Comprehensive spatial distribution of patients with first-episode psychosis (FEP) and its relation to socio-economic factors.

BACKGROUND: The functional-cognitive impact of first-episode psychosis (FEP) is extremely relevant and implies dysfunction from early life stages like adolescence and youth. Like other illnesses, FEP incidence is also influenced by environmental factors. It is necessary to attend to this age group with early interventions and to act on the environmental factors that the literature correlates with increased FEP incidence: socio-economic aspects, social adversity, bullying at school or cannabis use. In this context, identifying the areas of cities where FEP patients concentrate is important to perform early interventions. The spatial analysis of patient distribution in a whole city is one way to identify the most vulnerable areas and to propose psycho-social interventions for the possible prevention and/or early detection of FEP by improving urban mental health. METHODS: An epidemiological study of point patterns to determine the areas of a city with a higher incidence of patients with FEP. To do so, the addresses of FEP cases were georeferenced from 1 January 2016 to 31 October 2022, and 109 FEP patients were analysed. Data from a random sample of 383 controls, comprising their addresses, age, and sex, were randomly obtained from the official city council database. By GIS, the areas with higher FEP incidence were analysed to see if they coincided with the zones where inhabitants with lower incomes lived. RESULTS: The risk ratio of the FEP patients was compatible with the constant risk ratio in Albacete (p = 0.22). When performing the process separately with cases and controls only in men and women, the results were not significant for both distributions (p value: 0.12 and 0.57, respectively). Nonetheless, areas within the city had a significantly higher risk. These groups of cases coincided with those who had lower income and more inequality for women, but this pattern was not clear for men. CONCLUSIONS: Classifying city areas per income can help to determine the zones at higher risk of FEP, which would allow early healthcare and preventive measures for these zones.

Serum levels of inflammatory cytokines in mercury mining workers in a precarious situation: A preliminary study.

Mercury is a ubiquitous environmental xenobiotic; the primary sources of exposure to this metal are artisanal gold mining and the direct production of mercury. In Mexico, artisanal mercury mining continues to be an important activity in different regions of the country. Exposure to mercury vapors releases can have severe health impacts, including immunotoxic effects such as alterations in cytokine profiling. Therefore, in the present work, we evaluated the inflammatory cytokines profile in the blood serum of miners exposed to mercury. A cross-sectional observational study was performed on 27 mining workers (exposed group) and 20 control subjects (nonexposed group) from central Mexico. The mercury urine concentration (U-Hg) was determined by atomic absorption spectrometry, and IL-2, IL-6, IL-8, IL-10, and TNF-α were measured using a Multiplex Assay. The results showed that the U-Hg in the miners had a median value of 552.70 µg/g creatinine. All cytokines showed a significant increase in the miner group compared with the control group, except for TNF-α. In addition, we observed a positive correlation between U-Hg concentration and cytokine levels. In conclusion, mercury exposure correlated with cytokine levels (considered acute inflammatory marker) in miners; therefore, workers exposed to this metal show an acute systemic inflammation that could lead to alterations in other organs and systems.

Creating Space for Adolescents and Families With Lived Experience of Homelessness to Build Familial Empathy, Communication, and Emotional Regulation: A Qualitative Study of Facilitators of Implementation.

Youth experiencing homelessness are vulnerable to commercial sexual exploitation (CSE). Structural racism disproportionately entraps marginalized youth into CSE while simultaneously obscuring their identification as victims. Adaptation and tailoring of effective interventions to mitigate associated sequelae and inequities is warranted. Support To Reunite, Involve, and Value Each Other (STRIVE) is a strengths-based dyadic intervention with demonstrated efficacy in reducing delinquency, substance use, and high-risk sexual behaviors among marginalized adolescents experiencing homelessness. The adapted STRIVE+ was piloted to explore potential for reducing youth risk factors for CSE. The current article reports findings from interviews exploring participants' experiences with STRIVE+. Youth and caregivers reported increased empathy, communication, and emotional regulation post-STRIVE+ and found relevance and meaning through participating in the adapted intervention. Feasibility of recruitment, engagement, and retention of minoritized adolescents and their caregivers were also demonstrated. Findings warrant larger scale implementation trials of STRIVE+ among minoritized youth at highest risk for CSE. [Journal of Psychosocial Nursing and Mental Health Services, 62(1), 27-35.].

