Genomic and phylogenomic characterization of carbapenem-resistant Pseudomonas aeruginosa 'high-risk' clone O4/ExoS+/ST654 circulating in Chilean hospitals.

INTRODUCTION: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a serious threat to public health. Globally, carbapenemases-producing CRPA isolates mainly belong to 'high-risk' clones; however, the molecular epidemiology of CRPA isolates circulating in Chile are scarce, where this pathogen is the main aetiological agent of ventilator-associated pneumonia. OBJECTIVES: To characterize the phylogenomics and molecular features of ST654 CRPA isolates collected in Chile between 2016 - 2022. METHODS: 89 CRPA isolates collected in different Chilean hospitals from clinical specimens between 2005 and 2022 were analyzed. Antibiotic susceptibility tests and carbapenemases production were carried out on the CRPA ST654 isolates. Also, they were subjected to whole-genome sequencing (WGS) from which in silico analyses were performed. RESULTS: Thirty-four strains (38.2%) belonged to the ST654 'high risk' clone, being the most predominant lineage of the collection. Most of these isolates belonged to a sub-clade including KPC-producers that also clustered with strains from Argentina and the USA, whereas few VIM and NDM co-producers clustered in two different smaller sub-clades. The isolates exhibited a broad resistome encompassing genes mediating resistance to several other clinically relevant drugs. Additionally, all the 34 ST654 isolates were ExoS+ as a virulence factor and associated to the O4-serotype. CONCLUSIONS: Our report represents the most comprehensive phylogenomic study of CRPA 'high risk' clone ST654 to date. Our analyses suggest that this lineage is undergoing a divergent evolutionary path in Chile, since most of the isolates were KPC-producers and were O4-serotype, differing from previous descriptions, which underline the relevance of performing molecular surveillance on this pathogen.

Nonylphenol releases arachidonic acid in rat Sertoli cells via activation of PKA and PLA2.

In brief: The endocrine disruptor, nonylphenol (NP) increases 20:4n-6 release in Sertoli cells via PKA/cPLA2 activation. Our data show that lipid metabolism could be a target of NP-induced abnormal reproductive outcomes. Abstract: Nonylphenol (NP), an endocrine-disrupting chemical, is an environmental contaminant, and many notorious effects on male fertility have been reported in animal models and wild-type species. Here, we evaluated the effects of NP in follicle-stimulating hormone (FSH) signal transduction pathways and lipid metabolism using an in vitro model of rat Sertoli cell (SC) primary culture. Results show that an acute (1 h) SC exposure to NP (10 µM) increased the intra- and extra-cellular concentrations of free fatty acids (FFAs), mainly arachidonic acid (20:4n-6). Phosphatidylinositol seemed to be the major phospholipid source of this 20:4n-6 release by activation of the protein kinase A (PKA)/cytoplasmic phospholipase A2 (cPLA2) pathway. NP also increased diacylglycerols (DAG) levels and the expression (mRNA) of cyclooxygenase 2 (Cox2) and prostaglandin E2 (PGE2) levels. It is noteworthy that accumulation of lipid droplets took place after 24 h NP exposition, which was prevented by both a PKA inhibitor and a PLA2 inhibitor. Like FSH, NP triggers the release of 20:4n-6, which is a substrate for PGE2 synthesis via PKA/PLA2 activation. In addition, NP induces the formation of DAG, which could be required as a cofactor of the PKC-mediated activation of the COX2 inflammatory pathway. Our findings suggest that NP alters lipid homeostasis in SCs by inducing the activation of pro-inflammatory pathways that may trigger adverse effects in testis physiology over time. Concomitantly, the SC enhances the acylation of surplus FFAs (including 20:4n-6) in neutral lipids as a protective mechanism to shield itself from lipotoxicity and pro-inflammatory signals.

Plica Neuropathica in 2 Hispanic Patients.

