The first European woolly rhinoceros mitogenomes, retrieved from cave hyena coprolites, suggest long-term phylogeographic differentiation.

The woolly rhinoceros (Coelodonta antiquitatis) is an iconic species of the Eurasian Pleistocene megafauna, which was abundant in Eurasia in the Pleistocene until its demise beginning approximately 10 000 years ago. Despite the early recovery of several specimens from well-known European archaeological sites, including its type specimen (Blumenbach 1799), no genomes of European populations were available so far, and all available genomic data originated exclusively from Siberian populations. Using coprolites of cave hyenas (Crocuta crocuta spelea) recovered from Middle Palaeolithic layers of two caves in Germany (Bockstein-Loch and Hohlenstein-Stadel), we isolated and enriched predator and prey DNA to assemble the first European woolly rhinoceros mitogenomes, in addition to cave hyena mitogenomes. Both coprolite samples produced copious sequences assigned to C. crocuta (27% and 59% mitogenome coverage, respectively) and woolly rhinoceros (Coelodonta antiquitatis; 27% and 81% coverage, respectively). The sequences suggested considerable DNA degradation, which may limit the conclusions to be drawn; however, the mitogenomes of European woolly rhinoceros are genetically distinct from the Siberian woolly rhinoceros, and analyses of the more complete mitogenome suggest a split of the populations potentially coinciding with the earliest fossil records of woolly rhinoceros in Europe.

Expressions of PD-L1 and Nectin-4 in urothelial cancer patients treated with pembrolizumab

ObjectivesRecently, the standard of care for advanced urothelial cancer (UC) has been changed by developing immune-checkpoint inhibitors (ICIs). However, its response rate is limited to 20–30%. The identification of biomarkers to predict the therapeutic effects of ICIs is urgently needed. The present study explored the association between immunohistochemical biomarkers and clinical outcomes in UC patients treated with pembrolizumab.Patients and methodsA total of 85 patients with UC who received pembrolizumab after chemotherapy from January 2018 to May 2020 were retrospectively reviewed. Tumor tissues were obtained for immunohistochemical study from 47 out of 85 patients. The protein expressions of PD-L1, WT1, Nectin-4, CD4, CD8, Foxp3, and CD68 in tumor cells and/or tumor infiltrating lymphocytes were immunohistochemically examined. The associations between protein expressions and overall survival (OS), progression-free survival (PFS), and disease control rate (DCR) were statistically analyzed.ResultsPatients with positive PD-L1 in tumor cells showed significantly worse OS (Log-rank test: HR 5.146, p = 0.001, Cox regression analysis: HR 4.331, p = 0.014) and PFS (Log-rank test: HR 3.31. p = 0.022), along with significantly lower DCR (14.3%) compared to the PD-L1 negative patients (67.5%). In addition, patients with strong expression of Nectin-4 in tumor cells showed significantly higher DCR (100%) than the other patients (50%).ConclusionPD-L1 expression in tumor cells was associated with poor prognosis (OS and PFS) and low DCR. Interestingly, the strong expression of Nectin-4 was correlated with high DCR. PD-L1 and Nectin-4 expression in tumor cells could be prognostic biomarkers useful for pembrolizumab in patients with advanced UC.

Expressions of PD-L1 and Nectin-4 in urothelial cancer patients treated with pembrolizumab.

