Canadian multidisciplinary expert consensus on the use of biologics in upper airways: a Delphi study.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) often coexists with lower airway disease. With the overlap between upper and lower airway disease, optimal management of the upper airways is undertaken in conjunction with that of the lower airways. Biologic therapy with targeted activity within the Type 2 inflammatory pathway can improve the clinical signs and symptoms of both upper and lower airway diseases. Knowledge gaps nevertheless exist in how best to approach patient care as a whole. There have been sixteen randomized, double-blind, placebo-controlled trails performed for CRSwNP targeted components of the Type 2 inflammatory pathway, notably interleukin (IL)-4, IL-5 and IL-13, IL- 5R, IL-33, and immunoglobulin (Ig)E. This white paper considers the perspectives of experts in various disciplines such as rhinology, allergy, and respirology across Canada, all of whom have unique and valuable insights to contribute on how to best approach patients with upper airway disease from a multidisciplinary perspective. METHODS: A Delphi Method process was utilized involving three rounds of questionnaires in which the first two were completed individually online and the third was discussed on a virtual platform with all the panelists. A national multidisciplinary expert panel of 34 certified specialists was created, composed of 16 rhinologists, 7 allergists, and 11 respirologists who evaluated the 20 original statements on a scale of 1-9 and provided comments. All ratings were quantitively reviewed by mean, median, mode, range, standard deviation and inter-rater reliability. Consensus was defined by relative interrater reliability measures-kappa coefficient ([Formula: see text]) value > 0.61. RESULTS: After three rounds, a total of 22 statements achieved consensus. This white paper only contains the final agreed upon statements and clear rationale and support for the statements regarding the use of biologics in patients with upper airway disease. CONCLUSION: This white paper provides guidance to Canadian physicians on the use of biologic therapy for the management of upper airway disease from a multidisciplinary perspective, but the medical and surgical regimen should ultimately be individualized to the patient. As more biologics become available and additional trials are published we will provide updated versions of this white paper every few years.

Manejo conservador del endometrioma ovárico con escleroterapia usando etanol previo a fecundación in vitro

El endometrioma ovárico es un quiste con tejido endometrial ectópico que se asocia a disminución de la reserva ovárica, siendo su manejo en infertilidad controversial. Presentamos el caso de una mujer de 32 años con reserva ovárica disminuida y endometrioma mayor de 100 mm. Fue sometida a aspiración transvaginal ecoguiada y a escleroterapia con etanol, lográndose reducción del tamaño en 65% a los tres meses. Posteriormente se realizó fecundación in vitro (FIV), consiguiéndose embarazo. La exéresis del endometrioma es controversial, debido a que reduce la reserva ovárica. La escleroterapia demuestra conservarla, se asocia a una tasa baja de recurrencia y facilita la accesibilidad ovárica. La escleroterapia con etanol del endometrioma es una técnica ambulatoria, segura y eficaz que permite el embarazo en mujeres con infertilidad.

Ovarian endometrioma is a cyst with ectopic endometrial tissue associated with decreased ovarian reserve. Its management in infertility is controversial. We present the case of a 32-year-old woman with decreased ovarian reserve and endometrioma larger than 100 mm. She underwent ultrasound-guided transvaginal aspiration and subsequent sclerotherapy with ethanol, achieving a 65% reduction in size after three months. Subsequently, in vitro fertilization (IVF) was performed, and pregnancy was achieved. The excision of the endometrioma is controversial because it reduces the ovarian reserve. Sclerotherapy has been shown to preserve ovarian reserve, is associated with a low recurrence rate and facilitates ovarian accessibility. Ethanol sclerotherapy of endometrioma is a safe and effective outpatient technique that allows pregnancy in women with infertility.

In vivo expansion of a CD9+ decidual-like NK cell subset following autologous hematopoietic stem cell transplantation.

