Designing cytochrome P450 enzymes for use in cancer gene therapy.

Cancer is a significant global socioeconomic burden, as millions of new cases and deaths occur annually. In 2020, almost 10 million cancer deaths were recorded worldwide. Advancements in cancer gene therapy have revolutionized the landscape of cancer treatment. An approach with promising potential for cancer gene therapy is introducing genes to cancer cells that encode for chemotherapy prodrug metabolizing enzymes, such as Cytochrome P450 (CYP) enzymes, which can contribute to the effective elimination of cancer cells. This can be achieved through gene-directed enzyme prodrug therapy (GDEPT). CYP enzymes can be genetically engineered to improve anticancer prodrug conversion to its active metabolites and to minimize chemotherapy side effects by reducing the prodrug dosage. Rational design, directed evolution, and phylogenetic methods are some approaches to developing tailored CYP enzymes for cancer therapy. Here, we provide a compilation of genetic modifications performed on CYP enzymes aiming to build highly efficient therapeutic genes capable of bio-activating different chemotherapeutic prodrugs. Additionally, this review summarizes promising preclinical and clinical trials highlighting engineered CYP enzymes' potential in GDEPT. Finally, the challenges, limitations, and future directions of using CYP enzymes for GDEPT in cancer gene therapy are discussed.

Long or complicated mpox in patients with uncontrolled HIV infection.

To date, former research about the impact of HIV infection on mpox poor outcomes is still limited and controversial. Therefore, the aim of this study was to assess the impact of HIV on the clinical course of mpox, in a large population of patients from Spain. Nationwide case-series study. Patients from 18 Spanish hospitals, with PCR-confirmed mpox from April 27, 2022 to June 30, 2023 were included in this study. The main outcome was the development of long or complicated (LC) mpox, defined as: (i) duration of the clinical course ≥ 28 days, or; (ii) disseminated disease, or: (iii) emergence of severe complications. One thousand eight hundred twenty-three individuals were included. Seven hundred eighty-six (43%) were people living with HIV (PLWH), of whom 11 (1%) had a CD4 cell count < 200 cells/mm3 and 33 (3%) <350 cells/mm3 . HIV viral load ≥ 1000 cp/mL was found in 27 (3%) PLWH, none of them were on effective ART. Fifteen (60%) PLWH with HIV-RNA ≥ 1000 cp/mL showed LC versus 182 (29%) PLWH with plasma HIV-RNA load < 1000 copies/mL and 192 (24%) individuals without HIV infection (p < 0.001). In multivariate analysis, adjusted by age, sex, CD4 cell counts and HIV viral load at the time of mpox, only plasma HIV-RNA ≥ 1000 cp/mL was associated with a greater risk of developing LC mpox [adjusted OR = 4.06 (95% confidence interval 1.57-10.51), p = 0.004]. PLWH with uncontrolled HIV infection, due to lack of ART, are at a greater risk of developing LC mpox. Efforts should be made to ensure HIV testing is carried out in patients with mpox and to start ART without delay in those tested positive.

Compromiso de Asunción. Un llamado a la acción / Commitment of Asunción. A call to action

La Federación Latinoamericana de Terapia Nutricional, Nutrición Clínica y Metabolismo – FELANPE, fue fundada en el año 1988. Reúne a Socie-dades y Asociaciones Interdisciplinarias de Nutrición Clínica y Terapia Nutricional de América Latina y el Caribe, además de España y Portugal.Actualmente la conforman representaciones de 18 países.Se describen los objetivos de la Federación teniendo en cuenta el compromiso asumido.Se trata de estudio observacional transversal, multicéntrico en que se incluyeron 132 hospitales con más de 100 camas, de alta complejidad,estatales y privados de 14 países de Latinoamérica miembros de FELANPE. Se evaluaron las características del hospital, la implementación dela valoración nutricional, el diagnóstico nutricional de pacientes, el equipo responsable de la terapia nutricional, la terapéutica nutricional (oral,enteral y parenteral), la monitorización y el seguimiento nutricional.Para tal, se diseñó y validó un cuestionario digital y un video explicativo para garantizar la calidad de los datos recolectados. La validación seefectúo mediante un estudio piloto realizado en Paraguay, aprobado por el Comité de ética en la Investigación de la Facultad de Ciencias Médicasde la Universidad Nacional de Asunción. La investigación actual cuenta con la aprobación del Comité de ética de Investigación de la Facultad deCiencias Químicas de la Universidad Nacional de Asunción y del Comité de ética de FELANPE.Los resultados presentados en el XVIII Congreso Latinoamericano de FELANPE, en Asunción del Paraguay, el 12 de octubre del 2023, sirven comobase para caracterizar la implementación de la Terapia Nutricional Parenteral y Enteral (terapia nutricional médica) en Hospitales de Latinoaméricay son utilizados como sustento técnico del presente Compromiso de Asunción.(AU)