Introduction: Plica neuropathica (PN) is a rare, acquired, and irreversible condition characterized by the formation of a compacted mass of tangled hair held together by a hard keratin cement. Case Presentation: In case 1, a 50-year-old woman with history of contact dermatitis of the scalp presented with hair tangling and difficulty combing. Physical examination revealed a matted mass of hair with a dirty appearance and non-scarring alopecia. Case 2 involved a 46-year-old woman who experienced spontaneous hair matting after using various products, resulting in a dreadlock-like appearance. Clinical examination showed a compact and matted mass of hair with irregular twists, dirt, and yellowish exudate. Conclusion: PN's exact pathogenesis is not fully understood, but it is believed to involve physical and chemical insults to the hair shaft. Risk factors include self-neglect, hair felting or rubbing, certain substances, religious practices, chemotherapy, immunosuppressive drugs, infections, and contact dermatitis. Trichoscopy can provide valuable clues for an accurate diagnosis, such as fractured hairs, bent hair shafts, trichorrhexis nodosa, retained telogen hairs, and twisted hairs. Treatment involves cutting the matted hair, and early-stage manual separation may be beneficial.

Evaluation of patients´ perspective on a multimorbidity patient-centered care model piloted in the chilean public health system.

BACKGROUND: The progressive multimorbidity explosion has challenged Chile's health systems and worldwide. The Centro de Innovación en Salud ANCORA UC implemented a new Multimorbidity Patient-Centered Care Model in Chile. OBJECTIVE: Evaluate the perspective of high-risk patients about the core elements of the model. METHODOLOGY: We conducted a cross sectional telephone-based survey that considered the application of a 13 items questionnaire. Of them, nine were Likert scale questions with scores from 1 to 7, one dichotomic question, and three open-ended questions. 231 high-risk patients who received care through the model at primary care centers participated in the study. Quantitative data were encoded, consolidated, and analyzed with the SPSS software. We performed descriptive and analytic statistics techniques to assess different variables and their potential associations. Thematic analysis was conducted for qualitative data. RESULTS: The overall score was 5.84 (range: 1 to 7), with a standard deviation of 1.25. Questions with the best scores were those related with personalized care and the primary care teams. The lowest scored was for the item regarding the continuity of care between primary nurses and inpatient care at the hospital. There was a difference in patient outcomes depending on their health center. Regarding sociodemographic characteristics, age did not significantly affect the results. CONCLUSIONS: The study reveals the perceptions about a complex multimorbidity intervention from the patient's perspective. It complements the impact on health services utilization evaluation that supports decision-makers currently scaling up a similar strategy in our country and could be considered in other countries dealing with non-communicable diseases.

Evaluation of a Transitional Care Strategy Implemented in Adults With High-Risk and Multimorbidity in Chile.

OBJECTIVES: Fragmentation of continuity of care impacts the health system's efficiency and increases inequity. It severely affects high-risk patients with multimorbidity, requiring coordinated care to avoid preventable complications. The Centro de Innovación en Salud ANCORA UC, together with the Servicio de Salud Metropolitano Sur Oriente, and the National Health Fund, implemented a transitional care strategy for high-risk adults with multimorbidity at 3 hospitals in the southeast of Santiago. The study aimed to evaluate the impact on length of hospital stay, consultations with primary care physicians and contacts after discharge, and also to describe the implementation process of the transition nurse activities. METHODS: A cohort study was performed between 2017 and 2019, with 137 hospitalizations from exposed patients and 167 hospitalizations from unexposed patients. The results of the study showed a significant decrease in the length of hospital stays and an increase in consultations with physicians. RESULTS: The results of the implementation process showed that the transition nurse followed-up in a mean of 24 hospitalizations monthly, and 91% of the discharged patients were contacted via the telephone within 7 days. The implementation process showed that the transition nurse's tasks merged with the daily clinical activities in which training on case management, transition care, and continuous support were key aspects of success. CONCLUSION: We conclude that transitional care intervention has a strong potential in addressing fragmentation of care and is feasible to install and sustain over time in the Chilean context. Finally, this study provides a detailed description of the intervention strategy contributing to its spread and scale-up.

Multiple clonal transmissions of clinically relevant extended-spectrum beta-lactamase-producing Escherichia coli among livestock, dogs, and wildlife in Chile.

