PD-1/PD-L1 axis: implications in immune regulation, cancer progression, and translational applications.

The PD-1/PD-L1 axis is a complex signaling pathway that has an important role in the immune system cells. Programmed cell death protein 1 (PD-1) acts as an immune checkpoint on the T lymphocytes, B lymphocytes, natural killer (NK), macrophages, dendritic cells (DCs), monocytes, and myeloid cells. Its ligand, the programmed cell death 1 ligand (PD-L1), is expressed in the surface of the antigen-presenting cells (APCs). The binding of both promotes the downregulation of the T cell response to ensure the activation to prevent the onset of chronic immune inflammation. This axis in the tumor microenvironment (TME) performs a crucial role in the tumor progression and the escape of the tumor by neutralizing the immune system, the engagement of PD-L1 with PD-1 in the T cell causes dysfunctions, neutralization, and exhaustion, providing the tumor mass production. This review will provide a comprehensive overview of the functions of the PD-1/PD-L1 system in immune function, cancer, and the potential therapeutic implications of the PD-1/PD-L1 pathway for cancer management.

The Usefulness of Intraepithelial Lymphocyte Immunophenotype Testing for the Diagnosis of Coeliac Disease in Clinical Practice.

BACKGROUND: The diagnosis of coeliac disease (CD) in adults is based on clinical, serological and histological criteria. The inappropriate performance of intestinal biopsies, non-specificity of mild histological lesions and initiation of a gluten-free diet (GFD) before biopsy may hamper the diagnosis. In these situations, determining the intraepithelial lymphogram of the duodenum by flow cytometry (IEL-FC) can be helpful. OBJECTIVES: To describe the clinical scenarios in which the IEL-FC is used and its impact on the diagnosis of CD. METHODS: All adult patients with suspected CD at three tertiary centres for whom the duodenal histology and IEL-FC were available were identified. Catassi and Fasano's diagnostic criteria and changes to a CD diagnosis after the IEL-FCs were collected. RESULTS: A total of 348 patients were included. The following indications for an IEL-FC formed part of the initial study for CD (38%): negative conventional work-up (32%), already on a GFD before duodenal biopsies (29%) and refractoriness to a GFD (2%). The IEL-FC facilitated a definitive diagnosis in 93% of patients with an uncertain diagnosis who had had a conventional work-up for CD or who were on a GFD before histology. CONCLUSIONS: The IEL-FC facilitates the confirmation or rejection of a diagnosis of CD in clinical scenarios in which a conventional work-up may be insufficient.

Assessing the impact of haemodynamic monitoring with CardioMEMS on heart failure patients: a cost-benefit analysis.

AIMS: The objective of this study was to perform a cost-benefit analysis of the CardioMEMS HF System (Abbott Laboratories, Abbott Park, IL, USA) in a heart failure (HF) clinic in Spain by evaluating the real-time remote monitoring of pulmonary artery pressures, which has been shown to reduce HF-related hospitalizations and improve the quality of life for selected HF patients. Particularly, the study aimed to determine the value of CardioMEMS in Southern Europe, where healthcare costs are significantly lower and its effectiveness remains uncertain. METHODS AND RESULTS: This single-centre study enrolled all consecutive HF patients (N = 43) who had been implanted with a pulmonary artery pressure sensor (CardioMEMS HF System); 48.8% were females, aged 75.5 ± 7.0 years, with both reduced and preserved left ventricular ejection fraction; 67.4% of them were in New York Heart Association Class III. The number of HF hospitalizations in the year before and the year after the sensor implantation was compared. Quality-adjusted life years gained based on a literature review of previous studies were calculated. The rate of HF hospitalizations was significantly lower at 1 year compared with the year before CardioMEMS implantation (0.25 vs. 1.10 events/patient-year, hazard ratio 0.22, P = 0.001). At the end of the first year, the usual management outperformed the CardioMEMS HF System. By the end of the second year, the CardioMEMS system is estimated to reduce costs compared with usual management (net benefits of €346). CONCLUSIONS: Based on the results, we suggest that remote monitoring of pulmonary artery pressure with the CardioMEMS HF System represents a midterm and long-term efficient strategy in a healthcare setting in Southern Europe.