Autologous hematopoietic stem cell transplantation (autoHSCT) is a treatment option for hematological disorders and pediatric solid tumors. After an autoHSCT, natural killer (NK) cells are the first lymphocyte subset returning to normal levels. To uncover global changes during NK cell reconstitution after autoHSCT, we performed RNA-sequencing on NK cells before and after autoHSCT. Results showed profound changes in the gene expression profile of NK cells immediately after autoHSCT. Several biological processes including cell cycle, DNA replication and the mevalonate pathway were enriched. Significantly, we observed that following autoHSCT, NK cells acquired a decidual-like gene expression profile, including the expression of CD9. By using multiparametric flow cytometry, we confirmed the expansion of NK cells expressing CD9 immediately after autoHSCT, which exhibited higher granzyme B and perforin expression levels than CD9- NK cells. These results provide insights into the physiopathology of NK cells during their reconstitution after autoHSCT.

Public stigma profile toward mental disorders across different university degrees in the University of Valencia (Spain).

Background: A large proportion of studies carried out in recent years in different populations have shown that stigma toward mental disorders is highly prevalent. In the present study we conducted a comprehensive assessment of stigma to describe and compare stigma toward mental disorders in students enrolled in five different university degrees. Methods: Three hundred and twenty-five students from the University of Valencia (Spain), attending the second term of their first-degree courses in the faculties of medicine, psychology, teaching, economics, and data science participated in this cross-sectional study. Stigma was measured using: the Reported and Intended Behavior Scale (RIBS), the Scale of Community Attitudes toward Mental Illness (CAMI), the Attribution Questionnaire (AQ-27), and the Knowledge about Mental Illness test (KMI). Results: We found different patterns of stigma according to gender, the fact of knowing or living with a person with mental disorders and the university degree studied. Overall, women show fewer stigmatizing attitudes than men but similar stereotypes and prejudice toward people with mental disorders. However, the pattern of results across degrees is more complex. Overall, students of medicine, psychology and teaching showed fewer stigmatizing attitudes than students of economics and data science but differences between degrees were more subtle in stereotypes and prejudice toward people with mental disorders. Conclusion: Our study suggests the existence of different profiles of stigma in relation to mental disorders in university students. These profiles varied in relation with the degree being studied, gender and already knowing or living with a person with mental disorders.

Cannabinoid receptor type 2 agonist JWH-133 decreases cathepsin B secretion and neurotoxicity from HIV-infected macrophages.

HIV-associated neurocognitive disorders (HAND) are prevalent despite combined antiretroviral therapy (cART), affecting 52% of people living with HIV. Our laboratory has demonstrated increased expression of cathepsin B (CATB) in postmortem brain tissue with HAND. Increased secretion of CATB from in vitro HIV-infected monocyte-derived macrophages (MDM) induces neurotoxicity. Activation of cannabinoid receptor type 2 (CB2R) inhibits HIV-1 replication in macrophages and the neurotoxicity induced by viral proteins. However, it is unknown if CB2R agonists affect CATB secretion and neurotoxicity in HIV-infected MDM. We hypothesized that HIV-infected MDM exposed to CB2R agonists decrease CATB secretion and neurotoxicity. Primary MDM were inoculated with HIV-1ADA and treated with selective CB2R agonists JWH-133 and HU-308. HIV-1 p24 and CATB levels were determined from supernatants using ELISA. MDM were pre-treated with a selective CB2R antagonist SR144528 before JWH-133 treatment to determine if CB2R activation is responsible for the effects. Neuronal apoptosis was assessed using a TUNEL assay. Results show that both agonists reduce HIV-1 replication and CATB secretion from MDM in a time and dose-dependent manner and that CB2R activation is responsible for these effects. Finally, JWH-133 decreased HIV/MDM-CATB induced neuronal apoptosis. Our results suggest that agonists of CB2R represent a potential therapeutic strategy against HIV/MDM-induced neurotoxicity.

The physiology of hemostasis.

The breakdown of vascular integrity triggers a series of reactions, initially involving a vasoconstriction phenomenon that reduces blood loss and leads to platelet plug formation under changing flow conditions. Once the platelet plug has formed, the coagulation system is activated in order to allow the formation of fibrin, which anchors the platelet plug to the vessel breach. Finally, once the damage has resolved, the fibrin is eliminated through fibrinolysis. This article explains all these regulatory mechanisms.

NK Cell Reconstitution After Autologous Hematopoietic Stem Cell Transplantation: Association Between NK Cell Maturation Stage and Outcome in Multiple Myeloma.

