Guide catheter extension use are associated with higher procedural success in chronic total occlusion percutaneous coronary interventions.

BACKGROUND: Guide catheter extensions (GCEs) increase support and facilitate equipment delivery, but aggressive instrumentation may be associated with a higher risk of complications. AIM: Our aim was to assess the impact of GCEs on procedural success and complications in patients submitted to chronic total occlusion (CTO) percutaneous coronary intervention (PCI). METHODS: We analyzed data from the multicenter LATAM CTO Registry. Procedural success was defined as <30% residual stenosis and TIMI 3 distal flow. Major adverse cardiac and cerebrovascular events (MACCE) was defined as the composite of all-cause death, myocardial infarction, target vessel revascularization, and stroke. Propensity score matching (PSM) was used to compare outcomes with and without GCE use. RESULTS: From August 2010 to August 2021, 3049 patients were included. GCEs were used in 438 patients (14.5%). In unadjusted analysis, patients in the GCE group were older and had more comorbidities. The median J-CTO score and its components were higher in the GCE group. After PSM, procedural success was higher with GCE use (87.7% vs. 80.5%, p = 0.007). The incidence of coronary perforation (odds ratio [OR]: 1.46, 95% confidence interval [CI]: 0.78-2.71, p = 0.230), bleeding (OR: 1.99, 95% CI: 0.41-2.41, p = 0.986), in-hospital death (OR: 1.39, 95% CI: 0.54-3.62, p = 0.495) and MACCE (OR: 1.07, 95% CI: 0.52-2.19, p = 0.850) were similar in both groups. CONCLUSION: In a contemporary, multicenter cohort of patients undergoing CTO PCI, GCEs were used in older patients, with more comorbidities and complex anatomy. After PSM, GCE use was associated with higher procedural success, and similar incidence of adverse outcomes.

Body Composition in Youths Aged 10‒17 Years by Deuterium Oxide Dilution, Air Displacement Plethysmography, and DXA: Validation of the Medical Body Composition Analyzer Bioimpedance Device by a 4-Compartment Model.

BACKGROUND: The medical body composition analyzer (mBCA) incorporates advances in multifrequency technology and has been validated using a 4-compartment (4C) model in adults but not in youths aged <18 y. OBJECTIVES: This study aimed to formulate a 4C model based on 3 reference methods and develop and validate a body composition prediction equation for the mBCA in youths aged 10‒17 y. METHODS: The body density of 60 female and male youths was measured by air displacement plethysmography, total body water by deuterium oxide dilution, and BMC by DXA. Data from the equation group (n = 30) were used to formulate a 4C model. The all-possible-regressions method was used to select variables. The model was validated in a second cohort (n = 30) in a random split design. The accuracy, precision, and potential bias were evaluated by the Bland and Altman procedure. RESULTS: Mean age, weight (W), height (H), waist circumference, and z-score of BMI were 13.6 ± 2.3 y, 54.5 ± 15.5 kg, 156 ± 11.9 cm, 75.5 ± 10.9 cm, and 0.70 ± 1.32 z, respectively. The prediction equation was as follows: FFM in kg (FFMkg) = ([0.2081] ∗ [W] + [0.8814] ∗ [H2cm/RΩ] + [0.2055 ∗ XcΩ])-15.343; R2 = 0.96; standardized root-mean-square error (SRMSE) = 2.18 kg. FFM did not differ between the 4C method (38.9 ± 12.0 kg) and the mBCA (38.4 ± 11.4 kg) (P > 0.05). The relationship between these 2 variables did not deviate from the identity line, was not significantly different from 0, and the slope was not significantly different from 1.0. In the precision prediction model of mBCA, the R2 value was 0.98 and SRMSE was 2.1. No significant bias was found when regressing differences between methods and their means (P = 0.08). CONCLUSIONS: The equation for the mBCA was accurate, precise, had no significant bias, had substantial strength of agreement and could be used in this age group when subjects were preferentially within the constraints of a specified body size.

How to Handle Arterial Conduits in Liver Transplantation? Evidence From the First Multicenter Risk Analysis.

