Association of sex and cardiovascular risk factors with atherosclerosis distribution pattern in lower extremity peripheral artery disease.

OBJECTIVE Atherosclerosis expression varies across not only coronary, cerebrovascular, and peripheral arteries but also within the peripheral vascular tree. The underlying pathomechanisms of distinct atherosclerosis phenotypes in lower extremity peripheral artery disease (PAD) is poorly understood. We investigated the association of cardiovascular risk factors (CVRFs) and atherosclerosis distribution in a targeted approach analyzing symptomatic patients with isolated anatomic phenotypes of PAD. METHODS In a cross-sectional analysis of consecutive patients undergoing first-time endovascular recanalization for symptomatic PAD, data of patients with isolated anatomic phenotypes of either proximal (iliac) or distal (infrageniculate) atherosclerosis segregation were extracted. We performed a multivariable logistic regression model with backward elimination to investigate the association of proximal and distal PAD with CVRFs. RESULTS Of the 637 patients (29% females) with endovascular recanalization, 351 (55%) had proximal and 286 (45%) had distal atherosclerosis. Female sex [odds ratio (OR) 0.33, 95% confidence interval (CI) 0.20-0.54, p = 0.01], active smoking (OR 0.16, 95% CI 0.09-0.28, p < 0.001), and former smoking (OR 0.33, 95% CI 0.20-0.57, p < 0.001) were associated with proximal disease. Diabetes mellitus (DM) (OR 3.25, 95% CI 1.93-5.46, p < 0.001), chronic kidney disease (CKD) (OR 1.18, 95% CI 1.08-1.28, p < 0.001), and older age (OR 1.31, 95% CI 1.06-1.61, p = 0.01) were associated with distal disease. CONCLUSION Female sex, particularly in the context of smoking, is associated with clinically relevant, proximal atherosclerosis expression. Our additional findings that distal atherosclerosis expression is associated with DM, CKD, and older age suggest that PAD has at least two distinct atherosclerotic phenotypes with sex-specific and individual susceptibility to atherogenic risk factors

Prevalence of Polyomavirus BK and JC Infection and Replication in 400 Healthy Blood Donors

BackgroundThe replication of BK virus (BKV) and JC virus (JCV) is linked to polyomavirus-associated nephropathy, hemorrhagic cystitis, and multifocal leukoencephalopathy in immunodeficient patients, but the behavior of these viruses in immunocompetent individuals has hardly been characterized MethodsWe used EIA to study samples obtained from 400 healthy blood donors aged 20-59 years for BKV- and JCV-specific antibodies against virus-like particles. We also studied BKV and JCV loads in plasma and urine among these individuals by use of real-time polymerase chain reaction ResultsIgG seroprevalence was 82% (328 of 400 donors) for BKV and 58% (231 of 400) for JCV. As age increased (age groups were divided by decade), the seroprevalence of BKV decreased from 87% (87 of 100) in the youngest group (aged 20-29 years) to 71% (71 of 100) in the oldest group (aged 50-59 years) (P=.006), whereas the seroprevalence of JCV increased from 50% (50 of 100) in the youngest group to 68% (68 of 100) in the oldest group (P=.06). Asymptomatic urinary shedding of BKV and JCV was observed in 28 (7%) and 75 (19%) of 400 subjects, respectively, with median viral loads of 3.51 and 4.64 log copies/mL, respectively (P<.001). Unlike urinary BKV loads, urinary JCV loads were positively correlated with IgG levels. The shedding of JCV was more commonly observed among individuals who were seropositive only for JCV, compared with individuals who were seropositive for both BKV and JCV, suggesting limited cross-protection from BKV immunity. Noncoding control regions were of archetype architecture in all cases, except for 1 rearranged JCV variant. Neither BKV nor JCV DNA was detected in plasma ConclusionsOur study provides important data about polyomavirus infection and replication in healthy, immunocompetent individuals. These data indicate significant differences between BKV and JCV with respect to virus-host interaction and epidemiolog

Quantity of HLA-C surface expression and licensing of KIR2DL+ natural killer cells

Natural killer (NK) cells require interaction of inhibitory surface receptors with human leukocyte antigen (HLA) ligands during development to acquire functional competence in a process termed "licensing.” The quantity of HLA required for this process is unknown. Two polymorphisms affecting HLA-C surface expression (rs9264942 and rs67384697) have recently been identified, and shown to influence progression of HIV infection. We typed a cohort of healthy donors for the two HLA-C-related polymorphisms, KIR2DL1 and KIR2DL3, and their respective HLA-C ligands and analyzed how HLA ligands influenced licensing status of killer cell immunoglobulin-like receptor (KIR)+ NK cells in terms of degranulation and cytokine production in response to HLA-deficient target cells. The presence of respective HLA class I ligands increased the function of KIR2DL1+ and KIR2DL3+ NK cells in a dose-dependent manner. In contrast, neither of the HLA-C-related polymorphisms nor the quantity of cell surface HLA-C had any significant effect on NK cell function. Interestingly, HLA-Cw7—an HLA-C allele with low surface expression—licensed KIR2DL3+ NK cells more strongly than any other KIR2DL3 ligand. The quantity of cell surface HLA-C does not appear to influence licensing of NK cells, and the HLA-C-related polymorphisms presumably influence HIV progression through factors unrelated to NK cell educatio

