Additional booster doses in patients with chronic lymphocytic leukemia induce humoral and cellular immune responses to SARS-CoV-2 similar to natural infection regardless ongoing treatments: A study by ERIC, the European Research Initiative on CLL.

Profound immune dysregulation and impaired response to the SARS-CoV-2 vaccine put patients with chronic lymphocytic leukemia (CLL) at risk of severe COVID-19. We compared humoral memory and T-cell responses after booster dose vaccination or breakthrough infection. (Green) Quantitative determination of anti-Spike specific antibodies. Booster doses increased seroconversion rate and antibody titers in all patient categories, ultimately generating humoral responses similar to those observed in the postinfection cohort. In detail, humoral response with overscale median antibody titers arose in >80% of patients in watch and wait, off-therapy in remission, or under treatment with venetoclax single-agent. Anti-CD20 antibodies and active treatment with BTK inhibitors (BTKi) represent limiting factors of humoral response, still memory mounted in ~40% of cases following booster doses or infection. (Blue) Evaluation of SARS-CoV-2-specific T-cell responses. Number of T-cell functional activation markers documented in each patient. The vast majority of patients, including those seronegative, developed T-cell responses, qualitatively similar between treatment groups or between vaccination alone and infection cases. These data highlight the efficacy of booster doses in eliciting T-cell immunity independently of treatment status and support the use of additional vaccination boosters to stimulate humoral immunity in patients on active CLL-directed treatments.

Pathways to adverse pregnancy outcomes: exploring the mediating role of intimate partner violence and depression: results from a South African rape cohort study.

Adverse pregnancy outcomes (APOs) are common occurrences that contribute to negative maternal and child health outcomes. Our aim was to test the hypothesis that trauma exposure and depression are drivers of the better-recognised risk factors for miscarriage, abortion and stillbirths. Our comparative cohort study based in Durban, South Africa recruited women who reported a recent rape (n = 852) and those who had never experienced rape (n = 853), with follow-up for 36 months. We explored APOs (miscarriage, abortion or stillbirth) among those having a pregnancy during follow-up (n = 453). Potential mediators were baseline depression, post-traumatic stress symptoms, substance abuse, HbA1C, BMI, hypertension and smoking. A structural equation model (SEM) was used to determine direct and indirect paths to APO. Overall, 26.6% of the women had a pregnancy in the follow-up period and 29.4% ended in an APO, with miscarriage (19.9%) the most common outcome, followed by abortion (6.6%) and stillbirths (2.9%). The SEM showed two direct pathways from exposure to childhood trauma, rape and other trauma, to APO which were ultimately mediated by hypertension and/or BMI, but all paths to BMI were mediated by depression and IPV-mediated pathways from childhood and other trauma to hypertension. Food insecurity mediated a pathway from experiences of trauma in childhood to depression. Our study confirms the important role of trauma exposure, including rape, and depression on APOs, through their impact on hypertension and BMI. It is critical that violence against women and mental health are more systematically addressed in antenatal, pregnancy and postnatal care.

[Cognitive impairment in the elderly patient with symptomatic severe aortic stenosis. Therapeutic decisions and impact on one-year mortality]. / Deterioro cognitivo en el paciente mayor con estenosis aórtica grave sintomática. Toma de decisiones terapéuticas e impacto sobre la mortalidad al año.

