Corrigendum Research priority-setting is an ethics exercise: lessons from the Global Forum on Bioethics in Research for the Region of the Americas / Corrigendum La priorización de la investigación es un ejercicio ético: lecciones del Foro Global de Bioética en la Investigación para la Región de las Américas / Corrigendum à Priorização da pesquisa é um exercício ético: lições do Fórum Global de Bioética em Pesquisa para a Região das Américas

The Pan American Journal of Public Health draws readers' attention to an error in the following article, pointed out by the authors: Saenz C, Carracedo S, Caballero C, Hurtado C, Leite Ribeiro A, Luna F, et al. Research priority-setting is an ethics exercise: lessons from the Global Forum on Bioethics in Research for the Region of the Americas. Rev Panam Salud Publica. 2024;48:e32. https://doi.org/10.26633/RPSP.2024.32 In article published on March 2024, reference 2 appears as follows: Global Forum on Bioethics in Research. GFBR 2023 Key- note presentation [Internet video]. Youtube. 2024 Feb 01 [cited 2024 Feb 13]. Available from: https://www.youtube.com/ watch?v=HlPgN6n6i8M The correct way to reference 2 is: Millum J. Ethics of health research priority setting [video]. Uploaded by Global Forum on Bioethics in Research, 1 February 2024. [Accessed on 13 February 2024] Available from: https://www.youtube.com/ watch?v=HlPgN6n6i8M.

Corrigendum La priorización de la investigación es un ejercicio ético: lecciones del Foro Global de Bioética en la Investigación para la Región de las Américas / Corrigendum Research priority-setting is an ethics exercise: lessons from the Global Forum on Bioethics in Research for the Region of the Americas / Corrigendum à Priorização da pesquisa é um exercício ético: lições do Fórum Global de Bioética em Pesquisa para a Região das Américas

La Revista Panamericana de Salud Pública llama la atención de los lectores sobre un error en el siguiente artículo, señalado por los autores: Saenz C, Carracedo S, Caballero C, Hurtado C, Leite Ribeiro A, Luna F, et al. La priorización de la investigación es un ejercicio ético: lecciones del Foro Global de Bioética en la Investigación para la Región de las Américas. Rev Panam Salud Publica. 2024;48:e26. https://doi.org/10.26633/RPSP.2024.26 En el artículo publicado en marzo 2024, la referencia 2 aparece de la siguiente manera: Global Forum on Bioethics in Research. GFBR 2023 Keynote presentation [video en internet]. Youtube. 1 de febrero de 2024 [citado 13 de febrero de 2024]. Disponible en: https://www.youtube.com/watch?v=HlPgN6n6i8M La forma correcta para la referencia 2 debe ser: Millum J. Ethics of health research priority setting [video]. Subido por Global Forum on Bioethics in Research, 1 de febrero de 2024. [citado 13 de febrero de 2024] Disponible en: https://www.youtube.com/ watch?v=HlPgN6n6i8M

Clinical, Functional, and Nutritional Efficacy of a Glutamine-Enriched Oligomeric Diet in Patients with Rectal Cancer.

AIMS: This work aims to evaluate the efficacy of nutritional supplementation with a glutamine-enriched oligomeric diet (GEOD) compared to a standard polymeric diet (SPD) in terms of oncology treatment-related diarrhea (OTRD) (frequency and consistency of stools), gastrointestinal toxicity, and functional and nutritional progress. METHODS: This prospective cohort study compared two groups of patients with rectal cancer in treatment with neoadjuvant chemotherapy and radiotherapy who were at risk of malnutrition. Patients were randomized to receive either 400 ml of GEOD or of SPD from the start of radiotherapy to 30 days after its completion. RESULTS: Eighty patients were recruited, 40 per arm. The GEOD arm had improved stool consistency and a greater reduction in the number of stools compared to the SPD arm (p < 0.001). The relative risk (RR) of developing diarrhea in the GEOD arm was 0.059 (95% CI 0.015-0.229). There was a reduced risk of developing intestinal mucositis in the GEOD arm compared to the SPD arm [RR 0.202 (95% CI 0.102 - 0.399)]. The GEOD arm had greater improvements in functional and nutritional status (p < 0.001). CONCLUSIONS: GEOD had a protective effect in terms of the development of gastrointestinal toxicity associated with chemotherapy and radiotherapy treatment in patients with rectal cancer.