The Latin American Federation of Nutritional Therapy, Clinical Nutrition, and Metabolism – FELANPE, was founded in 1988. It brings togetherinterdisciplinary societies and associations in Clinical Nutrition and Nutritional Therapy from Latin America and the Caribbean, as well as Spainand Portugal. Currently, it comprises representations from 18 countries.The objectives of the Federation are described, taking into account the assumed commitment. This is an observational cross-sectional, multicenterstudy that included 132 hospitals with more than 100 beds, of high complexity, both state-owned and private, from 14 countries in Latin Americathat are members of FELANPE. The study assessed hospital characteristics, implementation of nutritional assessment, nutritional diagnosis ofpatients, the team responsible for nutritional therapy, nutritional therapy (oral, enteral, and parenteral), monitoring, and nutritional follow-up.For this purpose, a digital questionnaire and an explanatory video were designed and validated to ensure the quality of the collected data. Validationwas carried out through a pilot study conducted in Paraguay, approved by the Ethics Committee for Research at the Faculty of Medical Sciences ofthe National University of Asunción. The current research has the approval of the Research Ethics Committee of the Faculty of Chemical Sciencesof the National University of Asunción and the Ethics Committee of FELANPE.The results presented at the XVIII Latin American Congress of FELANPE in Asunción, Paraguay, on October 12, 2023, serve as a basis for cha-racterizing the implementation of Parenteral and Enteral Nutritional Therapy (medical nutritional therapy) in hospitals in Latin America and areused as technical support for the present Asunción Commitment.(AU)

The absence of seroconversion after exposition to hepatitis C virus is not related to KIR-HLA genotype combinations (GEHEP-012 study).

BACKGROUND & AIMS: It has been reported that specific killer-cell immunoglobulin-like receptors (KIRs) and HLA genotype combinations, such as KIR2DS4/HLA-C1 with presence of KIRDL2 or KIRDL3, homozygous KIRDL3/HLA-C1 and KIR3DL1/≥2HLA-Bw4, are strongly associated with the lack of active infection and seroconversion after exposition to hepatitis C virus (HCV). OBJECTIVE: To determine whether these KIR-HLA combinations are relevant factors involved in that phenotype. PATIENTS AND METHODS: In this retrospective case-control study, genotype data from a genome-wide association study previously performed on low susceptibility to HCV-infection carried out on 27 high-risk HCV-seronegative (HRSN) individuals and 743 chronically infected (CI) subjects were used. HLA alleles were imputed using R package HIBAG v1.2223 and KIR genotypes were imputed using the online resource KIR*IMP v1.2.0. RESULTS: It was possible to successfully impute at least one KIR-HLA genotype combination previously associated with the lack of infection and seroconversion after exposition to HCV in a total of 23 (85.2%) HRSN individuals and in 650 (87.5%) CI subjects. No KIR-HLA genotype combination analyzed was related to the HRSN condition. CONCLUSIONS: Our results suggest that those KIR-HLA genotype combinations are not relevant factors involved in the lack of infection and seroconversion after exposition to HCV. More studies will be needed to completely understand this phenotype.

[Commitment of Asunción. A call to action]. / Compromiso de Asunción. Un llamado a la acción.

