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Summary: Metabolic syndrome (MetS) is a collection of cardiovascular risk factors; however, the high prevalence and heterogeneity impede effective clinical management. We conducted unsupervised clustering on individuals from UK Biobank to reveal endotypes. Five MetS subgroups were identified: Cluster 1 (C1): non-descriptive, Cluster 2 (C2): hypertensive, Cluster 3 (C3): obese, Cluster 4 (C4): lipodystrophy-like, and Cluster 5 (C5): hyperglycemic. For all of the endotypes, we identified the corresponding cardiometabolic traits and their associations with clinical outcomes. Genome-wide association studies (GWASs) were conducted to identify associated genotypic traits. We then determined endotype-specific genotypic traits and constructed polygenic risk score (PRS) models specific to each endotype. GWAS of each MetS clusters revealed different genotypic traits. C1 GWAS revealed novel findings of TRIM63, MYBPC3, MYLPF, and RAPSN. Intriguingly, C1, C3, and C4 were associated with genes highly expressed in brain tissues. MetS clusters with comparable phenotypic and genotypic traits were identified in Taiwan Biobank.

A phenome-wide association study and polygenic risk score analysis identifies several loci linked to metabolic disease and type 2 diabetes in the Taiwanese population.

Background: The Dysfunctional Voiding Score Symptoms (DVSS) questionnaire is commonly used to evaluate dysfunctional voiding and incontinence (DVI)., Objectives: To translate and culturally adapt the DVSS questionnaire into Spanish (DVSS-Sp) in pediatric population and to assess its psychometric properties., Methods: The process of translation and cultural validation were done. To obtain evidence of validity and reliability, we evaluated the fit of different factor models and calculated internal consistency coefficients. Also, the diagnostic capacity of the DVSS-Sp scale was assessed through a logistic regression analysis and a receiver operating characteristic (ROC) curve. Accordingly, a total sample of 248 participants was recruited (204 with a diagnosis of DVIs and 44 with no medical problems)., Results: The cross-cultural adaptation showed an adequate correspondence with the original version. The DVSS-Sp was configured with 2 factors: Overactive Bladder (OB) symptoms (items 1, 2, 6, and 7) and Dysfunctional Elimination (DE) symptoms (items 3, 4, 8, and 9), showing excellent goodness-of-fit indices. The relationship between the factors OB and DE was low. The reliability of the OB factor was α = 0.68, ω = 0.71, and the DE factor was α = 0.56, ω = 0.57. A logistic regression analysis suggests a good diagnostic capacity of the DVSS-Sp scale. Additionally, ROC analysis showed a cut-off score of 3.5 on the DVSS-Sp scale, where the specificity was 0.907, and the sensitivity was 0.636., Conclusion: The results of this study support the use of the DVSS-Sp for assessing DVIs in Spanish-speaking children., Competing Interests: Declaration of competing interest The authors declare no competing interest., (Copyright © 2024 Associação Brasileira de Pesquisa e Pós-Graduação em Fisioterapia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: The purpose of this study was to evaluate the effectiveness of collaborative trauma-informed care (CTIC) for treating depression in primary care in Chile., Methods: From August 2021 through June 2023, 16 primary care teams in the Maule Region of Chile, were randomly assigned to either the CTIC or usual treatment (UT) group. At baseline, 3 months, and 6 months, 115 patients in the CTIC group, and 99 in the UT group, were blindly evaluated. The primary outcome was reduction in depressive symptoms. Secondary outcomes included improvement in anxiety symptoms, interpersonal and social functioning, emotional regulation, and adherence. Intention-to-treat data analysis, using analysis of covariance was conducted., Results: There were 214 patients recruited; 85% were women, and 61% had 4 or more adverse childhood experiences. At 6 months, depressive symptoms declined significantly in the CTIC arm relative to UT (adjusted mean difference [AMD]= -3.09, 95% CI, -4.94 to -1.23; d = -0.46, 95% CI,-0.73 to -0.18; P = .001). Anxiety symptoms exhibited a trend toward improvement in the CTIC vs UT group (AMD = -1.50, 95% CI, -3.03 to 0.31; P = .055). No significant differences were observed in other secondary outcomes, except for adherence, which was significantly higher in the CTIC vs UT groups (AMD = 2.59, 95% CI, 1.80-4.99; P = .035)., Conclusions: The CTIC approach demonstrated superior outcomes in treating depression and improving adherence compared with UT. Moreover, the observed trends in anxiety improvement warrant further exploration in future research with a larger sample size. It is necessary to assess the effectiveness of this approach in treating more complex, difficult-to-treat forms of depression., (© 2024 Annals of Family Medicine, Inc.)