Updated progression-free survival and final overall survival with maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial.

OBJECTIVE: In the PAOLA-1/ENGOT-ov25 trial (NCT02477644), adding maintenance olaparib to bevacizumab provided a substantial progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and homologous recombination deficiency (HRD)-positive tumors, irrespective of clinical risk. Subsequently, a clinically meaningful improvement in overall survival was reported with olaparib plus bevacizumab in the HRD-positive subgroup. We report updated progression-free survival and overall survival by clinical risk and HRD status. METHODS: Patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab received maintenance olaparib (up to 24 months) plus bevacizumab (up to 15 months in total) or placebo plus bevacizumab. This post hoc analysis evaluated 5-year progression-free survival and mature overall survival in patients classified by clinical risk and HRD status. RESULTS: Of 806 randomized patients, 74% were higher-risk and 26% were lower-risk. In higher-risk HRD-positive patients, the hazard ratio (HR) for progression-free survival was 0.46 (95% confidence interval (95% CI) 0.34 to 0.61), with 5-year progression-free survival of 35% with olaparib plus bevacizumab versus 15% with bevacizumab alone; and the HR for overall survival was 0.70 (95% CI 0.50 to 1.00), with 5-year overall survival of 55% versus 42%, respectively. In lower-risk HRD-positive patients, the HR for progression-free survival was 0.26 (95% CI 0.15 to 0.45), with 5-year progression-free survival of 72% with olaparib plus bevacizumab versus 28% with bevacizumab alone; and the HR for overall survival was 0.31 (95% CI 0.14 to 0.66), with 5-year overall survival of 88% versus 61%, respectively. No benefit was seen in HRD-negative patients regardless of clinical risk. CONCLUSION: This post hoc analysis indicates that in patients with newly diagnosed advanced HRD-positive ovarian cancer, maintenance olaparib plus bevacizumab should not be limited to those considered at higher risk of disease progression. Five-year progression-free survival rates support long-term remission and suggest an increased potential for cure with particular benefit suggested in lower-risk HRD-positive patients.

Research priority-setting is an ethics exercise: lessons from the Global Forum on Bioethics in Research for the Region of the Americas

Following the 2023 meeting of the Global Forum on Bioethics in Research (GFBR), this letter to the editor makes a call to consider health research priority-setting as an ethical exercise in Latin America and the Caribbean. This implies that research priority-setting processes are not limited to a matter of procedures, but rather include an explicit discussion of the substantive ethical criteria that guide prioritization.

La priorización de la investigación es un ejercicio ético: lecciones del Foro Global de Bioética en la Investigación para la Región de las Américas

A raíz de la reunión del 2023 del Foro Global de Bioética en la Investigación (GFBR por su sigla en inglés), esta carta al editor hace un llamado a considerar la priorización de la investigación en salud como un ejercicio ético en América Latina y el Caribe. Ello implica que los procesos de priorización de la investigación no se limiten a cuestiones procedimentales, sino que incluyan una discusión explícita sobre los criterios éticos sustantivos que guían la priorización.

Long-Term Analyses of SARS-CoV-2 Humoral and T Cell Responses and Breakthrough SARS-CoV-2 Infections after Two Doses of BNT162b2 Followed by mRNA-1273 and Bivalent Omicron-Adapted BNT162b2 Vaccines: A Prospective Study over 2 Years in Non-Immunocompromised Individuals.