OBJECTIVES: Extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-E. coli) are a main cause of human deaths associated with antimicrobial resistance (AMR). Despite hundreds of reports of the faecal carriage of ESBL-E. coli in domestic and wild animals, the dynamics of its circulation remains poorly understood. METHODS: We used whole genome sequencing of 19 ESBL-E. coli previously isolated in the same local setting from dogs, livestock, and a wild rodent in Central Chile to assess potential cross-species transmission of ESBL-E. coli. RESULTS: Isolates harboured a large number of AMR (n = 95) and virulence (n = 45) genes, plasmids replicons (n = 24), and E. coli sequence types including top extraintestinal pathogenic E. coli ST410, ST58, ST88, and ST617. Almost identical clones (<50 single nucleotide polymorphisms difference, same antibiotic and heavy metal resistance genes, virulence genes, and plasmids) were found in faeces of dogs, cattle, or sheep from the same farm, and in a dog and a wild rodent living in proximity. CONCLUSIONS: To our knowledge, this is the first report of multiple clonal cross-species transmission of ESBL-E. coli in domestic and potentially wild animals of Latin America. Our results suggest that relatively rare spread of AMR across animal species can still occur by both clonal and plasmid dissemination. Our study highlights the need for establishing preventive measures to limit the circulation of these bacteria among animals in agricultural settings, particularly given the highly pathogenic profile of several E. coli strains detected in these animals.

Evaluation of the implementation progress through key performance indicators in a new multimorbidity patient-centered care model in Chile.

BACKGROUND: Complex health interventions involve deep organizational, structural, and cultural changes that challenge health teams and decision-makers. The explosion of chronic diseases has made the multimorbidity approach a global priority. The Centro de Innovación en Salud ANCORA UC implemented a Multimorbidity Patient-Centered Care Model in the Chilean public health system. OBJECTIVE: This study aims to evaluate the progress of the implementation of the Multimorbidity Patient-Centered Care Model in seven primary care centers through key performance indicators. METHODS: a set of indicators was designed to evaluate change management, operations, installation of new roles, and services and activities of the intervention strategy of the model. Key performance indicators were identified to monitor the implementation progress on minimal components for the model's sustainability. Each item was assigned against an expected minimum score of 67% of progress from the overall score. They were monitored twice in seven primary health centers in 2019 and 2020, which intervened 22,642 patients with the intervention. RESULTS: The results showed that six of the seven primary care centers reached the minimum implementation threshold. The main advances were in operational conditions, and those with minor progress in implementation were the clinical services. Population size, organization, coordination of the health care teams, additional training, and decision-makers support were key factors that determined the degree of progress in a complex intervention. CONCLUSION: It was possible to measure the progression of the implementation of a complex intervention through key performance indicators delivering relevant information for decision-makers that pursue a successful and faithful implementation. This study provides a valuable tool for the national scale-up of a similar model started in Chile by the Ministry of Health and other countries.

The interaction of the oxytocin receptor gene and child abuse subtypes on social cognition in euthymic patients with bipolar disorder type I.

Background: Most studies on cognitive impairment in bipolar disorder have neglected the role of early stress, despite the high frequency of childhood maltreatment in this clinical group. The aim of this study was to establish a connection between a history of emotional, physical, and sexual abuse in childhood and social cognition (SC) in patients with bipolar disorder type I (BD-I) in euthymia, and to test a possible moderating effect of the single nucleotide polymorphism rs53576 in the oxytocin receptor gene (OXTR). Methods: One hundred and one participants were included in this study. History of child abuse was evaluated using the Childhood Trauma Questionnaire-Short Form. Cognitive functioning was appraised using The Awareness of Social Inference Test (social cognition). The interaction effect between the independent variables OXTR rs53576 (AA/AG and GG) and the absence or presence of any one type of child maltreatment or a combination of types was analyzed using a generalized linear model regression. Results: BD-I patients who had been victims of physical and emotional abuse in childhood and were carriers of the GG genotype at OXTR rs53576 displayed greater SC alterations, specifically in emotion recognition. Discussion: This gene-environment interaction finding suggests a differential susceptibility model of a genetic variants that can be plausibly associated with SC functioning and might help to identify at-risk clinical subgroups within a diagnostic category. Future research aimed at testing the interlevel impact of early stress constitutes an ethical-clinical duty given the high rates of childhood maltreatment reported in BD-I patients.

Dysregulation of ADAM10 shedding activity in naked mole-rat fibroblasts is due to deficient phosphatidylserine externalization.

