Safety and immunogenicity of a recombinant protein RBD fusion heterodimer vaccine against SARS-CoV-2.

In response to COVID-19 pandemic, we have launched a vaccine development program against SARS-CoV-2. Here we report the safety, tolerability, and immunogenicity of a recombinant protein RBD fusion heterodimeric vaccine against SARS-CoV-2 (PHH-1V) evaluated in a phase 1-2a dose-escalation, randomized clinical trial conducted in Catalonia, Spain. 30 young healthy adults were enrolled and received two intramuscular doses, 21 days apart of PHH-1V vaccine formulations [10 µg (n = 5), 20 µg (n = 10), 40 µg (n = 10)] or control [BNT162b2 (n = 5)]. Each PHH-1V group had one safety sentinel and the remaining participants were randomly assigned. The primary endpoint was solicited events within 7 days and unsolicited events within 28 days after each vaccination. Secondary endpoints were humoral and cellular immunogenicity against the variants of concern (VOCs) alpha, beta, delta and gamma. All formulations were safe and well tolerated, with tenderness and pain at the site of injection being the most frequently reported solicited events. Throughout the study, all participants reported having at least one mild to moderate unsolicited event. Two unrelated severe adverse events (AE) were reported and fully resolved. No AE of special interest was reported. Fourteen days after the second vaccine dose, all participants had a >4-fold change in total binding antibodies from baseline. PHH-1V induced robust humoral responses with neutralizing activities against all VOCs assessed (geometric mean fold rise at 35 days p < 0.0001). The specific T-cell response assessed by ELISpot was moderate. This initial evaluation has contributed significantly to the further development of PHH-1V, which is now included in the European vaccine portfolio.ClinicalTrials.gov Identifier NCT05007509EudraCT No. 2021-001411-82.

Disposition of Work-Related Asthma in a Spanish Asthma Cohort: Comparison of Asthma Severity Between Employed and Retired Workers.

BACKGROUND: Exposure to certain agents in the workplace can trigger occupational asthma or work-exacerbated asthma, both of which come under the heading of work-related asthma (WRA). Understanding the burden that WRA represents can help in the management of these patients. OBJECTIVE: To assess the influence of occupation on asthma in real life and analyze the characteristics of patients with WRA included in an asthma cohort. METHODS: This was a prospective multicenter study of a cohort of consecutive patients with asthma. A standardized clinical history was completed. Patients were classified as having WRA or non-WRA. All patients underwent respiratory function tests, FeNO test, and methacholine challenge (methacholine concentration that causes a 20% drop in FEV1) at the beginning of the study. They were classified into two groups, depending on their employment status: employed (group 1) or unemployed (group 2). RESULTS: Of the 480 patients included in the cohort, 82 (17%) received the diagnosis of WRA. Fifty-seven patients (70%) were still working. Mean age (SD) was 46 (10.69) years in group 1 and 57 (9.91) years in group 2 (P < .0001). Significant differences were observed in adherence to treatment (64.9% in group 1 vs 88% in group 2; P = .0354) and in severe asthma exacerbations (35.7% in group 1 vs 0% in group 2; P = .0172). No significant differences were observed in the rest of the variables analyzed. CONCLUSIONS: The burden of WRA in specialized asthma units is not negligible. The absence of differences in the severity of asthma, the treatment administered, alterations in lung function, and the number of exacerbations in those working versus not working may support the idea that advice regarding changing jobs should be customized for individual patients.

¿Cuál es la utilidad del test de inhibidores de la bomba de protones en el dolor torácico no cardíaco? / What is the utility of proton pump inhibitor testing in non-cardiac chest pain?

