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Natural killer (NK) cells are prototypic cytotoxic innate lymphocytes that can kill target cells, such as tumor cells, in the absence of antigen-restriction. Peripheral NK cells exhibit a high degree of heterogeneity. Here, we set out to broadly assess intrinsic modulators of NK cell degranulation in an unbiased manner. We stimulated human primary blood-borne NK cells pre-treated with different cytokine regimens with the HCT116 human colon cancer cell line and used detection of lysosome-associated membrane glycoprotein 1 (LAMP1) as an identifier of rapid NK cell degranulation. RNA sequencing of FACS-sorted LAMP1 hi NK cells showed CXCR4 and S1PR5 were top down-regulated genes. Using compounds that modulate activity of CXCR4 and S1P receptor family members S1P1 and S1P5, we confirmed they play an important immunosuppressive role in NK cell cytotoxicity. Mechanistically, engagement of CXCR4 and S1P1/5 receptors triggered phosphorylation of p42 and Ca 2+ influx. CXCR4 activation promoted S1P5 upregulation and vice versa, and joint activation of both receptors amplified the defect NK cell degranulation. Intriguingly, in tumor samples the expression of both receptors and the synthesis of their ligands themselves appear to be coordinately regulated. Together, these data suggest that specifically and simultaneously targeting CXCR4 and S1P5 activity in the tumor microenvironment (TME) could be a beneficial strategy to unleash full cytotoxic potential of cytotoxic NK effector cells in the tumor.

Given that most evidence-based recommendations for managing type 2 diabetes mellitus (T2DM) are generated in high-income settings, significant challenges for their implementation exist in Latin America and the Caribbean region (LAC), where the rates of T2DM and related mortality are increasing. The aim of this study is to identify the facilitators and barriers to successful management of T2DM in LAC, from the perspectives of patients, their families or caregivers, healthcare professionals, and/or other stakeholders. We conducted a systematic review in MEDLINE, Web of Science, SciELO, and LILACS. We included studies of disease management, prevention of complications and risk factor management. We qualitatively synthesized the verbatim text referring to barriers and/or facilitators of diabetes management according to the Theoretical Domain Framework and described their relative frequencies. We included 60 studies from 1,595 records identified. 54 studies (90%) identified factors related to the environmental context and resources, highlighting the importance of questions related to health care access or lack of resources in the health system, and the environmental context and living conditions of the patients. Issues related to \"social influences\" (40 studies) and \"social/professional role and identity\" (37 studies) were also frequently addressed, indicating the negative impact of lack of support from family and friends and clinicians' paternalistic attitude. 25 studies identified patients beliefs as important barriers, identifying issues such as a lack of patients' trust in the effectiveness of the medication and/or the doctor's advice, or preferences for alternative therapies. Successful diabetes management in LAC is highly dependent on factors that are beyond the control of the individual patients. Successful disease control will require emphasis on public policies to reinforce health care access and resources, the promotion of a patient-centred care approach, and health promoting infrastructures at environmental level.

This paper empirically investigates the short and the long run impact of public debt on economic growth. We use annual data from both the central and the peripheral countries of the euro area (EA) for the 1961–2013 period and estimate a production function augmented with a debt stock term by applying the Autoregressive Distributed Lag (ARDL) bounds testing approach. Our results suggest different patterns across the EA countries and tend to support the view that public debt always has a negative impact on the long-run performance of EA member states, whilst its short-run effect may be positive depending on the country.

Idiopathic pulmonary fibrosis (IPF) is an aggressive disease in which normal lung parenchyma is replaced by a stiff dysfunctional scar rich in activated fibroblasts and collagen-I. We examined how the mechanochemical pro-fibrotic microenvironment provided by matrix stiffening and TGF-β1 cooperates in the transcriptional control of collagen homeostasis in normal and fibrotic conditions. For this purpose we cultured fibroblasts from IPF patients or control donors on hydrogels with tunable elasticity, including 3D collagen-I gels and 2D polyacrylamide (PAA) gels. We found that TGF-β1 consistently increased COL1A1 while decreasing MMP1 mRNA levels in hydrogels exhibiting pre-fibrotic or fibrotic-like rigidities concomitantly with an enhanced activation of the FAK/Akt pathway, whereas FAK depletion was sufficient to abrogate these effects. We also demonstrate a synergy between matrix stiffening and TGF-β1 that was positive for COL1A1 and negative for MMP1. Remarkably, the COL1A1 expression upregulation elicited by TGF-β1 alone or synergistically with matrix stiffening were higher in IPF-fibroblasts compared to control fibroblasts in association with larger FAK and Akt activities in the former cells. These findings provide new insights on how matrix stiffening and TGF-β1 cooperate to elicit excessive collagen-I deposition in IPF, and support a major role of the FAK/Akt pathway in this cooperation.