Long-term course of haemoglobin and ferritin values in high-frequency donors of whole blood and double erythrocyte apheresis

Background: High-intensity donation is a risk factor for iron deficiency in blood donors. Interdonation intervals for whole blood (WB) donation and double unit red blood cell apheresis (2RBC) vary among countries. We retrospectively evaluated the course of haemoglobin (Hb) and ferritin values in men regularly donating WB 4 times a year or 2RBC twice a year (i.e., maximal frequency) over a period of 48 months. Methods: Data of male donors with 16 WB or 8 2RBC consecutive donations were analysed. The minimum Hb levels for WB donation and 2RBC apheresis (collection of 360 mL RBC) were 135 and 140 g/L, respectively. There was no lower limit set for ferritin, and no iron was substituted. Results: We identified 294 WB (mean age 53 years, SD 11) and 151 2RBC donors (mean age 48 years, SD 9) who donated at a mean interval of 97 (SD 18) and 201 days (SD 32), respectively, between January 1, 2008, and December 31, 2013. At baseline, Hb and ferritin values were lower in WB donors compared to 2RBC donors, with a mean Hb of 153 g/L (SD 13) versus 159 g/L (SD 8) and a mean ferritin of 44 μg/L (SD 52) versus 73 μg/L (SD 56; p < 0.001 for both parameters), respectively. Ferritin was below 15 μg/L in 40 WB (14%) and in 4 (3%) 2RBC donors. In WB donors, the mean Hb levels at baseline versus last donation showed no significant difference (153 vs. 152g/L, p = 0.068), whereas the mean ferritin levels decreased significantly (44 vs. 35 μg/L, p < 0.001). The 2RBC donor group displayed a statistically different decrease in both the mean Hb levels (158 vs. 157 g/L; p < 0.05) and the mean ferritin levels (73 vs. 66 μg/L; p = 0.052). The lowest Hb was measured at the 11th WB donation (152 g/L; p < 0.05) and at the 4th 2RBC apheresis (157 g/L; p < 0.05). There was no deferral due to low Hb at any time. The lowest ferritin was shown at the 4th WB (37 μg/L) and at the 3rd 2RBC donation (60 μg/L), respectively. At the last visit, ferritin was below 15 μg/L in 23 WB donors (8%) and in 2 2RBC donors (1%). Conclusions: High-intensity male donors with an interdonation interval of 12 weeks for WB donation and 24 weeks for 2RBC apheresis maintain acceptable Hb levels and, after an initial decline,stable ferritin levels despite ongoing blood donation

Potent neutralization by monoclonal human IgM against SARS-CoV-2 is impaired by class switch.

To investigate the class-dependent properties of anti-viral IgM antibodies, we use membrane antigen capture activated cell sorting to isolate spike-protein-specific B cells from donors recently infected with SARS-CoV-2, allowing production of recombinant antibodies. We isolate 20, spike-protein-specific antibodies of classes IgM, IgG, and IgA, none of which shows any antigen-independent binding to human cells. Two antibodies of class IgM mediate virus neutralization at picomolar concentrations, but this potency is lost following artificial switch to IgG. Although, as expected, the IgG versions of the antibodies appear to have lower avidity than their IgM parents, this is not sufficient to explain the loss of potency

Association of sex and cardiovascular risk factors with atherosclerosis distribution pattern in lower extremity peripheral artery disease