OBJECTIVE: The aims of the present study were to identify independent risk factors for conduit occlusion, compare outcomes of different AC placement sites, and investigate whether postoperative platelet antiaggregation is protective. BACKGROUND: Arterial conduits (AC) in liver transplantation (LT) offer an effective rescue option when regular arterial graft revascularization is not feasible. However, the role of the conduit placement site and postoperative antiaggregation is insufficiently answered in the literature. STUDY DESIGN: This is an international, multicenter cohort study of adult deceased donor LT requiring AC. The study included 14 LT centers and covered the period from January 2007 to December 2016. Primary endpoint was arterial occlusion/patency. Secondary endpoints included intra- and perioperative outcomes and graft and patient survival. RESULTS: The cohort was composed of 565 LT. Infrarenal aortic placement was performed in 77% of ACs whereas supraceliac placement in 20%. Early occlusion (≤30 days) occurred in 8% of cases. Primary patency was equivalent for supraceliac, infrarenal, and iliac conduits. Multivariate analysis identified donor age >40 years, coronary artery bypass, and no aspirin after LT as independent risk factors for early occlusion. Postoperative antiaggregation regimen differed among centers and was given in 49% of cases. Graft survival was significantly superior for patients receiving aggregation inhibitors after LT. CONCLUSION: When AC is required for rescue graft revascularization, the conduit placement site seems to be negligible and should follow the surgeon's preference. In this high-risk group, the study supports the concept of postoperative antiaggregation in LT requiring AC.

Pinto Bean Amino Acid Digestibility and Score in a Mexican Dish with Corn Tortilla and Guacamole, Evaluated in Adults Using a Dual-Tracer Isotopic Method.

BACKGROUND: Ultra-processed foodstuffs have been replacing traditional beans with tortillas in the Mexican diet in the last decades. Therefore, scientific support is needed to promote a return to good-quality traditional dishes. OBJECTIVES: This study aims to evaluate the amino acid digestibility and score of pinto beans (Phaseolus vulgaris) consumed with corn tortillas and guacamole in adults using the dual-tracer method. METHODS: The pinto beans were intrinsically labeled using 250 mL of 2H2O (99.8%) per 19 L pot with 3 plants. A paste of cooked beans on toasted corn tortillas and guacamole topping were administered to 3 male and 3 female adults (21-25 years old; BMI, 19-23.5 kg/m2). The protocol was plateau feeding given along with U-[13C]-spirulina protein to evaluate indispensable amino acid (IAA) digestibility using the dual-tracer method. Blood samples were taken in the plateau state. The digestibility of each IAA of the bean protein was calculated by the ratio of its enrichment in the beans to the spirulina in the meal and its appearance in plasma collected in the plateau state, as a percentage corrected by spirulina digestibility. Additionally, the digestible IAA score (DIAAS) was calculated. RESULTS: The 2H enrichment of IAA in the pinto beans was 471 parts per million excess. The isotopic enrichment of 2H and 13C in IAA at 5-8 hours presented plateau states with mean CVs of 12.2% and 13.3%, respectively. The mean digestibility of IAA from pinto beans was 77% ± 1.6%, with the lowest value for threonine. The DIAAS calculated with respect to the pattern requirement for children older than 3 years, adolescents, and adults was 83%, with methionine and cysteine being the limiting amino acids. CONCLUSIONS: A Mexican dish of pinto beans, tortillas, and guacamole is a good source of protein as evaluated in adults and could be promoted as a nutritious snack. The assay is registered with the Ethical Committee of the Centro de Investigación en Alimentación y Desarrollo, A.C. as CE/015/2019.

First Long-term Oncologic Results of the ALPPS Procedure in a Large Cohort of Patients With Colorectal Liver Metastases.

OBJECTIVES: To analyze long-term oncological outcome along with prognostic risk factors in a large cohort of patients with colorectal liver metastases (CRLM) undergoing ALPPS. BACKGROUND: ALPPS is a two-stage hepatectomy variant that increases resection rates and R0 resection rates in patients with primarily unresectable CRLM as evidenced in a recent randomized controlled trial. Long-term oncologic results, however, are lacking. METHODS: Cases in- and outside the International ALPPS Registry were collected and completed by direct contacts to ALPPS centers to secure a comprehensive cohort. Overall, cancer-specific (CSS), and recurrence-free (RFS) survivals were analyzed along with independent risk factors using Cox-regression analysis. RESULTS: The cohort included 510 patients from 22 ALPPS centers over a 10-year period. Ninety-day mortality was 4.9% and median overall survival, CSS, and RFS were 39, 42, and 15 months, respectively. The median follow-up time was 38 months (95% confidence interval 32-43 months). Multivariate analysis identified tumor-characteristics (primary T4, right colon), biological features (K/N-RAS status), and response to chemotherapy (Response Evaluation Criteria in Solid Tumors) as independent predictors of CSS. Traditional factors such as size of metastases, uni versus bilobar involvement, and liver-first approach were not predictive. When hepatic recurrences after ALPPS was amenable to surgical/ablative treatment, median CSS was significantly superior compared to chemotherapy alone (56 vs 30 months, P < 0.001). CONCLUSIONS: This large cohort provides the first evidence that patients with primarily unresectable CRLM treated by ALPPS have not only low perioperative mortality, but achieve appealing long-term oncologic outcome especially those with favorable tumor biology and good response to chemotherapy.

