Comprehensive Analysis of Adverse Events Associated with Gastric Peroral Endoscopic Myotomy: An International Multicenter Study.

BACKGROUND: Gastric peroral endoscopic myotomy (G-POEM) has emerged as an effective management approach for patients with refractory gastroparesis. This study aims to comprehensively study the safety of G-POEM and describe the predictive factors of adverse events (AEs) occurrence. METHODS: This study is a retrospective study involving 13 tertiary care centers (7 USA, 1 South America, 4 Europe, and 1 Asia). Patients who underwent G-POEM for refractory gastroparesis were included. Cases were identified by the occurrence of AEs. For each case, two controls were randomly selected and matched for age (± 10 years), gender, and etiology of gastroparesis. RESULTS: A total of 216 patients underwent G-POEM for gastroparesis. Overall, 31 (14%) AEs were encountered [mild 24 (77%), moderate 5 (16%), and severe 2 (6%)] during the duration of the study. The most common AE was abdominal pain (n = 16), followed by mucosotomy (n = 5) and capnoperitoneum (n = 4), and AEs were most commonly identified within the first 48-h post-procedure 18 (58%). The risk of adverse event occurrence was significantly higher for endoscopists with experience of < 20 G-POEM procedures (OR 3.03 [1.03-8.94], p < 0.05). CONCLUSION: G-POEM seems to be a safe intervention for refractory gastroparesis. AEs are most commonly mild and managed conservatively. Longitudinal mucosal incision, use of hook knife, use of clips for mucosal closure and endoscopist's experience with > 20 G-POEM procedures is significantly associated with decreased incidence of AEs.

Determining the health-related quality of life in individuals with haemophilia in developing economies: results from the Brazilian population.

INTRODUCTION: Several studies show the negative impact of haemophilia in health-related quality of life (HRQOL). This issue is not well explored in developing countries. OBJECTIVES: This cross-sectional study aimed to evaluate the HRQOL and its associated factors in patients with haemophilia A/B in Brazil. Data were collected by questionnaire and in medical records, including a Portuguese version of Haem-A-Qol. RESULTS: Brazilian patients were invited to the study and 175 participants (147 haemophilics A and 28 haemophilics B) were included. The total score of the Haem-A-QoL had a median of 36.96 (range of 0-100), with worse performance in 'sport and leisure' and best on 'relationships' fields. HRQOL was worst among the older participants, the less educated, non-white, non-working, who were hospitalized in the last year, who did not have a single medical consultation and among those with the highest number of affected joints. Moreover, patients with hepatitis B had a significantly worse HRQOL in the domain 'sports and leisure', also observed in married patients. Otherwise, married individuals reported better HRQOL on 'dealing with the disease' domain. Patients with haemophilia B reported worse HRQOL in the domain 'self-perception'. CONCLUSION: The results obtained could be helpful in guidance of haemophilia treatment which is determinant to improve HRQoL of the most vulnerable groups of patients. This work also reinforced the relevance of joint bleeds in all aspects of HRQoL in haemophilic patients. The use of prophylactic factor concentrates and multidisciplinary treatments could contribute to improve the quality of life in haemophilia.

Effect of red blood cell preservation by droplet freezing with non-permeable cryoprotective agents in blood group antigen reactivity.

BACKGROUND: In the last few decades, various red blood cell (RBC) freezing techniques have been developed and improved to enable the preservation of erythrocytes for future use in pre-transfusion tests in reference immunohaematology laboratories. However, not all these techniques have been sufficiently evaluated for the preservation of blood group antigens. OBJECTIVES: In this study, we evaluated the antigenic pattern of RBCs preserved by droplet freezing in liquid nitrogen in a blood bank context. METHODS: Blood samples were evaluated for the reactivity of blood group antigens after droplet freezing using the non-permeable cryoprotective agent polyvinylpyrrolidone (PVP) and sucrose-dextrose (S + D) solutions. RESULTS: No qualitative changes were observed in RBC reactivity after freezing and thawing for the antigens Fyb , Leb , C, E, Cw , Lua , Lub , Kpa , Kpb and Dia . However, cryopreservation using PVP resulted in a significant increase in reactivity of Fyb antigen on comparing fresh and frozen samples (P < 0·001). CONCLUSION: The establishment of detailed protocols for cryopreservation of RBCs, which take into account the maintenance of antigenic characteristics, is necessary to increase security in pre-transfusion testing using frozen RBCs.