The naked mole-rat (NMR, Heterocephalus glaber) is of significant interest to biogerontological research, rarely developing age-associated diseases, such as cancer. The transmembrane glycoprotein CD44 is upregulated in certain cancers and CD44 cleavage by a disintegrin and metalloproteinase 10 (ADAM10) regulates cellular migration. Here we provide evidence that mature ADAM10 is expressed in NMR primary skin fibroblasts (NPSF), and that ionomycin increases cell surface ADAM10 localization. However, we observed an absence of ADAM10 mediated CD44 cleavage, as well as shedding of exogenous and overexpressed betacellulin in NPSF, whereas in mouse primary skin fibroblasts ionomycin induced ADAM10-dependent cleavage of both CD44 and betacellulin. Overexpressing a hyperactive form of the Ca2+ -dependent phospholipid scramblase ANO6 in NPSF increased phosphatidylserine (PS) externalization, which rescued the ADAM10 sheddase activity and promoted cell migration in NPSF in an ADAM10-dependent manner. These findings suggest that dysregulation of ADAM10 shedding activity is due to a deficient PS externalization in NMR.

Influence of serum vitamin D level in the response of actinic keratosis to ingenol mebutate.

Vitamin D (VD) serum levels, and keratinocytic basal expression of vitamin D receptor (VDR) before treatment of actinic keratoses (AK) have been previously reported as possible biomarkers of the response of AK to treatments. We intended to evaluate the association between these and other serum and immunohistochemical parameters with the response of AK to treatment with topical ingenol mebutate (IM). Twenty-five patients with AK on the head were treated with topical IM 0.015% gel once daily for 3 days. Biopsies were taken at baseline and 6 weeks after treatment. Immunohistochemical staining was performed for VDR, P53, Ki67, Aurora B, Survivin and ß-catenin. Basal serum 25(OH)D levels were determined. IM was more effective for KIN I and II AKs than in KIN III, and histological responders showed significantly higher serum VD levels (30.278 [SD 8.839] ng/mL) than nonresponders (21.14 [SD 7.079] ng/mL, p = 0.023). In addition, mean basal expression of VDR (45.63 [SD 16.105] %) increased significantly (57.92 [SD 14.738] %, p = 0.003) after treatment with IM. A significant decrease after treatment in the expression of several markers of aggressiveness and progression to squamous cell carcinoma, namely P53, Ki-67, aurora B kinase and survivin, was also observed. Our results support a relationship between VD status and the response of AK to treatment with topical IM, suggesting that its previous correction to proper serum levels in VD-deficient patients could improve the response of AK to the treatment.

Fully home-based methyl aminolevulinate daylight photodynamic therapy for actinic keratosis of the face or scalp: A real life open study.

Methyl aminolevulinate daylight photodynamic therapy (MAL DL-PDT) is highly efficacious for the treatment of nonhyperkeratotic actinic keratosis (AK), even when partially performed at home. To evaluate the long-term effectiveness, safety, and patient-reported outcomes of MAL DL-PDT performed completely by the patient in real life conditions. An open prospective study was conducted in Spain among patients diagnosed with at least five AK lesions on the face or the scalp. Patients received instruction and information in infographic format to perform MAL DL-PDT at home. All had been treated with 30% urea daily for 7 days before the day of MAL DL-PDT. Meteorological conditions on the day of the treatment and adverse effects were recorded. Patients underwent follow-up, and a second session of home-based MAL DL-PDT if deemed necessary, 3, 6, and 12 months after the initial treatment session. The study population consisted of 22 patients (19 men and three women, mean [standard deviation, SD] age, 72.05 [6.96] years). A complete response was observed in 47.7% of AK lesions at 3 months (p < 0.001) and 65.9% (n = 199) at 12 months (p < 0.001). Olsen grade II lesions showed the highest rate of response (76.07% at 12 months). The mean (SD) actinic keratosis area and severity index score decreased significantly from 4.99 (2.43) at baseline to 2.33 (1.01) at 12 months (p = 0.0234). Adverse effects were mild and expected. A majority of patients were "satisfied" or "very satisfied" with the treatment instruction provided (90.9%) and the treatment outcome (72.7%). MAL DL-PDT can be applied at home like any other topical treatment for AK. Our results indicate good long-term effectiveness, a high level of patient satisfaction, and no significant side effects.