We describe the prevalence of Non-Communicable Disease (NCD) risk factors in a low-income health district in the South of Quito, Ecuador. We conducted a cross-sectional study between November 2020 and October 2021. We used multi-stage cluster sampling to select 656 of población total adult residents of 17D06 health district, enabling a prevalence estimation with at least ±5.73% absolute precision. We collected socio-demographic information and behavioural risk factors using the expanded WHO STEPwise approach to NCD surveillance. We measured height, weight, and blood pressure, and collected blood samples to assess glucose levels, lipid profiles, and renal function. We estimated the prevalence of behavioural and metabolic NCD risk factors by sex and age groups (18-44, 45-69, and >70). One-third of participants were obese (33.2% overall, 148 women, 38,7%, and 41 men, 22%), and more than half had a raised waist circumference (56.8%, N = 322). Hypertension affected 26.9% of participants (63 men, 33% and 90 women, 24%). Hyperglycaemia affected 7.9% (N = 45) of participants and increased with age and peaked at 22% among women over 70. More than half of the participants presented hypercholesterolemia (317 individuals, 56.2%). Low consumption of fruit and vegetables, high salt consumption and high sugar consumption were common in all population groups (88.4%, N = 580, 33.2%. N = 218 and 72.4%, N = 475, respectively). The critical prevalence of NCD risk factors in this low-income urban district of Quito, alongside similar trends observed in other settings across Latin America, underscores the need for ecological public health strategies to create healthy environments and promote healthier behaviours. Gender-sensitive approaches may be useful to address differences between sexes.

Background Type 2 diabetes mellitus (T2DM) is a pressing public health challenge in Latin America, with an increasing prevalence and negative impacts on population health. Achieving optimal blood glucose levels is critical for preventing complications, yet significant socioeconomic inequities persist in disease management and optimal glucose control. We aimed to investigate the patient characteristics associated with optimal fasting capillary glucose in individuals living with T2DM in a hard-to-reach setting in Esmeraldas, Ecuador. Methods We carried out a cross-sectional study of individuals with T2DM in the Eloy Alfaro health district of Esmeraldas, using a complex sample design with some limitations. Data collection took place between October 2020 and May 2022 and involved face-to-face interviews to collect sociodemographic and clinical data and a Fasting Capillary Blood Glucose test. Perceived social support was measured with the Multidimensional Scale of Perceived Social Support (MSPSS). We estimated the prevalence of optimal glucose levels according to patient characteristics and calculated odds ratios (OR) with 95% confidence intervals using multivariable logistic regression. Results Of the 474 participants surveyed, only 18.1% (86; 95%CI: 14.9–21.9) had optimal fasting capillary glucose levels. In this sample, optimal glucose was nearly four times more frequent among men compared to women (aOR = 3.92, 95%CI: 2.08–7.40, p  < 0.001). Furthermore, older age (aOR = 1.03, 95%CI: 1.01–1.05, p  = 0.006), living in an urbanised setting (aOR = 2.04, 95%CI: 1.22–3.40, p  = 0.006) and unemployment (aOR = 0.48, 95%CI: 0.25–0.94, p  = 0.031) were also linked to optimal blood glucose levels. While perceived social support in this population was moderate (median = 2.33, on a scale of 1 to 4), high family support appeared to reduce optimal glycaemic levels (aOR = 0.35, 95%CI: 0.18–0.70, p  = 0.003). Conclusions The intricate interplay of factors influencing diabetes management and optimal blood sugar suggests that targeted, context-specific and gender-sensitive public health strategies may be needed to address diabetes disparities in vulnerable populations.

Introduction We aimed to explore the impact of the COVID‐19 pandemic and the resulting restrictions on the emotional state of people with type 2 diabetes mellitus (T2DM) and/or hypertension in Ecuador and Spain. Given the differences in sociopolitical and socioeconomic contexts between these two countries, the research focused on how these diverse environments and their management of social policies and pandemic strategies influenced the emotional well‐being of individuals with chronic illnesses. Methods We conducted 36 semi‐structured telephone interviews between August and December 2020 with adults diagnosed with T2DM and/or hypertension (19 in Ecuador, 17 in Spain). The interviews were recorded, anonymized and transcribed for thematic analysis. This approach allowed us to systematically identify and analyse themes related to the participants' emotional experiences during the pandemic. Results The results revealed a significant deterioration in the emotional state of participants, attributable to the stress generated by the health crisis and concerns related to their chronic illnesses. The situation elicited a range of emotions among participants, from boredom and apathy to fear, uncertainty and depression. The study highlighted how the impact on emotional well‐being was shaped by the interplay between conjunctural determinants (measures to control COVID‐19 infections) and structural factors driving inequalities (social class, gender, ethnicity). Conclusion We developed a conceptual framework illustrating how measures to control COVID‐19 infections directly influenced economic, health and social determinants, which interacted with pre‐existing inequalities and had a differential impact on individuals' emotional well‐being. This framework can be useful for designing more effective and equitable social policies during future health crises, ensuring they address social needs and safeguard psychological and emotional well‐being, particularly among vulnerable groups such as those with chronic illnesses. Patient and Public Contribution Thirty‐six participants diagnosed with T2DM and/or hypertension (19 in Ecuador, 17 in Spain) contributed to the study by sharing their emotional experiences during the pandemic. Their detailed accounts enriched the research by providing valuable insights into how the pandemic affected their emotional well‐being. There was no additional involvement or contribution from the public in the design, conduct, analysis or interpretation of the study, nor in the preparation of the manuscript.