Cytokine profile and FVIII inhibitors development in haemophilia A.

Haemophilia A is a hereditary bleeding disorder linked to the X chromosome characterized by a deficiency or defect in the coagulation factor VIII (FVIII). Individuals with this coagulopathy require constant infusions of FVIII to maintain their physical integrity and haemostasis. During treatment, some patients develop an immune response that produces antibodies to FVIII, also called inhibitors, affecting the pro-coagulant activity of this protein. Despite the clinical relevance of FVIII inhibitors, the immune mechanisms that lead to their production are not known. This study investigated the immunological cytokine profile using plasma from HA patients which were either positive or negative for FVIII inhibitors and from healthy individuals. The results showed that healthy individuals and HA patients that do not develop FVIII inhibitors have a mixed immune response profile with high secretion of IFN-γ, TNF-α IL-2 and IL-5. In contrast, HA patients with FVIII inhibitors exhibited an anti-inflammatory/regulatory immune response characterized by low levels of all measured cytokines except for IL-4 and IL-10. This profile may be related to the development and maintenance of the FVIII inhibitors. By comparing the cytokine profiles of the three different groups we have established a model explaining the immune activation resulting in the production of FVIII inhibitors in haemophilia A patients.

Comparative proteomic analysis between early developmental stages of the Coffea arabica fruits.

Coffee is one of the most valuable agricultural commodities. There is much agronomic research on coffee, but molecular knowledge of its fruit development and ripening is limited. This study reports a comparative proteomic investigation of immature coffee fruits in two early developmental stages: stage 1, cell division and elongation of the perisperm; and stage 2, early growth of the endosperm progressively replacing the perisperm. Proteins were extracted using a modified SDS-phenol method and two-dimensional electrophoresis gels stained with Coomassie blue revealed about 300 well-resolved polypeptide spots in the pH range of 3 to 10. The differentially expressed polypeptides spots were excised, trypsin-digested, and analyzed by MALDI-TOF mass spectrometry. Peptide MS data were searched against the coffee EST database. Most of the identified protein spots are involved in the glycolytic pathway and energy reserve, and are more highly expressed at stage 2.

Differential gene expression pattern and plasma sex steroids during testicular development in Genyatremus luteus (Perciforme: Haemulidae) (Bloch, 1790).

The aim of the current study is to evaluate gene expression patterns of LH (lhr) and estrogen (er) receptors and plasma steroid levels during testicular development in Genyatremus luteus. Males were histologically classified as immature (n=7), maturing (n=7) and mature (n=7), based on the cellular structure of their testes. Plasma 11-KT concentration recorded peak at the final maturation stage. The highest plasma 17α-OHP concentrations were observed at the immature stage; they decreased at the maturation and mature stages. On the other hand, 17ß-estradiol (E2) recorded higher concentrations at the maturation stage. Er expression has significantly increased along the maturational development of animals' testes. The mRNA observed for the LH receptor has decreased from immature to maturing stage; it presented expression peak at the mature stage. There was high association between receptor gene expression and plasma steroid levels, mainly E2. The current study was the first to feature different reproductive maturation stages in male G. luteus specimens, based on cellular, endocrine and molecular aspects. In addition, it has shown that the gene expression profile for er and lhr receptors, as well as plasma 11-KT and E2 concentrations, are directly linked to testicular maturation, although they are not necessarily associated with the gonadosomatic index.