Isolation of an Extensively Drug-Resistant Pseudomonas aeruginosa exoS+/O4 Strain Belonging to the "High-Risk" Clone ST654 and Coproducer of NDM-1 and the Novel VIM-80.

The aim of this study was to investigate the genomic features of an extensively drug-resistant (XDR) Pseudomonas aeruginosa isolate (P-469) emerging in Chile. Antibiotic susceptibility was determined by disk diffusion and "colistin agar" test. Whole-genome sequencing (WGS) was performed by the Illumina NextSeq 2000 platform, and epidemiologically and clinically relevant data (i.e., sequence-type, serotype, mobile genetic elements, virulome, resistome, plasmidome, prophages, and CRISPR-Cas systems) were retrieved using multiple bioinformatic tools. The P-469 strain displayed an XDR profile, remaining susceptible to colistin. Genomic analysis revealed that this isolate belonged to the "high-risk" clone ST654 (CC654), serotype O4, and genotype exoS+. Strikingly, two CRISPR-Cas systems, five intact prophages sequences, and a broad resistome that included blaNDM-1 and the novel blaVIM-80 carbapenemase genes were predicted. Our results revealed the genomic characteristics of P. aeruginosa belonging to the high-risk clone ST654/O4 coproducing NDM-1 and VIM-80 in Chile, supporting that genomic surveillance is necessary to track the emergence and spread of epidemiologically successful WHO's critical priority pathogens in order to prevent their rapid dissemination.

Contribución de una estrategia de atención centrada en la persona con multimorbilidad al Modelo de Atención Integral de Salud Familiar y Comunitario en Chile / Contribution of a multimorbidity person-centered care strategy to the Comprehensive Family and Community Healthcare Model in Chile

BACKGROUND: The Multimorbidity Person-Centered Care Model allows to customize care according the needs of each person. AIM: To characterize the perception of health teams about the contribution of the Multimorbidity Person-Centered Care Model (MACEP) to the development of the key principles of the Comprehensive Family and Community Health Care Model (MAIS). MATERIAL AND METHODS: A qualitative collaborative study with 35 interviews and the participation of 67 professionals from the primary healthcare network. Content analysis using mixed code system with MAXQDA2020 program. RESULTS: The innovations and complex interventions that positively affect the development and implementation of the essential principles of MAIS were recognized by participants as a contribution of the central elements of MACEP. CONCLUSIONS: This contribution is an opportunity for the expeditious implementation of Family Health principles in the health network. Incorporating the vision of implementers and users, who are part of these changes, is essential. It is necessary to establish, project and evaluate innovations to identify, implement and promote learning at Health Services throughout the country.

Effect of COVID-19 pandemic on the implementation of a multimorbidity person-centered care model: A qualitative study from health teams' perspective.

The COVID-19 pandemic has abruptly changed care priority and delivery, delaying others like the multimorbidity approach. The Centro de Innovación en Salud ANCORA UC, the Health National Fund, and the Servicio de Salud Metropolitano Sur Oriente implemented a Multimorbidity Patient-Centered Care Model as a pilot study in the public health network from 2017 to 2020. Its objective was to reorganize the single diagnosis standard care into a new one based on multimorbidity integrated care. It included incorporating new roles, services, and activities according to each patient's risk stratification. This study aims to describe the perception of the health care teams regarding the impact of the COVID-19 pandemic on four main topics: how the COVID-19 pandemic affected the MCPM implementation, how participants adapted it, lessons learned, and recommendations for sustainability. We conducted a qualitative study with 35 semi-structured interviews between October and December 2020. Data analysis was codified, triangulated, and consolidated using MAXQDA 2020. Results showed that the pandemic paused the total of the implementation practically. Positive effects were the improvement of remote health care services, the activation of self-management, and the cohesion of the teamwork. In contrast, frequent abrupt changes and reorganization forced by pandemic evolution were negative effects. This study revealed the magnitude of the pandemic in the cancelation of health services and identified the urgent need to restart chronic services incorporating patient-centered care in our system.

Impact of a high-risk multimorbidity integrated care implemented at the public health system in Chile.

