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Recent studies have shown that both glomerular and tubulointerstitial damage are important factors in the pathophysiology and progression of diabetic nephropathy. To examine whether markers of tubular damage are useful in monitoring the progression of disease, we measured urinary levels of neutrophil gelatinase-associated lipocalin (NGAL), liver-fatty acid-binding protein (LFABP), and kidney injury molecule-1 (KIM-1) in a 3-year intervention study of 63 type 1 diabetic patients with kidney disease. The baseline mean glomerular filtration rate (GFR) was 87 ml/min per 1.73 m2 and urinary albumin excretion 1141 mg/24 h. Patients with the highest compared with the lowest quartile of urinary NGAL at baseline had higher urinary KIM-1 levels and a significant decrease in their GFR each year. Using linear regression analysis, we found that elevated urinary NGAL and KIM-1 concentrations were associated with a faster decline in GFR, but not after adjustment for known promoters of progression. Urinary LFABP was not related to decline in GFR. Losartan treatment (100 mg/day) reduced urinary KIM-1 by 43% over a 12-month period. Thus, urine biomarker measurements in patients with type 1 diabetic nephropathy did not provide additional prognostic information to that of known progression promoters. [ABSTRACT FROM AUTHOR]

Reduction of urinary connective tissue growth factor by Losartan in type 1 patients with diabetic nephropathy.Background.Connective tissue growth factor (CTGF) is an important profibrotic cytokine implicated in development of diabetic glomerulosclerosis. Urinary CTGF is reported to be significantly increased in patients with diabetic nephropathy. The present study aimed to investigate the short- and long term effects of angiotensin II receptor blockade by Losartan on urinary CTGF levels in hypertensive type 1 diabetic patients with diabetic nephropathy.Methods.Seventy-one hypertensive type 1 diabetic patients with diabetic nephropathy were included in the study. After a washout period of 4 weeks, the patients received Losartan 50 mg, 100 mg, and 150 mg once daily in treatment periods each lasting 2 months. Thereafter, patients were followed prospectively during treatment with Losartan 100 mg o.d. with a total mean follow-up time of 36 months. At baseline, after 2, 4, and 6 months and then biannually, urinary and plasma CTGF levels[enzyme linked immunosorbent assay (ELISA) fibroGen], albuminuria (Turbidimetry), glomerular filtration rate (GFR)[51-creatinine ethylenediaminetetraacetic acid (51Cr-EDTA plasma clearance)] and 24 hours blood pressure (TM2420)) were determined.Results.Baseline levels of urinary and plasma CTGF were 7076 (5708 to 8770) ng/24 hours[geometric mean (95% CI)] and 12.7 (7.3) ng/mL[mean (SD)], respectively. Albuminuria, GFR, and arterial blood pressure at baseline were 1152 (937 to 1416) mg/24 hours, 88 (24) mL/min/1.73 m2, and 153/80 (17/9) mm Hg, respectively. Losartan significantly reduced urinary CTGF by 21% (9 to 31) (95% CI) initially (P<0.05 vs. baseline), with no further reduction after increasing dose. The sustained reduction in urinary CTGF was 22% (12 to 32) (P<0.05 vs. baseline). Rate of decline in GFR during the study was 3.2 (−1.6 to 15.9) mL/min/year[median (range)]. Reduction in urinary CTGF was correlated with a lower rate of decline in GFR (r= 0.23,P= 0.05). Plasma CTGF remained unchanged throughout the study.Conclusion.Our 3-year study demonstrates that Losartan persistently reduces urinary CTGF excretion, which is associated with a slower rate of decline in GFR. [ABSTRACT FROM AUTHOR]

Renoprotection with and without blood pressure reduction. AT1-receptor blockade dose dependently lowers blood pressure (BP) and albuminuria. Reduction of BP and albuminuria are independent treatment targets for renoprotection, but whether this requires similar dose titration is unknown. We tested this in two studies designed to find the optimal antialbuminuric dose of losartan in type 1 diabetic (DM, N = 50) and nondiabetic renal patients (ND, N = 12). After baseline, treatment followed with losartan 50, 100, and 150 mg/day, each dose for eight (DM) or six weeks (ND). At the end of each period, albuminuria (24-hour samples) and mean arterial pressure (MAP) were measured. Patients were divided into "good" and "poor" BP responders (BP+, BP-) according to BP response above or below group median. Baseline MAP in the BP- groups was 102 (97, 104) mm Hg in DM (median, 95% CI) and 91 (80, 108) mm Hg in ND. The top of the dose response for BP (obtained at losartan 100 mg) in the BP- groups was -2 (-4, 3) mm Hg in DM and –1 (-6, 2) mm Hg in ND, versus -15 (-18, -12) mm Hg and -16 (-26, -18) mm Hg in BP+ groups (both P < 0.05). Albuminuria was reduced dose dependently both in BP- and BP+: with 100 mg, the reduction in albuminuria in DM BP- was -32% (-49, 13) versus -45% (-60, -38) in DM BP+ and -45% (-70,-7) versus –25% (-58, -6) in ND BP- and BP+ (all P > 0.05). Moreover, in patients in whom BP fell below the recommended treatment target of 130/80 mm Hg (13 in DM and 10 in ND), albuminuria was progressively reduced, with further increasing the dose of losartan in most patients. Absence of BP response to losartan does not preclude a reduction in albuminuria, and optimal reduction of albuminuria may require titration beyond the predefined BP target. [ABSTRACT FROM AUTHOR]