A shift towards a T cell cytokine deficiency along with an anti-inflammatory/regulatory microenvironment may enable the synthesis of anti-FVIII inhibitors in haemophilia A patients.

Despite the clinical relevance of anti-factor VIII (FVIII) antibodies (anti-FVIII inhibitors) impairing haemostatic activity of haemophilia A (HA) patients, the immunological mechanisms underlying their production are unknown. Aiming to understand more clearly the immune response in patients with [HAα-FVIII(+)] and without [HAα-FVIII(-)] anti-FVIII inhibitors, we have characterized the cytokine pattern of peripheral blood leucocytes, using an in vitro stimulation of whole blood samples with plasma-derived (pFVIII) or recombinant FVIII (rFVIII). The results highlighted decreased levels of tumour necrosis factor (TNF)-α(+) neutrophils with higher interleukin (IL)-5/TNF-α ratio in HAα-FVIII(+). All HA samples displayed decreased levels of IL-10(+) monocytes when compared to the blood donor (BD) samples. HAα-FVIII(+) showed lower levels of TNF-α(+) monocytes and increased IL-10/TNF-α ratio. Analysis of adaptive immunity revealed increased levels of interferon (IFN)-γ(+) , TNF-α(+) and IL-4(+) T-cells, from both CD4(+) and CD8(+) T cells, in HAα-FVIII(-) when compared to BD. Moreover, increased frequency of IL-10(+) B cells and higher levels of α-FVIII IgG1 were observed in HAα-FVIII(-). Basal levels of cytokine(+) B-cells, similar to BD, and higher levels of α-FVIII IgG4 are major features in HAα-FVIII(+). The global cytokine profile demonstrated a major anti-inflammatory/regulatory pattern in HAα-FVIII(+), confirmed by the in vitro stimuli with pFVIII or rFVIII. The polarized anti-inflammatory/regulatory immune response in HAα-FVIII(+) and the mixed pattern with a bias towards an inflammatory cytokine profile, modulated by IL-4 in HAα-FVIII(-), may be the key element to drive the development of distinct subclasses of anti-FVIII antibodies. These finding have implications for the design of safe and effective therapeutic protocols to control inhibitors synthesis in HA patients.

Analysis of cytokine genes polymorphism as markers for inhibitor development in haemophilia A.

Antibodies that block factor VIII (FVIII) activity appear in some haemophilia A patients treated with FVIII replacement therapy and severely impaired treatment. To date, the mechanisms that lead to this immune response are unknown. In this work, haplotypes of cytokine interleukin 10 (IL-10) gene have been associated with the presence of FVIII inhibitors in a group of Brazilian haemophilia A patients. The coexistence of a haplotype defining high IL-10 synthesis and one defining an intermediate production of cytokines is found to be associated with the group of patients who have a history of inhibitor development. Additionally, the coexistence of haplotypes defining high and low IL-10 syntheses is strongly associated with the group of negative inhibitors. These results have shown that the simple association considering only the presence or the absence of a haplotype and the development of inhibitors in haemophilia A is not sufficient. Data obtained in this work sustain the idea that the genetic studies may partly explain why only approximately 25% of haemophilia A patients develop FVIII inhibitors. Other genetic issues and details of the protein replacement therapy should be considered to measure the chances of a patient to develop anti-FVIII antibodies.

An evidence-based consensus statement on the role and application of endosonography in clinical practice.

