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This paper describes the reforms recommended by the Advisory Committee on the Financing of Pharmaceuticals (CAPF) for the National Health System (NHS) of Spain from 2019 to 2024 for the drug pricing and reimbursement process, to integrate economic evaluations and improve efficiency and sustainability. The CAPF has proposed a three-phase reform of the economic evaluation (EE) and budget impact analysis (BIA) processes. The first phase involves the mandatory submission of EE and BIA by applicants for new drugs. The second phase involves the assessment of these submissions, coordinated by the Directorate-General for Pharmaceuticals. The third phase focuses on the application of these assessments to decision-making on drug positioning, pricing and financing. The CAPF's recommendations emphasise improved regulation, transparency and the development of methodological guidelines for economic evaluations. These proposals include a dynamic appraisal system and the creation of official NHS guidance on EE and BIA. The process is designed to ensure compliance with established criteria and to incorporate efficiency into decision-making. The initiatives of the CAPF aim to make progress towards the integration of efficiency in Spanish pharmaceutical policy seeking to improve the methodological quality and transparency of economic evaluations, ultimately contributing to more informed decision-making and sustainable healthcare practices. Resumen: Este artículo describe las reformas recomendadas por el Comité Asesor para la Financiación de la Prestación Farmacéutica (CAPF) del Sistema Nacional de Salud (SNS) de España entre 2019 y 2024 en el proceso de fijación de precios y reembolso de medicamentos, con el fin de integrar evaluaciones económicas y mejorar la eficiencia y la sostenibilidad. El CAPF ha propuesto una reforma en tres fases de los procesos de evaluación económica (EE) y análisis de impacto presupuestario (AIP). La primera fase implica la presentación obligatoria de EE y AIP por parte de los solicitantes de nuevos medicamentos. La segunda fase implica la evaluación de estas presentaciones, coordinada por la Dirección General de Farmacia. La tercera fase se centra en la aplicación de estas evaluaciones en la toma de decisiones sobre el posicionamiento, la fijación de precios y la financiación de los medicamentos. Las recomendaciones del CAPF destacan la mejora de la regulación, la transparencia y el desarrollo de directrices metodológicas para las EE. Estas propuestas incluyen un sistema de evaluación dinámico y la creación de una guía oficial del SNS sobre EE y AIP. El proceso está diseñado para garantizar el cumplimiento de los criterios establecidos e incorporar la eficiencia en la toma de decisiones. Las propuestas del CAPF tienen como objetivo avanzar hacia la integración de la eficiencia en la política farmacéutica española y buscan mejorar la calidad metodológica y la transparencia de las EE, contribuyendo en última instancia a una toma de decisiones más informada y a prácticas de atención sanitaria sostenibles.

Summary: Nerve growth factor receptor (NGFR) is expressed by follicular dendritic cells (FDCs). However, the role of NGFR in the humoral response is not well defined. Here, we study the effect of Ngfr loss on lymph node organization and function, demonstrating that Ngfr depletion leads to spontaneous germinal center (GC) formation and an expansion of the GC B cell compartment. In accordance with this effect, stromal cells are altered in Ngfr−/− mice with a higher frequency of FDCs, characterized by CD21/35, MAdCAM-1, and VCAM-1 overexpression. GCs are located ectopically in Ngfr−/− mice, with lost polarization together with impaired high-affinity antibody production and an increase in circulating autoantibodies. We observe higher levels of autoantibodies in Bcl2 Tg/Ngfr−/− mice, concomitant with a higher incidence of autoimmunity and lower overall survival. Our work shows that NGFR is involved in maintaining GC structure and function, participating in GC activation, antibody production, and immune tolerance.