The "Super-Child" Approach Is Applied To Estimate Retinol Kinetics and Vitamin A Total Body Stores in Mexican Preschoolers.

BACKGROUND: Retinol isotope dilution (RID) and model-based compartmental analysis are recognized techniques for assessing vitamin A (VA) status. Recent studies have shown that RID predictions of VA total body stores (TBS) can be improved by using modeling and that VA kinetics and TBS in children can be effectively studied by applying population modeling ("super-child" approach) to a composite data set. OBJECTIVES: The objectives were to model whole-body retinol kinetics and predict VA TBS in a group of Mexican preschoolers using the super-child approach and to use model predictions of RID coefficients to estimate TBS by RID in individuals. METHODS: Twenty-four healthy Mexican children (aged 3-6 y) received an oral dose (2.96 µmol) of [13C10]retinyl acetate in corn oil. Blood samples were collected from 8 h to 21 d after dosing, with each child sampled at 4 d and at 1 other time. Composite data for plasma labeled retinol compared with time were analyzed using a 6-component model to obtain group retinol kinetic parameters and pool sizes. Model-predicted TBS was compared with mean RID predictions at 4 d; RID estimates at 4 d were compared with those calculated at 7-21 d. RESULTS: Model-predicted TBS was 1097 µmol, equivalent to ∼2.4 y-worth of VA; using model-derived coefficients, group mean RID-predicted TBS was 1096 µmol (IQR: 836-1492 µmol). TBS at 4 d compared with a later time was similar (P = 0.33). The model predicted that retinol spent 1.5 h in plasma during each transit and recycled to plasma 13 times before utilization. CONCLUSIONS: The super-child modeling approach provides information on whole-body VA kinetics and can be used with RID to estimate TBS at any time between 4 and 21 d postdose. The high TBS predicted for these children suggests positive VA balance, likely due to large-dose VA supplements, and warrants further investigation.

MAIT cells launch a rapid, robust and distinct hyperinflammatory response to bacterial superantigens and quickly acquire an anergic phenotype that impedes their cognate antimicrobial function: Defining a novel mechanism of superantigen-induced immunopathology and immunosuppression.

Superantigens (SAgs) are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion a "cytokine storm" with severe and sometimes life-threatening consequences typically encountered in toxic shock syndrome (TSS). Given the rapidity with which TSS develops, designing timely and truly targeted therapies for this syndrome requires identification of key mediators of the cytokine storm's initial wave. Equally important, early host responses to SAgs can be accompanied or followed by a state of immunosuppression, which in turn jeopardizes the host's ability to combat and clear infections. Unlike in mouse models, the mechanisms underlying SAg-associated immunosuppression in humans are ill-defined. In this work, we have identified a population of innate-like T cells, called mucosa-associated invariant T (MAIT) cells, as the most powerful source of pro-inflammatory cytokines after exposure to SAgs. We have utilized primary human peripheral blood and hepatic mononuclear cells, mouse MAIT hybridoma lines, HLA-DR4-transgenic mice, MAIThighHLA-DR4+ bone marrow chimeras, and humanized NOD-scid IL-2Rγnull mice to demonstrate for the first time that: i) mouse and human MAIT cells are hyperresponsive to SAgs, typified by staphylococcal enterotoxin B (SEB); ii) the human MAIT cell response to SEB is rapid and far greater in magnitude than that launched by unfractionated conventional T, invariant natural killer T (iNKT) or γδ T cells, and is characterized by production of interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-2, but not IL-17A; iii) high-affinity MHC class II interaction with SAgs, but not MHC-related protein 1 (MR1) participation, is required for MAIT cell activation; iv) MAIT cell responses to SEB can occur in a T cell receptor (TCR) Vß-specific manner but are largely contributed by IL-12 and IL-18; v) as MAIT cells are primed by SAgs, they also begin to develop a molecular signature consistent with exhaustion and failure to participate in antimicrobial defense. Accordingly, they upregulate lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin-3 (TIM-3), and/or programmed cell death-1 (PD-1), and acquire an anergic phenotype that interferes with their cognate function against Klebsiella pneumoniae and Escherichia coli; vi) MAIT cell hyperactivation and anergy co-utilize a signaling pathway that is governed by p38 and MEK1/2. Collectively, our findings demonstrate a pathogenic, rather than protective, role for MAIT cells during infection. Furthermore, we propose a novel mechanism of SAg-associated immunosuppression in humans. MAIT cells may therefore provide an attractive therapeutic target for the management of both early and late phases of severe SAg-mediated illnesses.