OBJECTIVES: Recently, the standard of care for advanced urothelial cancer (UC) has been changed by developing immune-checkpoint inhibitors (ICIs). However, its response rate is limited to 20-30%. The identification of biomarkers to predict the therapeutic effects of ICIs is urgently needed. The present study explored the association between immunohistochemical biomarkers and clinical outcomes in UC patients treated with pembrolizumab. PATIENTS AND METHODS: A total of 85 patients with UC who received pembrolizumab after chemotherapy from January 2018 to May 2020 were retrospectively reviewed. Tumor tissues were obtained for immunohistochemical study from 47 out of 85 patients. The protein expressions of PD-L1, WT1, Nectin-4, CD4, CD8, Foxp3, and CD68 in tumor cells and/or tumor infiltrating lymphocytes were immunohistochemically examined. The associations between protein expressions and overall survival (OS), progression-free survival (PFS), and disease control rate (DCR) were statistically analyzed. RESULTS: Patients with positive PD-L1 in tumor cells showed significantly worse OS (Log-rank test: HR 5.146, p = 0.001, Cox regression analysis: HR 4.331, p = 0.014) and PFS (Log-rank test: HR 3.31. p = 0.022), along with significantly lower DCR (14.3%) compared to the PD-L1 negative patients (67.5%). In addition, patients with strong expression of Nectin-4 in tumor cells showed significantly higher DCR (100%) than the other patients (50%). CONCLUSION: PD-L1 expression in tumor cells was associated with poor prognosis (OS and PFS) and low DCR. Interestingly, the strong expression of Nectin-4 was correlated with high DCR. PD-L1 and Nectin-4 expression in tumor cells could be prognostic biomarkers useful for pembrolizumab in patients with advanced UC.

Five-year point prevalence survey of healthcare-associated infections and antimicrobial use in a Japanese university hospital.

BACKGROUND: Periodic point prevalence surveys (PPSs) provide a method for assessing changes in healthcare-associated infections (HAIs) and antimicrobial use over time. Following the introduction of an antimicrobial stewardship programme at Nagoya University Hospital (Aichi, Japan) a five-year PPS study was performed to highlight any epidemiological changes. METHODS: One-day PPSs were performed annually in July at Nagoya University Hospital. Data on patient characteristics, medical devices, active HAIs and antimicrobial use were collected using a standard data-collection form. RESULTS: A total of 4339 patients were included. Over the five-year study period the median patient age was 62 years, median duration of hospital admission was nine days, 9% of patients had an HAI and 35.2% received at least one antimicrobial. Overall there were 406 HAIs (95% confidence interval, 369-447) with surgical site infection, pneumonia and febrile neutropenia occurring most frequently. Enterobacterales were the most common pathogens (N = 78, 28.6%) and 32.1% were third-generation cephalosporin-resistant. Meropenem was the most frequently prescribed antimicrobial for HAIs. Surgical antimicrobial prophylaxis changed drastically, with shorter durations and a marked reduction in oral cephalosporin use. However, antimicrobials for medical prophylaxis gradually increased. CONCLUSIONS: This five-year PPS study shows consistent data for patient background, HAIs and causative pathogens and highlights changes in antimicrobial use during the era of the National Action Plan on Antimicrobial Resistance. To describe the epidemiology of Japanese hospitals by PPS, multicentre PPSs including in community hospitals should be performed annually.

Three-dimensional conformal radiation therapy for canine aortic body tumour: 6 cases (2014-2019).

OBJECTIVE: To determine the feasibility of three-dimensional conformal radiation therapy for canine aortic body tumours. MATERIALS AND METHODS: Medical records of dogs that had undergone three-dimensional conformal radiation therapy with presumptive diagnosis of aortic body tumour were reviewed for clinical characteristics, treatment modality and outcomes. RESULTS: Eight dogs were diagnosed with aortic body tumour and were treated with three-dimensional conformal radiation therapy. One dog had proliferation of a mass in the right atrium during treatment and died of respiratory distress. Another dog did not undergo follow-up CT to evaluate the treatment response due to the increased blood urea nitrogen values. The remaining 6 dogs were included in the case series. Radiotherapy was performed using a median dose per fraction of 7 Gy (3.3-7.14 Gy), a median of seven divided doses (7-15) and a total median dose of 49 Gy (45-50 Gy). The median number of CT scans during the follow-up period was 5 (range: 3-8 times). CT revealed acute side effects in four dogs-grade 1 effects related to the lung (n = 4) and skin (n = 2). Self-limiting or asymptomatic late side effects (grade 1 lung-related effect) were observed in three dogs. After therapy, one dog demonstrated a complete response, another demonstrated a partial response and the disease remained stable in four animals. The median follow-up period was 514.5 (235-1219) days. After three-dimensional conformal radiation therapy, the aortic body tumour reduced gradually over time without regrowth in all these 6 dogs. CLINICAL SIGNIFICANCE: In this small case series, aortic body tumours responded to three-dimensional conformal radiation therapy. Transient and self-limiting side effects of the treatments were common. Further controlled studies are required to prove the effectiveness and the safety of this intervention.