Summary: Background: Anti-COVID-19 hyperimmune immunoglobulin (hIG) can provide standardized and controlled antibody content. Data from controlled clinical trials using hIG for the prevention or treatment of COVID-19 outpatients have not been reported. We assessed the safety and efficacy of subcutaneous anti-COVID-19 hyperimmune immunoglobulin 20% (C19-IG20%) compared to placebo in preventing development of symptomatic COVID-19 in asymptomatic individuals with SARS-CoV-2 infection. Methods: We did a multicentre, randomized, double-blind, placebo-controlled trial, in asymptomatic unvaccinated adults (≥18 years of age) with confirmed SARS-CoV-2 infection within 5 days between April 28 and December 27, 2021. Participants were randomly assigned (1:1:1) to receive a blinded subcutaneous infusion of 10 mL with 1 g or 2 g of C19-IG20%, or an equivalent volume of saline as placebo. The primary endpoint was the proportion of participants who remained asymptomatic through day 14 after infusion. Secondary endpoints included the proportion of individuals who required oxygen supplementation, any medically attended visit, hospitalisation, or ICU, and viral load reduction and viral clearance in nasopharyngeal swabs. Safety was assessed as the proportion of patients with adverse events. The trial was terminated early due to a lack of potential benefit in the target population in a planned interim analysis conducted in December 2021. ClinicalTrials.gov registry: NCT04847141. Findings: 461 individuals (mean age 39.6 years [SD 12.8]) were randomized and received the intervention within a mean of 3.1 (SD 1.27) days from a positive SARS-CoV-2 test. In the prespecified modified intention-to-treat analysis that included only participants who received a subcutaneous infusion, the primary outcome occurred in 59.9% (91/152) of participants receiving 1 g C19-IG20%, 64.7% (99/153) receiving 2 g, and 63.5% (99/156) receiving placebo (difference in proportions 1 g C19-IG20% vs. placebo, −3.6%; 95% CI -14.6% to 7.3%, p = 0.53; 2 g C19-IG20% vs placebo, 1.1%; −9.6% to 11.9%, p = 0.85). None of the secondary clinical efficacy endpoints or virological endpoints were significantly different between study groups. Adverse event rate was similar between groups, and no severe or life-threatening adverse events related to investigational product infusion were reported. Interpretation: Our findings suggested that administration of subcutaneous human hyperimmune immunoglobulin C19-IG20% to asymptomatic individuals with SARS-CoV-2 infection was safe but did not prevent development of symptomatic COVID-19. Funding: Grifols.

Scrophularia arguta (Scrophulariaceae) is a rare amphicarpic annual species with a fragmented distribution in North Africa, part of the Arabian Peninsula, and Macaronesia, with several peripheral populations on the Iberian Peninsula (south-western Europe) as well. The Iberian populations have a disjunct distribution: several endangered or critically endangered populations are present in the southeast versus a few non-listed ones representing a relict lineage with a unique plastid haplotype inhabiting the west-central region (Extremadura). In this study, we examined the largest and most important population of this relict lineage to assess potential threats to its survival. We evaluated pollination and reproductive systems, floral rewards, fruit and seed set from chasmogamous and cleistogamous flowers, and population dynamics (i.e., phenology, survival, reproductive success, and predation level). We found that the main threats to the population are predation by wild herbivores, such as red deer and, to a lesser extent, Cucullia scrophulariae caterpillars. These threats decrease reproductive success to such an extent that population survival may be in jeopardy if no action is taken to reduce the effects of herbivores. In addition, the existence of nearby beehives alters the presence and density of wild pollinators that contribute to gene flow via pollen transfer and increase genetic variability. Cleistogamous seeds may help maintain the population in specific microhabitats (mainly quartzite rock cracks), although at the cost of reducing genetic variability. Finally, we recommend that regional/national administrations responsible for biodiversity matters adopt measures to ensure the conservation and survival of west-central populations.

Background/purpose: There are few studies comparing the expression of enamel proteins, such as amelogenin, and cytokeratins in cyst and odontogenic tumors like in ameloblastoma and odontogenic keratocyst, indicating that amelogenin could be a potential biomarker for the aggressiveness in the odontogenic tumors. The aim of this study was to evaluate if the expression of amelogenin, cytokeratin AE1/AE3 (CKAE1/AE3) and cytokeratin 14 (CK14) in cysts and odontogenic tumors with calcified matrices such as calcifying odontogenic cyst (COC), compound (CdO) and complex (CxO) odontomas, adenomatoid odontogenic tumor (AOT) and calcifying epithelial odontogenic tumor (CEOT) as an aggressiveness indicator. Materials and methods: Three COC, eight CxO, three CdO, twelve AOT, two CEOT and three dental germs were submitted to an immunohistochemistry panel of antibodies composed of amelogenin, CKAE1/AE3 and CK14. Results: CKAE1/AE3 and CK14 was present in all odontogenic epithelia. The amelogenin protein was detected in prismatic and amorphous calcified matrices of epithelial origin belonging to CxO, CdO, AOT, COC and the tooth germs used as controls. On the other hand, the CEOT was the only tumor or cyst studied that did not present immunostaining for amelogenin in calcified matrices. Conclusion: Amelogenin was detected in pathologies with a low or absent recurrence rate and excellent prognosis. CEOT was the lesion of greater clinical aggressiveness which did not express amelogenin. The presence of amelogenin in calcified matrices of odontogenic arise could be an indicator of low aggressiveness.

