Tukey's multiple comparisons test, p = 0.004). No correlation was observed for ACE activity increases and symptom severity reductions in FEP as assessed by total PANSS (r = -0.131, p = 0.434). FEP subgrouped by ACE I/D genotype showed significant ACE activity increases, mainly in the DD genotype subgroup. No correlation between ACE activity and age was observed in FEP or HC groups separately (r = 0.210, p = 0.392), but ACE activity levels differences observed between these groups were influenced by age. CONCLUSIONS: The importance of measuring the ACE activity in blood plasma, associated to ACE I/D genotyping to support the follow-up of FEP patients did not show correlation with general symptoms amelioration in the present study. However, new insights into the influence of age and I/D genotype for ACE activity changes in FEP individuals upon treatment was demonstrated.

Toward the Characterization of DAPT Interactions with γ-Secretase.

DAPT is a potent γ-secretase (GS) inhibitor that blocks the production of short amyloid-ß (Aß) peptides. Aggregation and oligomerization of Aß peptides have been associated with the development and progression of Alzheimer's disease. A recent cryo-electron microscopy density map disclosed DAPT binding at the GS active site. In this study, we employed the density map data to assign a possible binding pose of DAPT to characterize its dynamic behavior through different molecular dynamics simulation approaches. Our simulations showed a high preference of DAPT for the intramembrane region of the protein and that its entry site is located between TM2 and TM3 of PS1. DAPT interaction with the active site led to a decreased flexibility of key PS1 regions related to the recognition and internalization of GS substrates. Moreover, our study showed that the proximity of DAPT to the catalytic aspartic acids should be able to modify its protonation states, preventing the enzyme from reaching its active form. These results provide valuable information toward understanding the molecular mechanism of a GS inhibitor for the development of novel Alzheimer's disease treatments.

Oligopeptidases activity in bipolar disorder: Ndel1 and angiotensin I converting enzyme.

BACKGROUND: Abnormal activity of two enzymes relevant to neurodevelopment, namely nuclear-distribution element-like 1 (Ndel1) and angiotensin I-converting enzyme (ACE), was reported in individuals with schizophrenia; to our knowledge, these oligopeptidases were never measured in bipolar disorder (BD). AIMS: Evaluate the enzyme activity of Ndel1 and ACE in euthymic individuals with BD type 1 which was compare to healthy control (HC) group. METHODS: Ndel1 and ACE activities were assessed in the serum of individuals with BD type 1 according to DSM-IV criteria (n = 70) and a HC group (n = 34). The possible differences between BD type 1 and HC groups were evaluated using Analysis of Covariance (ANCOVA), and the results were adjusted for age, gender and body mass index. RESULTS: We observed a positive correlation between Ndel1 activity and the total YMRS score in BD group (p = 0.030) and a positive correlation between ACE activity and Ham-D score (p = 0.047). ANCOVA analysis showed lower Ndel1 activity in BDs compared to HCs. Interestingly, we did not observe between-groups differences in ACE activity, despite the recognized correlation of ACE activity levels with cognitive functions, also described to be worsened in psychiatric patients. CONCLUSION: Oligopeptidases, especially Ndel1, which has been strongly correlated with neurodevelopment and brain formation, are potentially a good new target in the study of the neurobiology of BD. LIMITATIONS: The relatively small sample size did not permit to examine the cause-effect relationship of clinical dimensions of BD and the enzymatic activity.

Corpus callosum volumes in the 5 years following the first-episode of schizophrenia: Effects of antipsychotics, chronicity and maturation.

Background: White matter (WM) structural changes, particularly affecting the corpus callosum (CC), seem to be critically implicated in psychosis. Whether such abnormalities are progressive or static is still a matter of debate in schizophrenia research. Aberrant maturation processes might also influence the longitudinal trajectory of age-related CC changes in schizophrenia patients. We investigated whether patients with first-episode schizophrenia-related psychoses (FESZ) would present longitudinal CC and whole WM volume changes over the 5 years after disease onset. Method: Thirty-two FESZ patients and 34 controls recruited using a population-based design completed a 5-year assessment protocol, including structural MRI scanning at baseline and follow-up. The linear effects of disease duration, clinical outcome and antipsychotic (AP) use over time on WM and CC volumes were studied using both voxelwise and volume-based morphometry analyses. We also examined maturation/aging abnormalities through cross-sectional analyses of age-related trajectories of total WM and CC volume changes. Results: No interaction between diagnosis and time was observed, and clinical outcome did not influence CC volumes in patients. On the other hand, FESZ patients continuously exposed to AP medication showed volume increase over time in posterior CC. Curve-estimation analyses revealed a different aging pattern in FESZ patients versus controls: while patients displayed a linear decline of total WM and anterior CC volumes with age, a non-linear trajectory of total WM and relative preservation of CC volumes were observed in controls. Conclusions: Continuous AP exposure can influence CC morphology during the first years after schizophrenia onset. Schizophrenia is associated with an abnormal pattern of total WM and anterior CC aging during non-elderly adulthood, and this adds complexity to the discussion on the static or progressive nature of structural abnormalities in psychosis.