Southern Annular Mode drives multicentury wildfire activity in southern South America.

The Southern Annular Mode (SAM) is the main driver of climate variability at mid to high latitudes in the Southern Hemisphere, affecting wildfire activity, which in turn pollutes the air and contributes to human health problems and mortality, and potentially provides strong feedback to the climate system through emissions and land cover changes. Here we report the largest Southern Hemisphere network of annually resolved tree ring fire histories, consisting of 1,767 fire-scarred trees from 97 sites (from 22 °S to 54 °S) in southern South America (SAS), to quantify the coupling of SAM and regional wildfire variability using recently created multicentury proxy indices of SAM for the years 1531-2010 AD. We show that at interannual time scales, as well as at multidecadal time scales across 37-54 °S, latitudinal gradient elevated wildfire activity is synchronous with positive phases of the SAM over the years 1665-1995. Positive phases of the SAM are associated primarily with warm conditions in these biomass-rich forests, in which widespread fire activity depends on fuel desiccation. Climate modeling studies indicate that greenhouse gases will force SAM into its positive phase even if stratospheric ozone returns to normal levels, so that climate conditions conducive to widespread fire activity in SAS will continue throughout the 21st century.

Randomized trial for the treatment of post-traumatic elbow stiffness: surgical release vs. rehabilitation.

BACKGROUND: There are no previous randomized trials comparing surgical to conservative treatment for post-traumatic elbow stiffness. The aim of our study was to compare elbow range of motion (ROM) and clinical outcomes among patients undergoing surgical treatment or a standardized rehabilitation for post-traumatic elbow stiffness. METHODS: Randomized clinical trial of patients with post-traumatic elbow stiffness for more than 6 months who failed conventional physical therapy for 4 months. Patients were randomized into 2 treatment groups. The conservative group underwent the rehabilitation protocol associated with the use of orthoses (static progressive for extension and dynamic for flexion) and continuous passive motion. The surgical group underwent surgical release by a posterior approach without triceps detachment, followed by a rehabilitation protocol similar to the conservative group. The primary outcome of the study was flexion-extension ROM at 6 months of follow-up. Secondary outcomes included the visual analog scale for pain, the Mayo Elbow Performance Score, the Disabilities of the Arm, Shoulder, and Hand score, absolute and relative increase in flexion-extension ROM, and complication rates. RESULTS: Thirty patients were analyzed in the study, 15 in each group. The mean elbow flexion-extension ROM at the end of 6 months of follow-up was 108° in the surgical group and 88° in the conservative group (P = .002). The mean absolute and the relative increase of elbow flexion-extension at 6 months were, respectively, 17° and 27% in the conservative group and 41° and 59% in the surgical group (P < .001). CONCLUSION: Surgical elbow release associated with the rehabilitation protocol resulted in a greater flexion-extension ROM, as well as a greater absolute and relative increase compared with rehabilitation alone at 6 months of follow-up. The groups did not differ regarding clinical scores and complication rates.

Prevalence of Sexual Dysfunctions in Transgender Persons: Results from the ENIGI Follow-Up Study.

INTRODUCTION: Studies about sexual functioning in trans persons have mainly focused on sexual functioning after genital gender-affirming surgery, have had small sample sizes, and have not explored the broad range of possible sexual dysfunctions. Measuring sexual functioning in trans persons during transitioning is important to determine the kind of care trans persons may need in order to regain their sexual health. AIM: The first aim of the present study was to explore the prevalence of sexual function disturbances and dysfunctions (with distress) in trans women and trans men 4 to 6 years after initial clinical entry. The second aim was to compare the prevalence of sexual dysfunctions among the various treatment trajectories and between trans persons with or without further genital treatment intentions. METHODS: An online follow-up questionnaire was filled out by 518 trans persons (307 identifying predominantly feminine, 211 identifying predominantly masculine) as a part of the European Network for the Investigation of Gender Incongruence initiative. All participants had their initial clinical appointments in gender clinics in Ghent, Amsterdam, or Hamburg. MAIN OUTCOME MEASURE: The main outcome measures were the prevalence of sexual dysfunctions and medical treatment data, measured via self-report items. RESULTS: The most frequent sexual dysfunctions experienced by trans women and trans men were difficulties initiating and seeking sexual contact (26% and 32%, respectively) and difficulties achieving an orgasm (29% and 15%, respectively). Compared with trans women after hormone treatment and non-genital surgery, trans women after vaginoplasty less often experienced arousal difficulties, sexual aversion, and low sexual desire. Compared with trans men without medical treatment, trans men after a phalloplasty experienced sexual aversion and low sexual desire less often. No significant differences were found between participants with or without further genital treatment intentions. CLINICAL IMPLICATIONS: Clinicians should consider sexual counseling after medical treatments, paying particular attention to potential social and psychological barriers to the sexual health of their patients. STRENGTHS & LIMITATIONS: This study included all trans persons irrespective of treatment decisions, and focused on a broad range of potential sexual difficulties taking the distress criteria into account. Limitations include the cross-sectional design, the limited power for the comparison of treatment groups and the absence of validated questionnaires about sexual functioning for transgender persons. CONCLUSION: Sexual dysfunctions among trans men and women were very common among the various treatment groups and were unrelated to intentions to have further genital treatment. Although medical treatment may be helpful or even essential to developing good sexual health, a significant group of trans persons experienced sexual dysfunctions after genital surgery. Kerckhof ME, Kreukels BPC, Nieder TO, et al. Prevalence of Sexual Dysfunctions in Transgender Persons: Results from the ENIGI Follow-Up Study. J Sex Med 2019; 16:2018-2019.