Objective: Patients included in MAINRITSAN2 trial received either an individually tailored or a fixed-schedule therapy with rituximab as maintenance treatment of antineutrophil cytoplasm antibody associated vasculitides. The aim of this study was to compare the real-world costs of both arms. Method: We performed a cost-minimization analysis over an 18-month time period, estimating direct costs –drug acquisition, preparation, administration and monitoring costs– from the health system perspective. We conducted a number of additional sensitivity analyses with different assumptions for unit costs, with further scenarios including the interquartile range of the tailored-infusion group results, different number of monitoring visits for fixed-schedule regimen and different number of reported severe adverse events. A cost- effectiveness analysis was conducted as a sensitivity analysis using the absolute difference in the relapse rate and its confidence interval. Results: The individually tailored maintenance therapy with rituximab was shown to be a cost-saving treatment compared to the fixed-schedule therapy (6,049 euros vs. 7,850 euros). Savings resulted primarily from lower drug acquisition costs (2,861 vs. 4,768 euros) and lower preparation and administration costs (892 vs. 1,486 euros), due to the lower number of infusions per patient in the tailored-infusion regimen. The tailoredinfusion regimen presented higher monitoring costs (2,296 vs. 1,596 euros). This result was replicated in all assumptions considered in the sensitivity analysis of cost-minimization approach. Conclusions: From the perspective of the health system, the tailoredtherapy regimen seems to be the preferable option in terms of direct costs. Further studies assessing all the effects and costs associated to vasculitides maintenance treatment with rituximab are needed to support clinical management and healthcare planning.

The addition of a fourth year to the hospital pharmacy residency program has allowed trainees to rotate through various inpatient clinical units where they can, under the supervision of a specialist pharmacist, work shoulder to shoulder with other healthcare providers to ensure that patients receive the care they need. In addition to sharing their pharmacotherapeutic and pharmacokinetic knowledge (among others) with their colleagues, hospital pharmacists can and should contribute with their expertise in the areas of drug evaluation, selection and positioning. As no other healthcare professional masters like a pharmacist the intricacies of treatment efficacy or effectiveness, or of therapeutic safety, conveying this knowledge is yet another of the many clinical activities a hospital pharmacist must perform as a member of a multidisciplinary team, while assisting fellow-team members in deciding what medications are best suited to each patient. Both the public authorities and the pharmaceutical profession as a whole should make sure the pharmacist’s role is rightfully valued and given the recognition it deserves.

This study aimed to evaluate the ages of attainment of the different stages of third molar development in Chileans. We evaluated of 1236 panoramic radiographs of individuals aged between 13 and 26 years. Demirjian's stages of dental development for the upper and lower third molars were recorded in relation to chronological age, and further statistical analysis was performed. The maxillary third molars reached almost all stages of development earlier than the mandibular third molars in both male and female individuals, but with significant differences in the chronological mean ages only at stages F and H for male individuals, and F, G, and H for females. The third molar tended to mature faster in male than in female individuals, but significant differences were found only at stage H for both the maxilla and mandible, and at stages F and G for the mandible. Comparison between the mean ages of Chileans with the mean ages reported previously in a Caucasian North American population showed that the Chilean sample had an earlier maturation of the third molar in stages D to G, up to 2.52 years. The data obtained in this study might be useful for the identification of modern Chilean human remains with incomplete third molar development.