FUNDAMENTOS Y OBJETIVO: El dolor torácico no cardíaco (DTNC) representa frecuentemente un problema diagnóstico y terapéutico complejo. Dado que la enfermedad por reflujo gastroesofágico (ERGE) es la causa más frecuente de DTNC, se ha propuesto la estrategia clínica de tratar con doble dosis de inhibidores de la bomba de protones (IBP) a todos los pacientes con DTNC, y reservar el estudio funcional únicamente para los pacientes que no respondan al tratamiento antisecretor. El objetivo del presente estudio es aportar evidencias de la utilidad clínica del test con doble dosis de pantoprazol en pacientes con DTNC. Pacientes y métodos: Estudio de rendimiento diagnóstico con diseño de cohortes en pacientes con DTNC remitidos por el Servicio de Cardiología. A todos los pacientes se les realizó endoscopia digestiva alta, manometría esofágica y pHmetría esofágica de 24 h antes del test de IBP con pantoprazol 40 mg cada 12 h durante un mes. Antes y después del tratamiento se evaluó la severidad (intensidad y frecuencia) del dolor torácico, la calidad de vida y la ansiedad y depresión mediante cuestionarios. El diagnóstico de ERGE se basó en la pHmetría de 24 h y se estableció por el criterio del porcentaje total de tiempo con un pH < 4 superior al 4,2% Se consideró respondedor al test de IBP si la mejoría del dolor torácico después de un mes de tratamiento con IBP fue > 50% respecto a la puntuación basal. Resultados: Se incluyeron 30 pacientes consecutivos (17 hombres/13 mujeres) con una media de edad de 49 años. Presentaban ERGE 20 de los 30 pacientes con DTNC (67%; IC 95%: 47-83%). Fueron respondedores al tratamiento con IBP 13 de los 30 (43%) pacientes con DTNC: 11 de los 20 (55%) pacientes del grupo ERGE-positivo y 2 de los 10 (20%) del grupo ERGE-negativo. La sensibilidad, la especificidad, el valor predictivo positivo, el valor predictivo negativo y la precisión del test de IBP fue del 55, del 80, del 85, del 47 y del 63%, respectivamente. El grupo ERGE-positivo con respecto al grupo ERGE-negativo presentó una reducción significativa del dolor torácico postratamiento con pantoprazol (p = 0,003) y una mejoría en la ansiedad y depresión que no alcanzó la significación estadística. La calidad de vida no se vio afectada. Conclusiones: En el DTNC, el test de IBP con pantoprazol tiene una baja sensibilidad para el diagnóstico de la ERGE y cuestiona reservar el estudio funcional únicamente para los pacientes que no respondan al tratamiento antisecretor. El estudio funcional permitiría un diagnóstico inicial más preciso y ofrecer un tratamiento dirigido más adecuado a todos los pacientes con DTNC

BACKGROUND AND AIMS: Noncardiac chest pain (NCCP) often represents a diagnostic and therapeutic challenge. Given that gastroesophageal reflux disease (GERD) is the most common cause of NCCP, initial treatment with proton-pump inhibitors (PPI) has been proposed for all patients (PPItesting), reserving esophageal function testing solely for non-responders. The aim of the present study was to provide evidence on the clinical utility of PPI testing with high-dose pantoprazole in patients with NCCP.PATIENTS AND METHODS: We carried out a study of diagnostic performance with a cohort design in patients with NCCP, who had been assessed by the Cardiology Service. All patients underwent upper endoscopy, esophageal manometry, and 24h esophageal pH monitoring before PPI testing with pantoprazole 40mg every 12h for 1month. Before and after treatment, we assessed the severity (intensity and frequency) of chest pain, quality of life, and anxiety and depression by means of specific questionnaires. The diagnosis of GERD was based on a pathological finding of esophageal pH monitoring. A positive response to PPI testing was defined as an improvement in chest pain >50% compared with the baseline score after 1month of PPI therapy. RESULTS: We included 30 consecutive patients (17men/13women) with a mean age of 49years. Of these 30 patients, 20 with NCCP had GERD (67%, 95%CI: 47%-83%). A positive response to PPI therapy was observed in 13 of the 30 (43%) patients with NCCP: 11 of the 20 (55%) patients in the GERD-positive group and 2 of the 10 (20%) in the GERD-negative group. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PPI testing was 55%, 80%, 85%, 47% and 63%, respectively. A significant reduction in chest pain after pantoprazole therapy (P=.003) and a slight non significant improvement in anxiety and depression was achieved in the GERD-positive group as compared to the GERD-negative group. Conclusions: In NCCP, PPI testing with pantoprazole has a low sensitivity for the diagnosis of GERD, placing in doubt the strategy of reserving functional study to non-responders to antisecretory therapy. Esophageal function testing and accurate diagnosis would allow appropriate targeted therapy for all patients with NCCP

[What is the utility of proton pump inhibitor testing in non-cardiac chest pain?]. / ¿Cuál es la utilidad del test de inhibidores de la bomba de protones en el dolor torácico no cardíaco?

BACKGROUND AND AIMS: Noncardiac chest pain (NCCP) often represents a diagnostic and therapeutic challenge. Given that gastroesophageal reflux disease (GERD) is the most common cause of NCCP, initial treatment with proton-pump inhibitors (PPI) has been proposed for all patients (PPI testing), reserving esophageal function testing solely for non-responders. The aim of the present study was to provide evidence on the clinical utility of PPI testing with high-dose pantoprazole in patients with NCCP. PATIENTS AND METHODS: We carried out a study of diagnostic performance with a cohort design in patients with NCCP, who had been assessed by the Cardiology Service. All patients underwent upper endoscopy, esophageal manometry, and 24h esophageal pH monitoring before PPI testing with pantoprazole 40 mg every 12h for 1 month. Before and after treatment, we assessed the severity (intensity and frequency) of chest pain, quality of life, and anxiety and depression by means of specific questionnaires. The diagnosis of GERD was based on a pathological finding of esophageal pH monitoring. A positive response to PPI testing was defined as an improvement in chest pain >50% compared with the baseline score after 1 month of PPI therapy. RESULTS: We included 30 consecutive patients (17 men/13 women) with a mean age of 49 years. Of these 30 patients, 20 with NCCP had GERD (67%, 95%CI: 47%-83%). A positive response to PPI therapy was observed in 13 of the 30 (43%) patients with NCCP: 11 of the 20 (55%) patients in the GERD-positive group and 2 of the 10 (20%) in the GERD-negative group. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PPI testing was 55%, 80%, 85%, 47% and 63%, respectively. A significant reduction in chest pain after pantoprazole therapy (P=.003) and a slight non significant improvement in anxiety and depression was achieved in the GERD-positive group as compared to the GERD-negative group. CONCLUSIONS: In NCCP, PPI testing with pantoprazole has a low sensitivity for the diagnosis of GERD, placing in doubt the strategy of reserving functional study to non-responders to antisecretory therapy. Esophageal function testing and accurate diagnosis would allow appropriate targeted therapy for all patients with NCCP.