Autologous hematopoietic stem cell transplantation (autoHSCT) is a standard of care for transplant-eligible patients with multiple myeloma (MM). Among factors that influence outcome after autoHSCT, it has been suggested that the number of natural killer (NK) cells plays an important role. However, the impact that different NK cell subsets and their phenotype could have in disease progression after autoHSCT are less clear. For this reason, we have phenotypically and functionally characterized NK cells during immune system reconstitution after autoHSCT in 54 MM patients. Shortly after leukocyte recovery, an extensive redistribution of NK cell subsets occurs in these patients. In addition, NK cells undergo a profound phenotypic change characterized, among others, by their increased proliferative capacity and immature phenotype. Importantly, MM patients who showed lower frequencies of the mature highly differentiated NKG2A-CD57+ NK cell subset at +30 and +100 days after autoHSCT experienced superior progression-free survival and had a longer time to the next treatment than those with higher frequencies. Our results provide significant insights into NK cell reconstitution after autoHSCT and suggest that the degree of NK cell maturation after autoHSCT affects the clinical outcome of MM patients treated with this therapeutic strategy.

Four-subtest short-form of the WAIS-IV for assessment of patients diagnosed with schizophrenia.

INTRODUCTION: The present study aimed to obtain a short form of the Spanish version of the WAIS-IV for patients diagnosed with schizophrenia that requires about half an hour to be administered. The reduced test can be very useful in clinical and research settings when an estimation of the intelligence quotient (IQ) is required to decide about intervention programs or to describe the sample. MATERIALS AND METHODS: A sample of 143 patients participated in the study, 91 out of them were the test group, and the other 52 were used for a cross-validation analysis. To increase the content validity, the decision was made to create a short form composed of a subtest of each of the four cognitive domains that the scale measures. RESULTS: Several analyses showed that the best combination was composed of the Information, Block Design, Arithmetic, and Symbol Search subtests. Nine different criteria were calculated to evaluate the quality of the short form. CONCLUSIONS: The data showed very good results for the criteria: correlations, difference of means, and cross-validation. The results were satisfactory for: category agreement, band of error, clinical accuracy, and reliability.

Management of Kidney Failure in Patients with Diabetes Mellitus: What Are the Best Options?

Diabetic kidney disease (DKD) is the most frequent cause of kidney failure (KF). There are large variations in the incidence rates of kidney replacement therapy (KRT). Late referral to nephrology services has been associated with an increased risk of adverse outcomes. In many countries, when patients reach severely reduced glomerular filtration rate (GFR), they are managed by multidisciplinary teams led by nephrologists. In these clinics, efforts will continue to halt chronic kidney disease (CKD) progression and to prevent cardiovascular mortality and morbidity. In patients with diabetes and severely reduced GFR and KF, treating hyperglycemia is a challenge, since some drugs are contraindicated and most of them require dose adjustments. Even more, a decision-making process will help in deciding whether the patient would prefer comprehensive conservative care or KRT. On many occasions, this decision will be conditioned by diabetes mellitus itself. Effective education should cover the necessary information for the patient and family to answer these questions: 1. Should I go for KRT or not? 2. If the answer is KRT, dialysis and/or transplantation? 3. Dialysis at home or in center? 4. If dialysis at home, peritoneal dialysis or home hemodialysis? 5. If transplantation is desired, discuss the options of whether the donation would be from a living or deceased donor. This review addresses the determinant factors with an impact on DKD, aiming to shed light on the specific needs that arise in the management and recommendations on how to achieve a comprehensive approach to the diabetic patient with chronic kidney disease.

Acquired thrombotic thrombocytopenic Purpura diagnosed during first trimester of pregnancy with excellent outcome after plasma exchange and rituximab, a case report.

Acquired thrombotic thrombocytopenic purpura is a life-threatening condition that rarely presents during pregnancy. Early diagnosis and treatment with plasma exchange is needed to achieve a good pregnancy outcome.

Preformed T cell alloimmunity and HLA eplet mismatch to guide immunosuppression minimization with tacrolimus monotherapy in kidney transplantation: Results of the CELLIMIN trial.