ObjectiveAtherosclerosis expression varies across not only coronary, cerebrovascular, and peripheral arteries but also within the peripheral vascular tree. The underlying pathomechanisms of distinct atherosclerosis phenotypes in lower extremity peripheral artery disease (PAD) is poorly understood. We investigated the association of cardiovascular risk factors (CVRFs) and atherosclerosis distribution in a targeted approach analyzing symptomatic patients with isolated anatomic phenotypes of PAD.MethodsIn a cross-sectional analysis of consecutive patients undergoing first-time endovascular recanalization for symptomatic PAD, data of patients with isolated anatomic phenotypes of either proximal (iliac) or distal (infrageniculate) atherosclerosis segregation were extracted. We performed a multivariable logistic regression model with backward elimination to investigate the association of proximal and distal PAD with CVRFs.ResultsOf the 637 patients (29% females) with endovascular recanalization, 351 (55%) had proximal and 286 (45%) had distal atherosclerosis. Female sex [odds ratio (OR) 0.33, 95% confidence interval (CI) 0.20–0.54, p = 0.01], active smoking (OR 0.16, 95% CI 0.09–0.28, p &lt; 0.001), and former smoking (OR 0.33, 95% CI 0.20–0.57, p &lt; 0.001) were associated with proximal disease. Diabetes mellitus (DM) (OR 3.25, 95% CI 1.93–5.46, p &lt; 0.001), chronic kidney disease (CKD) (OR 1.18, 95% CI 1.08–1.28, p &lt; 0.001), and older age (OR 1.31, 95% CI 1.06–1.61, p = 0.01) were associated with distal disease.ConclusionFemale sex, particularly in the context of smoking, is associated with clinically relevant, proximal atherosclerosis expression. Our additional findings that distal atherosclerosis expression is associated with DM, CKD, and older age suggest that PAD has at least two distinct atherosclerotic phenotypes with sex-specific and individual susceptibility to atherogenic risk factors

Multicenter Validation of Histopathologic Tumor Regression Grade After Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Carcinoma

Response classification after neoadjuvant chemotherapy in muscle-invasive bladder carcinoma is based on the TNM stage at radical cystectomy. We recently showed that histopathologic tumor regression grades (TRGs) add prognostic information to TNM. Our aim was to validate the prognostic significance of TRG in muscle-invasive bladder cancer in a multicenter setting. We enrolled 389 patients who underwent cisplatin-based chemotherapy before radical cystectomy in 8 centers between 2010 and 2016. Median follow-up was 2.2 years. TRG was determined in radical cystectomy specimens by local pathologists. Central pathology review was conducted in 20% of cases, which were randomly selected. The major response was defined as ≤pT1N0. The remaining patients were grouped into partial responders (≥ypT2N0-3 and TRG 2) and nonresponders (≥ypT2N0-3 and TRG 3). TRG was successfully determined in all cases, and interobserver agreement in central pathology review was high (κ=0.83). After combining TRG and TNM, 47%, 15%, and 38% of patients were major, partial, and nonresponders, respectively. Combination of TRG and TNM showed significant prognostic discrimination of overall survival (major responder: reference; partial responder: hazard ratio 3.5 [95% confidence interval: 1.8-6.8]; nonresponder: hazard ratio 6.1 [95% confidence interval: 3.6-10.3]). This discrimination was superior compared with TNM staging alone, supported by 2 goodness-of-fit criteria (P=0.041). TRG is a simple, reproducible histopathologic measurement of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer. Integrating TRG with TNM staging resulted in significantly better prognostic stratification than TNM staging alone

Verteilungsmuster der Atherosklerose bei peripherer arterieller Verschlusskrankheit in Abhängigkeit von vaskulären Risikofaktoren