Longitudinal quantitative magnetic resonance imaging in adrenomyeloneuropathy.

BACKGROUND AND PURPOSE: Adrenomyeloneuropathy (AMN) is the most frequent metabolic hereditary spastic paraplegia. Accordingly, its main site of pathological changes is the spinal cord. It is difficult to quantify AMN progression because commonly used clinical scales have limitations and reliable biomarkers are lacking. The goal was to investigate whether spinal cord and brain quantitative magnetic resonance imaging may assess structural changes in AMN over a relatively short time period. METHODS: In this longitudinal observational study, the total cord areas (TCAs) from the C2-C3 to T2-T3 level and diffusion tensor imaging (DTI) metrics of the cervical spinal cord and brain portion of the corticospinal tracts in six AMN and six age-matched control subjects at baseline and at a mean follow-up of 22.6 months were assessed. RESULTS: A significant reduction of the mean TCA at the T1-T2 level (-3.79%) and a trend of reduction at the lowest cervical levels were observed only in AMN patients. Additionally, DTI metrics revealed significant changes in fractional anisotropy (-8.84%), mean diffusivity (+12.62%) and radial diffusivity (+25.91%) at the C2-C3 level. DISCUSSION: The study encourages the assessment of TCAs and spinal cord DTI metrics as surrogate outcome measures in AMN, by focusing on the cervical-thoracic junction and the uppermost part of the cervical spinal cord. Despite the limitation of the results due to the small number of investigated subjects, these observations are useful for forthcoming clinical trials in AMN and possibly other hereditary diseases with predominant spinal cord involvement.

Diagnostic accuracy of MRI for detection of tears and instability of proximal long head of biceps tendon: an evaluation of 100 shoulders compared with arthroscopy.

OBJECTIVE: To evaluate the diagnostic accuracy of magnetic resonance imaging (MRI) for detection of instability and tears of the proximal long head of biceps tendon (LHBT). To assess intraobserver and interobserver agreement. MATERIALS AND METHODS: We performed a retrospective analysis of prospectively collected data of 100 consecutive shoulders who underwent non-contrast 1.5-T MRI prior to arthroscopic surgery due to rotator cuff injury. Images were independently analyzed by two musculoskeletal radiologists. LHBT was evaluated for presence of tearing (intact, longitudinal split, partial-thickness, or full-thickness) and position (normal, subluxated, and dislocated). Anterosuperior rotator cuff tears were also assessed. The reference standard was arthroscopic surgery. The ramp test was performed in order to evaluate LHBT stability. Diagnostic performance measures were determined and Kappa coefficients assessed agreement. RESULTS: Concerning the detection of overall tears, sensitivity ranged from 71 to 73% and specificity was 73%. The specificity for full-thickness tears ranged from 75 to 96%. Overall displacement showed sensitivity ranging from 51 to 58% and specificity ranging from 70 to 86%. The specificity of overall displacement combined with anterosuperior rotator cuff tears ranged from 73 to 91%. Interobserver Kappa values were between 0.59 and 0.69. Intraobserver Kappa values were between 0.74 and 0.82. CONCLUSIONS: MRI has moderate accuracy and good agreement for detection of LHBT tears and instability. There is a tendency for increased specificity for full-thickness tears and for instability in the coexistence of anterosuperior rotator cuff tears.

Acquired Haemophilia A. Which is the best therapeutic choice in older adults? Single center study of 4 cases.