INTRODUCTION: Interventional treatment of severe aortic stenosis includes valve replacement by surgery or transcatheter - transcatheter aortic valve implantation (TAVI). In order to make an adequate selection and to rule out patients with little/no therapeutic benefit, it is recommended to assess comorbidities, frailty and cognitive impairment. AIMS: a) To determine the prevalence of cognitive impairment in older patients with severe aortic stenosis; b) to analyse its influence on decision-making (surgery, TAVI or conservative treatment); and c) to analyse its impact on mortality at one year. MATERIAL AND METHODS: Prospective, longitudinal epidemiological study of patients aged 75 years and older with severe aortic stenosis treated by the Heart-Team. VARIABLES: sociodemographic, clinical, cardiological, functional and mental variables; cognitive impairment assessed by applying the Mini-Mental State Examination (MMSE). RESULTS: We included 300 patients in the study (83.99 ± 4.02 years old; 61.2%, women). Prevalence of cognitive impairment of 15.3%, which was associated with albumin level - odds ratio (OR): 0.082; p = 0.011 - and Barthel (OR: 0.962; p = 0.02) and Lawton (OR: 0.787; p = 0.025) index scores. Surgery was chosen in 24.7% of cases; TAVI in 63.3%; and conservative treatment in 12%. This decision was associated with the score on the Barthel (OR: 0.93; p = 0.012) and Lawton indices (OR: 0.678; p = 0.014), the Short Physical Performance Battery (OR: 0.75; p = 0.037) and the MMSE (OR: 0.691; p < 0.001). Mortality at one year was 14%, and higher in patients with MMSE scores <24 (23.5% vs. 12.8%; p = 0.094). CONCLUSIONS: Cognitive impairment is a very common geriatric syndrome in older patients with severe aortic stenosis that is associated with functional disability in activities of daily living. Cognitive impairment has a high impact on decision-making and appears to be a variable associated with increased mortality.

TITLE: Deterioro cognitivo en el paciente mayor con estenosis aórtica grave sintomática. Toma de decisiones terapéuticas e impacto sobre la mortalidad al año.Introducción. El tratamiento intervencionista de la estenosis aórtica grave incluye el recambio valvular mediante cirugía o vía transcatéter ­implante transcatéter de la válvula aórtica (TAVI)­. Para realizar una adecuada selección y descartar pacientes con escaso/nulo beneficio terapéutico, se recomienda evaluar las comorbilidades, la fragilidad y el deterioro cognitivo. Objetivos. a) Determinar la prevalencia de deterioro cognitivo en pacientes mayores con estenosis aórtica grave; b) analizar su influencia en la toma de decisiones (cirugía, TAVI o tratamiento conservador), y c) analizar su impacto sobre la mortalidad al año. Material y métodos. Estudio epidemiológico longitudinal y prospectivo sobre pacientes de 75 años o más con estenosis aórtica grave atendidos por el Heart-Team. Variables: sociodemográficas, clínicas, cardiológicas, funcionales y mentales; deterioro cognitivo evaluado aplicando el Minimental State Examination (MMSE). Resultados. Incluimos a 300 pacientes en el estudio (83,99 ± 4,02 años; 61,2%, mujeres). Prevalencia de deterioro cognitivo del 15,3%, que se asoció con el nivel de albúmina ­odds ratio (OR): 0,082; p = 0,011­ y las puntuaciones en los índices de Barthel (OR: 0,962; p = 0,02) y Lawton (OR: 0,787; p = 0,025). En el 24,7% de los casos se decidió cirugía; en el 63,3%, TAVI; y en el 12%, tratamiento conservador. Esta decisión se asoció con la puntuación en los índices de Barthel (OR: 0,93; p = 0,012) y Lawton (OR: 0,678; p = 0,014), la Short Physical Performance Battery (OR: 0,75; p = 0,037) y el MMSE (OR: 0,691; p menor de 0,001). La mortalidad al año fue del 14%, superior en los pacientes con puntuaciones en el MMSE menor de 24 (23,5% frente a 12,8%; p = 0,094). Conclusiones. El deterioro cognitivo es un síndrome geriátrico muy frecuente en pacientes mayores con estenosis aórtica grave que se asocia con incapacidad funcional en las actividades de la vida diaria. El deterioro cognitivo tiene un elevado impacto en la toma de decisiones y parece presentarse como una variable asociada a mayor mortalidad.

Prescription patterns of somatostatin analogs in patients with acromegaly and neuroendocrine tumors.