Hepatosplenic T-cell lymphoma and inflammatory bowel disease.

A 48-year-old man with a diagnosis of ulcerative colitis 18 years ago, under immunosuppressive treatment with azathioprine in the last 6 years due to corticosteroid dependence, was admitted to the Emergency Department due to fever of one week's evolution. Blood tests showed thrombocytopenia, CRP 96.9mg/L, ferritin 3021ng/mL and hypertriglyceridemia. Blood and urine cultures were negative. Viral serologies (hepatitis B and C, HIV, parvovirus, CMV, HSV), atypical bacteria (Borrelia, Chlamydia, Coxiella) and screening for latent tuberculosis were also negative. Thoracoabdominal CT scan only showed splenomegaly. The bone marrow aspirate revealed immature lymphoid cells and a hemophagocyte figure, fulfilling the criteria for hemophagocytic syndrome, starting corticosteroid therapy at a dose of 1mg/Kg. Subsequently, the existence of an intrasinusoidal CD3 + CD5- lymphoid infiltrate and a FISH study with isochromosome 7q was reported, a characteristic pattern of hepatosplenic T-cell lymphoma (HSTCL). The study was completed with liver biopsy appreciating a 70% infiltration of T lymphocytes (50% gamma-delta) therefore the diagnosis was confirmed. Chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide) was started with the aim of considering hematopoietic stem cell transplantation. Unfortunately, the patient died 6 months later.

The tonoplast localized protein PtNPF1 participates in the regulation of nitrogen response in diatoms.

Diatoms are a highly successful group of phytoplankton, well adapted also to oligotrophic environments and capable of handling nutrient fluctuations in the ocean, particularly nitrate. The presence of a large vacuole is an important trait contributing to their adaptive features. It confers diatoms the ability to accumulate and store nutrients, such as nitrate, when they are abundant outside and then to reallocate them into the cytosol to meet deficiencies, in a process called luxury uptake. The molecular mechanisms that regulate these nitrate fluxes are still not known in diatoms. In this work, we provide new insights into the function of Phaeodactylum tricornutum NPF1, a putative low-affinity nitrate transporter. To accomplish this, we generated overexpressing strains and CRISPR/Cas9 loss-of-function mutants. Microscopy observations confirmed predictions that PtNPF1 is localized on the vacuole membrane. Furthermore, functional characterizations performed on knock-out mutants revealed a transient growth delay phenotype linked to altered nitrate uptake. Together, these results allowed us to hypothesize that PtNPF1 is presumably involved in modulating intracellular nitrogen fluxes, managing intracellular nutrient availability. This ability might allow diatoms to fine-tune the assimilation, storage and reallocation of nitrate, conferring them a strong advantage in oligotrophic environments.

Bioceramic versus traditional biomaterials for endodontic sealers according to the ideal properties.

Odontology, as a scientific discipline, continuously collaborates with biomaterials engineering to enhance treatment characteristics and patients' satisfaction. Endodontics, a specialized field of dentistry, focuses on the study, diagnosis, prevention, and treatment of dental disorders affecting the dental pulp, root, and surrounding tissues. A critical aspect of endodontic treatment involves the careful selection of an appropriate endodontic sealer for clinical use, as it significantly influences treatment outcomes. Traditional sealers, such as zinc oxide-eugenol, fatty acid, salicylate, epoxy resin, silicone, and methacrylate resin systems, have been extensively used for decades. However, advancements in endodontics have given rise to bioceramic-based sealers, offering improved properties and addressing new challenges in endodontic therapy. In this review, a classification of these materials and their ideal properties are presented to provide evidence-based guidance to clinicians. Physicochemical properties, including sealing ability, stability over time and space, as well as biological properties such as biocompatibility and antibacterial characteristics, along with cost-effectiveness, are essential factors influencing clinicians' decisions based on individual patient evaluations.