Background: Understanding the characteristics of the Covid-19 pandemic in different geographical regions, ethnic and socioeconomic settings are of emerging importance. This study presents the demographic and clinical features of SARS-CoV-2 infected patients in a large private healthcare center in Santiago, Chile, during the first month of the pandemic., Methods: We analyzed the demographics, laboratory and clinical characteristics including severity and outcome of all patients diagnosed with Covid-19 during the first month of the pandemic. SARS-2-CoV infection was confirmed by RT-PCR in nosopharyngeal samples. The primary outcome was a composite of ICU admission or all-cause, in-hospital mortality. Clinical and laboratory parameters of hospitalized patients were analyzed regarding their association with the primary outcome., Results: From March 3 to April 4, 2020, 3679 individuals were tested for SARS-CoV-2 in our hospital. Of those, 381 had Covid-19 and were included into this analysis. Most patients (99.2%) were Chileans, 12% returning from recent travel. The median age was 39 years (IQR 31-49) and 52% were female. A total of 88 patients (23.1%) were hospitalized; 18 (3.7%) required ICU and/or died. The overall mortality was 0.7%. Increased body mass index (BMI) and elevated C-reactive protein (CRP) were independently associated with ICU care or death., Conclusion: During the first weeks of the pandemic in Chile, most Covid-19 patients were young, with low rates of hospitalization, ICU requirement, and fatality. BMI and CRP on admission were predictors for severity. Our data provide important information on the clinical course and outcome of Covid-19 in a Latin American setting.

Introduction/objectives: An interleukin-6 inhibition strategy could be effective in selected COVID-19 patients. The objective is to present our experience of tocilizumab use in patients with severe COVID-19. Methods: Observational retrospective cohort study. Hospitalized patients were evaluated by our multidisciplinary team for eventual use of tocilizumab. Patients with progressive ventilatory impairment and evidence of a hyperinflammatory state despite usual treatment received tocilizumab 8 mg/kg intravenous (maximum dose 800 mg), in addition to standard treatment. The use and time of use of mechanical ventilation (MV), the change of the Alveolar-arterial (A-a) gradient, of the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO 2 /FiO 2 ) and of inflammation laboratory parameters after 72 h of tocilizumab use was evaluated. Results: 29 patients received tocilizumab. 93.1% were men, 37.9% were obese, and 34.5% had hypertension. Of the 20 patients who were not on MV when receiving tocilizumab, 11 required non-invasive MV, for an average of 5 days, and one of them required intubation. A-a gradient, PaO 2 /FiO 2 , and inflammation parameters improved significantly. A better lymphocyte count, which improved significantly after tocilizumab use, was significantly associated with less use of MV. Five patients presented positive culture samples after tocilizumab, three being of clinical significance. A lower lymphocyte count was associated with having a positive culture. No other significant adverse events were seen. Conclusion: Our study suggests the utility and shows the safety of tocilizumab use in COVID-19 patients who have respiratory failure and evidence of hyperinflammation. Lymphocyte improvement was a predictor of good response., (Copyright © 2020 Valenzuela, Ibáñez, Poli, Roessler, Aylwin, Roizen, Iruretagoyena, Agar, Donoso, Fierro and Montes.)