Introduction: The Latin American Federation of Nutritional Therapy, Clinical Nutrition, and Metabolism - FELANPE, was founded in 1988. It brings together interdisciplinary societies and associations in Clinical Nutrition and Nutritional Therapy from Latin America and the Caribbean, as well as Spain and Portugal. Currently, it comprises representations from 18 countries. The objectives of the Federation are described, taking into account the assumed commitment. This is an observational cross-sectional, multicenter study that included 132 hospitals with more than 100 beds, of high complexity, both state-owned and private, from 14 countries in Latin America that are members of FELANPE. The study assessed hospital characteristics, implementation of nutritional assessment, nutritional diagnosis of patients, the team responsible for nutritional therapy, nutritional therapy (oral, enteral, and parenteral), monitoring, and nutritional follow-up. For this purpose, a digital questionnaire and an explanatory video were designed and validated to ensure the quality of the collected data. Validation was carried out through a pilot study conducted in Paraguay, approved by the Ethics Committee for Research at the Faculty of Medical Sciences of the National University of Asunción. The current research has the approval of the Research Ethics Committee of the Faculty of Chemical Sciences of the National University of Asunción and the Ethics Committee of FELANPE. The results presented at the XVIII Latin American Congress of FELANPE in Asunción, Paraguay, on October 12, 2023, serve as a basis for characterizing the implementation of Parenteral and Enteral Nutritional Therapy (medical nutritional therapy) in hospitals in Latin America and are used as technical support for the present Asunción Commitment.

Introducción: La Federación Latinoamericana de Terapia Nutricional, Nutrición Clínica y Metabolismo ­ FELANPE, fue fundada en el año 1988. Reúne a Sociedades y Asociaciones Interdisciplinarias de Nutrición Clínica y Terapia Nutricional de América Latina y el Caribe, además de España y Portugal. Actualmente la conforman representaciones de 18 países. Se describen los objetivos de la Federación teniendo en cuenta el compromiso asumido. Se trata de estudio observacional transversal, multicéntrico en que se incluyeron 132 hospitales con más de 100 camas, de alta complejidad, estatales y privados de 14 países de Latinoamérica miembros de FELANPE. Se evaluaron las características del hospital, la implementación de la valoración nutricional, el diagnóstico nutricional de pacientes, el equipo responsable de la terapia nutricional, la terapéutica nutricional (oral, enteral y parenteral), la monitorización y el seguimiento nutricional. Para tal, se diseñó y validó un cuestionario digital y un video explicativo para garantizar la calidad de los datos recolectados. La validación se efectúo mediante un estudio piloto realizado en Paraguay, aprobado por el Comité de Ética en la Investigación de la Facultad de Ciencias Médicas de la Universidad Nacional de Asunción. La investigación actual cuenta con la aprobación del Comité de Ética de Investigación de la Facultad de Ciencias Químicas de la Universidad Nacional de Asunción y del Comité de Ética de FELANPE. Los resultados presentados en el XVIII Congreso Latinoamericano de FELANPE, en Asunción del Paraguay, el 12 de octubre del 2023, sirven como base para caracterizar la implementación de la Terapia Nutricional Parenteral y Enteral (terapia nutricional médica) en Hospitales de Latinoamérica y son utilizados como sustento técnico del presente Compromiso de Asunción.

Hepatic Steatosis and Weight Gain During the Coronavirus Disease 2019 Pandemic Among People With Human Immunodeficiency Virus: Impact of Therapy With Tenofovir Alafenamide.

Background: Lockdown due to the coronavirus disease 2019 (COVID-19) pandemic led to increases in weight in part of the population. Weight gain leads to hepatic steatosis (HS). Antiretroviral treatment could also influence HS in people with human immunodeficiency virus (PWH). The impact of lockdown on HS in PWH is unknown. The aim of this study was to analyze the changes in HS, as measured by the controlled attenuation parameter (CAP), during the COVID-19 pandemic in PWH. Methods: This was a cohort study that included PWH who attended a tertiary care center in southern Spain from January 2018 to December 2021. The CAP was evaluated by transient elastography. Only those who had a valid CAP before and after March 2020 were included. HS was defined as CAP ≥248 dB/m. Results: Six hundred eighty PWH were attended and 488 (71.8%) were included. Two hundred and fourteen (43.9%) had HS at baseline and 239 (49%) at the end of the follow-up (P = .036). The median change in CAP among PWH taking tenofovir alafenamide (TAF) was 8.5 (interquartile range [IQR], -24 to 46.3) dB/m versus -4 (IQR, -35 to 27) dB/m among PWH receiving TAF-free regimens (P = .003). After multivariate analysis, adjusted by sex and age, weight gain (adjusted odds ratio [AOR], 1.09 [95% confidence interval {CI}, 1.05-1.14]; P < .001), TAF therapy (AOR, 1.59 [95% CI, 1.07-2.35]; P = .021), plasma triglycerides (AOR, 1.01 [95% CI, 1-1.01]; P < .001), and fasting blood glucose (AOR, 1.01 [95% CI, 1-1.02]; P = .027) were associated with HS at the end of follow-up. Conclusions: The frequency of HS increased during the COVID-19 pandemic among PWH. TAF is associated with HS development, regardless of metabolic factors.