Hepatosplenic T-cell lymphoma and inflammatory bowel disease

A 48-year-old man with a diagnosis of ulcerative colitis 18 years ago, under immunosuppressive treatment with azathioprine in the last 6 years due to corticosteroid dependence, was admitted to the Emergency Department due to fever of one week’s evolution. Blood tests showed thrombocytopenia, CRP 96.9mg/L, ferritin 3021ng/mL and hypertriglyceridemia. Blood and urine cultures were negative. Viral serologies (hepatitis B and C, HIV, parvovirus, CMV, HSV), atypical bacteria (Borrelia, Chlamydia, Coxiella) and screening for latent tuberculosis were also negative. Thoracoabdominal CT scan only showed splenomegaly. The bone marrow aspirate revealed immature lymphoid cells and a hemophagocyte figure, fulfilling the criteria for hemophagocytic syndrome, starting corticosteroid therapy at a dose of 1mg/Kg. Subsequently, the existence of an intrasinusoidal CD3 + CD5- lymphoid infiltrate and a FISH study with isochromosome 7q was reported, a characteristic pattern of hepatosplenic T-cell lymphoma (HSTCL). The study was completed with liver biopsy appreciating a 70% infiltration of T lymphocytes (50% gamma-delta) therefore the diagnosis was confirmed. Chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide) was started with the aim of considering hematopoietic stem cell transplantation. Unfortunately, the patient died 6 months later. (AU)

Evaluating Person-Centred Integrated Care to People with Complex Chronic Conditions: Early Implementation Results of the ProPCC Programme.

Introduction: The evaluation of integrated care programmes for high-need high-cost older people is a challenge. We aim to share the early implementation results of the ProPCC programme in the North-Barcelona metropolitan area, in Catalonia, Spain. Methods: We analysed the intervention with retrospective data from May 2018 to December 2021 by describing the cohort complexity and by showing its 6-months pre-post impact on time spent at home and resources used: primary care visits, emergency department visits, hospital admissions and hospital stay. Findings: 264 cases were included (91% at home; 9% in nursing homes). 6-month pre vs. 6-months post results were (mean, p-value): primary care visits 8.2 vs. 11.5 (p < 0.05); emergency department visits 1.4 vs. 0.9 (p < 0.05); hospital admissions 0.7 vs. 0.5 (p < 0.05); hospital stay 12.8 vs. 7.9 days (p < 0.05). Time spent at home was 169.2 vs.174.2 days (p < 0.05). Conclusion: Early implementation of the ProPCC programme results in an increase in time spent at home (up to 3%) and significant reductions in emergency department attendance (-37.2%) and hospital stays (-38.3%). The increased use of primary care resources is compensated by the hospital resources savings, with a result in the average total cost of -46.3%.

Prediction of adverse outcome by ophthalmic artery Doppler and angiogenic markers in pregnancies with new onset hypertension.

OBJECTIVES: To compare the ophthalmic artery Doppler peak systolic velocity ratio (OA PSV-ratio) and soluble fms-like tyrosine kinase-1/placental growth factor ratio (sFlt-1/PlGF ratio) in predicting adverse maternal and perinatal outcomes in women presenting with new onset hypertension. STUDY DESIGN: Prospective cohort study in a specialist hypertension clinic, within a tertiary referral centre. MAIN OUTCOME MEASURES: Comparison between the OA PSV-ratio and sFlt-1/PlGF ratio in predicting delivery within one week from presentation and adverse maternal and perinatal outcomes e.g. severe hypertension, neonatal unit admission, small for gestational age. RESULTS: Women who delivered within one week, compared to those who did not, had a higher OA PSV-ratio (0.82 vs 0.71, p < 0.01) and sFlt-1/PlGF ratio (93.3 vs 40.5, p = 0.08). Independent predictors of the OA PSV-ratio included mean arterial pressure and maternal weight and predictors of the sFlt-1/PlGF ratio included diastolic blood pressure and use of antihypertensive medications. Prediction of adverse outcomes with both ratios were similar and only modest e.g. AUROC for predicting delivery within one week for OA PSV-ratio was 0.57 (95% CI 0.47-0.67) and for sFlt-1/PlGF ratio was 0.61 (95% CI 0.52-0.70) (p = 0.53). CONCLUSIONS: In women presenting with new onset hypertension, the OA PSV-ratio and sFlt-1/PlGF ratio have similar and modest performance in predicting adverse outcomes.