Background: Scrub typhus is a neglected vector-borne zoonosis causing life-threatening illnesses, endemic in the Asian-Pacific region and, as recently discovered, in southern Chile. Scrub typhus is rarely reported in travelers, most probably due to the lack of clinical experience and diagnostic tests in non-endemic countries. We report the first case of imported scrub typhus in South America., Case Presentation: A 62-year-old tourist from South Korea presented severely ill with fever, rash, and eschar in Santiago, Chile. Laboratory exams showed thrombocytopenia and elevated inflammation parameters, hepatic enzymes, and LDH. With the clinical suspicion of scrub typhus, empirical treatment with doxycycline was initiated and the patient recovered rapidly and without complications. The diagnosis was confirmed by IgM serology and by real-time PCR, which demonstrated infection with Orientia tsutsugamushi (Kawasaki clade)., Conclusions: Only due to the emerging clinical experience with endemic South American scrub typhus and the recent implementation of appropriate diagnostic techniques in Chile, were we able to firstly identify and adequately manage a severe case of imported scrub typhus in South America. Physicians attending febrile travelers need to be aware of this rickettsiosis, since it requires prompt treatment with doxycycline to avoid complications., Competing Interests: Ethics approval for this case report was not sought as there was no human subjects study in which to participate. The patient consented that his personal and clinical information was used for scientific and teaching reasons.The patient consented that information regarding his case was presented in this manuscript.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Cachexia is a wasting condition that manifests in several types of cancer, and the main characteristic is the profound loss of muscle mass., Methods: The Yoshida AH-130 tumor model has been used and the samples have been analyzed using transmission electronic microscopy, real-time PCR and Western blot techniques., Results: Using in vivo cancer cachectic model in rats, here we show that skeletal muscle loss is accompanied by fiber morphologic alterations such as mitochondrial disruption, dilatation of sarcoplasmic reticulum and apoptotic nuclei. Analyzing the expression of some factors related to proteolytic and thermogenic processes, we observed in tumor-bearing animals an increased expression of genes involved in proteolysis such as ubiquitin ligases Muscle Ring Finger 1 (MuRF-1) and Muscle Atrophy F-box protein (MAFBx). Moreover, an overexpression of both sarco/endoplasmic Ca(2+)-ATPase (SERCA1) and adenine nucleotide translocator (ANT1), both factors related to cellular energetic efficiency, was observed. Tumor burden also leads to a marked decreased in muscle ATP content., Conclusions: In addition to muscle proteolysis, other ATP-related pathways may have a key role in muscle wasting, both directly by increasing energetic inefficiency, and indirectly, by affecting the sarcoplasmic reticulum-mitochondrial assembly that is essential for muscle function and homeostasis., General Significance: The present study reports profound morphological changes in cancer cachectic muscle, which are visualized mainly in alterations in sarcoplasmic reticulum and mitochondria. These alterations are linked to pathways that can account for energy inefficiency associated with cancer cachexia.

Neuronal discharge and local field potential (LFP) oscillations in the olfactory bulb (OB) are modulated by odorant stimulation. The LFP oscillations have been proposed as the mechanism that facilitates synchronization of OB output neurons and the representation of similar odorants. Gamma LFP oscillations depend on the OB inhibitory network and early sensory deprivation modifies this inhibitory network. However, little is known about the LFP oscillations and neuronal discharge in the deprived OB. We examined the mitral/tufted (MT) cells' oscillatory activity and LFP oscillations in both sensory-deprived and normal OBs in urethane anesthetized rats. We found that MT cells in deprived and normal OBs have similar basal mean firing rate; 44% of the recorded cells in deprived OB and only 8% of the cells in normal OB showed firing rate modulation by odorants, both exhibiting a similar ratio of excitatory to inhibitory responses. A fraction of MT cells exhibited oscillatory discharge centered on gamma (60-70 Hz) and beta (20 Hz) frequencies, although this feature was not consistently dependent on odorant stimulation. Odorants decreased the LFP oscillatory power in the gamma band (35-90 Hz) and increased the power in the beta band (12-30 Hz). The modulation of LFP oscillations by odorants was also predominant in the deprived (53%) compared to the normal OB (17%). In contrast, a higher fraction of MT cells' discharge was locked to the gamma LFP cycle in the normal OB. These results suggest that early unilateral olfactory deprivation increases the OB sensitivity to odorants and reduce the temporal synchrony between unitary activity and gamma LFP oscillations without altering the basal neuronal discharge.

Olfactory perception initiates in the nasal epithelium wherefrom olfactory receptor neurons--expressing the same receptor protein--project and converge in two different glomeruli within each olfactory bulb. Recent evidence suggests that glomeruli are isolated functional units, arranged in a chemotopic manner in the olfactory bulb. Exposure to odorants leads to the activation of specific populations of glomeruli. In rodents, about 25-50 mitral/tufted cells project their primary dendrites to a single glomerulus receiving similar sensory input. Yet, little is known about the properties of neighboring mitral/tufted cells connected to one or a few neighboring glomeruli. We used tetrodes to simultaneously record multiple single-unit activity in the mitral cell layer of anesthetized, freely breathing rats while exposed to mixtures of chemically related compounds. First, we characterized the odorant-induced modifications in firing rate of neighboring mitral/tufted cells and found that they do not share odorant response profiles. Individual units showed a long silent (11.01 ms) period with no oscillatory activity. Cross-correlation analysis between neighboring mitral/tufted cells revealed negligible synchronous activity among them. Finally, we show that respiratory-related temporal patterns are dissimilar among neighboring mitral/tufted cells and also that odorant stimulation results in an individual modification that is not necessarily shared by neighboring mitral/tufted cells. These results show that neighboring mitral/tufted cells frequently exhibit dissimilar response properties, which are not consistent with a precise chemotopic map at the mitral/tufted cell layer in the olfactory bulb.