IMRT: preliminary results in a series of advanced head-and-neck cancer patients.

PURPOSE: To determine retrospectively 2-3 year local and regional control (LRC), free-of-disease survival (FDS) and overall survival (OS), as well as summarized toxicities in a group of 31 advanced head-and-neck cancer patients, treated at our institution between 2004 and 2011 with definitive IMRT low-dose concomitant boost, the majority of them with concurrent chemotherapy based on cisplatin. The results are also shown in the sub-group of nasopharyngeal cancer patients (NPC: 15 cases). PATIENTS AND METHODS: Radiological basal and contrasted CT series, MR-CT or PET/CT fused images in the setup position with immobilization mask were registered in simulation therapy patients. Planed doses were: 70 Gy in primary tumor and positive nodes >1 cm; 63 Gy in high-risk areas of microscopic diseases +10 mm safety margin; and 56 Gy in low risk of diseases regional lymph nodes. Treatment was delivered using a Varian 2100 Clinac with sliding windows IMRT. Spinal cord doses were limited to a strict maximum of 45 Gy, and optimization aimed for mean doses in parotid glands below 26 Gy, especially in the contralateral parotid gland. Online DRR-portal X-ray comparison images were taken every day with a deviation module tolerance ≤3 mm. RESULTS: The mean follow-up since IMRT was 34 months (interval: 8-89; median 31 months). Median follow-up in living patients was 22 months. The 2-year rate for global LRC was 64 %, for FDS 61 % and OS 77 %. For the NPC group after 2 years, LRC was 73 %, FDS 73 % and OS 93 %. The 3-year rates were similar. Seven patients died as a consequence of local and/or regional progression (mean time 10 months). Relapses were observed in eight patients (26 %), but only seven could be confirmed by biopsy (22.6 %; mean time to relapse: 8.6 months). Global acute mucositis was 61 % and chronic mucositis was shown in six cases which developed xerostomia (19 %) in the first control after IMRT, but 1 year later it was reduced to only four patients, two Grade 2 and two Grade 1. CONCLUSIONS: No excessive, unwarranted toxicities were observed using concomitant low doses boost in IMRT. High rates of compliance to concurrent chemotherapy were achieved. Late xerostomia associated with this regime decreased 1 year after conclusion of treatment. The implementation of IMRT requires advances in imaging for better tumor delineation; otherwise the physician loses the advantage of dose modulation or faces a risk of geographical miss.

A randomized, double-blind, placebo controlled-trial of triflusal in mild cognitive impairment: the TRIMCI study.

BACKGROUND: Amnestic mild cognitive impairment represents, in many cases, the earliest clinical phases of Alzheimer disease. Anti-inflammatory agents have epidemiologic support as drugs potentially beneficial in Alzheimer disease. In vivo studies have shown that Triflusal and its active metabolite 2-hydroxy-4-trifluoromethyl-benzoic acid have potent anti-inflammatory actions in the central nervous system. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of Triflusal in patients with amnestic mild cognitive impairment. Subjects were randomly assigned to receive 900 mg of Triflusal or placebo for 18 months. The primary outcome was a change in Cognitive subscale of the Alzheimer Disease Assessment Scale; conversion to dementia was a secondary outcome. RESULTS: A slow rate of recruitment forced a premature cessation of the study. Two hundred and fifty-seven subjects were enrolled and followed-up for an average of 13 months. The significance level was not reached for the primary outcome even though a trend in favor of Triflusal was observed. However, there was a significant difference in the probability of progression to dementia of Alzheimer's type with a lower risk in the Triflusal compared with the placebo group (hazard ratio, 2.10; 95% confidence interval, 1.10-4.01; P=0.024). CONCLUSIONS: In this study, Triflusal therapy was associated with a significant lower rate of conversion to dementia that is likely to be clinically relevant. Because the trial was prematurely halted, these results should be interpreted with caution and require further confirmation.