A spin-orbital-entangled quantum liquid on a honeycomb lattice.

The honeycomb lattice is one of the simplest lattice structures. Electrons and spins on this simple lattice, however, often form exotic phases with non-trivial excitations. Massless Dirac fermions can emerge out of itinerant electrons, as demonstrated experimentally in graphene, and a topological quantum spin liquid with exotic quasiparticles can be realized in spin-1/2 magnets, as proposed theoretically in the Kitaev model. The quantum spin liquid is a long-sought exotic state of matter, in which interacting spins remain quantum-disordered without spontaneous symmetry breaking. The Kitaev model describes one example of a quantum spin liquid, and can be solved exactly by introducing two types of Majorana fermion. Realizing a Kitaev model in the laboratory, however, remains a challenge in materials science. Mott insulators with a honeycomb lattice of spin-orbital-entangled pseudospin-1/2 moments have been proposed, including the 5d-electron systems α-Na2IrO3 (ref. 5) and α-Li2IrO3 (ref. 6) and the 4d-electron system α-RuCl3 (ref. 7). However, these candidates were found to magnetically order rather than form a liquid at sufficiently low temperatures, owing to non-Kitaev interactions. Here we report a quantum-liquid state of pseudospin-1/2 moments in the 5d-electron honeycomb compound H3LiIr2O6. This iridate does not display magnetic ordering down to 0.05 kelvin, despite an interaction energy of about 100 kelvin. We observe signatures of low-energy fermionic excitations that originate from a small number of spin defects in the nuclear-magnetic-resonance relaxation and the specific heat. We therefore conclude that H3LiIr2O6 is a quantum spin liquid. This result opens the door to finding exotic quasiparticles in a strongly spin-orbit-coupled 5d-electron transition-metal oxide.

Combination of p53-DC vaccine and rAd-p53 gene therapy induced CTLs cytotoxic against p53-deleted human prostate cancer cells in vitro.

Recently, the US FDA approved sipuleucel-T, which is composed of autologous DCs stimulated with a recombinant fusion protein of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF), as the first immunotherapeutic agent for metastatic castration resistant prostate cancer (mCRPC). However, sipuleucel-T demonstrated only modest efficacy in mCPRC patients. Researchers are now investigating the potential of p53 protein as a tumor-associated antigen (TAA) loaded in DC-based cancer vaccine. Approximately half of all tumors overexpress p53, and up to 20% of prostate cancer cells overexpresses p53. In this study, we evaluated the feasibility of combining p53-DC vaccine and rAd-p53 gene therapy, using the p53-overexpressing and non-expressing prostate cancer cells in vitro. We successfully generated the p53-DC vaccine by culturing autologous DCs infected with rAd-p53. This p53-DC vaccine can differentiate CTLs specifically cytotoxic to p53-overexpressing prostate cancer cells. In addition, rAd-p53 infection can induce overexpression of p53 and thus the cytotoxicity of CTLs differentiated by the p53-DC vaccine in p53 non-expressing prostate cancer cells. These findings suggest that this combination therapy using p53-DC vaccine and rAd-p53 gene therapy together may represent a new paradigm for the treatment of mCRPC.

Measurement of residual platelet thrombogenicity under arterial shear conditions in cerebrovascular disease patients receiving antiplatelet therapy.