PURPOSE: Acromegaly and neuroendocrine tumors are rare diseases that, under certain conditions, can be treated with somatostatin analogs. The aim was to determine the prescription patterns of somatostatin analogs in a group of patients with acromegaly and neuroendocrine tumors affiliated with the Colombian Health System. METHODS: A retrospective study. A cohort of patients from a drug dispensing database that collected all prescriptions of long-acting somatostatin analogs (octreotide, lanreotide, pasireotide). Sociodemographic variables, clinical variables (diagnosis and comorbidities) and pharmacological therapy variables (dose, changes, persistence of use, comedications) were considered. RESULTS: A total of 213 patients were identified, including 139 (65.3%) with acromegaly and 74 (34.7%) with neuroendocrine tumors. There was a predominance of women (58.7%) and a mean age of 59.7 ± 14.5 years. The most commonly used medications were lanreotide autogel (n = 107; 50.2%), octreotide LAR (n = 102; 47.9%) and pasireotide LAR (n = 4; 1.9%). During follow-up, 11.3% of patients experienced modifications of therapy, with a mean duration from the beginning of treatment to the change in medication of 25 ± 15.9 months. A total of 48.9% of the patients with acromegaly and 87.1% of individuals with neuroendocrine tumors received maximum approved doses of the drug. CONCLUSION: Patients with acromegaly and neuroendocrine tumors in Colombia are mainly women and are most frequently treated with lanreotide autogel for acromegaly and with octreotide LAR for neuroendocrine tumors. In addition, a high proportion are managed with maximum doses of long-acting somatostatin analogs.

Clinical trial to determine whether the timing of tranexamic acid administration influences perioperative bleeding in total knee arthroplasty.

BACKGROUND AND OBJECTIVES: The ideal timing of tranexamic acid administration in total knee arthroplasty with tourniquet remains unclear. Our primary objective was to prove if administering it before surgical incision, instead of before releasing the tourniquet, reduces postoperative bleeding. A second objective was to determine whether a second dose reduces post-operative bleeding. MATERIAL AND METHODS: A prospective, double-blind clinical trial was performed on 212 patients scheduled for total knee arthroplasty. They were randomised into 4 groups. Tranexamic acid was administered before the surgical incision in "pre-induction groups" (1 and 2), and just before the tourniquet release in "pre-release groups" (3 and 4). Groups 2 and 4 received a second dose 3h post-surgery. Main outcome was postoperative bleeding (visible blood loss and calculated total bleeding). Secondary outcomes were haemoglobin variations, complications and transfusion rate. RESULTS: The mean calculated total bleeding was 1563ml (95%CI: 1445-1681) in preinduction groups versus 1576ml (95%CI: 1439-1713) in pre-release groups (P=0.9); 1579ml (95%CI: 1452-1706) in single-dose groups versus 1559ml (95%CI: 1431-1686) in double-dose groups (P=0.82). One patient was transfused. The mean haemoglobin at discharge was 10.4g/dl (95%CI: 10.2-10.7) in singledose groups versus 10.8 (95%CI: 10.6-11.1) in double-dose groups (P=0.06). CONCLUSIONS: There were no differences in bleeding or transfusion regarding the time of tranexamic acid administration. The second dose had not impact on outcomes. TRIAL REGISTRATION: EudraCT 2016-000071-24.

Prediction of phosphenes occurrence in patients undergoing photon irradiation to ocular structures due to brain tumor.

BACKGROUND AND OBJECTIVE: Phosphenes are visual light phenomena that are experienced when there is no apparent light that stimulates the eye. In oncology, phosphenes are also present during radiation therapy for patients with tumors of the central nervous system, eyes, head and neck. Due to the discomfort of patients treated with irradiation to the head regions, research is conducted to determine whether the dose to the ocular structures is predictive for the occurrence of phosphenes. The objective was to demonstrate the relationship between the doses of the retina and vitreous humour with the appearance of phosphenes. MATERIAL AND METHOD: A descriptive study was carried out in a prospective cohort in 25 patients older than 18 years, with malignant tumours located at the level of the brain, both of primary and secondary origin, subjected to irradiation in 6 MV linear accelerators, during February 2020 to January 2021. As independent variables: Retinal dose and vitreous humour dose, and as dependent variables: Light flashes and stable light. Logistic regression analysis was used for prediction, using the SPSS statistical program (version 26.0). RESULT: A final date of 380 external radiotherapy treatments. The presence of any of the events in a prevalence of 58.7% of the total of fractions. The distribution for the presence of both events, flash of light and stable light, was 69.1%, 20.6% and 10.3% respectively. In the logistic regression analysis, for the light flare, only the dose factor in vitreous was significant (OR: 1.74, IC [1.059-2.419] p: 0.001). For stable light, the dose in the retina (OR: 1.73, IC [1.121-2.341] p: 0.005), and dose in the vitreous humor (OR: 1.82, IC [1.335-2.315] p: 0.003). CONCLUSIONS: There is a predictive relationship between the doses of irradiation of the retina and vitreous humour, for the generation of phosphenes. These results help radiotherapy centres take these anatomical structures into account to reduce the presence of phosphenes in patients. Likewise, it would help to reduce phosphenes, keeping the bunker area illuminated during the treatment.