Personalizing immunosuppression is a major objective in transplantation. Transplant recipients are heterogeneous regarding their immunological memory and primary alloimmune susceptibility. This biomarker-guided trial investigated whether in low immunological-risk kidney transplants without pretransplant DSA and donor-specific T cells assessed by a standardized IFN-γ ELISPOT, low immunosuppression (LI) with tacrolimus monotherapy would be non-inferior regarding 6-month BPAR than tacrolimus-based standard of care (SOC). Due to low recruitment rates, the trial was terminated when 167 patients were enrolled. ELISPOT negatives (E-) were randomized to LI (n = 48) or SOC (n = 53), E+ received the same SOC. Six- and 12-month BPAR rates were higher among LI than SOC/E- (4/35 [13%] vs. 1/43 [2%], p = .15 and 12/48 [25%] vs. 6/53 [11.3%], p = .073, respectively). E+ patients showed similarly high BPAR rates than LI at 6 and 12 months (12/55 [22%] and 13/66 [20%], respectively). These differences were stronger in per-protocol analyses. Post-hoc analysis revealed that poor class-II eplet matching, especially DQ, discriminated E- patients, notably E-/LI, developing BPAR (4/28 [14%] low risk vs. 8/20 [40%] high risk, p = .043). Eplet mismatch also predicted anti-class-I (p = .05) and anti-DQ (p < .001) de novo DSA. Adverse events were similar, but E-/LI developed fewer viral infections, particularly polyoma-virus-associated nephropathy (p = .021). Preformed T cell alloreactivity and HLA eplet mismatch assessment may refine current baseline immune-risk stratification and guide immunosuppression decision-making in kidney transplantation.

The ERA-EDTA Registry Annual Report 2017: a summary.

BACKGROUND: This article presents a summary of the 2017 Annual Report of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry and describes the epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in 37 countries. METHODS: The ERA-EDTA Registry received individual patient data on patients undergoing RRT for ESRD in 2017 from 32 national or regional renal registries and aggregated data from 21 registries. The incidence and prevalence of RRT, kidney transplantation activity and survival probabilities of these patients were calculated. RESULTS: In 2017, the ERA-EDTA Registry covered a general population of 694 million people. The incidence of RRT for ESRD was 127 per million population (pmp), ranging from 37 pmp in Ukraine to 252 pmp in Greece. A total of 62% of patients were men, 52% were ≥65 years of age and 23% had diabetes mellitus as the primary renal disease. The treatment modality at the onset of RRT was haemodialysis for 85% of patients. On 31 December 2017, the prevalence of RRT was 854 pmp, ranging from 210 pmp in Ukraine to 1965 pmp in Portugal. The transplant rate in 2017 was 33 pmp, ranging from 3 pmp in Ukraine to 103 pmp in the Spanish region of Catalonia. For patients commencing RRT during 2008-12, the unadjusted 5-year patient survival probability for all RRT modalities combined was 50.8%.

Use of tocilizumab in kidney transplant recipients with COVID-19.

Acute respiratory distress syndrome associated with coronavirus infection is related to a cytokine storm with large interleukin-6 (IL-6) release. The IL-6-receptor blocker tocilizumab may control the aberrant host immune response in patients with coronavirus disease 2019 (COVID-19) . In this pandemic, kidney transplant (KT) recipients are a high-risk population for severe infection and showed poor outcomes. We present a multicenter cohort study of 80 KT patients with severe COVID-19 treated with tocilizumab during hospital admission. High mortality rate was identified (32.5%), related with older age (hazard ratio [HR] 3.12 for those older than 60 years, P = .039). IL-6 and other inflammatory markers, including lactic acid dehydrogenase, ferritin, and D-dimer increased early after tocilizumab administration and their values were higher in nonsurvivors. Instead, C-reactive protein (CRP) levels decreased after tocilizumab, and this decrease positively correlated with survival (mean 12.3 mg/L in survivors vs. 33 mg/L in nonsurvivors). Each mg/L of CRP soon after tocilizumab increased the risk of death by 1% (HR 1.01 [confidence interval 1.004-1.024], P = .003). Although patients who died presented with worse respiratory situation at admission, this was not significantly different at tocilizumab administration and did not have an impact on outcome in the multivariate analysis. Tocilizumab may be effective in controlling cytokine storm in COVID-19 but randomized trials are needed.

