Universidad del Desarrollo

Niemann‐Pick type C (NPC) disease, caused by NPC1 or NPC2 variants, disrupts cholesterol and glycolipid trafficking, leading to diverse clinical manifestations. To understand the genetic basis of neurological resilience, we analyzed an NPC family with variable phenotypes, identifying loss‐of‐function variants in CCDC115 , SLC4A5 , DEPDC5 , ETFDH , SNRNP200 , and DOCK1 that co‐segregated with milder neurological involvement. Using yeast models, we successfully predicted NPC‐like severity based on orthologous gene variants. RNA‐seq revealed a positive correlation between mitochondrial transcripts and cellular fitness. Modeling NPC in yeast lacking the SLC4A5 ortholog, bor1 , enhanced cellular fitness, improved mitochondrial function, and reduced sterol accumulation. Our findings identify potential modifiers and biomarkers of NPC severity, highlighting mitochondrial pathways and SLC4A5 as a therapeutic target. Impact statement Niemann‐Pick type C (NPC) disease is a progressive neurovisceral lysosomal storage disorder. Here, we identified genomic modifiers of neurological resilience in an NPC family, with SLC4A5 emerging as a key biomarker and therapeutic target. Additionally, our study highlighted mitochondrial transcripts and metabolites as potential biomarkers of severity.

Individuals with monoallelic gain-of-function variants in the histone lysine methyltransferase DOT1L display global developmental delay and varying congenital anomalies. However, the impact of monoallelic loss of DOT1L remains unclear. Here, we sought to define the effects of partial DOT1L loss by applying bulk and single-nucleus RNA-sequencing, ChIP-sequencing, imaging, multielectrode array recordings, and behavioral analysis of zebrafish and multiple mouse models. We present a cohort of 16 individuals (12 females, 4 males) with neurodevelopmental disorders and monoallelic DOT1L variants, including a frameshift deletion, an in-frame deletion, a nonsense, and missense variants clustered in the catalytic domain. We demonstrate that specific variants cause loss of methyltransferase activity. In primary cortical neurons, Dot1l knockdown disrupts transcription of synaptic genes, neuron branching, expression of a synaptic protein, and neuronal activity. Further in the cortex of heterozygous Dot1l mice, Dot1l loss causes sex-specific transcriptional responses and H3K79me2 depletion, including within down-regulated genes. Lastly using both zebrafish and mouse models, we found behavioral disruptions that include developmental deficits and sex-specific social behavioral changes. Overall, we define how DOT1L loss leads to neurological dysfunction by demonstrating that partial Dot1l loss impacts neuronal transcription, neuron morphology, and behavior across multiple models and systems.

Objective The SCN9A gene is primarily expressed in nociceptive pathways within the peripheral nervous system, and pathogenic variants are associated with human pain disorders. In recent years, several studies have proposed SCN9A as a monogenic cause of epilepsy. Our objective was to critically appraise the SCN9A–epilepsy gene–disease relationship. Methods We assessed “epilepsy‐associated” SCN9A variants from four sources: (1) the literature up to December 2023 (n = 27), (2) epilepsy patients referred for genetic testing at a regional service in Glasgow, UK over a 5‐year period (n = 30), (3) the Human Genetics Mutation Database (n = 25), and (4) ClinVar (n = 1546). The latter two are genome‐wide variant databases, accepting submissions from genetic laboratories and research groups. We checked whether each SCN9A variant is present in the Genome Aggregation Database (gnomAD) V4 (a reference population database for variant interpretation), and classified its pathogenicity based on the American College of Molecular Genetics and Genomics/Association of Molecular Pathologists guidelines. Results Only three SCN9A variants were classified as “likely pathogenic,” of which two were identified in healthy individuals in gnomAD. A total of 1540 of the 1546 SCN9A variants in ClinVar labeled as being associated with epilepsy were also reported in association with hereditary sensory and autonomic neuropathy. No further clinical data were provided in 1482 of these submissions. Significance There is no convincing genetic evidence to support SCN9A as a causative epilepsy gene. As such, the inclusion of SCN9A in epilepsy genetic testing panels should be reassessed. Research centers and genetic testing laboratories should be rigorous and consistent in their submissions to variant databases.