Could thymoglobulin increase hemorrhagic risk in the perioperative transplantation period of sensitized kidney recipients?

OBJECTIVE: It has been described that thymoglobulin could increase the risk of infections and malignancies, in comparison to basiliximab. Leukopenia and thrombocytopenia are also more common within the first days after transplantation among thymoglobulin patients. Our objective was to analyze bleeding complications in this subset of patients. MATERIAL AND METHODS: Bleeding complications were evaluated among 515 renal transplants carried out at our institution between 2012 and 2018. We compared patients treated with thymoglobulin (Group 1, N=91) with those treated with basiliximab (Group 2, N=424). RESULTS: We found differences in platelet decrease: 95,142.2 (55,339.6) in Group 1 and 52,364.3 (69,116.6) in Group 2 (P=0.001), number of patients with severe thrombocytopenia (<75,000/mm3) (20.8% vs. 3.7%, P=0.001), number of blood units transfused (3.25 (0.572) vs. 2.2 (0.191, P=0.028) and percentage of patients that required surgery due to bleeding (18.2% vs. 7.7%, P=0.046). In a multiple lineal regression multivariable analysis (dependent variable was number of blood units transfused), only age [OR 0.037, 95% CI (0.003-0.070)] and type of immunosuppression [OR 1.592, 95% CI (1.38-2.84)] showed statistical significance. CONCLUSIONS: The use of thymoglobulin in the perioperative transplantation period could increase bleeding complications. In our series, in the group of patients with thymoglobulin, severe thrombocytopenia was 6 times more frequent, and active bleeding that required surgery was also 2.5 times more frequent. One way to continue with the use of this immunosuppression agent, might be to adjust the dose instead of discontinuing it. The use of thymoglobulin should be a factor to consider in the postoperative period of these patients.

Innovations in liver transplantation in 2020, position of the Belgian Liver Intestine Advisory Committee (BeLIAC).

Liver transplantation (LT) remains the only curative option for patients suffering from end-stage liver disease, acute liver failure and selected hepatocellular carcinomas and access to the LT-waiting list is limited to certain strict indications. However, LT has shown survival advantages for patients in certain indications such as acute alcoholic hepatitis, hepatocellular carcinoma outside Milan criteria and colorectal cancer metastases. These newer indications increase the pressure in an already difficult context of organ shortage. Strategies to increase the transplantable organ pool are therefore needed. We will discuss here the use of HCV positive grafts as the use of normothermic isolated liver perfusion. Belgian Liver Intestine Advisory Committee (BeLIAC) from the Belgian Transplant Society (BTS) aims to guarantee the balance between the new indications and the available resources.

Biomolecular study and conjugation of two para-aminobenzoic acid derivatives with serum proteins: drug binding efficacy and protein structural analysis.