Readiness for Change in the Implementation of a 3D Printing Initiative in a Catalan Tertiary Hospital Using the Normalization Process Theory: Survey Study.

BACKGROUND: The high failure rate of innovation projects motivates us to understand the perceptions about resistances and barriers of the main stakeholders to improving success rates. OBJECTIVE: This study aims to analyze the readiness for change in the implementation of a 3D printing project in a Catalan tertiary hospital prior to its implementation. METHODS: We used a web-based, voluntary, and anonymous survey using the Normalization Measurement Development questionnaire (NoMAD) to gather views and perceptions from a selected group of health care professionals at Germans Trias i Pujol University Hospital. RESULTS: In this study, 58 professionals, including heads of service (n=30, 51%), doctors (n=18, 31%), nurses (n=7, 12%), and support staff (n=3, 5%), responded to the questionnaire. All groups saw the value of the project and were willing to enroll and support it. Respondents reported the highest scores (out of 5) in cognitive participation (mean 4.45, SD 0.04), coherence (mean 3.72, SD 0.13), and reflective monitoring (mean 3.80, SD 0.25). The weakest score was in collective action (mean 3.52, SD 0.12). There were no statistically significant differences in scores among professions in the survey. CONCLUSIONS: The 3D printing project implementation should pay attention to preparing, defining, sharing, and supporting the operational work involved in its use and implementation. It should also understand, assess, and communicate the ways in which the new set of practices can affect the users and others around them. We suggest that health officers and politicians consider this experience as a solid ground toward the development of a more efficient health innovation system and as a catalyst for transformation.

Implementation of a vascular access specialist team in a tertiary hospital: a cost-benefit analysis.

BACKGROUND: The use of peripherally inserted central catheters and midline catheters is growing due to their potential benefits. These devices can increase patient safety and satisfaction while reducing the use of resources. As a result, many hospitals are establishing vascular access specialist teams staffed by nurses who are trained in the insertion and maintenance of these catheters. The objective of the study is to evaluate previously to the implementation whether the benefits of introducing ultrasound-guided peripheral venous catheters, midline catheters and peripherally inserted central catheters compared to current practice by a vascular access specialist team outweigh their costs. METHODS: Cost-benefit analysis from the perspective of the healthcare provider based on administrative data. The study estimates the reduction in resources used when changing the current practice for the use of ultrasound-guided midline and PICC catheters, as well as the additional resources required for their use. RESULTS: The use of an ultrasound-guided device on peripherally inserted central carheter, results in a measurable resource reduction of approximately €31. When 3 peripheral venous catheters are replaced by an ultrasound-guided peripherally inserted central catheter, the saving is €63. Similarly, the use of an ultrasound-guided device on a midline catheter, results in a reduction of €16, while each ultrasound-guided midline catheter replacing 3 peripheral venous catheters results in a reduction of €96. CONCLUSION: The benefits of using ultrasound-guided midline and PICC catheters compared to current practice by introducing a vascular access specialist team trained in the implantation of ultrasound-guided catheters, outweigh its cost mainly because of the decrease in hospital stay due to the lowered risk of phebitis. These results motivate the implementation of the service, adding to previous experience suggesting that it is also preferable from the point of view of patient safety and satisfaction.

Old poisons, new signaling molecules: the case of hydrogen cyanide.

The high phenotypic plasticity developed by plants includes rapid responses and adaptations to aggressive or changing environments. To achieve this, they evolved extremely efficient mechanisms of signaling mediated by a wide range of molecules, including small signal molecules. Among them, hydrogen cyanide (HCN) has been largely ignored due to its toxic characteristics. However, not only is it present in living organisms, but it has been shown that it serves several functions in all kingdoms of life. Research using model plants has changed the traditional point of view, and it has been demonstrated that HCN plays a positive role in the plant response to pathogens independently of its toxicity. Indeed, HCN induces a response aimed at protecting the plant from pathogen attack, and the HCN is provided either exogenously (in vitro or by some cyanogenic bacteria species present in the rhizosphere) or endogenously (in reactions involving ethylene, camalexin, or other cyanide-containing compounds). The contribution of different mechanisms to HCN function, including a new post-translational modification of cysteines in proteins, namely S-cyanylation, is discussed here. This work opens up an expanding 'HCN field' of research related to plants and other organisms.