Hepatic steatosis after switching to integrase inhibitor-based regimens does not parallel short-term weight gain.

We studied hepatic steatosis in people with HIV (PWH) who switched to an integrase inhibitor (INSTI)-based regimen. One hundred and fifty-four PWH were included. After 48 weeks, median (Q1-Q3) weight gain was 1.2 (-0.6 to 3.8) kg and median (Q1-Q3) controlled attenuation parameter (CAP) change was -4 (-33 to 27) dB/m. Weight gain was weakly correlated with CAP change [R2 95% confidence interval (CI) = 0.144 (-0.014 to 0.296); P = 0.074)]. Changes in hepatic steatosis after switching to INSTI-based regimens do not seem to parallel weight gain after 1 year.

Immunogenicity of Adalimumab in Patients with Non-Infectious- Uveitis: Systematic Review and Meta-Analysis.

OBJECTIVE: To review the prevalence, incidence, and risk factors for developing anti-drug antibodies (AAA) in patients with non-infectious uveitis (NIU) treated with Adalimumab (ADA). METHODS: A systematic literature search was performed on PubMed, EMBASE, Virtual Health Library, Cochrane, and medRxiv. Meta-analysis was performed using random effects. RESULTS: Nine out of 2,373 studies were included. The prevalence of AAA in NIU patients treated with ADA was 9% (95% CI: 2% to 37%, I2 = 95% with a P<0.01), it was significantly higher in real-life scenarios (observational studies) than in clinical trials. The pooled incidence at 12 months was 27% (CI 95% 16%-42% I2 = 0%). Several factors have been associated with AAA generation in NIU patients, including the non-use of concomitant immunosuppressants, presence of autoimmune systemic disease, female gender, etc. CONCLUSION: This study showed that AAA prevalence is higher in real-life scenarios compared to clinical trials. Further research is needed to elucidate the factors that trigger AAA generation in NIU patients.

Temporal changes in the genotypes of Paslahepevirus balayani in southern Spain and their possible link with changes in pig trade imports.

Introduction: Paslahepevirus balayani (HEV) is an endemic zoonotic disease ranked as a major cause of acute hepatitis in Europe. Most infections occurring in Europe are due to the endemic several subtypes of genotype 3, through the consumption of raw or undercooked pork, observing a genotype geographical distribution pattern among countries Because of global changes in the pig and pork trading markets, subtype distribution might vary. We aimed to evaluate the temporal distribution of HEV genotypes in patients from southern Spain with acute hepatitis to determine whether these changes were related to the pig import trade during the study period between 2018 and 2022. Methods: Prospective longitudinal study including patients with acute hepatitis from southern Spain between 2018 and 2022. HEV RNA and antibodies was tested in all patients. In patients with detectable HEV RNA, genotype was obtained. To determine the number of imported pigs and their origins, we checked the official data from the Spanish statistics on international trade of Spanish Minister of Industry during by country of origin during the same study period. Results: A total of 659 patients with acute hepatitis were included in the study. Among them, 162 (24.5%) had at least one marker (IgM or RNA) of acute HEV infection. Among the 71 patients with detectable viral RNA, genotypes could be obtained for 58 (81.6%). The most prevalent HEV genotype was 3f (n = 48; 78.6%), showing a decreasing prevalence of over time, from 100% in 2018 to 70.6% in 2022. Since 2021, the emergence of other genotypes has been determined. A significant increase in the number of animals imported was observed since the beginning of the study. Denmark experienced a significant rise, from 0.03% in 2018 of total imports to 10.4% in 2022. Conclusions: HEV molecular diversity is changing in Spain, could be linked to changes in fattening pig import origin.

Low rate of vaccination and risk of incident hepatitis A among HIV-infected men who have sex with men in Seville, Southern Spain.