Two aminobenzoic acid derivatives DAB-0 and DAB-1 showed distinct biological properties on murine bladder cancer (BCa) cell line MB49-I. In contrast to DAB-1, DAB-0 does not possess any anti-inflammatory activity and is less toxic. Furthermore, DAB-0 does not interfere with INFγ-induced STAT1 activation and TNFα-induced IκB phosphorylation, while DAB-1 does. In order to rationalize these results, the binding efficacy of DAB-0 and DAB-1 with serum proteins such a human serum albumin (HSA), bovine serum albumin (BSA) and beta-lactoglobulin (ß-LG) was investigated in aqueous solution at physiological pH. Multiple spectroscopic methods and thermodynamic analysis were used to determine the binding efficacy of DAB-0 and DAB-1 with serum proteins. Drug-protein conjugation was observed via through ionic contacts. DAB-1 forms stronger adducts than DAB-0, while ß-LG shows more affinity with the order of stability ß-LG > BSA > HSA. The stronger complexation of DAB-1 with serum proteins might account for its biological potential and transport in the blood. The binding efficacy ranged from 40 to 60%. Major alterations of protein secondary structures were detected upon drug complexation. Serum proteins are capable of delivering DAB-1 in vitro.Communicated by Ramaswamy H. Sarma.

Characterization of Chilean patients with sporadic colorectal cancer according to the three main carcinogenic pathways: Microsatellite instability, CpG island methylator phenotype and Chromosomal instability.

Molecular classification of colorectal cancer is difficult to implement in clinical settings where hundreds of genes are involved, and resources are limited. This study aims to characterize the molecular subtypes of patients with sporadic colorectal cancer based on the three main carcinogenic pathways microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and chromosomal instability (CIN) in a Chilean population. Although several reports have characterized colorectal cancer, most do not represent Latin-American populations. Our study includes 103 colorectal cancer patients who underwent surgery, without neoadjuvant treatment, in a private hospital between 2008 and 2017. MSI, CIN, and CIMP status were assessed. Frequent mutations in KRAS, BRAF, and PIK3CA genes were analyzed by Sanger sequencing, and statistical analysis was performed by Fisher's exact and/or chi-square test. Survival curves were estimated with Kaplan-Meier and log-rank test. Based on our observations, we can classify the tumors in four subgroups, Group 1: MSI-high tumors (15%) are located in the right colon, occur at older age, and 60% show a BRAF mutation; Group 2: CIN-high tumors (38%) are in the left colon, and 26% have KRAS mutations. Group 3: [MSI/CIN/CIMP]-low/negative tumors (30%) are left-sided, and 39% have KRAS mutations; Group 4: CIMP-high tumors (15%) were more frequent in men and left side colon, with 27% KRAS and 7% presented BRAF mutations. Three percent of patients could not be classified. We found that CIMP-high was associated with a worse prognosis, both in MSI-high and MSI stable patients (p = 0.0452). Group 3 (Low/negative tumors) tend to have better overall survival compared with MSI-high, CIMP-high, and CIN-high tumors. This study contributes to understanding the heterogeneity of tumors in the Chilean population being one of the few characterizations performed in Latin-America. Given the limited resources of these countries, these results allow to improve molecular characterization in Latin-American colorectal cancer populations and confirm the possibility of using the three main carcinogenic pathways to define therapeutic strategies.

Determinación de la eficacia de antihelmínticos para el tratamiento de la gastroenteritis verminosa en caprinos de la provincia de Tucumán / Determination of the efficacy of anthelmintics used in the control of gastrointestinal nematodes of goats from Tucumán, Argentina

Resumen En la Argentina, el 93% de la producción caprina en la Argentina es desarrollada por pequeños productores de agriculturas de subsistencia, quienes, por lo general, utilizan antihelmínticos sin asesoramiento profesional, lo que, probablemente, ha llevado al desarrollo de resistencia, comprometiendo seriamente la sustentabilidad del control de nematodos. El objetivo de este estudio es determinar la eficacia de la ivermectina, el albendazol y el levamisol para el tratamiento de la gastroenteritis verminosa en cuatro grupos de ocho caprinos cada uno, mediante el Test de Reducción del Conteo de Huevos (TRCH). Los resultados demostraron un 100% de reducción del número de HPG para los grupos tratados con albendazol y levamisol y un 17% de reducción para el grupo tratado con ivermectina, con respecto al grupo control, lo que permite inferir que existe resistencia a este fármaco.