PURPOSE Women represent a growing force in oncology but remain underrepresented in high-level positions. Gender-related challenges affect academic progression, research, and clinical practice. This manuscript aims to describes gender-based professional development challenges faced by women in oncology in Latin America (LATAM). MATERIALS AND METHODS We conducted a multicenter, cross-sectional study among LATAM oncologists using a 27-item questionnaire on the basis of the European Society for Medical Oncology Women for Oncology Survey. Our analysis focused on male-female disparities, excluding other gender identities. Logistic regression models were used to calculated odds ratios (ORs) for gender inequity, wage disparity, workplace and sexual harassment, and family development. Statistical analyses were performed using SPSS version 26, with the significance set at P < .05. RESULTS We analyzed 254 participants from Argentina, Chile, Mexico, and Peru, mostly females (88%) and based in Mexico (55%). Most were attending physicians (68%), 51.5% worked 41-60 hours, and 33.4% reported gender equity initiatives. Gender inequity was significantly higher among women (83%) than among men (37%), with the female gender identified as a risk factor (OR, 15.67; P < .001). Workplace harassment was reported by 60% of women and 19% of men, whereas sexual harassment was experienced by 34% of women and 16% of men (OR, 2.78; P < .05). Sixty-five percent reported that men had the highest salaries. Logistic regression indicated that working 20-40 hours per week was associated with the likelihood of women having children (OR, 3.0; P < .01), as was working 41-60 hours (OR, 1.97; P < .01). However, holding an attending or resident position was associated with significantly lower childbearing rates CONCLUSION Our findings indicate that Women oncologists in LATAM report experiencing higher rates of gender-based inequity and harassment and remain underrepresented in leadership and high-earning roles.

This chapter delves into the rise and fall of contemporary Chilean nationalism through an in-depth case study of the Movimiento Social Patriota (MSP). Established in 2017, MSP sought to defend national identity and social justice against what it perceived as the decay of Western liberalism. This study examines MSP's ideological foundations, significant actions, and public interventions, including their provocative protests and campaigns. Utilizing ethnographic research, document analysis, and interviews, this chapter reveals the complexities of MSP’s doctrines and the social dynamics within the movement. Furthermore, it contextualizes MSP within the broader historical and socio-political landscape of Chilean nationalism, tracing its roots back to the late nineteenth century. The chapter also addresses the implications of MSP's rise for contemporary political discourse in Chile, particularly in light of increasing concerns over immigration and national sovereignty.

Running is one of the most accessible and popular physical activities worldwide; however, injuries are the main barrier to sustaining running practice. While quantitative studies have explored prevalence and risk factors, a critical gap exists in understanding subjective experiences, perceptions and contextual influences on injury management and prevention. This qualitative study aimed to explore the perspectives of runners and experts regarding injury perception, management and prevention, as well as the contextual influence of these processes. Using a secondary data analysis approach, this study drew from qualitative semistructured interviews with Chilean runners (n=15) and running experts (n=6). Thematic analysis, guided by an interpretivist approach, uncovered intrinsic factors (identity, motivation, stress and self-learning) and extrinsic factors (environment, information sources, marketing, peer advice, professional guidance, racing, stereotype and clothing) that shaped runners’ behaviours. Less experienced runners associated injury risk with asphalt surfaces, faced challenges in discerning online information reliability and found motivation in peer advice. Experts emphasised the multifactorial nature of running-related injuries, including previous injuries and training-related factors. Both groups acknowledged a global tendency among runners to resist rest when discomfort arose. This research contributed to a nuanced understanding of injury perception, management and prevention, bridging scientific knowledge with individual experiences. Clinicians may use this information to enhance the therapy alliance and set realistic expectations about the runner’s rehabilitation process.