A Mango Leaf Extract (Zynamite®) Combined with Quercetin Has Exercise-Mimetic Properties in Human Skeletal Muscle.

Zynamite PX®, a mango leaf extract combined with quercetin, enhances exercise performance by unknown molecular mechanisms. Twenty-five volunteers were assigned to a control (17 males) or supplementation group (8 males, receiving 140 mg of Zynamite® + 140 mg quercetin/8 h for 2 days). Then, they performed incremental exercise to exhaustion (IE) followed by occlusion of the circulation in one leg for 60 s. Afterwards, the cuff was released, and a 30 s sprint was performed, followed by 90 s circulatory occlusion (same leg). Vastus lateralis muscle biopsies were obtained at baseline, 20 s after IE (occluded leg) and 10 s after Wingate (occluded leg), and bilaterally at 90 s and 30 min post exercise. Compared to the controls, the Zynamite PX® group showed increased basal protein expression of Thr287-CaMKIIδD (2-fold, p = 0.007) and Ser9-GSK3ß (1.3-fold, p = 0.005) and a non-significant increase of total NRF2 (1.7-fold, p = 0.099) and Ser40-NRF2 (1.2-fold, p = 0.061). In the controls, there was upregulation with exercise and recovery of total NRF2, catalase, glutathione reductase, and Thr287-CaMKIIδD (1.2-2.9-fold, all p < 0.05), which was not observed in the Zynamite PX® group. In conclusion, Zynamite PX® elicits muscle signaling changes in resting skeletal muscle resembling those described for exercise training and partly abrogates the stress kinases responses to exercise as observed in trained muscles.

Importance of multiplanar reformation angiographic images for the detection of carotid web: A case series.

Carotid web (CW) is considered a variant of intimal fibromuscular dysplasia. CW represents between 9.4% and 37% of ischemic strokes that were initially misclassified as "cryptogenic." However, in Latin America, there is a lack of detection. We present 5 cases of ischemic stroke due to CW and discuss the usefulness of multiplanar reformatting (MPR) imaging in computed tomography angiography. The identification of CW with the use of tridimensional (3D) reconstructions and maximum intensity projection was 20%, the rest was misdiagnosed as atherosclerotic plaque. With the MPR, the identification of typical CW findings was improved, such as a thin septum, a shelf-like image, and a mountain shadow-like image. However, one must be alert to changes in the 3D disposition of the carotid bifurcation, as they may mask the typical CW findings. A good practice is to align the internal carotid artery exactly posterior to the external carotid artery in the sagittal plane.

Appropriateness of routine pre-endoscopic SARS-CoV-2 screening with RT-PCR in asymptomatic individuals and its impact on delayed diagnosis / Idoneidad del cribado pre-endoscópico rutinario de SARS-CoV-2 con RT-PCR en individuos asintomáticos y su impacto en la demora diagnóstica