BACKGROUND: Endoscopic ultrasonography (EUS) has evolved over the past 20 years with the emergence of novel diagnostic and therapeutic indications. Our goal was to identify the best evidence supporting the use of EUS. MATERIALS AND METHODS: A six-step approach was employed to develop recommendations using accepted methodology. Twenty-two experienced endosonographers identified topics and reviewed studies using MeSH (medical subject headings) terminology and free text in PubMed. Medline and society abstracts were reviewed if necessary. The quality of evidence, the strength of recommendations, and level of consensus were graded and voted on. RESULTS: Consensus was reached for several clinical scenarios for which the impact of EUS findings was supported by a high level of evidence. These included diagnosis and staging of esophageal cancer, differential diagnosis of subepithelial lesions, thickened gastric folds, assessment of peritoneal involvement in patients with gastric cancer, mucosa-associated lymphoid tissue lymphoma, diagnosis of common bile duct/gallbladder stones, diagnosis of chronic pancreatitis, differential diagnosis of a solid mass in patients with chronic pancreatitis, differential diagnosis of pancreatic cyst, rectal cancer staging, and diagnosis and staging of non-small-cell lung cancer. The recommendations were adopted by the Brazilian Society of Gastrointestinal Endoscopy. Several indications continue to emerge and require additional validation.

Reactivity profile of anti-factor VIII antibodies with designed synthetic peptides mimicking epitopes of the C2 and a1 domains.

Antibodies (Abs) that block factor VIII (FVIII) activity occur in hemophilia A patients treated with FVIII replacement therapy and severely impair treatment. In this work, we designed and synthesized ten peptides whose sequences are found in putative epitopes at the surface of a1 and C2 domains of the FVIII molecule. These peptides were screened for their ability to inhibit the binding of anti-FVIII Abs from plasmas of hemophilia A patients to FVIII. All peptides were efficient in inhibiting anti-FVIII Abs in plasma from patients with inhibitors, with however different efficiencies. It was found that each tested patient's plasma had a different profile of reactivity with peptides, consistent with an individual anti-FVIII Ab specificity. The profile of recognized peptides was also changing during the treatment of the patients. Three peptides were used in an affinity chromatography assay to attempt to remove anti-FVIII Abs from patients' plasma. Anti-FVIII IgGs were significantly captured by the peptide-Sepharose affinity matrixes as assessed by enzyme-linked immunosorbent assay. However, due to the low level of Abs in the plasma samples, other methods (Chromogenic and Bethesda assays) were not sensitive enough to properly detect the reduction of inhibitors.

Standardization and comparison of nonautomated assays to measure the collagen binding activity of von Willebrand factor.

INTRODUCTION: Diagnosis of von Willebrand disease (VWD) is difficult due to the heterogenic phenotype of patients and to the complex tests that are required for an adequate investigation. The collagen binding assay (VWF:CB) reveals the adhesion capacity of von Willebrand factor (VWF) to collagen and can be useful to reduce the misleading diagnosis of VWD. This study aimed the standardization of 2 nonautomated VWF:CB assays based on ELISA and flow cytometry. METHODS: Plasma samples from 87 patients previously diagnosed with VWD and 22 healthy controls were analyzed. Measurement of the VWF-collagen binding activity was performed using a commercial assay and the 2 tests proposed. VWF:CB/VWF:Ag ratio was calculated for samples and the differentiation between types 1, 2A, and 2M was analyzed. RESULTS: ELISA and flow cytometry tests presented strong correlation with the gold standard test (r2  = .8976 and r2  = .8143, respectively). Tests based on ELISA and flow cytometry presented a bias of +7.2% and -3.6%, respectively. CONCLUSION: The ELISA test demonstrated better performance to detect VWF-collagen binding activity in healthy individuals and VWD patients. This test could differentiate 2A and 2M subtypes using a feasible protocol that can be easily implemented.

Caracterización clínica y epidemiológica de los pacientes con trastorno por uso de opioides atendidos en una institución de cuarto nivel en la ciudad de Medellín, entre 2017 y 2022 / Clinical and epidemiological characterization of patients with opioid use disorder treated at a fourth level institution in the city of Medellín, between 2017 and 2022