UNLABELLED: Essentials A consensus methodology for assessing the effects of antiplatelet agents has not been established. Measuring platelet thrombus formation (PTF) for evaluating antiplatelet effects was assessed. PTF differentially reflected antiplatelet effects compared to other tests. PTF may be associated with the severity of carotid or intracranial arterial stenosis. Click to hear a presentation on platelet function testing in the clinic by Gresele and colleagues SUMMARY: Background A consensus methodology for assessing the effects of antiplatelet agents has not been established. Objective We investigated the usefulness of directly measuring platelet thrombus formation (PTF) using a microchip-based flow chamber system for evaluating antiplatelet therapy. Patients/Methods Platelet thrombus formation in the whole blood of 94 patients with ischemic cerebrovascular disease treated with clopidogrel and/or aspirin was measured in a flow chamber system at a shear rate of 1500 s(-1) and was compared with the results of assays for agonist-induced platelet aggregability, phosphorylation of vasodilator-stimulated phosphoprotein, platelet p-selectin expression (PS), and platelet-monocyte complexes. Results In all patients tested, area under the flow pressure curve (AUC10), which represents platelet thrombogenicity, showed weak correlation with platelet aggregation induced by either adenosine diphosphate or collagen. In addition, AUC10 was lower in patients treated with dual antiplatelet therapy (median 79.4) compared with patients treated with aspirin or clopidogrel alone (217.7 and 301.0, respectively), whereas the parameters evaluated by the other assays did not reflect the combined treatment efficacy. In clopidogrel monotherapy patients, AUC10 was associated with the severity of arterial stenosis (R(2) = 0.127, ß = 1.25), and AUC10 and PS were higher in patients with severe carotid or intracranial arterial stenosis than in those with mild stenosis. Conclusions Platelet thrombus formation measurement using a flow-chamber system was useful for evaluating the efficacy of treatment with aspirin and clopidogrel, both alone and in combination. The present findings indicate that high residual platelet thrombogenicity in patients treated with clopidogrel may be associated with the severity of carotid or intracranial arterial stenosis.

Interleukin-6, interleukin-6 receptor gene variant, small-vessel disease and incident dementia.

BACKGROUND AND PURPOSE: Mixed neurogenerative and vascular dementia has emerged as the leading cause of dementia in the elderly. Inflammation is implicated in atherosclerosis, cerebral small-vessel disease (SVD) as well as cognitive impairment. However, longitudinal data on the predictive value of circulating inflammatory markers including gene variants and magnetic resonance imaging (MRI) findings in incident dementia are scarce. It was investigated whether circulating interleukin-6 (IL-6), C-reactive protein (CRP) and gene variants increase dementia risk. METHODS: In a cohort of Japanese participants with vascular risk factors in an observational study from 2001, the association between baseline IL-6, CRP levels, gene variants [interleukin-6 receptor (IL-6R), rs2228145; IL-6, rs2097677; CRP, rs3093059] and incident all-cause dementia was evaluated. Baseline MRI was used to determine SVD (lacuna, white matter hyperintensities) and atrophy (medial-temporal lobe atrophy, bicaudate ratio). Cox proportional hazards analyses were performed for predictors of dementia, adjusting for age, sex, apolipoprotein Eε4, education, cerebrovascular events, vascular risk factors and MRI findings. RESULTS: Of 803 subjects (mean 67.0 ± 8.5 years, males 59%), during a mean of 7.5 ± 3.2 years follow-up, 60 incident dementia patients (Alzheimer's disease 31; vascular dementia 17; mixed-type six; other six) were diagnosed. In multivariable analyses adjusted for age, sex, cerebrovascular events, MRI findings and IL-6R variant (rs2228145), IL-6 levels (relative risk 1.68, P = 0.048) or highest tertile (relative risk 2.38, P = 0.031) for all-cause dementia remained significant. Although subjects with rs2228145 carrier had significantly higher IL-6 levels, a significant association between rs2228145 and dementia was not observed. Conversely, CRP and remaining gene variants were not associated with dementia. CONCLUSIONS: The deleterious effect of higher IL-6 on dementia remains consistent irrespective of conventional risk factors, MRI findings and IL-6R variant.

Serum high-molecular-weight adiponectin level and incident dementia in patients with vascular risk factors.