BACKGROUND: Periodic outbreaks of hepatitis A (HAV) infection in men who have sex with men (MSM) have been reported. Low vaccination uptake in HIV-infected individuals could drive new outbreaks. We aimed at evaluating the incidence of and risk factors for HAV infection in people living with HIV (PLWH) in our area. We also assessed the rates of HAV vaccination. METHODS: This was a prospective cohort study. 915 patients were included, 272 (30%) of them were anti-HAV seronegative at baseline. RESULTS: Twenty-six (9.6%) susceptible individuals became infected. Incident cases peaked in 2009-2010 and 2017-2018. Incident HAV infection was independently associated with MSM [adjusted odds ratio (95% confidence ratio): 4.39 (1.35-14.27), p=0.014]. One hundred and five (38.6%) HAV seronegative patients were vaccinated, 21 (20%) of them did not respond, and one (1%) patient lost immunity against HAV. Four (29%) non-responders to vaccination showed incident HAV 5-9 years afterwards. CONCLUSIONS: The incidence of HAV infection in a cohort of well-controlled PLWH remains low and stable, with intermittent outbreaks involving mainly non-immunized MSM. A significant proportion of PLWH remain susceptible to HAV infection due to insufficient vaccine uptake and limited response to vaccination. Importantly, patients not responding to HAV vaccination continue at risk of infection.

Prospective PTCTC trial of myeloablative haplo-BMT with posttransplant cyclophosphamide for pediatric acute leukemias.

Promising results have been reported for adult patients with high-risk hematologic malignancies undergoing haploidentical bone marrow transplant (haploBMT) with posttransplant cyclophosphamide (PTCy). To our knowledge, we report results from the first multicenter trial for pediatric and young adult patients with high-risk acute leukemias and myelodysplastic syndrome (MDS) in the Pediatric Transplantation and Cellular Therapy Consortium. Nine centers performed transplants in 32 patients having acute leukemias or MDS, with myeloablative conditioning (MAC), haploBMT with PTCy, mycophenolate mofetil, and tacrolimus. The median patient age was 12 years. Diagnoses included AML (15), ALL (11), mixed-lineage leukemia (1), and MDS (5). Transplant-related mortality (TRM) at 180 days was 0%. The cumulative incidence (CuI) of grade 2 acute graft-versus-host disease (aGVHD) on day 100 was 13%. No patients developed grades 3-4 aGVHD. The CuI of moderate-to-severe chronic GVHD (cGVHD) at 1 year was 4%. Donor engraftment occurred in 27 patients (84%). Primary graft failures included 3 patients who received suboptimal bone marrow grafts; all successfully engrafted after second transplants. The CuI of relapse at 1 year was 32%, with more relapse among patients MRD positive pre-BMT vs MRD negative. Overall survival rates at 1 and 2 years were 77% and 73%, and event-free survival rate at 1 and 2 years were 68% and 64%. There was no TRM or severe aGVHD, low cGVHD, and favorable relapse and survival rates. This successful pilot trial has led to a phase 3 trial comparing MAC haploBMT vs HLA-matched unrelated donor BMT in the Children's Oncology Group. This trial was registered at www.clinicaltrials.gov as #NCT02120157.

Prognostic value of non-invasive scores based on liver stiffness measurement, spleen diameter and platelets in HIV-infected patients.

BACKGROUND AND AIMS: People living with HIV (PLWH) are at high risk for advanced chronic liver disease and related adverse outcomes. We aimed to validate the prognostic value of non-invasive scores based on liver stiffness measurement (LSM) and on markers of portal hypertension (PH), namely platelets and spleen diameter, in PLWH. METHODS: We combined data from eight international cohorts of PLWH with available non-invasive scores, including LSM and the composite biomarkers liver stiffness-spleen size-to-platelet ratio score (LSPS), LSM-to-Platelet ratio (LPR) and PH risk score. Incidence and predictors of all-cause mortality, any liver-related event and classical hepatic decompensation were determined by survival analysis, controlling for competing risks for the latter two. Non-invasive scores were assessed and compared using area under the receiver operating curve (AUROC). RESULTS: We included 1695 PLWH (66.8% coinfected with hepatitis C virus). During a median follow-up of 4.7 (interquartile range 2.8-7.7) years, the incidence rates of any liver-related event, all-cause mortality and hepatic decompensation were 13.7 per 1000 persons-year (PY) (95% confidence interval [CI], 11.4-16.3), 13.8 per 1000 PY (95% CI, 11.6-16.4) and 9.9 per 1000 PY (95% CI, 8.1-12.2), respectively. The AUROC of LSM was similar to that of the composite biomarkers, ranging between 0.83 and 0.86 for any liver-related event, 0.79-0.85 for all-cause mortality and 0.87-0.88 for classical hepatic decompensation. All individual non-invasive scores remained independent predictors of clinical outcomes in multivariable analysis. CONCLUSIONS: Non-invasive scores based on LSM, spleen diameter and platelets predict clinical outcomes in PLWH. Composite biomarkers do not achieve higher prognostic performance compared to LSM alone.