Acquired haemophilia A (AHA) is a rare bleeding disorder due to autoantibodies directed against coagulation factor VIII. The treatment is based on recombinant activated factor VII and activated prothrombin complex concentrate. However, mainly in older patients, severe thrombotic complications have been reported. Here we report the different therapeutic approaches in 4 cases of elderly patients with AHA and co-morbidities.

Bioelectric Impedance Vector Analysis (BIVA) in Breast Cancer Patients: A Tool for Research and Clinical Practice.

Background and objectives: Body composition assessment can provide information associated with breast cancer patients' (BCP) prognosis, that can lead interventions to improve survival outcomes. The aim of this study was to evaluate the effect of an individualized nutrition intervention program on breast cancer patients using bioelectrical impedance vector analysis (BIVA). Materials and Methods: This is a pretest-posttest study in recently diagnosed nonmetastatic BCP undergoing antineoplastic treatment, free of co-morbidities and dietary supplementation. Body composition was assessed at baseline and 6 months after an individualized nutrition intervention program, by dual-energy X-ray absorptiometry and BIVA. According to BIVA, each participant was located in the bivariate tolerance ellipses for Mexican population (50%, 75%, and 95%). In clinical practice, the 50% and 75% ellipses are considered within normality ranges. Results: Nine nonmetastatic BCP completed the intervention and were included in the analysis. After the intervention, they decreased by 5.8 kg of body weight (IQR, 3-6; p < 0.05), 3.8 kg of fat mass (IQR, 0.1-4.2; p < 0.05), and 1.4 kg of fat-free mass (IQR, -0.1 to 4; p < 0.05) while appendicular skeletal muscle mass remained unchanged (-0.2 kg, IQR, -0.8 to 2.3; p = 0.4). Using BIVA at baseline, five participants were among the 50% and 75% ellipses, mainly located in the area corresponding to edema and low lean tissue, two in the cachexia quadrant and two in the athletic quadrant (≥95% ellipse). After 6 months of intervention, six out of nine participants were in the athletic quadrant and eight of nine BCP were above the 5° phase angle cut-off point. One patient initially presented cachexia (≥95% ellipse); at postintervention her vector changed to the 50% ellipse. Conclusions: An individualized nutrition intervention program designed for nonmetastatic BCP was effective to improve the nutritional status of BCP as assessed by BIVA, therefore BIVA can be a useful tool to monitor changes in nonmetastatic BCP body composition in research and clinical practice.

Analysis of type 2 diabetes and obesity genetic variants in Mexican Pima Indians: Marked allelic differentiation among Amerindians at HLA.

Prevalence of diabetes and obesity in Mexican Pima Indians is low, while prevalence in US Pima Indians is high. Although lifestyle likely accounts for much of the difference, the role of genetic factors is not well explored. To examine this, we genotyped 359 single nucleotide polymorphisms, including established type 2 diabetes and obesity variants from genome-wide association studies (GWAS) and 96 random markers, in 342 Mexican Pimas. A multimarker risk score of obesity variants was associated with body mass index (BMI; ß = 0.81 kg/m2 per SD, P = 0.0066). The mean value of the score was lower in Mexican Pimas than in US Pimas (P = 4.3 × 10-11 ), and differences in allele frequencies at established loci could account for approximately 7% of the population difference in BMI; however, the difference in risk scores was consistent with evolutionary neutrality given genetic distance. To identify loci potentially under recent natural selection, allele frequencies at 283 variants were compared between US and Mexican Pimas, accounting for genetic distance. The largest differences were seen at HLA markers (e.g., rs9271720, difference = 0.75, P = 8.7 × 10-9 ); genetic distances at HLA were greater than at random markers (P = 1.6 × 10-46 ). Analyses of GWAS data in 937 US Pimas also showed sharing of alleles identical by descent at HLA that exceeds its genomic expectation (P = 7.0 × 10-10 ). These results suggest that, in addition to the widely recognized balancing selection at HLA, recent directional selection may also occur, resulting in marked allelic differentiation between closely related populations.

Mannose-Binding Lectin-Deficient Donors Increase the Risk of Bacterial Infection and Bacterial Infection-Related Mortality After Liver Transplantation.