Summary: B lymphocytes are exquisitely sensitive to fluctuations in nutrient signaling by the Rag GTPases, and 15% of follicular lymphomas (FLs) harbor activating mutations in RRAGC. Hence, a potential therapeutic approach against malignant B cells is to inhibit Rag GTPase signaling, but because such inhibitors are still to be developed, efficacy and safety remain unknown. We generated knockin mice expressing a hypomorphic variant of RagC (Q119L); RagCQ119L/+ mice are viable and show attenuated nutrient signaling. B lymphocyte activation is cell-intrinsically impaired in RagCQ119L/+ mice, which also show significant suppression of genetically induced lymphomagenesis and autoimmunity. Surprisingly, no overt systemic trade-offs or phenotypic alterations caused by partial suppression of nutrient signaling are seen in other organs, and RagCQ119L/+ mice show normal longevity and normal age-dependent health decline. These results support the efficacy and safety of moderate inhibition of nutrient signaling against pathological B cells.

Objective: to determine the incidence of linezolid-induced haematological toxicity and study the influence of renal clearance on its appearance and the preventive effect of pyridoxine. Methods: a retrospective observational study was conducted. Every patient treated with linezolid in a university hospital during 6 months was included. Haematological toxicity was defined as a decrease of 25% in hemoglobin, of 25% in platelets and/or 50% in neutrophils from baseline. The incidence of haematological toxicity and the percentage decrease in analytical variables were compared in patients with and without renal failure (creatinine clearance lower than 50 mL/min), using the 30 mL/min threshold, and with or without pyridoxine; using Chi -Square and U Mann-Whitney tests, respectively. Results: thirty-eight patients were evaluated. Sixteen (42%) presented haematological toxicity (2 due to a decrease in haemoglobin, 9 in platelets and 8 in neutrophils). Two patients (5%) discontinued treatment due to thrombocytopenia. Toxicity incidence was similar in patients with and without renal failure, 42% vs 42%, p = 0.970, with more or less than 30 ml/min, 67% vs 40%, p = 0.369, or with or without pyridoxine, 47.8% vs 33%, p = 0.376. Patients with renal failure had a significantly greater reduction in platelet count, p = 0.0185. Conclusion: forty-two percent of patients had haematological toxicity, being more frequent platelets and neutrophils reduction. This was not significantly higher in patients with renal failure or in those without pyridoxine. Greater reduction in platelet count was observed in patients with renal failure

Objective: economic evaluation is a fundamental criterion when deciding a drug’s place in therapy. The MADRE method (Method for Assistance in making Decisions and Writing Drug Evaluation Reports) is widely used for drug evaluation. This method was developed by the GENESIS group of the Spanish Society of Hospital Pharmacy (SEFH), including economic evaluation. We intend to improve the economic aspects of this method. As for the direction to take, we have to first analyze our previous experiences with the current methodology and propose necessary improvements. Method: economic evaluation sections in collaboratively conducted drug evaluation reports (as the scientific society, SEFH) with the MADRE method were reviewed retrospectively. Results: thirty-two reports were reviewed, 87.5% of them included an economic evaluation conducted by authors and 65.6% contained published economic evaluations. In 90.6% of the reports, a Budget impact analysis was conducted. The cost per life year gained or per Quality Adjusted Life Year gained was present in 14 reports. Twenty-three reports received public comments regarding the need to improve the economic aspect. Main difficulties: low quality evidence in the target population, no comparative studies with a relevant comparator, non-final outcomes evaluated, no quality of life data, no fixed drug price available, dosing uncertainty, and different prices for the same drug. Conclusions: proposed improvements: incorporating different forms of aid for non-drug costs, survival estimation and adapting published economic evaluations; establishing criteria for drug price selection, decision-making in conditions of uncertainty and poor quality evidence, dose calculation and cost-effectiveness thresholds depending on different situations.

The long-term risk of malignancy associated with stem cell therapies is a significant concern in the clinical application of this exciting technology. We report a cancer-selective strategy to enhance the safety of stem cell therapies. Briefly, using a cell engineering approach, we show that aggressive cancers derived from human or murine induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) are strikingly sensitive to temporary MYC blockade. On the other hand, differentiated tissues derived from human or mouse iPSCs can readily tolerate temporary MYC inactivation. In cancer cells, endogenous MYC is required to maintain the metabolic and epigenetic functions of the embryonic and cancer-specific pyruvate kinase M2 isoform (PKM2). In summary, our results implicate PKM2 in cancer’s increased MYC dependence and indicate dominant MYC inhibition as a cancer-selective fail-safe for stem cell therapies.