During recent years, multimorbidity has taken relevance because of the impact of causes in the system, people, and their families, which has been a priority in the health care plan. Interventions strategies and their implementation are still an emerging topic. In this context, Centro de Innovación en Salud ANCORA UC, together with Servicio de Salud Metropolitano Sur Oriente, implemented as a pilot study High-Risk Multimorbidity Integrated Care strategy. This study aimed to evaluate the impact of this strategy in terms of health services utilization and mortality. A cohort study was conducted with high-risk patients with multimorbidity, stratified by ACG®, intervened between April 2017 and December 2019. The studied population was 3,933 patients who belonged to similar size and location primary care centers. The impact analysis was performed used generalized linear models. Results showed that intervened patients had a significantly lower incidence in mortality (OR 0.56; 95% CI 0.40-0.77), hospital admissions, length of stay, and the number of hospital emergency consultancies. With the proper barriers and facilitators of a real context intervention, the implementation process allowed the systematization and consolidation of the intervention provided in this study. The training for new roles and the constant implementation support from the Centro de Innovación en Salud ANCORA UC team were essential in the progress and success of the intervention. A complete description of the high-risk intervention strategy is provided to contribute to this emerging topic and facilitate its scale-up. We can conclude that this complex intervention was feasible to be implemented in a real context. The Ministry of Health has taken the systematization and consolidation of the conditions for the national scale-up.

[Contribution of a multimorbidity person-centered care strategy to the Comprehensive Family and Community Healthcare Model in Chile]. / Contribución de una estrategia de atención centrada en la persona con multimorbilidad al Modelo de Atención Integral de Salud Familiar y Comunitario en Chile.

BACKGROUND: The Multimorbidity Person-Centered Care Model allows to customize care according the needs of each person. AIM: To characterize the perception of health teams about the contribution of the Multimorbidity Person-Centered Care Model (MACEP) to the development of the key principles of the Comprehensive Family and Community Health Care Model (MAIS). MATERIAL AND METHODS: A qualitative collaborative study with 35 interviews and the participation of 67 professionals from the primary healthcare network. Content analysis using mixed code system with MAXQDA2020 program. RESULTS: The innovations and complex interventions that positively affect the development and implementation of the essential principles of MAIS were recognized by participants as a contribution of the central elements of MACEP. CONCLUSIONS: This contribution is an opportunity for the expeditious implementation of Family Health principles in the health network. Incorporating the vision of implementers and users, who are part of these changes, is essential. It is necessary to establish, project and evaluate innovations to identify, implement and promote learning at Health Services throughout the country.

Rendimiento de dos índices predictores de mortalidad (PSI y CURB-65) en pacientes adultos inmunocompetentes hospitalizados por neumonía adquirida en la comunidad / Yield of two mortality predictors in immunocompetent patients with community acquired pneumonia

Background: The severity of community acquired pneumonia (CAP) can be evaluated by the PSI and CURB-65 scales. However, it is unknown whether their predictive capacity varies according to the etiology of the disease. Aim: To compare the performance of these scales in adults with viral, bacterial, mixed, and no agent detected CAP. Material and Methods: We studied 725 patients hospitalized for CAP aged 18 to 95 years (47% females) Urinary S. pneumoniae and Legionella antigens were detected by immuno-chromatography (Binax®). Respiratory viruses and bacteria were detected by PCR in nasopharyngeal smears. The proportions of deaths, admission to the intensive care unit (ICU), and oxygen therapy were compared between mild and non-severe patients defined by PSI (I/II and I-III) and CURB-65 (1 and 1-2), according to the causative agent. Results: Ten percent of patients died. A causative agent was detected in 65%. The proportion of mild and non-severe patients according to PSI and CURB-65, and of deceased patients, admitted to the ICU and with oxygen therapy was similar in the four categories per agent. There were no deaths among non-severe patients with bacterial CAP. However, 6% of patients with CAP caused by virus or without causative agents, died. No deaths occurred among mild patients with bacterial CAP. In viral CAP, no deaths occurred among patients classified as mild only by PSI. The yields of PSI were greater than those of CURB-65 in non-severe patients who died and were admitted to the ICU with bacterial and viral CAP (5 and 14%; 7 and 12% respectively, p = 0.04). Conclusions: The prognostic performance of PSI in CAP varies according to the causative agent in adults. It is higher in non-severe bacterial cases, and superior to CURB-65.