Interstitial lung disease in ANCA-associated vasculitis: associated factors, radiographic features and mortality.

OBJECTIVE: To evaluate the prevalence, clinical and radiographic features, and long-term outcomes of interstitial lung disease (ILD) in a United States-based ANCA-associated vasculitis (AAV) cohort. METHODS: In this retrospective cohort study, we identified cases of ILD within the 2002-2019 Mass General Brigham AAV Cohort, a consecutive inception cohort of PR3- or MPO-ANCA+ AAV patients. ILD diagnosis and classification as fibrotic or non-fibrotic were confirmed by review of available chest imaging by two board-certified radiologists. Cox proportional hazard models, with age as the time scale, were used to estimate the association of AAV-ILD with all-cause mortality. RESULTS: Of 684 patients in the MGB AAV Cohort, 91 (13%) had ILD which preceded the diagnosis of AAV by a mean of 2.2 years. AAV-ILD patients were older (67 vs 60 years, P < 0.001) than patients without ILD but the distribution of sex and race was similar. AAV-ILD patients were more often MPO-ANCA+ (93% vs 65%, P < 0.001); among MPO-ANCA+ patients (n = 470), 85 (18%) had ILD. The majority of ILD was fibrotic (76%) and UIP was the most common ILD pattern (42%). The baseline forced vital capacity (FVC) % predicted among ILD patients was 81 ± 20%. Fibrotic AAV-ILD was associated with a 58% higher risk of death (aHR 1.58, 95% CI 1.06, 2.37) compared with AAV patients without ILD. CONCLUSION: ILD is a frequent complication of AAV, especially MPO-ANCA+ AAV, often preceding recognition of AAV. Fibrotic AAV-ILD is associated with a higher risk of death than AAV without ILD.

A short form of the Crisis in Family Systems (CRISYS) in a racially diverse sample of pregnant women.

Assessing stressful life events in large-scale epidemiologic studies is challenged by the need to measure potential stressful events in a reasonably comprehensible manner balanced with burden on participants and research staff. The aim of this paper was to create a short form of the Crisis in Family Systems-Revised (CRISYS-R) plus 17 acculturation items, a measure that captures contemporary life stressors across 11 domains. Latent class analysis (LCA) was used to segment the sample of 884 women from the PRogramming of Intergenerational Stress Mechanisms (PRISM) study experiencing different patterns of exposure to stressful events and identify items from each domain that best discriminate between individuals with different patterns of stressful-event exposures (high vs. low stress exposure). The results from the LCA, in conjunction with the expert opinions provided by the original developers of the CRISYS, yielded a 24-item item short form (CRISYS-SF) with at least one question from each of the original domains. Scores on the 24-item CRISYS-SF had high correlations with scores on the 80-item CRISYS. Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-021-02335-w.

High-Resolution Computed Tomography of Fibrotic Interstitial Lung Disease.

While radiography is the first-line imaging technique for evaluation of pulmonary disease, high-resolution computed tomography (HRCT) provides detailed assessment of the lung parenchyma and interstitium, allowing normal anatomy to be differentiated from superimposed abnormal findings. The fibrotic interstitial lung diseases have HRCT features that include reticulation, traction bronchiectasis and bronchiolectasis, honeycombing, architectural distortion, and volume loss. The characterization and distribution of these features result in distinctive CT patterns. The CT pattern and its progression over time can be combined with clinical, serologic, and pathologic data during multidisciplinary discussion to establish a clinical diagnosis. Serial examinations identify progression, treatment response, complications, and can assist in determining prognosis. This article will describe the technique used to perform HRCT, the normal and abnormal appearance of the lung on HRCT, and the CT patterns identified in common fibrotic lung diseases.

Profile of urinary exosomal microRNAs and their contribution to diabetic kidney disease through a predictive classification model.