Reduced neutralizing antibody response to SARS-CoV-2 vaccine booster dose in people living with HIV with severe immunosuppression.

The aim of this study was to assess the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines among people living with HIV (PLWH) with severe immunosuppression, after a booster dose. The design was a case-control study nested in a prospective cohort of PLWH. All patients with CD4 cell count <200 cells/mm3 who had received additional dose of messenger RNA (mRNA) COVID-19 vaccine, after a standard immunization scheme were included. Control group: patients age- and sex-matched, with CD4 ≥ 200 cells/mm3 , in the ratio of 2:1. Antibody response to a booster dose (anti-S levels 33.8 ≥ BAU/mL) and neutralizing activity against SARS-CoV-2 B.1, B.1.617.2, and Omicron BA.1, BA.2, and BA.5 strains were assessed after the booster shot. Fifty-four PLWH were included, 18 with CD4 counts < 200 cells/mm3 . Fifty-one (94%) showed response to a booster dose. Response was less frequent in PLWH with CD4 < 200 cells/mm3 than in those with CD4 counts ≥ 200 cells/mm3 (15 [83%] vs. 36 [100%], p = 0.033). In the multivariate analysis, CD4 counts ≥ 200 cells/mm3 [incidence rate ratio (IRR) = 18.1 (95% confidence interval [CI]: 16.8-19.5), p < 0.001] was associated with a higher probability of showing antibody response. Neutralization activity against SARS-CoV-2 B.1, B.1.617, BA.1, and BA.2 strains was significantly inferior among individuals with CD4 counts < 200 cells/mm3 . In conclusion, among PLWH with CD4 counts < 200 cells/mm3 , the immune response elicited by mRNA additional vaccine dose is reduced.

Poor increase on HAV vaccination coverage among people living with HIV after an immunization-based intervention.

OBJECTIVES: To assess HAV serologic and vaccination status among people who live with HIV (PLWH), and to evaluate the impact of a vaccination-based strategy on HAV-negative patients in Seville, Spain. METHODS: Study with two time-overlapping phases: (i) cross-sectional study of HAV immunity prevalence among PLWH followed at a Spanish hospital between August 2019 and March 2020. (ii) Patients seronegative for HAV, reliably unvaccinated were included in a before-and-after quasi-experimental study, with an intervention focused on HAV vaccination according to national recommendations in force. RESULTS: Six hundred and fifty-six patients were included, of which 111 [17%, 95% confidence interval (95% CI) 14-20%] were seronegative for HAV. Of these, 48 [43% (95% CI, 34-53%)] individuals were MSM. The absence of HAV immunity was attributed in 69 [62% (95% CI, 52-71%)] patients to non-referral to vaccination, followed by lack of achievement of a correct vaccination scheme [n=26; 23% (95% CI, 16-32%)]. After the program implementation, 96 [15% (95% CI, 12-18%)] individuals were seronegative (17% vs. 15%, p=0.256), of whom 42 [41% (95% CI, 32-51%)] were MSM. The absence of immunity after the intervention was mainly attributed to: adherence failure in 23 [24.0% (95% CI, 15.8-33.7%)] patients, on-course immunization scheme in 34 [33% (95% CI, 24-43%)] individuals and pending appointment at the vaccine delivery unit in 20 [20.8% (95% CI, 13.2-30.3%)] patients. CONCLUSIONS: A sizeable proportion of PLWH remains susceptible for HAV infection in future outbreaks. A program based on referral to the vaccine delivery unit yields poor results, largely due to program adherence failures. New strategies are needed to increase HAV vaccination coverage.

Optimization of the molecular diagnosis of the acute hepatitis E virus infection.