Basic and translational research in lung cancer is a rapidly evolving field with transformational impact in early detection, diagnosis, therapeutic development and personalization of care. Recent advances have greatly increased our understanding in the molecular genomics, proteomics, pathogenesis and cellular biology of this deadly malignancy. The International Association for the Study of Lung Cancer (IASLC) recently formed a Basic and Translational Science (BaTS) Committee to further enhance the scientific leadership of IASLC in thoracic cancer research. This review by members of the committee highlights the breadth of current research in NSCLC, with a focus on molecular risk factors and processes in tumorigenesis, heterogeneity, phenotypic plasticity, metabolic reprograming, immunobiology, the immune microenvironment and microbiome. This review also identifies future research areas that may lead to further improvement in survival outcomes and curative therapies especially for patients with advanced NSCLC.

Background Lung recruitment maneuvers (LRM) and high positive end-expiratory pressure (PEEP) may benefit some patients by reopening non- or poorly aerated alveoli. However, the effects of opening the lung with LRM on hemodynamics remain uncertain. This study aimed to evaluate the direct impact of LRM on cardiac function in patients with moderate-to-severe acute respiratory distress syndrome (ARDS). Methods This post-hoc analysis included 34 patients with moderate-to-severe ARDS from two prospective cohort studies. The LRM consisted in a gradual increase in PEEP, starting from 25 cmH2O (PEEPpre, before the recruitment maneuver at PEEP 25 cmH2O) until reaching 40 cmH2O. After LRM, PEEP was decreased to 25 cmH2O (PEEPpost, after the recruitment maneuver, also at PEEP 25 cmH2O) followed by a decremental PEEP titration. We compared the size and function of the right ventricle (RV) and left ventricle (LV) between PEEPpre and PEEPpost. Results The respiratory system compliance significantly increased from 21 ± 7 ml/cmH2O at PEEPpre to 24 ± 7 ml/cmH2O at PEEPpost (p < 0.001), indicating effective lung recruitment. The RV end-diastolic diameter and the RV/LV ratio decreased after LRM (51 ± 11 vs. 41 ± 9 mm; p < 0.001, and 1.05 ± 0.21 vs. 0.90 ± 0.18; p < 0.001, respectively), suggesting reduced pulmonary vascular resistance. The RV free wall strain improved from -22 ± 10 to -25 ± 8% (p = 0.040). The cardiac index significantly increased from 2.1 ± 0.6 to 2.4 ± 0.7 L/min/m2 (p < 0.001) due to improved LV function, as demonstrated by a lower LV global longitudinal strain at PEEPpost (-16 ± 4% vs. -19 ± 3%, p = 0.002). Conclusions LRM may benefit both the lungs and the heart. The increase in transpulmonary pressure leads to an expansion in aerated lung volume, potentially reducing lung overdistension and collapse, thereby lowering RV afterload and improving RV systolic function.

Tumor hypoxia, a hallmark of the tumor microenvironment (TME), profoundly impacts the antitumor functionality of immune cells, particularly natural killer (NK) cells, which play a critical role in cancer immunosurveillance and immunotherapy success. This review provides a comprehensive analysis of the mechanisms by which hypoxia impairs NK cell-mediated cytotoxicity and antitumor activities, emphasizing the molecular pathways and cellular adaptations that enable cancer cell to evade NK cell attack. Key factors that participate in this phenomenon include the stabilization of hypoxia-inducible factors, metabolic reprogramming, angiogenesis, cancer stemness, autophagy, and the secretion of immunosuppressive molecules. Moreover, hypoxia induces phenotypic and functional changes in both cancer and NK cells, promoting tumor progression and resistance to immunotherapy. Emerging strategies to counteract hypoxia-induced immunosuppression are being explored, including nanotechnology-based approaches, cytokine-mediated NK cell preconditioning, and vascular normalization techniques. These interventions highlight promising avenues for enhancing NK cell functionality and synergizing with existing cancer therapies. By addressing the immunosuppressive challenges of the hypoxic TME, in this review, we underscore the potential of innovative strategies to improve therapeutic outcomes in cancer treatment.