AIM: Evaluate the expression of exomiRs-126, -146, and -155 in urinary exosomes of patients with T2DM and diabetic kidney disease to establish a predictive classification model with exomiRs and clinical variables in order to determine their contribution to DKD. METHODS: The study group included 92 subjects: 64 patients diagnosed with T2DM subclassified into two groups with albuminuria (T2DM with albuminuria, n = 30) and without albuminuria (TD2M, n = 34) as well as 28 healthy, non-diabetic participants. Exosomes were isolated from urine and identified by TEM and flow cytometry. Profile expression of exomiRs-126, -146 and -155 was evaluated by RT-qPCR. Data were analysed by permutational multivariate analysis of variance (PERMANOVA), similarity percentage (SIMPER), principal coordinate analysis (PCO), and canonical analysis of principal coordinates (CAP). RESULTS: T2DM patients with and without albuminuria showed higher levels of miR-155 and miR-146 compared with controls. In addition, T2DM patients with albuminuria presented a significant increase in miR-126 contrasted to controls and patients without albuminuria. PCO analysis explained 34.6% of the total variability of the data (PERMANOVA; p < .0001). Subsequently, SIMPER analysis showed that miR-146, miR-155, and miR-126 together, with some clinical parameters, contributed to 50% of the between-group significance. Finally, the CAP analysis developed showed a correct classification of 89.01% with the analysed parameters. CONCLUSION: A platform using a combination of clinical variables and exomiRs could be used to classify individuals with T2D as risk for developing DKD.

Bacillus Calmette-Guérin-Induced Human Mast Cell Activation Relies on IL-33 Priming.

Bacillus Calmette-Guérin (BCG) vaccine is an attenuated strain of Mycobacterium bovis that provides weak protection against tuberculosis (TB). Mast cells (MCs) are tissue-resident immune cells strategically that serve as the first line of defence against pathogenic threats. In this study, we investigated the response of human MCs (hMCs) to BCG. We found that naïve hMCs exposed to BCG did not secrete cytokines, degranulate, or support the uptake and intracellular growth of bacteria. Since we could show that in hMCs IL-33 promotes the transcription of host-pathogen interaction, cell adhesion and activation genes, we used IL-33 for cell priming. The treatment of hMCs with IL-33, but not IFN-γ, before BCG stimulation increased IL-8, MCP-1 and IL-13 secretion, and induced an enhanced expression of the mycobacteria-binding receptor CD48. These effects were comparable to those caused by the recombinant Mycobacterium tuberculosis (Mtb) 19-KDa lipoprotein. Finally, stimulation of hMCs with IL-33 incremented MC-BCG interactions. Thus, we propose that IL-33 may improve the immunogenicity of BCG vaccine by sensitising hMCs.

In silico discovery and biological validation of ligands of FAD synthase, a promising new antimicrobial target.

New treatments for diseases caused by antimicrobial-resistant microorganisms can be developed by identifying unexplored therapeutic targets and by designing efficient drug screening protocols. In this study, we have screened a library of compounds to find ligands for the flavin-adenine dinucleotide synthase (FADS) -a potential target for drug design against tuberculosis and pneumonia- by implementing a new and efficient virtual screening protocol. The protocol has been developed for the in silico search of ligands of unexplored therapeutic targets, for which limited information about ligands or ligand-receptor structures is available. It implements an integrative funnel-like strategy with filtering layers that increase in computational accuracy. The protocol starts with a pharmacophore-based virtual screening strategy that uses ligand-free receptor conformations from molecular dynamics (MD) simulations. Then, it performs a molecular docking stage using several docking programs and an exponential consensus ranking strategy. The last filter, samples the conformations of compounds bound to the target using MD simulations. The MD conformations are scored using several traditional scoring functions in combination with a newly-proposed score that takes into account the fluctuations of the molecule with a Morse-based potential. The protocol was optimized and validated using a compound library with known ligands of the Corynebacterium ammoniagenes FADS. Then, it was used to find new FADS ligands from a compound library of 14,000 molecules. A small set of 17 in silico filtered molecules were tested experimentally. We identified five inhibitors of the activity of the flavin adenylyl transferase module of the FADS, and some of them were able to inhibit growth of three bacterial species: C. ammoniagenes, Mycobacterium tuberculosis, and Streptococcus pneumoniae, where the last two are human pathogens. Overall, the results show that the integrative VS protocol is a cost-effective solution for the discovery of ligands of unexplored therapeutic targets.