Abstract Determination of the efficacy of anthelmintics used in the control of gastrointestinal nematodes of goats from Tucumán, Argentina. Almost 93% of goat production in Argentina is developed by small farmers, who generally use anthelmintics without professional advice, which has led to the development of resistance, seriously compromising the sustainability of nematode control. This study aims to determine the efficacy of ivermectin, albendazole and levamisole for the treatment of verminous gastroenteritis in four groups of eight goats each, using the Faecal Egg Count Reduction Test (FECRT). The results showed a 100% reduction in the number of EPG for the groups treated with albendazole and levamisole and a 17% reduction for the group treated with ivermectin, compared to the control group, which allows us to infer that there is resistance to this drug.

Nicotinamide reduces inflammation and oxidative stress via the cholinergic system in fructose-induced metabolic syndrome in rats.

AIMS: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) have been associated with risk factors for metabolic syndrome (MetS). Our objective was to evaluate the effect of nicotinamide (NAM) on the activities, expression and protein content of cholinesterases in a MetS model. MAIN METHODS: MetS was induced in male rats administrating 40% fructose to the drinking water for 16 weeks. Additionally, from 5th week onward, the carbohydrate solution was replaced by NAM, at several concentrations for 5 h each morning for the next 12 weeks. In the 15th week, the glucose tolerance test was conducted, and blood pressure was measured. After the treatment period had concluded, the biochemical profile; oxidant stress; proinflammatory markers; and the activity, quantity and expression of cholinesterases were evaluated, and molecular docking analysis was performed. KEY FINDINGS: The MetS group showed anthropometric, hemodynamic and biochemical alterations and increased cholinesterase activity, inflammation and stress markers. In the liver, cholinesterase activity and mRNA, free fatty acid, tumor necrosis factor-alpha (TNF-α), and thiobarbituric acid-reactive substance (TBARS) levels were increased, while reduced glutathione (GSH) levels were decreased. NAM partially or totally decreased risk factors for MetS, markers of stress and inflammation, and the activity (serum and liver) and expression (liver) of cholinesterases. Molecular docking analysis showed that NAM has a greater affinity for cholinesterases than acetylcholine (ACh), suggesting NAM as an inhibitor of cholinesterases. SIGNIFICANCE: Supplementation with 40% fructose induced MetS, which increased the activity and expression of cholinesterases, oxidative stress and the inflammation. NAM attenuated these MetS-induced alterations and changes in cholinesterases.

Incorporating posttransplant cyclophosphamide-based prophylaxis as standard-of-care outside the haploidentical setting: challenges and review of the literature.

Posttransplant high-dose cyclophosphamide (PTCy) effectively prevents GvHD after haploidentical SCT. However, its use in HLA-matched SCT has been less explored. Fifty-six consecutive patients who underwent allo-SCT for hematological malignancies have been included in this prospective single-center protocol. Donors have been HLA-identical siblings, fully-matched unrelated or 1-allele-mismatched unrelated donors in 30%, 32%, and 37% of cases, respectively. Nine patients have received a TBI-containing MAC regimen, while the remaining (84%) received RIC platforms based on Fludarabine plus Busulfan/Melphalan. Due to the high graft failure (GF) rate (21%) in a preliminary analysis in the allo-RIC cohort (n = 29), protocol amendments have been implemented, with no further cases of GF after the introduction of mini-thiotepa (0/18). The overall incidence of grade II-IV acute GvHD is 24% (95% CI: 17-31%) with four steroid-refractory cases. Severe chronic GvHD has occurred in only 1 of 43 evaluable cases. The 1-year NRM and relapse are 18% (95% CI: 12-26%) and 30% (18-42%) and the OS and DFS are 78% and 64%, respectively. These outcomes support the feasibility of using PTCy as a SOC outside the haplo-setting, albeit mini-thiotepa (3 mg/kg) was incorporated in the standard allo-RIC platforms to prevent GF. Despite the limitations of a single-center experience and the short follow-up, these protocols show promising results with particular benefit in reducing the occurrence of moderate-to-severe GvHD.