Background. Cow’s milk allergy (CMA) is one of the most common food allergies in infancy, with prevalence estimates of 0.5–7.5% in high-income countries. Data from low- and middle-income regions remain limited, and the predominant immune mechanism (IgE or non-IgE mediated) may vary across populations. Objective. We aimed to determine the prevalence and clinical characteristics of CMA in infants from an urban, low-income Chilean population. Methods. A prospective cohort study was conducted at Padre Hurtado Hospital in Santiago, Chile. Healthy term newborns were recruited and followed for up to 12 months. Sociodemographic, perinatal data and parental atopy were recorded. Parents were contacted monthly to screen for CMA symptoms. Infants with ≥two symptoms underwent clinical evaluation, a 4-week cow’s milk protein exclusion diet, and an open oral food challenge (OFC). Diagnosis followed international consensus guidelines. Results. Of 552 enrolled infants (48% male), 27 were diagnosed with CMA, yielding a prevalence of 4.9% (95% CI 3.1–7.0%). All cases exhibited non-IgE-mediated symptoms, including vomiting, dermatitis, colic, and perianal erythema. CMA was diagnosed before 6 months of age in 74% of cases. At 12 months, 40% had developed oral tolerance. Sociodemographic and perinatal characteristics were similar between groups, but some self-reported parental atopic traits were more frequent in CMA cases. Conclusions. CMA prevalence in this Chilean cohort was comparable to that reported in high-income countries, with a predominance of non-IgE-mediated forms. These findings support the need for standardized diagnostic protocols, including OFC, in diverse populations. Future studies should explore long-term outcomes and risk factors in non-IgE-mediated CMA.

Background HEARTS in the Americas is the regional adaptation of the WHO Global HEARTS Initiative, aimed at helping countries enhance hypertension and cardiovascular disease (CVD) risk management in primary care settings. Its core implementation tool, the HEARTS Clinical Pathway, has been adopted by 28 countries. To improve the care of hypertension, diabetes, and chronic kidney disease (CKD), HEARTS 2.0 was developed as a three-phase process to integrate evidence-based interventions into a unified care pathway, ensuring consistency across fragmented guidelines. This paper focuses on Phase 1, highlighting targeted interventions to improve and update the HEARTS Clinical Pathway. Methods First, the coordinating group defined the project’s scope, objectives, principles, methodological framework, and tools. Second, international experts from different disciplines proposed interventions to enhance the HEARTS Clinical Pathway. Third, the coordinating group harmonized these proposals into unique interventions. Fourth, experts appraised the appropriateness of the proposed interventions on a 1-to-9 scale using the adapted RAND/UCLA Appropriateness Method. Finally, interventions with a median score above 6 were deemed appropriate and selected as candidates to enhance the HEARTS Clinical Pathway. Results Building on the existing HEARTS Clinical Pathway, 45 unique interventions were selected, including community-based screening, early detection and management of risk factors, lower blood pressure thresholds for diagnosing hypertension in high-CVD-risk patients, reinforcement of single-pill combination therapy, inclusion of sodium-glucose cotransporter-2 inhibitors for patients with diabetes, CKD, or heart failure, expanded roles for non-physician health workers in team-based care, and strengthened clinical documentation, monitoring, and evaluation. Conclusion HEARTS 2.0 Phase 1 identifies key interventions to integrate and improve hypertension and cardiovascular-kidney-metabolic care within primary care, enabling their seamless incorporation into a unified and effective clinical pathway. This process will inform an update to the HEARTS Clinical Pathway, optimizing resources, reducing care fragmentation, improving care delivery, and advancing health equity, thereby supporting global efforts to combat the leading causes of death and disability.