Flexi-pharma: a molecule-ranking strategy for virtual screening using pharmacophores from ligand-free conformational ensembles.

Computer-aided strategies are useful for reducing the costs and increasing the success-rate in drug discovery. Among these strategies, methods based on pharmacophores (an ensemble of electronic and steric features representing the target active site) are efficient to implement over large compound libraries. However, traditional pharmacophore-based methods require knowledge of active compounds or ligand-receptor structures, and only few ones account for target flexibility. Here, we developed a pharmacophore-based virtual screening protocol, Flexi-pharma, that overcomes these limitations. The protocol uses molecular dynamics (MD) simulations to explore receptor flexibility, and performs a pharmacophore-based virtual screening over a set of MD conformations without requiring prior knowledge about known ligands or ligand-receptor structures for building the pharmacophores. The results from the different receptor conformations are combined using a "voting" approach, where a vote is given to each molecule that matches at least one pharmacophore from each MD conformation. Contrarily to other approaches that reduce the pharmacophore ensemble to some representative models and score according to the matching models or molecule conformers, the Flexi-pharma approach takes directly into account the receptor flexibility by scoring in regards to the receptor conformations. We tested the method over twenty systems, finding an enrichment of the dataset for 19 of them. Flexi-pharma is computationally efficient allowing for the screening of thousands of compounds in minutes on a single CPU core. Moreover, the ranking of molecules by vote is a general strategy that can be applied with any pharmacophore-filtering program.

Identification of metabolic markers in patients with type 2 Diabetes by Ultrafast gas chromatography coupled to electronic nose. A pilot study.

Metabolomics is a potential tool for the discovery of new biomarkers in the early diagnosis of diseases. An ultra-fast gas chromatography system equipped to an electronic nose detector (FGC eNose) was used to identify the metabolomic profile of Volatile Organic Compounds (VOCs) in type 2 diabetes (T2D) urine from Mexican population. A cross-sectional, comparative, and clinical study with translational approach was performed. We recruited twenty T2D patients and twenty-one healthy subjects. Urine samples were taken and analyzed by FGC eNose. Eighty-eight compounds were identified through Kovats's indexes. A natural variation of 30% between the metabolites, expressed by study groups, was observed in Principal Component 1 and 2 with a significant difference (p < 0.001). The model, performed through a Canonical Analysis of Principal coordinated (CAP), allowed a correct classification of 84.6% between healthy and T2D patients, with a 15.4% error. The metabolites 2-propenal, 2-propanol, butane- 2,3-dione and 2-methylpropanal, were increased in patients with T2D, and they were strongly correlated with discrimination between clinically healthy people and T2D patients. This study identified metabolites in urine through FGC eNose that can be used as biomarkers in the identification of T2D patients. However, more studies are needed for its implementation in clinical practice.

Comparison of Psychological and Physiological Responses to Imposed vs. Self-selected High-Intensity Interval Training.

Kellogg, E, Cantacessi, C, McNamer, O, Holmes, H, von Bargen, R, Ramirez, R, Gallagher, D, Vargas, S, Santia, B, Rodriguez, K, and Astorino, TA. Comparison of psychological and physiological responses to imposed vs. self-selected high-intensity interval training. J Strength Cond Res 33(11): 2945-2952, 2019-High-intensity interval training elicits similar physiological adaptations as moderate intensity continuous training (MICT). Some studies report greater enjoyment to a bout of high-intensity interval exercise (HIIE) vs. MICT, which is surprising considering that HIIE is more intense and typically imposed on the participant. This study compared physiological and perceptual responses between imposed and self-selected HIIE. Fourteen adults (age = 24 ± 3 years) unfamiliar with HIIE initially performed ramp exercise to exhaustion to measure maximal oxygen uptake (VO2max) followed by 2 subsequent sessions whose order was randomized. Imposed HIIE consisted of eight 60 seconds bouts at 80 percent peak power output (%PPO) separated by 60 seconds recovery at 10 %PPO. Self-selected HIIE (HIIESS) followed the same structure, but participants freely selected intensity in increments of 10 %PPO to achieve a rating of perceived exertion (RPE) ≥7. During exercise, heart rate, VO2, blood lactate concentration (BLa), affect (+5 to -5), and RPE were assessed. Physical Activity Enjoyment Scale was measured after exercise. Results showed higher VO2 (+10%, p = 0.013), BLa (p = 0.001), and RPE (p = 0.001) in HIIESS vs. HIIEIMP, and lower affect (p = 0.01), and enjoyment (87.6 ± 15.7 vs. 95.7 ± 11.7, p = 0.04). There was a significantly higher power output in self-selected vs. imposed HIIE (263.9 ± 81.4 W vs. 225.2 ± 59.6 W, p < 0.001). Data suggest that intensity mediates affective responses rather than the mode of HIIE performed by the participant.