BACKGROUND AND PURPOSE: The involvement of metabolic factors in the development of dementia has received much attention. However, previous studies have yielded conflicting results regarding how blood adipocytokine level impacts cognitive decline and dementia. This study aimed to clarify whether serum high-molecular-weight (HMW) adiponectin level is related to incident dementia. METHODS: Data were from 466 patients (mean age 67.8 years, male 57%)--who had normal cognitive function and received brain magnetic resonance imaging--from amongst the 1106 patients in the Osaka Follow-up Study for Carotid Atherosclerosis, Part 2, a prospective cohort study of cardiovascular events and dementia amongst patients with vascular risk factors enrolled between 2001 and 2009. Baseline HMW adiponectin levels were measured using frozen serum. Dementia occurrence was examined in June 2013. RESULTS: Serum HMW adiponectin level was 4.33 ± 2.95 µg/ml; the levels were lower in men than in women and negatively correlated with body mass index. During the follow-up period (median 6.9 years), 47 patients had incident dementia including Alzheimer's disease dementia (27), vascular dementia (13), mixed dementia (four), other dementia (three). Risks of dementia in patients with high versus low HMW adiponectin levels were almost identical (P = 0.689). No association was found between adiponectin levels and Alzheimer's disease dementia or vascular dementia in the whole group or amongst men and women separately. CONCLUSIONS: This study demonstrated that serum HMW adiponectin level has little association with future dementia. Determination of metabolic factors involved in dementia requires evaluation of other biomarkers or parameters.

The oncogenic role of the cochaperone Sgt1.

Sgt1/Sugt1, a cochaperone of Hsp90, is involved in several cellular activities including Cullin E3 ubiqutin ligase activity. The high level of Sgt1 expression in colorectal and gastric tumors suggests that Sgt1 is involved in tumorigenesis. Here, we report that Sgt1 is overexpressed in colon, breast and lung tumor tissues and in Ewing sarcoma and rhabdomyosarcoma xenografts. We also found that Sgt1 heterozygous knockout resulted in suppressed Hras-mediated transformation in vitro and tumor formation in p53(-/-) mouse embryonic fibroblast cells and significantly increased survival of p53(-/-) mice. Moreover, depletion of Sgt1 inhibited the growth of Ewing sarcoma and rhabdomyosarcoma cells and destabilized EWS-FLI1 and PAX3-FOXO1 oncogenic fusion proteins, respectively, which are required for cellular growth. Our results suggest that Sgt1 contributes to cancer development by stabilizing oncoproteins and that Sgt1 is a potential therapeutic target.

Sulcus subarachnoid hemorrhage is a common stroke subtype in patients with implanted left ventricular assist devices.

BACKGROUND AND PURPOSE: Stroke is one of the major complications observed in patients with an implanted left ventricular assist device (LVAD). The purpose of this study was to clarify the types and characteristics of acute stroke in patients after LVAD implantation by using brain computed tomography (CT) findings. METHODS: Between 2005 and 2012, 110 consecutive patients who underwent LVAD implantation were reviewed. The most commonly used device was the pulsatile extracorporeal LVAD. Amongst them, 49 patients suffered from acute stroke at least once with a total of 115 stroke events. The clinical categories, lesion sites, laboratory data and CT findings of each acute stroke event were analyzed. RESULTS: Cerebral infarction (35 patients, 72 events), cerebral hemorrhage (25 patients, 31 events) and subarachnoid hemorrhage (SAH) (23 patients, 33 events) were identified. A mean of 2.3 stroke events occurred per person. Of the 72 infarction events, multiple infarctions were observed in 29 events. Of the cerebral hemorrhage events (n = 31), almost all were subcortical lesions (n = 27) and none were observed in the basal ganglia. Of the 23 patients with SAH events (n = 33), SAH localized within a single sulcus, sulcus SAH, was observed in 25 events. CONCLUSIONS: Computed tomography findings of acute stroke after implantation of an LVAD are characteristically multifocal cortical lesions, regardless of brain infarction and hemorrhage. Unexpectedly, sulcus SAH was a common stroke subtype in patients with implanted LVADs. Sulcus SAH should be carefully examined in patients after LVAD implantation, when they complain of non-specific neurological complaints.