Cytotoxic CD8 +T lymphocytes (CTLs) are key players of adaptive anti-tumor immunity based on their ability to specifically recognize and destroy tumor cells. Many cancer immunotherapies rely on unleashing CTL function. However, tumors can evade killing through strategies which are not yet fully elucidated. To provide deeper insight into tumor evasion mechanisms in an antigen-dependent manner, we established a human co-culture system composed of tumor and primary immune cells. Using this system, we systematically investigated intrinsic regulators of tumor resistance by conducting a complementary CRISPR screen approach. By harnessing CRISPR activation (CRISPRa) and CRISPR knockout (KO) technology in parallel, we investigated gene gain-of-function as well as loss-of-function across genes with annotated function in a colon carcinoma cell line. CRISPRa and CRISPR KO screens uncovered 187 and 704 hits, respectively, with 60 gene hits overlapping between both. These data confirmed the role of interferon-γ (IFN-γ), tumor necrosis factor α (TNF-α) and autophagy pathways and uncovered novel genes implicated in tumor resistance to killing. Notably, we discovered that ILKAP encoding the integrin-linked kinase-associated serine/threonine phosphatase 2 C, a gene previously unknown to play a role in antigen specific CTL-mediated killing, mediate tumor resistance independently from regulating antigen presentation, IFN-γ or TNF-α responsiveness. Moreover, our work describes the contrasting role of soluble and membrane-bound ICAM-1 in regulating tumor cell killing. The deficiency of membrane-bound ICAM-1 (mICAM-1) or the overexpression of soluble ICAM-1 (sICAM-1) induced resistance to CTL killing, whereas PD-L1 overexpression had no impact. These results highlight the essential role of ICAM-1 at the immunological synapse between tumor and CTL and the antagonist function of sICAM-1.

Obstructive sleep apnea (OSA) is a prevalent disease associated with significant morbidity and high healthcare costs. Information and communication technology could offer cost-effective management options. To evaluate an out-of-hospital Virtual Sleep Unit (VSU) based on telemedicine to manage all patients with suspected OSA, including those with and without continuous positive airway pressure (CPAP) therapy. This was an open randomized controlled trial. Patients with suspected OSA were randomized to hospital routine (HR) or VSU groups to compare the clinical improvement and cost-effectiveness in a non-inferiority analysis. Improvement was assessed by changes in the Quebec Sleep Questionnaire (QSQ), EuroQol (EQ-5D and EQ-VAS), and Epworth Sleepiness Scale (ESS). The follow-up was 3 months. Cost-effectiveness was assessed by a Bayesian analysis based on quality-adjusted life-years (QALYs). The HR group (n: 92; 78% OSA, 57% CPAP) compared with the VSU group (n: 94; 83% OSA, 43% CPAP) showed: CPAP compliance was similar in both groups, the QSQ social interactions domain improved significantly more in the HR group whereas the EQ-VAS improved more in the VSU group. Total and OSA-related costs were lower in the VSU group than the HR. The Bayesian cost-effectiveness analysis showed that VSU was cost-effective for a wide range of willingness to pay for QALYs. The VSU offered a cost-effective means of improving QALYs than HR. However, the assessment of its clinical improvement was influenced by the choice of the questionnaire; hence, additional measurements of clinical improvement are needed. Our findings indicate that VSU could help with the management of many patients, irrespective of CPAP use.

The main features of SG-WAS (SkyGlow Wireless Autonomous Sensor), a low-cost device for measuring Night Sky Brightness (NSB), are presented. SG-WAS is based on the TSL237 sensor –like the Unihedron Sky Quality Meter (SQM) or the STARS4ALL Telescope Encoder and Sky Sensor (TESS)–, with wireless communication (LoRa, WiFi, or LTE-M) and solar-powered rechargeable batteries. Field tests have been performed on its autonomy, proving that it can go up to 20 days without direct solar irradiance and remain hibernating after that for at least 4 months, returning to operation once re-illuminated. A new approach to the acquisition of average NSB measurements and their instrumental uncertainty (of the order of thousandths of a magnitude) is presented. In addition, the results of a new Sky Integrating Sphere (SIS) method have shown the possibility of performing mass device calibration with uncertainties below 0.02 mag/arcsec2. SG-WAS is the first fully autonomous and wireless low-cost NSB sensor to be used as an independent or networked device in remote locations without any additional infrastructure.