Long-term analyses of the immune response following SARS-CoV-2 mRNA vaccines are essential to determining its characteristics and providing the basis for vaccination strategies. We conducted a prospective study in a cohort of 268 healthy adults followed for >2 years after two doses of BNT162b2. Antibodies targeting the receptor-binding domain of the S1 subunit of the spike of SARS-CoV-2 (anti-RBD) were measured at eight time points; T cell response was analyzed using an interferon-γ release assay. A total of 248 (93%) subjects received mRNA-1273 on month 9; 93 (35%) received the bivalent Omicron-adapted BNT162b2 vaccine between months 19 and 26. Breakthrough infections occurred in 215 (80%) participants, with frequencies unaffected by the additional vaccines. Anti-RBD declined over the initial 9 months, increased after mRNA-1273, and declined gradually thereafter. In 50 (17%) previously infected subjects, anti-RBD levels were significantly higher up to month 9 (p < 0.05) but subsequently declined below those of uninfected individuals. Anti-RBD titers protective against SARS-CoV-2 could not be defined. Most subjects developed a positive T cell response that remained after 26 months. Waning of protection against SARS-CoV-2 infection occurred over time, resulting in non-severe breakthrough infections in most participants. The evolution of anti-RBD suggests modulation of the immune response through immune imprinting.

Exploring the Disease-Associated Microglia State in Amyotrophic Lateral Sclerosis.

BACKGROUND: Neuroinflammation, and specifically microglia, plays an important but not-yet well-understood role in the pathophysiology of amyotrophic lateral sclerosis (ALS), constituting a potential therapeutic target for the disease. Recent studies have described the involvement of different microglial transcriptional patterns throughout neurodegenerative processes, identifying a new state of microglia: disease-associated microglia (DAM). The aim of this study is to investigate expression patterns of microglial-related genes in ALS spinal cord. METHODS: We analyzed mRNA expression levels via RT-qPCR of several microglia-related genes in their homeostatic and DAM state in postmortem tissue (anterior horn of the spinal cord) from 20 subjects with ALS-TDP43 and 19 controls donors from the Navarrabiomed Biobank. RESULTS: The expression levels of TREM2, MS4A, CD33, APOE and TYROBP were found to be elevated in the spinal cord from ALS subjects versus controls (p-value < 0.05). However, no statistically significant gene expression differences were observed for TMEM119, SPP1 and LPL. CONCLUSIONS: This study suggests that a DAM-mediated inflammatory response is present in ALS, and TREM2 plays a significant role in immune function of microglia. It also supports the role of C33 and MS4A in the physiopathology of ALS.

Tweak/Fn14 system is involved in rhabdomyolysis-induced acute kidney injury.

BACKGROUND: Rhabdomyolysis is a severe clinical syndrome associated to acute kidney injury (AKI) and chronic kidney disease (CKD). TWEAK/Fn14 signaling axis regulates renal inflammation and tubular cell death. However, the functional role of TWEAK/Fn14 in rhabdomyolysis remains unknown. METHODS: Rhabdomyolysis was induced in wild-type, TWEAK- and Fn14-deficient mice or mice treated with TWEAK blocking antibody. Renal injury, inflammation, fibrosis and cell death were assessed. Additionally, we performed in vivo and in vitro studies to explore the possible signalling pathways involved in Fn14 regulation. FINDINGS: Fn14 renal expression was increased in mice with rhabdomyolysis, correlating with decline of renal function. Mechanistically, myoglobin (Mb) induced Fn14 expression via ERK and p38 pathway, whereas Nrf2 activation diminished Mb-mediated Fn14 upregulation in cultured renal cells. TWEAK or Fn14 genetic depletion ameliorated rhabdomyolysis-associated loss of renal function, histological damage, tubular cell death, inflammation, and expression of both tubular and endothelial injury markers. Deficiency of TWEAK or Fn14 also decreased long-term renal inflammation and fibrosis in mice with rhabdomyolysis. Finally, pharmacological treatment with a blocking TWEAK antibody diminished the expression of acute renal injury markers and cell death and lessened residual kidney fibrosis and chronic inflammation in rhabdomyolysis. INTERPRETATION: TWEAK/Fn14 axis participates in the pathogenesis of rhabdomyolysis-AKI and subsequent AKI-CKD transition. Blockade of this signaling pathway may represent a promising therapeutic strategy for reducing rhabdomyolysis-mediated renal injury. FUNDING: Spanish Ministry of Science and Innovation, ISCIII and Junta de Andalucía.