Pressure-induced valence crossover and novel metamagnetic behavior near the antiferromagnetic quantum phase transition of YbNi_{3}Ga_{9}.

We report electrical resistivity, ac magnetic susceptibility, and x-ray absorption spectroscopy measurements of intermediate valence YbNi_{3}Ga_{9} under pressure and magnetic field. We have revealed a characteristic pressure-induced Yb valence crossover within the temperature-pressure phase diagram, and a first-order metamagnetic transition is found below P_{c}∼9 GPa where the system undergoes a pressure-induced antiferromagnetic transition. As a possible origin of the metamagnetic behavior, a critical valence fluctuation emerging near the critical point of the first-order valence transition is discussed on the basis of the temperature-field-pressure phase diagram.

Association between carotid stenosis or lacunar infarction and incident dementia in patients with vascular risk factors.

BACKGROUND AND PURPOSE: The association between vascular risk factors and dementia is of interest. Several studies have shown that cerebral small vessel disease (SVD) is associated with dementia. However, the association between cerebral large vessel disease (LVD) and dementia has not been thoroughly examined. METHODS: The Osaka Follow-up Study for Carotid Atherosclerosis, Part 2, was a prospective cohort study of cardiovascular events and dementia in which patients (n = 1106) with vascular risk factors underwent carotid ultrasound. Of these patients, 600 who had normal cognitive function were included and underwent brain magnetic resonance imaging. The presence of lacunar infarction and carotid stenosis served as markers for SVD and LVD, respectively. RESULTS: Amongst 600 patients (mean 68 years, 57% men), 261 (44%) showed lacunar infarction and 94 (16%) showed carotid stenosis. During the follow-up period (median 8.0 years), 57 patients had incident dementia. Patients with carotid stenosis and lacunar infarction were significantly more likely to be diagnosed with dementia (log-rank test, P = 0.037 and P < 0.001, respectively). The association between lacunar infarction and dementia remained significant after adjusting for risk factors including stroke history, apolipoprotein E genotype and years of education (hazard ratio 2.64, 95% confidence interval 1.22-6.09). However, the presence of carotid stenosis was not associated with incident dementia after adjusting for age and sex (P = 0.477). CONCLUSIONS: This study demonstrated that carotid stenosis had little association with dementia, but lacunar infarction had a significant association. The impact of SVD on dementia could be much greater than that of LVD.

Thyroid antibodies are associated with stenotic lesions in the terminal portion of the internal carotid artery.

BACKGROUND AND PURPOSE: Several studies have reported moyamoya syndrome associated with thyroid disease, and the mechanism involved in this relationship is unknown. This study aimed to clarify the involvement of thyroid antibodies and thyroid function in intracranial arterial stenosis. METHODS: The study included 30 patients <65 years of age with intracranial arterial steno-occlusion. Patients with definitive moyamoya disease were excluded. Thyroid function and thyroid antibody levels were evaluated. The steno-occlusive site and the presence of moyamoya vessels were evaluated using digital subtraction angiography. The characteristics of intracranial arterial lesions were compared between patients with and without elevated thyroid antibody levels, and between patients with increased thyroid function and those with normal thyroid function. RESULTS: Five patients had increased thyroid function and seven had elevated thyroid antibody levels. Four were diagnosed with Graves' disease, 13 with atherosclerotic intracranial stenosis, two with intracranial arterial dissection, one with vasculitis syndrome and 10 with intracranial stenosis of unknown cause. All patients with Graves' disease and patients with elevated antithyroid peroxidase antibody levels had steno-occlusion in the terminal portion of the internal carotid arteries, whereas most of the patients with normal thyroid function or without elevated thyroid antibody levels had stenosis in the middle cerebral arteries. CONCLUSIONS: In young and middle-aged patients, a lesion in the terminal portion of the internal carotid artery was associated with elevated thyroid antibody levels and increased thyroid function. Stenoses found in the terminal portion of the internal carotid artery and immune-mediated thyroid diseases may share a common background.

Physiological responses in Alpine skiers during on-snow training simulation in the cold.