A NKp80-Based Identification Strategy Reveals that CD56neg NK Cells Are Not Completely Dysfunctional in Health and Disease.

Natural killer (NK) cells are usually identified by the absence of other lineage markers, due to the lack of cell-surface-specific receptors. CD56neg NK cells, classically identified as CD56negCD16+, are very scarce in the peripheral blood of healthy people but they expand in some pathological conditions. However, studies on CD56neg NK cells had revealed different results regarding the phenotype and functionality. This could be due to, among others, the unstable expression of CD16, which hinders CD56neg NK cells' proper identification. Hence, we aim to determine an alternative surface marker to CD16 to better identify CD56neg NK cells. We have found that NKp80 is superior to CD16. Furthermore, we found differences between the functionality of CD56negNKp80+ and CD56negCD16+, suggesting that the effector functions of CD56neg NK cells are not as diminished as previously thought. We proposed NKp80 as a noteworthy marker to identify and accurately re-characterize human CD56neg NK cells.

Regulatory T-cell Number in Peripheral Blood at 1 Year Posttransplant as Predictor of Long-term Kidney Graft Survival.

BACKGROUND: Regulatory T (Treg) cells play a role in limiting kidney transplant rejection and can potentially promote long-term transplant tolerance. There are no large prospective studies demonstrating the utility of peripheral blood Treg cells as biomarkers for long-term graft outcome in kidney transplantation. The aim of our study was to analyze the influence of the absolute number of peripheral blood Treg cells after transplantation on long-term death-censored graft survival. METHODS: We monitored the absolute numbers of Treg cells by flow cytometry in nonfrozen samples of peripheral blood in 133 kidney transplant recipients, who were prospectively followed up to 2 years after transplantation. Death-censored graft survival was determined retrospectively in January 2017. RESULTS: The mean time of clinical follow-up was 7.4 ± 2.9 years and 24.1% patients suffered death-censored graft loss (DCGL). Patients with high Treg cells 1 year after transplantation and above the median value (14.57 cells/mm3), showed better death-censored graft survival (5-year survival, 92.5% vs 81.4%, Log-rank P = .030). One-year Treg cells showed a receiver operating characteristic - area under curve of 63.1% (95% confidence interval, 52.9-73.2%, P = 0.026) for predicting DCGL. After multivariate Cox regression analysis, an increased number of peripheral blood Treg cells was a protective factor for DCGL (hazard ratio, 0.961, 95% confidence interval, 0.924-0.998, P = 0.041), irrespectively of 1-year proteinuria and renal function. CONCLUSIONS: Peripheral blood absolute numbers of Treg cells 1 year after kidney transplantation predict a better long-term graft outcome and may be used as prognostic biomarkers.

A proliferation-inducing ligand increase precedes IgA nephropathy recurrence in kidney transplant recipients.

BACKGROUND: IgA nephropathy (IgAN) may recur in kidney transplant recipients. B-cell-activating factor (BAFF), a proliferation-inducing ligand (APRIL), and α-defensins are involved in the pathogenesis of native IgAN; however, their role on IgAN recurrence has not been previously analyzed. METHODS: Thirty-five patients with IgAN who received a kidney transplant in our center between January 1, 1993, and December 31, 2015, were included. Recurrence was diagnosed and ruled out in 14 and 11 patients, respectively, by indication biopsies. Pre-transplant, 6-month, 1-, 3-, and 5-year sera selected to measure BAFF, APRIL, and defensin by ELISA. RESULTS: Six months post-transplantation, APRIL levels (300.1 vs 1203.8 pg/mL, P = 0.033) and the mean APRIL values from 6 months to 3 years (409.8 vs 1258.0 pg/mL, P = 0.003) were higher in recurrent patients. Both 6-month APRIL levels (AUC-ROC 0.753, P = 0.033) and mean APRIL values (AUC-ROC 0.844, P = 0.004) discriminated patients with recurrence risk. By logistic regression, APRIL at 6 months (P = 0.044) and mean APRIL (P = 0.021) related to the risk of IgAN recurrence independently. Neither BAFF nor defensin related to recurrence. CONCLUSIONS: Serum APRIL increased at 6 months and mean APRIL remained higher the first 3 years in patients in whom IgAN was going to recur.