Aims: Endoscopy units are considered to be at an increased risk of infection by SARS-CoV-2. Our aim is to assess the correlation between pre-endoscopic screening with reverse-transcription-polymerase-chain-reaction (RT-PCR) in asymptomatic individuals scheduled for elective endoscopy and the epidemiological data published by the local Health Administration. Patients and methods: Observational retrospective study collecting the results of our screening strategy spanning June/2020–June/2021, the effective potential growth (EPG), an index measuring the outbreak risk, and the 7 and 14-day cumulative incidence (CI). Indication, delay and the findings of the endoscopic examinations were registered for RT-PCR positive patients. Results: A total of 5808 tests were performed, yielding 125 positive results (2.15%). All positive tests occurred in weeks of high/very high risk (EPG>100) with the highest monthly rate being 9.36%, recorded in January/2021. A significant correlation (rho=0.796; p<0.001) between weekly positive rates and EPG was observed, and a significantly lower weekly number of positive tests was recorded when EPG<100. Planning the screening strategy one week ahead according to EPG>100 would have avoided up to 826 tests with only one positive result to account for. One hundred and thirteen individuals tested positive and 89 endoscopies were delayed. The most common findings were colon polyps, colorectal cancer and gastric metaplasia. Oncological diagnosis was delayed 50±3 days. Conclusions: No positive RT-PCR test were registered out of high-risk periods. Epidemiological administrative data in the preceding two weeks showed a significant correlation with screening results and could be useful to plan pre-endoscopic screening and avoid unnecessary tests.(AU)

Antecedentes: La actividad endoscópica comporta un riesgo elevado de transmisión de la infección por SARS-CoV-2. Nuestro objetivo es valorar la correlación entre el cribado pre-endoscópico con reverse-transcription-polymerase-chain-reaction (RT-PCR) en individuos asintomáticos programados para una endoscopia ambulatoria y los datos epidemiológicos publicados por el departamento de salud pública. Pacientes y métodos: Estudio observacional retrospectivo de los resultados del cribado realizado entre junio/2020 y junio/2021. Se registró el índice de crecimiento potencial (ICP) y la incidencia acumulada a 7 y 14 días. En los pacientes con RT-PCR positiva se registraron indicación, demora y hallazgos endoscópicos. Resultados: Se identificaron un total de 5.808 test con 125 resultados positivos (2,15%). Todos los resultados positivos se registraron en semanas consideradas de alto/muy alto riesgo (ICP>100), con una tasa máxima de positivos del 9,26% en enero/2021. Se observó una correlación significativa (rho=0,796; p<0,001) entre la tasa de positivos y el ICP, así como una diferencia estadísticamente significativa con la tasa de positivos en las semanas con el ICP<100. Planificar el cribado acorde al ICP>100 en la semana previa, habría evitado hasta 876 test, con un único resultado positivo. Ciento trece pacientes resultaron positivos y se demoraron 89 endoscopias; los hallazgos más frecuentes fueron pólipos, cáncer colorrectal y metaplasia gástrica. El diagnóstico oncológico se demoró 50±3 días. Conclusiones: No se registraron RT-PCR positivas fuera de los períodos de alto riesgo. Los datos epidemiológicos de las dos semanas anteriores mostraron una correlación significativa con los resultados del cribado y podrían ser útiles para planificar el mismo y evitar pruebas innecesarias.(AU)

Cost-effectiveness analysis of the daily HIV pre-exposure prophylaxis in men who have sex with men in Barcelona.

INTRODUCTION: Pre-Exposure Prophylaxis (PrEP) for HIV prevention has been implemented in several countries. Previous literature has shown that its cost-effectiveness (and, under some specifications, cost-saving character) is dependent on the reduction in price due to generics, the time-horizon and its effectiveness. The intervention has never been studied in Catalonia after the approval of the PrEP, a territory with extensive implementation. METHODS: Economic evaluation of the implementation of HIV pre-exposition prophylaxis using administrative data from Men who have Sex with Men (MSM) who receive the treatment (at the generic price) compared with non-implementation. A deterministic compartmental model and a social perspective with a micro-costing approach over the time horizon 2022-2062 are used. A baseline 86% effectiveness of PrEP is assumed. RESULTS: Daily oral PrEP is found to be cost-saving: discounted savings in costs are attained after 16 years, and after 40 years they reach 81 million euros. In terms of health indicators, 10,322 additional discounted QALYs are generated by the intervention. Results are sensitive to sexual behavioral patterns among MSM, the price of PrEP (reduced if offered on-demand), its effectiveness and the discount rate. CONCLUSIONS: The use and promotion of PrEP in Catalonia is predicted to result in substantial health and monetary benefits because of reductions in HIV infections. Short-term investments in the promotion of PrEP will result in important cost-savings in the long term.