Medium-term visual and refractive outcomes in patients with pseudoexfoliation implanted with a toric or multifocal intraocular lens.

PURPOSE: To report medium-term visual acuity and refractive outcomes of patients with pseudoexfoliation implanted with toric or multifocal intraocular lenses (IOLs). METHODS: We retrospectively reviewed patients with pseudoexfoliation who had undergone phacoemulsification between 2016 and 2020 with at least 24 months follow-up. RESULTS: Mean follow-up was 44.17 ± 14.95 months. Toric IOLs were implanted in 48 eyes: mean uncorrected LogMAR visual acuity one month after surgery was 0.03 ± 0.09, decreasing to 0.08 ± 0.11 at the last visit (p = .01). Mean refractive cylinder was -0.12 ± 0.36 diopters one month after surgery and -0.25 ± 0.44 diopters at the last follow-up visit, p = .012. Multifocal IOLs were implanted in 42 patients: binocular uncorrected distance visual acuity was -0.02 ± 0.04 one month after surgery and 0.01 ± 0.05 at the last visit (p = .004); near acuity was 0.01 ± 0.03 and 0.04 ± 0.06 respectively (p = .001). In eyes with pseudoexfoliation, absolute spherical equivalent prediction error was 0.22 ± 0.20 diopters for toric and 0.21 ± 0.19 diopters for multifocal IOLs. One month after surgery 68.6% of eyes with toric IOLs and 74.2% of eyes with multifocal IOLs were within ±0.25 diopters of target spherical equivalent and 91.6% and 90.5% were within ±0.5 diopters, respectively. Spherical equivalent did not change significantly during follow-up for either group. CONCLUSION: Prediction error in eyes with pseudoexfoliation implanted with toric or multifocal IOLs was low and similar to values reported for normal eyes. Postoperative refractive cylinder with toric IOLs was low, with little change during follow-up. Visual function in patients receiving multifocal IOLs was excellent. Therefore, the implantation of these IOLs in eyes with pseudoexfoliation does not seem to cause medium-term problems.

Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade.

Intravascular hemolysis is a common feature of different clinical entities, including sickle cell disease and malaria. Chronic hemolytic disorders are associated with hepatic damage; however, it is unknown whether heme disturbs lipid metabolism and promotes liver steatosis, thereby favoring the progression to nonalcoholic fatty liver disease (NAFLD). Using an experimental model of acute intravascular hemolysis, we report here the presence of liver injury in association with microvesicular lipid droplet deposition. Hemolysis promoted serum hyperlipidemia and altered intrahepatic triglyceride fatty acid composition, with increments in oleic, palmitoleic, and palmitic acids. These findings were related to augmented expression of transporters involved in fatty acid uptake (CD36 and MSR1) and deregulation of LDL transport, as demonstrated by decreased levels of LDL receptor and increased PCSK9 expression. Hemolysis also upregulated hepatic enzymes associated with cholesterol biosynthesis (SREBP2, HMGC1, LCAT, SOAT1) and transcription factors regulating lipid metabolism (SREBP1). Increased LC3II/LC3I ratio and p62/SQSTM1 protein levels were reported in mice with intravascular hemolysis and hepatocytes stimulated with heme, indicating a blockade of lipophagy. In cultured hepatocytes, cell pretreatment with the autophagy inductor rapamycin diminished heme-mediated toxicity and accumulation of lipid droplets. In conclusion, intravascular hemolysis enhances liver damage by exacerbating lipid accumulation and blocking the lipophagy pathway, thereby promoting NAFLD. These new findings have a high translational potential as a novel NAFLD-promoting mechanism in individuals suffering from severe hemolysis episodes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Medicina física y rehabilitación en pacientes con COVID-19

El sistema de salud se enfrentó a una pandemia mundial provocada por el SARS-CoV-2. Los planes de preparación para emergencias, por lo general, no consideraban cuestiones específicas de rehabilitación para pacientes en sus diferentes niveles de atención, a pesar de que la Organización Mundial de la Salud aconsejó incluir a toda la comunidad médica, además del personal de rehabilitación, lo antes posible. Se realizó una revisión de lo publicado en los últimos cinco años, referenciándose 25 bibliografías. La revisión se hizo con el objetivo de compartir información con la comunidad médica, incluidos profesionales y técnicos dedicados a la rehabilitación, que atendieron pacientes con COVID-19 en los diferentes niveles de atención. Se resumió y analizó la información disponible sobre la COVID-19, basada en una búsqueda de la literatura científica y en la experiencia en el tratamiento de los pacientes con diferentes tipos de discapacidad, para planificar la continuidad asistencial de rehabilitación y orientar las pautas a seguir en las diferentes fases y niveles de atención, aspecto que aún resulta incierto.