Lowered paraoxonase 1 (PON1) activity is associated with increased cytokine levels in drug naïve first episode psychosis.

BACKGROUND: Activated immune-inflammatory pathways play an important role in the pathophysiology of schizophrenia. Paraoxonase 1 (PON1) activity is inversely associated with inflammatory responses in numerous clinical conditions. The aims of this study were to delineate serum arylesterase PON1 activity in drug-naïve first episode psychosis (FEP) patients and a healthy control group, and to assess whether there are inverse relationships between PON1 activity and cytokine levels. METHODS: A total of 51 drug-naïve FEP patients and 61 healthy controls were enrolled in this study. Levels of interleukin (IL)-4, IL-10, IL-6, tumor necrosis factor (TNF)-α and activity of PON1 were quantified. RESULTS: Compared to healthy controls, FEP patients showed lower serum PON1 activity and higher levels of IL-4, IL-10 and TNF-α. A significant inverse relationship between PON1 activity and IL-4, IL-6 and IL-10 levels was detected, but not for TNF-α. Subjects with very low PON1 activity (25th quartile) presented significantly higher levels of IL-6, IL-10 and IL-4 than those with higher PON1 activity (75th quartile). CONCLUSION: The present study provides evidence that FEP is characterized by an inverse relationship between lowered activity of the anti-inflammatory/antioxidant enzyme PON1 and increased cytokine levels, including IL-6, IL-4 and IL-10. It is hypothesized that lowered PON1 activity may play a role in the immune-inflammatory response that accompanies FEP and that increased cytokine levels may further modulate PON1 activity.

Effects of depression on the cytokine profile in drug naïve first-episode psychosis.

Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalities in cytokine profile. The immune assessment of patients in a first episode of psychosis (FEP) and particularly in drug naïve patients is very important to further elucidate this association. The objectives of this study are to delineate the cytokine profile (IL-2, IL-10, IL-4, IL-6, IFNγ, TNFα and IL-17) in FEP patients (n=55) versus healthy controls (n=57) and to examine whether the presence of depressive symptoms in FEP is accompanied by a specific cytokine profile. We found increased levels of IL-6, IL-10 and TNFα in FEP patients when compared to healthy controls. FEP patients with depression showed higher IL-4 and TNFα levels versus those without depression. Cytokine levels were not correlated to the total PANSS and the positive or negative subscale scores. Our results suggest that FEP is accompanied by a cytokine profile indicative of monocytic and T regulatory cell (Treg) activation. Depression in FEP is accompanied by monocytic and Th-2 activation, whereas FEP without depression is characterized by Treg activation only. In conclusion, depression emerged as a key component explaining the cytokines imbalance in FEP that is responsible for a large part of the immune-inflammatory abnormalities described.

Tratamiento farmacológico para el control de la crisis aguda de asma

En el manejo del episodio agudo de asma, dos aspectos son básicos: la valoración de la gravedad del cuadro y los diferentes escalones en el tratamiento del mismo. La clasificación de la gravedad se basa en parámetros clínicos y funcionales. Los síntomas del asma se asocian no sólo con la broncoconstricción, sino también con inflamación de la vía aérea. Los β2-Agonistas inhalados tienen un rápido inicio de acción broncodilatadora mediada principalmente por un efecto relajante sobre el músculo liso respiratorio. Los corticosteroides también tienen efectos clínicos rápidos que pueden suprimir la inflamación de las vías inferiores. La decisión de hospitalizar se debe basar en el criterio clínico del médico (severidad de la crisis y respuesta a la terapia inicial), así como en factores sociales y comportamentales de cada paciente.

Two aspects are basic in the management of an acute episode of asthma: the assessment of its severity and the different steps that should be taken in its treatment. Classification of severity is based on clinical and functional parameters. Asthma symptoms are associated not only with bronchoconstriction but also with inflammation of the respiratory airway. Inhaled β2-agonists have a rapid onset of bronchodilator action that is mainly mediated by a relaxing effect on the airway smooth muscle. Corticosteroids also have rapid clinical effects that can suppress lower airway inflammation. The decision to hospitalize should be based on the physician's clinical criteria (severity of the crisis and response to initial therapy), as well as social and behavioral factors of each patient.