Mannose-binding lectin (MBL) is synthesized by the liver and binds to microbes. MBL2 gene polymorphisms produce intermediate/low/null or normal MBL serum levels (MBL-deficient or MBL-sufficient phenotypes, respectively). We aimed to evaluate the incidence and severity of infection, rejection, and survival within 1 year after liver transplantation (LT) according to donor and recipient MBL2 gene polymorphisms. A repeated-event analysis for infection episodes (negative binomial regression, Andersen-Gill model) was performed in 240 LTs. Four hundred twenty-eight infectious episodes (310 bacterial, 15 fungal, 65 cytomegalovirus [CMV]-related, and 38 viral non-CMV-related episodes) and 48 rejection episodes were recorded. The main bacterial infections were urinary (n = 82, 26%) and pneumonia (n = 69, 22%). LT recipients of MBL-deficient livers had a higher risk of bacterial infection (incidence rate ratio [IRR] 1.48 [95% confidence interval 1.04-2.09], p = 0.028), pneumonia (IRR 2.4 [95% confidence interval 1.33-4.33], p = 0.013), and septic shock (IRR 5.62 [95% confidence interval 1.92-16.4], p = 0.002) compared with recipients of MBL-deficient livers. The 1-year bacterial infection-related mortality was higher in recipients of MBL-deficient versus MBL-sufficient livers (65.8% vs. 56.1%, respectively; p = 0.0097). The incidence of rejection, viral, or fungal infection was similar in both groups. Recipient MBL2 genotype did not significantly increase the risk of bacterial infection. LT recipients of MBL-deficient livers have a higher risk of bacterial infection, pneumonia, septic shock, and 1-year bacterial infection-related mortality after LT.

Mucosa-associated invariant T cells infiltrate hepatic metastases in patients with colorectal carcinoma but are rendered dysfunctional within and adjacent to tumor microenvironment.

Mucosa-associated invariant T (MAIT) cells are innate-like T lymphocytes that are unusually abundant in the human liver, a common site of colorectal carcinoma (CRC) metastasis. However, whether they contribute to immune surveillance against colorectal liver metastasis (CRLM) is essentially unexplored. In addition, whether MAIT cell functions can be impacted by chemotherapy is unclear. These are important questions given MAIT cells' potent immunomodulatory and inflammatory properties. Herein, we examined the frequencies and functions of peripheral blood, healthy liver tissue, tumor-margin and tumor-infiltrating MAIT cells in 21 CRLM patients who received no chemotherapy, FOLFOX, or a combination of FOLFOX and Avastin before they underwent liver resection. We found that MAIT cells, defined as CD3ε+Vα7.2+CD161++ or CD3ε+MR1 tetramer+ cells, were present within both healthy and tumor-afflicted hepatic tissues. Paired and grouped analyses of samples revealed the physical proximity of MAIT cells to metastatic lesions to drastically influence their functional competence. Accordingly, unlike those residing in the healthy liver compartment, tumor-infiltrating MAIT cells failed to produce IFN-γ in response to a panel of TCR and cytokine receptor ligands, and tumor-margin MAIT cells were only partially active. Furthermore, chemotherapy did not account for intratumoral MAIT cell insufficiencies. Our findings demonstrate for the first time that CRLM-penetrating MAIT cells exhibit wide-ranging functional impairments, which are dictated by their physical location but not by preoperative chemotherapy. Therefore, we propose that MAIT cells may provide an attractive therapeutic target in CRC and that their ligands may be combined with chemotherapeutic agents to treat CRLM.

Higher serum sclerostin levels and insufficiency of vitamin D are strongly associated with vertebral fractures in hemodialysis patients: a case control study.

In hemodialysis patients, vertebral fractures were associated with elevated sclerostin levels, suggesting that sclerostin could reflect bone fragility in these patients. INTRODUCTION: Fragility fractures are common in hemodialysis patients. The aims of our study were to determine the prevalence of vertebral fracture and analyze associations between sclerostin serum levels and vertebral fractures in hemodialysis patients. METHODS: Ninety-two hemodialysis patients and 100 controls matched for age and sex were studied. Bone mineral density was measured by ultrasonography at non-dominant heel. The markers of bone turnover included serum osteocalcin, C-terminal telopeptide, and sclerostin. All participants underwent radiography of the thoracic and lumbar spine to ascertain the presence of vertebral fractures. RESULTS: Bone ultrasound parameters at calcaneus were significantly lower in hemodialysis patients compared with controls; bone turnover markers and parathyroid hormone level were significantly higher, while serum of 25-OH-D3 was significantly lower in hemodialysis group. One or more moderate or severe vertebral fractures were found in 38 hemodialysis patients, whereas in control group, 10 patients had a vertebral fracture. In hemodialysis group, the comparison between patients with and without vertebral fractures showed that the patients with vertebral fractures had the serum sclerostin levels statistically higher than patients without vertebral, while serum levels of 25-OH-D3 was significantly lower in patients with vertebral fractures compared to the patients without vertebral fractures. Multivariate analysis disclosed that sclerostin levels were associated with an increased risk of vertebral fractures in hemodialysis patients after adjusting for multiple variables. CONCLUSIONS: Our data shows high prevalence of vertebral fractures in hemodialysis patients and that it is associated with elevated sclerostin levels, reflecting bone fragility in these patients.