Los analgésicos opioides son una opción importante en el manejo del dolor agudo grave, crónico e intratable, sin embargo, sus efectos euforizantes y gratificantes han motivado a que algunos pacientes continúen su uso una vez resuelta la condición médica inicial, haciendo entonces un uso indebido de opioides (UIO) y con el potencial riesgo de desarrollar un trastorno por uso de opioides (TUO). El objetivo del presente trabajo fue caracterizar clínica y epidemiológicamente a los pacientes con trastorno por uso de opioides atendidos en una institución de cuarto nivel de Medellín. Para ello, se realizó un estudio observacional, descriptivo, transversal de fuente secundaria; se incluyeron 309 registros de pacientes adultos, con diagnóstico CIE-10, trastornos causados por opiáceos. TUO e UIO constituyeron las variables de interés, se procesó la información en Jamovi® versión 2.2 y se analizaron los datos de variables cuantitativas con test de Sahpiro Wilk y análisis bivariado exploratorio de las variables clínicas y sociodemográficas. Resultados: El TUO obtuvo una prevalencia del 39.9% frente al 25,6 % del UIO. De los pacientes con TUO el 50% tenían 35 años o menos, el 57.7% fueron mujeres, 58.7% solteros, y predominaron los niveles de educación secundaria y universitaria. En cuanto al UIO, el 50% fueron menores de 37 años el 54% de sexo femenino, en su mayoría solteros (61.5%), y predominó el nivel de educación secundaria (48.7%). En el 71% de los pacientes con TUO hay antecedentes de enfermedad mental predominando los trastornos del afecto: ansiedad y depresión. El opioide más usado fue tramadol (17.04%), seguido de morfina e hidromorfona. Conclusión: Ante el aumento en la prevalencia de UIO y TUO es necesario nuevas políticas salud pública que permitan ejercer un control más estricto en la formulación, comercialización y administración segura de este tipo de medicamentos.(AU)

Opioids analgesics are an important option in the management of severe acute, chronic, and intractable pain; however, their euphoric and rewarding effects have motivated some patients to continue their use once the initial medical condition has resolved, thus misusing them. these (UIO) and with the potential risk of developing an opioid use disorder (OUD).Objectives: to clinically and epidemiologically characterize patients with opioid use disorder treated at a fourth-level institution in Medellín.Methodology: Observational, descriptive, cross-sectional study of secondary source; 309 records of adult patients with ICD-10, diagnosis caused by opioids agents were included. TUO and IOU were the variables of interest, the information was processed in Jamovi® version 2.2 and the data of quantitative variables were analyzed with the Sahpiro Wilk test and exploratory bivariate analysis of the clinical and sociodemographic variables.Results: The TUO obtained a prevalence of 39.9% compared to 25.6% of the UIO. Of the patients with OT, 50% were 35 years of age or younger, 57.7% were women, 58.7% were single, and secondary and university education levels predominated. Regarding the UIO, 50% were under 37 years of age, 54% female, mostly single (61.5%), and the secondary education level predominated (48.7%).In 71% of patients with OLW there is a history of mental illness, predominantly affective disorders: anxiety and depression. The most used opioid was tramadol (17.04%), followed by morphine and hydromorphone. Conclusion: Given the increase in the prevalence of UIO and OTU, new public health policies are necessary to exercise stricter control in the formulation, marketing and safe administration of this type of medication.(AU)

Active layer and permafrost thermal regime in a patterned ground soil in Maritime Antarctica, and relationship with climate variability models.