To evaluate the diagnostic value of the combination of two broad-range PCR assays targeting two different and conserved regions of the viral genome for the diagnosis of acute Hepatitis E virus (HEV) infection. Patients with acute hepatitis were prospectively recruited. In all, HEV-IgM antibodies were tested together with evaluation of HEV viraemia by two PCR assays (ORF3 and ORF1). The number of individuals exhibiting negative IgM antibody results but carrying viral RNA was calculated by each PCR assay. Four-hundred and seventy individuals were included, of whom 145 (30.8%) were diagnosed as having acute HEV. Of them, 122 (84.1%) exhibited HEV-IgM antibodies, and 81 (55.8%) had detectable viral RNA for at least one PCR. Using the ORF3 molecular assay, 70 (48.3%) individuals were identified with HEV infection. When the ORF1 molecular assay was applied, 49 (33.8%) individuals were identified. The ORF3 assay detected viral RNA in 32 patients not detected by the ORF1 assay. In contrast, the ORF1 assay could amplify viral RNA in 11 patients who were not detected by the ORF3 assay. The parallel use of two broad-range PCR assays significantly increased the performance of the molecular diagnosis of HEV.

How to become a pediatric neurosurgeon in Latin America: training opportunities, current status, and future challenges.

PURPOSE: To provide an analysis of pediatric neurosurgery educational opportunities in Latin America in order to characterize and evaluate the strengths, weaknesses, and limitations to assume a career in pediatric neurosurgery. METHODS: An online survey was distributed to pediatric neurosurgeons in Latin America to assess aspects of pediatric neurosurgical education, working conditions, and training opportunities. The survey was open to neurosurgeons that treat pediatric patients, whether or not they had completed fellowship training in pediatrics. A descriptive analysis was done with a subgroup analysis stratified the results among certified pediatric neurosurgeons and non-certified pediatric neurosurgeons. RESULTS: In total, 106 pediatric neurosurgeons completed the survey, of whose the vast majority completed their training in a Latin American pediatric neurosurgery program. A total of 19 accredited academic programs in pediatric neurosurgery were found in Latin America distributed in 6 different countries. On average, the pediatric neurosurgical training in America Latina has a duration of 278 years, ranging from 1 to > 6 years. CONCLUSIONS: This study is the first of its kind to review pediatric neurosurgical training in Latin America, in which both pediatric and general neurosurgeons provide neurosurgical care to children in the continent; however, we found that in the majority of the cases, children are treated by certified pediatric neurosurgeons, of whose the vast majority were trained in Latin American programs. On the other hand, we found areas of improvement in the specialty in the continent, including regulation of training opportunities, increased support for funding, and more opportunities for education among all countries.

Oportunistic diagnosis based on age and hepatitis C virus clearance: an essential step to improve the overall health of the liver.

Back in January 2022, an EASL-Lancet Commission on the impact of liver disorders in the European region commissioned by the WHO demonstrated that this condition is, actually, the second leading cause of loss of labor years in Europe after ischemic heart disease (1). This is a very relevant piece of information since this is something that is going to impact the new generations of Europeans unless a significant change is made in public health policies. Despite the advances made over the last few years in hepatitis C virus clearance-understood as a significant reduction of morbidity and mortality associated with Hepatitis B and C viruses-there are still challenges ahead to improve liver health due to the high use of alcohol, and the inseparable triad obesity / diabetes mellitus / metabolic associated fatty liver disease. Also, access to healthcare for several population groups at risk of presenting higher rates of liver disease has become a problem.

Immunotherapy approaches for rare pediatric solid tumors: advances and future directions.

PURPOSE OF REVIEW: Immunotherapy for pediatric tumors is rapidly evolving. From major successes in pediatric hematologic malignancies, immunotherapy utility increased in the pediatric solid tumor landscape. Numerous pediatric solid tumors are defined as rare with limitations in diagnosis and treatment. This review will describe four major immunotherapies used in pediatrics and discuss results seen in rare pediatric tumors. We will also briefly review the challenges of immunotherapy in solid tumors and opportunities to drive this therapy forward. RECENT FINDINGS: Despite rare success employing immunotherapy for pediatric solid tumors, recently there have been several successes in pediatric rare solid tumors. After describing the evolving landscape of rare pediatric tumors, we will demonstrate the successes or disappointments of immunotherapy. We will describe the mechanism of four immunotherapies used in the pediatrics, followed by the published results. Finally, we will discuss the challenges and opportunities for immunotherapies in pediatric rare tumors. SUMMARY: Pediatric rare tumors are lacking in treatment options. Despite numerous disappointments utilizing immunotherapies in the more common pediatric solid tumors, there have been several successes within the pediatric rare tumor landscape. Much work is still needed to enhance our understanding and knowledge on utilizing these immunotherapies for pediatric rare solid tumors.