Background: Macrohemodynamic optimization does not always ensure adequate microcirculatory perfusion in patients with septic shock. The vasopressor test (VPT), a controlled and transitory increase in the mean arterial pressure (MAP), has been proposed to assess the functional coherence between systemic circulation and microvascular flow. However, the physiological determinants of capillary refill time (CRT) in response to VPT remain poorly understood. Objectives: 1) To evaluate macro-to-microcirculatory coupling during VPT in patients with septic shock using CRT as a dynamic marker of perfusion, 2) to explore the association between CRT and splanchnic perfusion indices, and 3) to identify baseline hemodynamic predictors of CRT response. Methods: This prospective multicenter study enrolled 32 patients with septic shock, persistent hypoperfusion, and fluid-unresponsive status. Hemodynamic, echocardiographic, and perfusion-related variables were recorded at baseline (MAP 65 mmHg) and during VPT (MAP 85 mmHg). We correlated changes in CRT with those instroke volume (SV), and coupling patterns were identified based on the slope of the ΔCRT/ΔSV relationship. Splanchnic perfusion was assessed by Doppler-derived resistive indices. The statistical models included logistic regression and linear mixed-effects analyses. Results: The CRT response to VPT was heterogeneous. Patients with macro-to-microcirculatory coupling were more likely to show CRT improvement, whereas patients without coupling showed no perfusion benefit. No correlation was found between CRT and splanchnic resistive indices. A normal mean systemic filling pressure (Pmsf) was independently associated with CRT improvement. Mixed models confirmed a significant inverse association between changes in SV and CRT. Conclusions: The CRT response to VPT may identify patients with preserved macro-to-microcirculatory coupling. The lack of association with splanchnic resistive indices emphasizes the need for multimodal monitoring strategies. Finally, the baseline Pmsf may be a powerful predictor of CRT responsiveness during a vasopressors test.

In recent times, women have been increasing their participation in company management positions, occupying positions on the board of directors, and making strategic decisions with a view to the international expansion of the firms. However, the evidence of the participation of women in the processes of internationalization of companies is not conclusive or adequate for emerging economies, such as those in Latin America. Based on this premise, we conducted this research using data from 1,246 firms included in the Fifth Longitudinal Survey of Chilean Companies. These companies are categorized into four industries: 98 in extractive, 149 in manufacturing, 285 in Commercial, and 714 in services. A Tobit regression model to estimate the influence of the presence of women in senior management and gender diversity on boards on the export intensity of the company. The main findings show that women in the position of CEO and a higher percentage of women on boards of directors do not affect the export intensity of the company. They also show that the relationship between foreign ownership and export intensity was positive and, finally, that export intensity did not depend on gender diversity in high-level administrative positions. An important limitation of this research is not having a data panel for each company to estimate their evolution over time thus, as well as information related to compensation contracts for management teams. For future research, we are interested in studying the effect of ownership on the internationalization process.

A 21-year-old immunocompromised female (advanced HIV, CD4 count: 9 cells/μL) presented with painful genital ulcers. A multiplex PCR panel detected Trichomonas vaginalis in both vaginal and ulcer swabs, while tests for Neisseria gonorrhoeae, Chlamydia trachomatis, and Mycoplasma genitalium were negative. The patient was treated with metronidazole, resulting in significant clinical improvement. This case underscores the importance of considering T. vaginalis in the differential diagnosis of genital ulcers, particularly in immunocompromised individuals, and highlights the utility of molecular testing in atypical presentations.

Despite the growing importance of corporate sustainability, research on strategic alliances between corporations and sustainable startups remains limited. While corporations struggle with implementing radical sustainability‐oriented innovation, sustainable startups face challenges in scaling and validation. Given their complementary resources, partnerships between these entities offer significant potential to accelerate sustainable transitions. However, existing literature has largely overlooked the distinct drivers, barriers, and shared resources that characterize sustainability‐oriented corporate‐startup alliances, focusing instead on conventional or digital‐oriented collaborations. This study addresses this gap through a multiple case study of eight sustainability‐driven corporate‐startup partnerships in Chile. Using a grounded theory approach, we identify 21 drivers, 14 barriers, and 10 shared resource types, revealing the dual role of resource acquisition and legitimacy‐building in fostering sustainable collaborations. Our findings offer new theoretical insights and practical recommendations for enhancing the success of sustainability‐oriented alliances.