Permafrost and active layer studies are important to understand and predict regional climate changes. The objectives of this work were: i) to characterize the soil thermal regime (active layer thickness and permafrost formation) and its interannual variability and ii) to evaluate the influence of different climate variability modes to the observed soil thermal regime in a patterned ground soil in Maritime Antarctica. The study was carried out at Keller Peninsula, King George Island, Maritime Antarctica. Six soil temperatures probes were installed at different depths (10, 30 and 80cm) in the polygon center (Tc) and border (Tb) of a patterned ground soil. We applied cross-correlation analysis and standardized series were related to the Antarctic Oscillation Index (AAO). The estimated active layer thickness was approximately 0.75cm in the polygon border and 0.64cm in the center, indicating the presence of permafrost (within 80cm). Results indicate that summer and winter temperatures are becoming colder and warmer, respectively. Considering similar active layer thickness, the polygon border presented greater thawing days, resulting in greater vulnerability to warming, cooling faster than the center, due to its lower volumetric heat capacity (Cs). Cross-correlation analysis indicated statistically significant delay of 1day (at 10cm depth) in the polygon center, and 5days (at 80cm depth) for the thermal response between atmosphere and soil. Air temperature showed a delay of 5months with the climate variability models. The influence of southern winds from high latitudes, in the south facing slopes, favored freeze in the upper soil layers, and also contributed to keep permafrost closer to the surface. The observed cooling trend is linked to the regional climate variability modes influenced by atmospheric circulation, although longer monitoring period is required to reach a more precise scenario.

Synthesis of 2'-C-methyl-beta-D-ribofuranosylimidazo [4,5-d]-pyridazine derivatives (2-aza-3-deazapurine nucleoside analogues).

In order to evaluate their antiviral properties, two imidazo[4,5-d]pyridazine 2'-C-methyl-beta-D-ribofuranonucleoside derivatives have been synthesized.

Synthesis of 5-aza-7-deazaguanine nucleoside derivatives as potential anti-flavivirus agents.

Coupling suitable sugars (D- or L-ribofuranose, 2' or 3-deoxysugar, branched sugars) with 2-aminoimidazo[1,2-a]-s-triazin-4-one was carried out using the different reaction conditions: 1) condensation in the presence of sodium hydride; or 2) condensation using Vorbrüggen's methods. The 5-aza- 7-deazaguanine nucleoside analogues obtained were evaluated in cell culture experiments for the inhibition of the replication of a number of RNA viruses, including BVDV, YFV, and WNV.

Effects of thalidomide, cyclosporine, and diclofenac on skin allograft survival in rabbits.

The present study evaluated the effects of thalidomide, cyclosporine, and diclofenac on skin allograft survival in 42 rabbits divided into the following groups (n = 6): group 1, autograft control; group 2, allograft control; group 3, allografts under thalidomide (100 mg/kg/d); group 4, allografts under sodium diclofenac (2 mg/kg/d); group 5, allografts under cyclosporine (10 mg/kg/d); group 6, allografts under cyclosporine (5 mg/kg/d); group 7, allografts under cyclosporine (5 mg/kg/d) plus thalidomide (100 mg/kg/d). The drugs were given via the orogastric tube the day before transplantation and daily during the postoperative period. Total circular skin grafts from the ear were exchanged between California and White New Zealand rabbits. Cyclosporine (10 mg/kg/d) increased allograft survival, an effect that was comparable to cyclosporine (5 mg/kg/d) plus thalidomide (100 mg/kg/d). Thalidomide and diclofenac given alone had minimally significant effects on the mean survival of skin allografts. The number of eosinophils around the necrotic skin was higher in the diclofenac group. The group receiving cyclosporine combined with thalidomide displayed the lowest number of eosinophils surrounding the allograft. In conclusion, the combination of thalidomide and cyclosporine in subtherapeutic doses may be useful for the treatment of skin allografts.

Comparative incidence of allergy in the presence or absence of cancer.

Depression of the immune system may be related to cancer development. Allergic manifestations are due to enhanced immunological activity. Several authors have found lower rates of malignancy in atopic individuals. To elucidate the relationship between cancer and allergy, the prevalence of allergic manifestations was surveyed in 400 healthy controls and 400 patients with cancer. The number of allergies was significantly higher (P < 0.001) in the control group than in patients with cancer. Women were more atopic than men in both groups (P < 0.001) but skin colour did not affect the prevalence of allergies. The type of cancer was not related to any specific allergic manifestation. The results suggest that allergies occur less frequently in men than in women and less frequently in patients with cancer than in healthy controls but these relationships are complex and depend on other factors that need further investigation.