Area postrema (AP) modulates cardiovascular function through excitatory projections to neurons in nucleus tractus solitarius (NTS), which also process primary sensory (including cardiovascular-related) input via the solitary tract (TS). The neurotransmitter(s) and their receptors in the AP-NTS pathway have not been fully characterized. We used whole cell recordings in voltage- and current-clamp modes in the rat brain stem slice to examine the role of ionotropic glutamatergic receptors and alpha2-adrenergic receptors in the pathway from AP to NTS neurons receiving visceral afferent information via the TS. In neurons voltage clamped at potentials from -100 to +80 mV, AP stimulation (0. 2 Hz) evoked excitatory postsynaptic currents having a fast component blocked by the non-N-methyl-D-aspartate (NMDA) receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2, 3-dioxobenzoquinoxaline-7-sulfonamide (NBQX; 3 microM, n = 7) and a slow component blocked by the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV; 50 microM, n = 8). Although NBQX (3 microM, n = 14) abolished AP-evoked action potentials, APV (50 microM, n = 9 or 500 microM, n = 6) or yohimbine, (200 nM, n = 5 or 2 microM, n = 10) did not. Thus, although AP stimulation activates both non-NMDA and NMDA receptors on NTS neurons receiving TS input, only non-NMDA receptors are required for synaptic transmission.

The nucleus of the solitary tract (NTS) is a principal site for coordinating the reflex control of autonomic function. The nucleus receives and organizes primary visceral (sensory) afferent inputs from the great vessels, heart, lung, and gastrointestinal organs. Glutamate, the excitatory neurotransmitter released by the primary afferent fibers, activates non-N-methyl-D-aspartate (non-NMDA) receptors on second-order neurons in the NTS. Still in question is whether NMDA receptors on the second-order neurons are also activated. Accordingly, the purpose of this study was to directly determine whether NMDA receptors contribute to synaptic transmission of primary visceral afferent input to second-order neurons in the NTS. Whole cell patch-clamp recordings were obtained from intermediate and caudal NTS neurons in rat coronal medullary slices. Excitatory postsynaptic currents (EPSCs) were evoked by stimulation of the solitary tract (1-25 V, 0.1 ms, 0.2 or 0.5 Hz) at membrane potentials ranging from -90 to +60 mV. In 28 of 32 neurons in which current-voltage relationships were obtained for solitary-tract-evoked EPSCs, the currents had short onset latencies (3.42 +/- 1.03 ms, mean +/- SD), indicating that they were the result of monosynaptic activation of second-order neurons. Solitary-tract-evoked EPSCs had both a fast and a slow component. The amplitude of the slow component was nonlinearly related to voltage (being revealed only at membrane potentials positive to -45 mV), blocked by the NMDA receptor antagonist DL-2-amino-5-monophosphovaleric acid (APV, 50 microM; n = 12; P = 0.0001), and enhanced in nominally Mg2+-free perfusate at membrane potentials negative to -45 mV (n = 5; P = 0.016), demonstrating that the slow component was mediated by NMDA receptors. The amplitude of the fast component was linearly related to voltage and blocked by the non-NMDA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX, 3 microM; n = 9; P = 0.0014), demonstrating that the fast component was mediated by non-NMDA receptors. The slow component of the EPSCs was not blocked by NBQX (n = 6; P = 0.134), nor was the fast component blocked by APV (n = 12; P = 0.124). These results show that both NMDA and non-NMDA receptors coexist on the same second-order NTS neurons and mediate primary visceral afferent transmission in the NTS. The participation of NMDA receptors suggests that second-order neurons in the NTS may have previously unrecognized integrative capabilities in the reflex control of autonomic function.

Affinity labeling studies have identified several conserved tyrosine residues in the alpha subunit of the nicotinic acetylcholine receptor (alpha Y93, alpha Y190, and alpha Y198) as being in or near the ligand binding site. Mutagenesis studies from several laboratories have shown that substitution of phenylalanine for tyrosine at these positions reduces the apparent affinity for ACh. We have examined this apparent reduction in affinity further through the use of multiple substitutions at each position. Substitution of either phenylalanine, tryptophan, or serine resulted in an apparent decrease in agonist affinity, but the degree of reduction depended on both the position and the nature of the substitution. Analysis of the effects of each substitution suggests that each residue interacts with the quaternary N of ACh, and that each residue may make a different type of interaction with the agonist.