Hintergrund: Die Atheroskleroseexpression unterscheidet sich nicht nur in unterschiedlichen Gefässbetten (koronar, zerebrovaskulär, peripher), sondern auch innerhalb des peripheren Gefässbettes. Der zugrundeliegende Mechanismus für unterschiedliche Atherosklerose-Phänotypen mit proximalem (iliakale Arterien) oder distalem (infragenikuläre Arterien) Atheroskleroseverteilungsmuster ist bis jetzt noch nicht abschliessend geklärt. Zielsetzung: Das Ziel dieser monozentrischen retrospektiven Kohortenstudie ist es, den Zusammenhang zwischen kardiovaskulären Risikofaktoren und dem Atheroskleroseverteilungs-muster bei Patienten mit PAVK zu untersuchen. Dafür werden symptomatische Patienten mit extremen Atherosklerosephänotypen (proximale vs. distale Atherosklerose) genauer untersucht. Methodik: Für diese Querschnittsstudie wurden Daten von 15’000 Patienten, welche sich im Zeitraum von 2000-2018 aufgrund einer symptomatischen PAVK einer primären endovaskulären Rekanalisation an den unteren Extremitäten unterziehen liessen, ausgewertet. Dabei wurden die Patienten herausgefiltert, welche angiographisch ein proximales (iliakal) oder distales (krural) Atheroskleroseexpressionsmuster aufwiesen. Von diesen Personen wurden in der Datenbank personen- und gesundheitsbezogene klinischen Angaben extrahiert. In einer multiplen logistischen Regressionsanalyse mit Rückwärtselimination der unabhängigen Variablen wurde der Einfluss verschiedener kardiovaskulärer Risikofaktoren mit proximaler oder distaler Atherosklerosexpression ermittelt. Resultate: Von insgesamt 637 indentifizierten Patienten (29% Frauen) mit einer primären endovaskulären Rekanalisation hatten 351 (55%) ein proximales und 286 (45%) ein distales Atheroskleroseverteilungsmuster. Weibliches Geschlecht (OR 0.33, (95%CI 0.20-0.54), p=0.011), aktiver Nikotinkonsum (OR 0.16, (95%CI 0.09-0.28), p<0.001), vormaliger Nikotinkonsum (OR 0.33, (95%CI 0.20-0.57), p<0.001), Hypertriglyzeridämie (OR 0.76, (95%CI 0.60-0.96), p=0.021) waren assoziiert mit einem proximalen Befall. Diabetes mellitus (OR 3.25, (95%CI 1.93-5.46), p<0.001), chronische Niereninsuffizienz (OR 1.18, (95%CI 1.08-1.28), p<0.001) und höheres Alter (OR 1.31, (95%CI 1.06-1.61), p=0.011) waren hin-gegen mit einem distalen Befall assoziiert. Andere Faktoren wie Body Mass Index, arterielle Hypertonie, HDL-, LDL-Cholesterin zeigten keine Assoziation mit den untersuchten atherosklerotischen Prädilektionsstellen. Die Resultate der primären Analysen konnten mit den Subgruppenanalysen (Geschlecht, Nikotinkonsum, Diabetes) bestätigt werden. Schlussfolgerung: Für distale (krurale) Atherosklerose wurden als Hauptrisikofaktoren Diabetes mellitus und chronische Niereninsuffizienz ermittelt. Obwohl kardiovaskuläre Risikofaktoren auf das gesamte Gefässbett wirken, lassen sich aus den Daten in Bezug auf das Atheroskleroseverteilungsmuster eine geschlechtspezifische und eine individuelle Suszeptibilität für kardiovaskuläre Risikofaktoren vermuten. Ausserdem deuten die Daten darauf hin, dass die PAVK mindestens zwei verschiedene atherosklerotische Phänotypen aufweist.Background: Atherosclerosis expression varies across different vascular beds, i.e. coronary, cerebrovascular and peripheral arteries, but also within the peripheral vascular tree. The underlying pathomechanisms of distinct atherosclerosis phenotypes in lower extremity peripheral artery disease (LEAD) with proximal (iliac) and distal (infrageniculate arteries) atherosclerosis expression is poorly understood and no therapeutic differences are made. Objectives: To investigate the association of cardiovascular risk factors (CRF) and atherosclerosis distribution patterns in a unique targeted approach, analyzing symptomatic patients with extreme phenotypes of peripheral atherosclerosis expression, i.e. proximal versus distal LEAD. Methods: In a cross-sectional analysis of 15.000 patients undergoing first-time endovascular recanalization for symptomatic LEAD, patients with proximal (iliac) or distal (infrageniculate) atherosclerosis expression patterns were extracted. A multivariate logistic regression model with backward elimination was performed to investigate the association of proximal and distal disease with CRFs. Results: Of 637 patients (29% women) with primary endovascular recanalization, 351 (55%) had a proximal, and 286 (45%) had a distal atherosclerosis manifestation. Female sex (OR 0.33, (95%CI 0.20-0.54), p=0.011), active smoking (OR 0.16, (95%CI 0.09-0.28), p<0.001), former smoking (OR 0.33, (95%CI 0.20-0.57), p<0.001), and hypertriglyceridemia (OR 0.76, (95%CI 0.60-0.96), p=0.021) were associated with proximal disease. Diabetes mellitus (OR 3.25, (95%CI 1.93-5.46), p<0.001), chronic kidney disease (CKD) (OR 1.18, (95%CI 1.08-1.28), p<0.001), and older age (OR 1.31, (95%CI 1.06-1.61), p=0.011) were associated with distal disease. Other factors, e.g. body mass index, arterial hypertension, HDL-, LDL-cholesterol, were not associated with atherosclerosis predilection sites. Findings were independent from sex, smoking status, and diabetes in subgroup analyses. Conclusions: Female sex and cigarette smoking were identified as main risk factors of proximal, diabetes mellitus and CKD as risk factors of distal clinically relevant atherosclerosis expression. Although risk factors impinge on the entire vascular bed, our data suggest a sex specific and individual susceptibility to atherogenic risk factors, and that LEAD has at least two different atherosclerotic phenotypes

The Remarkable Journey of a Low-Frequency Alloantibody

Herein we describe a case of febrile non-hemolytic reaction (FNHTR) in a 64-year-old male 20 min after the transfusion of one red blood cell unit. 20 days prior the patient had undergone an allogeneic hematopoietic stem cell transplantation (HCT) from an unrelated donor with minor ABO disparity. The patient had been treated for plasma cell myeloma with multiple transfusions in the past, but no transfusion reactions or alloimmunization had been reported