The health system faced a global pandemic caused by SARS-CoV-2. Emergency preparedness plans generally did not consider specific rehabilitation issues for patients at their different levels for care, although the World Health Organization advised the inclusion of the entire medical community in addition to rehabilitation staff as soon as possible. A review of what was published in the last five years was carried out, referencing 25 bibliographies. The review was made with the objective of sharing information with the medical community, including professionals and technicians dedicated to rehabilitation, who treated patients with COVID-19 at different levels of care. The available information on COVID-19 was summarized and analyzed, based on a search of the scientific literature and on the experience in the treatment of patients with different levels of disabilities, to plan the continuity of the rehabilitation care and to guide the guidelines to follow in the different phases and levels of care, an aspect that is still uncertain.

Indoxyl sulfate impairs erythropoiesis at BFU-E stage in chronic kidney disease.

Chronic kidney disease (CKD) is a global health condition characterized by a progressive deterioration of kidney function. It is associated with high serum levels of uremic toxins (UT), such as Indoxyl Sulfate (IS), which may participate in the genesis of several uremic complications. Anemia is one of the major complications in CKD patients that contribute to cardiovascular disease, increase morbi-mortality, and is associated with a deterioration of kidney failure in these patients. Our study aimed to characterize the impact of IS on CKD-related erythropoiesis. Using cellular and pre-clinical models, we studied cellular and molecular effects of IS on the growth and differentiation of erythroid cells. First, we examined the effect of clinically relevant concentrations of IS (up to 250 µM) in the UT7/EPO cell line. IS at 250 µM increased apoptosis of UT7/EPO cells at 48 h compared to the control condition. We confirmed this apoptotic effect of IS in erythropoiesis in human primary CD34+ cells during the later stages of erythropoiesis. Then, in IS-treated human primary CD34+ cells and in a (5/6 Nx) mice model, a blockage at the burst-forming unit-erythroid (BFU-E) stage of erythropoiesis was also observed. Finally, IS deregulates a number of erythropoietic related genes such as GATA-1, Erythropoietin-Receptor (EPO-R), and ß-globin. Our findings suggest that IS could affect cell viability and differentiation of erythroid progenitors by altering erythropoiesis and contributing to the development of anemia in CKD.

Role of Toll-like receptor 4 in intravascular hemolysis-mediated injury.

Massive intravascular hemolysis is a common characteristic of several pathologies. It is associated with the release of large quantities of heme into the circulation, promoting injury in vulnerable organs, mainly kidney, liver, and spleen. Heme activates Toll-like receptor 4 (TLR4), a key regulator of the inflammatory response; however, the role of TLR4 in hemolysis and whether inhibition of this receptor may protect from heme-mediated injury are unknown. We induced intravascular hemolysis by injection of phenylhydrazine in wildtype and Tlr4-knockout mice. In this model, we analyzed physiological parameters, histological damage, inflammation and cell death in kidney, liver, and spleen. We also evaluated whether heme-mediated-inflammatory effects were prevented by TLR4 inhibition with the compound TAK-242, both in vivo and in vitro. Induction of massive hemolysis elicited acute kidney injury characterized by loss of renal function, morphological alterations of the tubular epithelium, cell death, and inflammation. These pathological effects were significantly ameliorated in the TLR4-deficient mice and in wildtype mice treated with TAK-242. In vitro studies showed that TAK-242 pretreatment reduced heme-mediated inflammation by inhibiting the TLR4/NF-κB (nuclear factor kappa B) axis. However, analysis in liver and spleen indicated that TLR4 deficiency did not protect against the toxic accumulation of heme in these organs. In conclusion, TLR4 is a key molecule involved in the renal inflammatory response triggered by massive intravascular hemolysis. TLR4 inhibition may be a potential therapeutic approach to prevent renal damage in patients suffering from hemolysis. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Refractive outcomes of toric intraocular lens in combined trabecular micro bypass stent implantation and cataract surgery in glaucomatous eyes.