This study examined the physiological responses to cold stimulus during intermittent high-intensity exercise simulating on-snow alpine ski training. 7 male alpine skiers performed intermittent high-intensity exercises composed of 4 bouts of cycling exercise at 140% VO 2max intensity for 30 s with 10-min rests on a cycle ergometer in cold (1°C) and control (22°C) conditions. The subjects wore racing suits, middle layers and half pants designed for alpine skiers. Rectal temperature and mean skin temperature were lower in the cold condition than in the control condition (36.8 ± 0.5 vs. 37.1 ± 0.1°C and 28.4 ± 0.6 vs. 33.3 ± 0.6°C, respectively). Oxygen consumption during rests and the last 2 bouts of exercise was higher in the cold condition than in the control condition. Although plasma noradrenaline and serum triglyceride were higher in the cold condition than in the control condition, plasma glucose, adrenaline and serum glycerol were lower. Serum free fatty acid and plasma lactate concentrations did not differ significantly between the 2 conditions. These results indicate that a cold stimulus affects body temperature and energy metabolism and may lead to a decrease in exercise capacity in alpine skiers during on-snow training.

Design and performance of hybrid constructed wetland systems for high-content wastewater treatment in the cold climate of Hokkaido, northern Japan.

The performance of six multistage hybrid constructed wetland systems was evaluated. The systems were designed to treat four kinds of high-content wastewater: dairy wastewater (three systems, average inflow content 2,400-5,000 mg·COD l(-1), 3-6 years of operation); pig farm wastewater, including liquid food washing wastewater (one system, 9,500 mg·COD l(-1), 3 years); potato starch processing wastewater (one system, 20,000-60,000 mg·COD l(-1), 3 years); and wastewater containing pig farm swine urine (one system, 6,600 mg·COD l(-1), 2.8 years) (COD = chemical oxygen demand). The systems contained three or four vertical (V) flow beds with self-priming siphons and surface partitions and no or one horizontal (H) flow bed (three to five beds). In some V flow beds, treated effluents were recirculated (Vr) through the inlet to improve performance. Mean annual temperature was 5-8 °C at all locations. To overcome clogging due to the high load in a cold climate, we applied a safety bypass structure and floating cover material to the V flow beds. Calculated average oxygen transfer rates (OTRs) increased proportionally with the influent load, and the OTR value was Vr > V> H. The relations of load-OTR, COD-ammonium, and a Arrhenius temperature-dependent equation enable the basic design of a reed bed system.

Common carotid intima-media thickness does not add to Framingham risk score in individuals with diabetes mellitus: the USE-IMT initiative.

AIMS/HYPOTHESIS: The aim of this work was to investigate whether measurement of the mean common carotid intima-media thickness (CIMT) improves cardiovascular risk prediction in individuals with diabetes. METHODS: We performed a subanalysis among 4,220 individuals with diabetes in a large ongoing individual participant data meta-analysis involving 56,194 subjects from 17 population-based cohorts worldwide. We first refitted the risk factors of the Framingham heart risk score on the individuals without previous cardiovascular disease (baseline model) and then expanded this model with the mean common CIMT (CIMT model). The absolute 10 year risk for developing a myocardial infarction or stroke was estimated from both models. In individuals with diabetes we compared discrimination and calibration of the two models. Reclassification of individuals with diabetes was based on allocation to another cardiovascular risk category when mean common CIMT was added. RESULTS: During a median follow-up of 8.7 years, 684 first-time cardiovascular events occurred among the population with diabetes. The C statistic was 0.67 for the Framingham model and 0.68 for the CIMT model. The absolute 10 year risk for developing a myocardial infarction or stroke was 16% in both models. There was no net reclassification improvement with the addition of mean common CIMT (1.7%; 95% CI -1.8, 3.8). There were no differences in the results between men and women. CONCLUSIONS/INTERPRETATION: There is no improvement in risk prediction in individuals with diabetes when measurement of the mean common CIMT is added to the Framingham risk score. Therefore, this measurement is not recommended for improving individual cardiovascular risk stratification in individuals with diabetes.