Coronary Plaque Burden at Coronary CT Angiography in Asymptomatic Men and Women.

Purpose To assess the relationship between total, calcified, and noncalcified coronary plaque burdens throughout the entire coronary vasculature at coronary computed tomographic (CT) angiography in relationship to cardiovascular risk factors in asymptomatic individuals with low-to-moderate risk. Materials and Methods This HIPAA-compliant study had institutional review board approval, and written informed consent was obtained. Two hundred two subjects were recruited to an ongoing prospective study designed to evaluate the effect of HMG-CoA reductase inhibitors on atherosclerosis. Eligible subjects were asymptomatic individuals older than 55 years who were eligible for statin therapy. Coronary CT angiography was performed by using a 320-detector row scanner. Coronary wall thickness and plaque were evaluated in all epicardial coronary arteries greater than 2 mm in diameter. Images were analyzed by using dedicated software involving an adaptive lumen attenuation algorithm. Total plaque index (calcified plus noncalcified plaque) was defined as plaque volume divided by vessel length. Multivariable regression analysis was performed to determine the relationship between risk factors and plaque indexes. Results The mean age of the subjects was 65.5 years ± 6.9 (standard deviation) (36% women), and the median coronary artery calcium (CAC) score was 73 (interquartile range, 1-434). The total coronary plaque index was higher in men than in women (42.06 mm(2) ± 9.22 vs 34.33 mm(2) ± 8.35; P < .001). In multivariable analysis controlling for all risk factors, total plaque index remained higher in men than in women (by 5.01 mm(2); P = .03) and in those with higher simvastatin doses (by 0.44 mm(2)/10 mg simvastatin dose equivalent; P = .02). Noncalcified plaque index was positively correlated with systolic blood pressure (ß = 0.80 mm(2)/10 mm Hg; P = .03), diabetes (ß = 4.47 mm(2); P = .03), and low-density lipoprotein (LDL) cholesterol level (ß = 0.04 mm(2)/mg/dL; P = .02); the association with LDL cholesterol level remained significant (P = .02) after additional adjustment for the CAC score. Conclusion LDL cholesterol level, systolic blood pressure, and diabetes were associated with noncalcified plaque burden at coronary CT angiography in asymptomatic individuals with low-to-moderate risk. (©) RSNA, 2015 Online supplemental material is available for this article.

Coronary artery plaque volume and obesity in patients with diabetes: the factor-64 study.