Patent Foramen Ovale and Hypoxemia.

Patent foramen ovale (PFO), an embryonic remnant of the fetal circulation, is present in 20-25% of adults. Although recent observational studies and clinical trials have established the link between PFO-mediated right-to-left shunting with cryptogenic stroke and migraine with aura, the role of a PFO in exacerbating hypoxemic medical conditions (ie, sleep apnea, chronic obstructive pulmonary disease, pulmonary hypertension, platypnea-orthodeoxia, pulmonary arteriovenous malformation, high-altitude pulmonary edema, and exercise desaturation) remains less understood. PFO-mediated hypoxemia occurs when deoxygenated venous blood from the right atrium enters and mixes with oxygenated arterial blood in the left atrium. Patients with an intracardiac right-to-left shunt may have profound hypoxemia out of proportion to underlying primary lung disease, even in the presence of normal right-sided pressures. The presence of right-to-left cardiac shunting can exacerbate the degree of hypoxemia in patients with underlying pulmonary disorders. In a subset of these patients, percutaneous PFO closure may result in marked improvement in dyspnea and hypoxemia. This review discusses the association between PFO-mediated right-to-left shunting with medical conditions associated with hypoxemia and explores the role of percutaneous PFO closure in alleviating the hypoxemia.

Berberine as Source of Antiproliferative Hybrid Compounds: In Vitro Antiproliferative Activity and Quantitative Structure-activity Relationship.

BACKGROUND: Despite advances for cancer treatment, it still remains a major worldwide public health problem. Compounds derived from natural sources are important alternatives to combat this mortal disease. Berberine is an isoquinoline alkaloid with a wide variety of pharmacological properties, including antiproliferative activity. Previously, we have found that fatty acids also show antiproliferative activity against cancer cell lines.. OBJECTIVE: To combine berberine and fatty acids, or carboxylic acids, in order to improve their antiproliferative properties. METHODS: We synthetized six new hybrid derivatives through a simple methylenedioxy group-cleavage method followed by the reaction with fatty acids, or carboxylic acids. The structure of the compounds was elucidated by IR, NMR and HRMS. The in vitro antiproliferative activity against four human cancer cell lines (HeLa, A-549, PC-3 and LS-180) and one normal cell line (ARPE-19), was evaluated by the MTT method. Chemical structures were drawn using SPARTAN '08 software and the conformational analysis was carried out with a molecular mechanic level of theory and the SYBIL force field. All molecular structures were subjected to geometrical optimization at the semi-empirical method PM3. Molecular descriptors were calculated using DRAGON 5.4 and SPARTAN ´08 programs. RESULTS: The geranic acid and berberine hybrid compound (6) improved the antiproliferative activity shown by natural berberine, even more than the 16- to 18-carbon atoms fatty acids. Compound 6 showed IC50 values of 2.40 ± 0.60, 1.5 ± 0.24, 5.85 ± 1.07 and 5.44 ± 0.24 µM, against HeLa, A-549, PC-3 and LS-180 human cancer cell lines, respectively. Using this information, we performed a quantitative structure-activity relationship (QSAR) of the hybrid molecules and found that the molecular descriptors associated with the antiproliferative activity are: hydrophobic constant associated with substituents (π(A) = 6.5), molecular volume descriptor (CPKvolume≈ 700 Å3), EHOMO, number of rotatable bonds (RBN) and number of 6-membered rings (nR06). CONCLUSION: The methylendioxy and methoxyl groups in berberine are important for the antiproliferative activity shown by its derivatives. Better results in antiproliferative activity were obtained in compound 6 with the prenyl moiety. The QSAR indicates that the molecular descriptors which associated positively with the antiproliferative activity are: hydrophobic constant associated with substituents (π(A) = 6.5), molecular volume descriptor (CPKvolume≈ 700 Å3) and EHOMO. This research gave the basis for the design and preparation of new, easily afforded molecules derived from berberine and carboxylic acids, with improved antiproliferative activity.