PURPOSE: To evaluate the impact of trabecular micro bypass stents (iStent Inject) on refractive outcomes with toric intraocular lens (IOL) in glaucomatous eyes. METHODS: We identified glaucomatous eyes receiving a toric IOL between October 2017 and December 2020. Eyes with iStent implantation were included in the study group and eyes undergoing isolated phacoemulsification served as controls. Corrected and uncorrected visual acuity, manifest refraction, intraocular pressure (IOP), and number of hypotensive drugs three months after surgery were evaluated. RESULTS: 26 eyes comprised the study group and 41 eyes the control group. Mean postoperative refractive cylinder was 0.26D in the control and 0.11D in the iStent group, with 63% and 85% of eyes with a cylinder of 0 and 85% and 92% of eyes with a cylinder ≤ 0.5D respectively. The mean absolute difference between target and outcome spherical equivalent was 0.26D in the control and 0.22D in the iStent group, with all eyes within 0.75D of target. LogMar uncorrected postoperative vision in eyes targeted for emmetropia was 0.04 in the control and 0.03 in the iStent group. There was a statistically significant reduction in IOP and number of hypotensive drugs in both groups, with a mean decrease in IOP of 8.6% in the control and 15.7% in the iStent group. The number of hypotensive drugs dropped from 1.63 ± 0.80 to 1.34 ± 0.91 in the control group and from 2.12 ± 0.65 to 0.44 ± 0.71 in the iStent group. CONCLUSION: Toric IOLs provide predictable refractive outcomes in glaucomatous eyes undergoing combined phacoemulsification with iStent implantation, reducing postoperative spectacle dependence.

Decline of antibody titres 3 months after two doses of BNT162b2 in non-immunocompromised adults.

OBJECTIVE: To assess the antibody response in non-immunocompromised adults after two doses of BNT162b2. METHODS: Prospective, single-centre observational study in non-immunocompromised adults aged 18 years or more who received two doses of BNT162b2. The study contemplates analyses of serum samples collected 1.5, 3, 6, 9 and 12 months after the second dose of BNT162b2; results of the 1.5- and 3-month time-points are presented in this report. Antibodies against the receptor binding domain of the S1 subunit of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (anti-RBD antibodies) were measured using a commercial quantitative immunoassay. A threshold of 4160 AU/mL (corresponding to an ID50 of 1:250) was used as surrogate marker for serum neutralizing activity. RESULTS: Of 273 hospital workers who received two doses of BNT162b2, 260 (95%) agreed to participate in the study; 2/260 (0.8%) were excluded because of immunocompromised conditions. At the time of this report, 230/258 (89%) participants (mean age 46.0 years (SD 11.4 years); 143/230 (62%) female; 87/230 (38%) male) had completed 3 months of follow up after the second dose of BNT162b2. Thirty-six (16%) of the 230 had documented mild SARS-CoV-2 infection before receiving the first dose of BNT162b2. Median (interquartile range (IQR)) anti-RBD titres 1.5 months after vaccination were 9356 (5844-16 876) AU/mL; 3 months after vaccination, median anti-RBD titres had declined to 3952 (2190-8561) AU/mL (p < 0.001). Of 199/230 (86.5%) participants who had anti-RBD titres above 4160 AU/mL 1.5 months after the second dose of BNT162b2, only 95/230 (41%) maintained anti-RBD titres above this level 3 months after vaccination (p < 0.001). CONCLUSIONS: The decline of anti-RBD antibodies 3 months after the second dose of BNT162b2 is of concern because it raises the possibility of a short-lived humoral immunity after vaccination. Booster doses of BNT162b2 might be required to maintain high titres of anti-RBD antibodies over time.