PURPOSE: To determine the relationship between coronary plaque detected with coronary computed tomographic (CT) angiography and clinical parameters and cardiovascular risk factors in asymptomatic patients with diabetes. MATERIALS AND METHODS: All patients signed institutional review board-approved informed consent forms before enrollment. Two hundred twenty-four asymptomatic diabetic patients (121 men; mean patient age, 61.8 years; mean duration of diabetes, 10.4 years) underwent coronary CT angiography. Total coronary artery wall volume in all three vessels was measured by using semiautomated software. The coronary plaque volume index (PVI) was determined by dividing the wall volume by the coronary length. The relationship between the PVI and cardiovascular risk factors was determined with multivariable analysis. RESULTS: The mean PVI (±standard deviation) was 11.2 mm(2) ± 2.7. The mean coronary artery calcium (CAC) score (determined with the Agatston method) was 382; 67% of total plaque was noncalcified. The PVI was related to age (standardized ß = 0.32, P < .001), male sex (standardized ß = 0.36, P < .001), body mass index (BMI) (standardized ß = 0.26, P < .001), and duration of diabetes (standardized ß = 0.14, P = .03). A greater percentage of soft plaque was present in younger individuals with a shorter disease duration (P = .02). The soft plaque percentage was directly related to BMI (P = .002). Patients with discrepancies between CAC score and PVI rank quartiles had a higher percentage of soft and fibrous plaque (18.7% ± 3.3 vs 17.4% ± 3.5 [P = .008] and 52.2% ± 7.2 vs 47.2% ± 8.8 [P < .0001], respectively). CONCLUSION: In asymptomatic diabetic patients, BMI was the primary modifiable risk factor that was associated with total and soft coronary plaque as assessed with coronary CT angiography.

Role of PTEN in basal cell derived lung carcinogenesis.

Lung adenocarcinoma (AdC) and lung squamous cell carcinoma (SCC) are the most common non-small cell lung cancer (NSCLC) subtypes, however, most genetic mouse models of lung cancer produce predominantly, if not exclusively, AdC. Whether this is secondary to targeting mutations to the distal airway cells or to the use of activating Kras mutations that drive AdC formation is unknown. We previously showed that targeting Kras(G12D) activation and transforming growth factor ß receptor type II (TGFßRII) deletion to airway basal cells via a keratin promoter induced formation of both lung AdC and SCC. In this study we assessed if targeting phosphatase and tensin homologue (PTEN) deletion to airway basal cells could initiate lung tumor formation or increase lung SCC formation. We found that PTEN deletion is capable of initiating both lung AdC and SCC formation when targeted to basal cells and although PTEN deletion is a weaker tumor initiator than Kras(G12D) with low tumor multiplicity and long latency, tumors initiated by PTEN deletion were larger and displayed more malignant conversion than Kras(G12D) initiated tumors. That PTEN deletion did not increase lung SCC formation compared to Kras(G12D) activation, suggests that the initiating genetic event does not dictate tumor histology when genetic alterations are targeted to a specific cell. These studies also confirm that basal cells of the conducting airway are capable of giving rise to multiple NSCLC tumor types.

Imaging of Small Airways Disease.

Bronchiolitis refers to a small airways disease and may be classified by etiology and histologic features. In cellular bronchiolitis inflammatory cells involve the small airway wall and peribronchiolar alveoli and manifest on CT as centrilobular nodules of solid or ground glass attenuation. Constrictive bronchiolitis refers to luminal narrowing by concentric fibrosis. Direct CT signs of small airway disease include centrilobular nodules and branching tree-in-bud opacities. An indirect sign is mosaic attenuation that may be exaggerated on expiratory CT and represent air trapping. Imaging findings can be combined with clinical and pathologic data to facilitate a more accurate diagnosis.

Amino acid degradation pathway inhibitory by-products trigger apoptosis in CHO cells.

Chinese hamster ovary (CHO) cells are widely used to produce complex biopharmaceuticals. Improving their productivity is necessary to fulfill the growing demand for such products. One way to enhance productivity is by cultivating cells at high densities, but inhibitory by-products, such as metabolite derivatives from amino acid degradation, can hinder achieving high cell densities. This research examines the impact of these inhibitory by-products on high-density cultures. We cultured X1 and X2 CHO cell lines in a small-scale semi-perfusion system and introduced a mix of inhibitory by-products on day 10. The X1 and X2 cell lines were chosen for their varied responses to the by-products; X2 was susceptible, while X1 survived. Proteomics revealed that the X2 cell line presented changes in the proteins linked to apoptosis regulation, cell building block synthesis, cell growth, DNA repair, and energy metabolism. We later used the AB cell line, an apoptosis-resistant cell line, to validate the results. AB behaved similar to X1 under stress. We confirmed the activation of apoptosis in X2 using a caspase assay. This research provides insights into the mechanisms of cell death triggered by inhibitory by-products and can guide the optimization of CHO cell culture for biopharmaceutical manufacturing.