Population Genetic Structure of Rhizoctonia oryzae-sativae from Rice in Latin America and Its Adaptive Potential to Emerge as a Pathogen on Urochloa Pastures.

The fungus Rhizoctonia oryzae-sativae is an important pathogen that causes the aggregated sheath spot disease on rice. In this study, we investigated the genetic structure of rice-adapted populations of R. oryzae-sativae sampled from traditional rice-cropping areas from the Paraíba Valley, São Paulo, Brazil, and from Meta, in the Colombian Llanos, in South America. We used five microsatellite loci to measure population differentiation and infer the pathogen's reproductive system. Gene flow was detected among the three populations of R. oryzae-sativae from lowland rice in Brazil and Colombia. In contrast, a lack of gene flow was observed between the lowland and the upland rice populations of the pathogen. Evidence of sexual reproduction including low clonality, Hardy-Weinberg equilibrium within loci and gametic equilibrium between loci, indicated the predominance of a mixed reproductive system in all populations. In addition, we assessed the adaptive potential of the Brazilian populations of R. oryzae-sativae to emerge as a pathogen to Urochloa spp. (signalgrass) based on greenhouse aggressiveness assays. The Brazilian populations of R. oryzae-sativae were probably only incipiently adapted as a pathogen to Urochloa spp. Comparison between RST and QST showed the predominance of diversifying selection in the divergence between the two populations of R. oryzae-sativae from Brazil.

Matrix Metalloproteases 1 and 3 Promoter Gene Polymorphism Is Associated With Rotator Cuff Tear.

BACKGROUND: Studies suggest that the collagen degeneration and disordered arrangement of collagen fibers in rotator cuff tears are associated with an increase in activity of matrix metalloproteases 1 and 3 (MMP-1 and MMP-3), and that MMP activity may be in part genetically mediated. The degree to which this might be clinically relevant in patients with rotator cuff tears has not been well characterized. QUESTIONS/PURPOSES: (1) Is genetic polymorphism of MMP-1 and MMP-3 associated with rotator cuff tears? (2) Are there haplotypes of MMP-1 and MMP-3 correlated with rotator cuff tears? (3) Compared with control subjects, do patients with rotator cuff tears have a higher proportion of relatives with the same disease? METHODS: We evaluated 64 patients with full-thickness rotator cuff tears and 64 asymptomatic control subjects. Patients younger 65 years, with nontraumatic tears, were included. The tear or integrity of the rotator cuff tear was evaluated by MRI or ultrasonography in all individuals. The patients and control subjects were paired by age. MMP-1 and MMP-3 genotypes were determined using the PCR-restriction fragment length polymorphism assays. RESULTS: Genetic polymorphisms in MMP-1 and MMP-3 are associated with rotator cuff tear, in which individuals with rotator cuff tears have associated genotypes 1G/2G (patients, 32 of 64 [50%], control subjects, 16 of 64 [25%]; odds ratio [OR], 4.8; 95% CI, 2.1-11.0; p < 0.001) and 2G/2G were at great risk (patients, 15 of 64 [23%], control subjects, seven of 64 [11%]; OR, 5.2; 95% CI,1.8-14.9; p < 0.001), and patients with rotator cuff tears were associated with a higher proportion of 2G allele distribution (62 of 128 [48%] versus 30 of 128 [23%]; p < 0.001). Patients with the 5A/5A genotype are at greater risk of rotator cuff tear (patients, 15 of 64 [23%]; control subjects, four of 64 [6%]; OR, 5.5; 95% CI, 1.4-20.9; p = 0.021), and there was higher 5A allele distribution in patients with rotator cuff tears (patients, 68 of 128 [53%]; control subjects, 52 of 128 [41%]; p = 0.045). Individuals with the haplotype 2G/5A were more likely to have rotator cuff tears develop (patients, 42 of 64 [66%]; control subjects, 17 of 64 [27%]; OR, 5.3; 95% CI, 2.5-11.3; p < 0.001). Patients with rotator cuff tears reported, in higher number, the existence of relatives who previously had treatment for rotator cuff tears (19 of 64 [30%] versus four of 64 [6%]; OR, 6.3; 95% CI, 2.0-19.9; p = 0.001). CONCLUSIONS: The genetic polymorphism of MMP-1 and MMP-3 is associated with rotator cuff tear. Individuals with haplotype 2G/5A were more susceptible to rotator cuff tears in the population studied. CLINICAL RELEVANCE: Knowledge of the genetic markers related to rotator cuff tears can enable identification of susceptible individuals and increase understanding of the pathogenesis of tendon degeneration.