Renoprotection with and without blood pressure reduction.Background.AT1-receptor blockade dose dependently lowers blood pressure (BP) and albuminuria. Reduction of BP and albuminuria are independent treatment targets for renoprotection, but whether this requires similar dose titration is unknown.Methods.We tested this in two studies designed to find the optimal antialbuminuric dose of losartan in type 1 diabetic (DM,N= 50) and nondiabetic renal patients (ND,N= 12). After baseline, treatment followed with losartan 50, 100, and 150 mg/day, each dose for eight (DM) or six weeks (ND). At the end of each period, albuminuria (24-hour samples) and mean arterial pressure (MAP) were measured. Patients were divided into“good” and“poor” BP responders (BP+, BP−) according to BP response above or below group median.Results.Baseline MAP in the BP− groups was 102 (97, 104) mm Hg in DM (median, 95% CI) and 91 (80, 108) mm Hg in ND. The top of the dose response for BP (obtained at losartan 100 mg) in the BP− groups was−2 (−4, 3) mm Hg in DM and–1 (−6, 2) mm Hg in ND, versus−15 (−18,−12) mm Hg and−16 (−26,−18) mm Hg in BP+ groups (bothP<0.05). Albuminuria was reduced dose dependently both in BP− and BP+: with 100 mg, the reduction in albuminuria in DM BP− was−32% (−49, 13) versus−45% (−60,−38) in DM BP+ and−45% (−70,−7) versus–25% (−58,−6) in ND BP− and BP+ (allP>0.05). Moreover, in patients in whom BP fell below the recommended treatment target of 130/80 mm Hg (13 in DM and 10 in ND), albuminuria was progressively reduced, with further increasing the dose of losartan in most patients.Conclusion.Absence of BP response to losartan does not preclude a reduction in albuminuria, and optimal reduction of albuminuria may require titration beyond the predefined BP target. [ABSTRACT FROM AUTHOR]

A simple and sensitive method has been developed and validated for purity determination of FF-MAS (also known as (3β,20R)-4,4-dimethylcholesta-8,14,24-trien-3-ol an endogenous substance usually present in the pre-ovulatory follicular fluid) at very low concentrations (200ng per unit) in pharmaceutical formulations containing RECOMBUMIN® (recombinant human albumin) as the matrix. The paper focuses on development of the sample preparation for the product containing recombinant human albumin.After removal of recombinant human albumin by precipitation using a mixture of water and ethanol, the FF-MAS was concentrated by evaporation using a vacuum centrifuge and the prepared sample was analyzed. The purity method was based on a reversed-phase high performance liquid chromatography (RP-HPLC) with ultraviolet absorption detection at 250nm.The method was validated according to ICH guidelines. The method indicated a significant degree of specificity with good selectivity and no significant effect from the matrix. The limit of detection was found to be 0.3–0.8% (depending on the impurity) corresponding to 1.9–5.1ng. The limit of quantification was found to be 0.8–2.5% (depending on the impurity) corresponding to 5.2–16ng. The recovery was found to be between 90 and 101% for the FF-MAS, and 100–129% for the six known impurities. The tested range for FF-MAS was from 320 to 960ng corresponding to 50–150% of the nominal concentration (640ng, injection volume is 100μl). The linearity of each compound (FF-MAS and the six impurities) was investigated. The squared correlation coefficient (r2) was 0.999 for FF-MAS (50–150% level) and 0.977–0.998 for the six known impurities (at four levels: 0.20, 0.50, 1.00, 2.00%). The R.S.D. in the repeatability study was found to be 9.2% for the total amount of impurities, and 10.4% for single impurities. The R.S.D. in the intermediate precision study was found to be 10.9% for total impurities, and 12.0% for single impurities.The validation results showed that the method was suitable for the purity analysis. The validated method was then ready for use for samples analysis of phase II clinical studies and the stability investigations of the pharmaceutical product. [Copyright &y& Elsevier]

OBJECTIVE — Irbesartan is renoprotective in patients with type 2 diabetes and microalbuminuria. Whether the observed reduction in microalbuminuria is reversible (hemodynamic) or persistent (glomerular structural/biochemical normalization) after prolonged antihypertensive treatment is unknown. Therefore, the present substudy of the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study (IRMA-2) investigated the reversibility of kidney function changes after withdrawal of 2 years' antihypertensive treatment. RESEARCH DESIGN AND METHODS — The substudy included 133 hypertensive type 2 diabetic patients with persistent microalbuminuria in IRMA-2, randomized to doublemasked treatment with either placebo, irbesartan 150 mg, or irbesartan 300 mg o.d. for 2 years. Arterial blood pressure, overnight urinary albumin excretion rate, and glomerular filtration rate (GFR) were determined repeatedly. RESULTS — Baseline characteristics were similar in the placebo, irbesartan 150-mg, and irbesartan 300-mg groups. At the end of the study, mean arterial blood pressure (MABP) was similarly lowered to 105 ± 2 (mean ± SE), 103 ± 2, and 102 ± 2 mmHg, respectively (P < 0.05 versus baseline), and urinary albumin excretion rate reduced by 8% (-16 to 27) (NS), 34% (95% CI 8-53), and 60% (46-70) (P < 0.05). Rates of decline in GFRwere 1.3 ± 0.7, 1.2 ± 0.7, and 1.0 ± 0.8 ml · min[sup -1] · 1.73 m[sup -2] per month, respectively, during the initial 3 months of the study and 0.3 ± 0.1, 0.3 ± 0.1, and 0.4 ± 0.1 ml · min[sup -2] · 1.73 m[sup -2] per month in the remaining study period. One month after withdrawal of all antihypertensive medication, MABP remained unchanged in the placebo group, 105 ± 2 mmHg, but increased significantly in the irbesartan groups, to 109 ± 2 and 108 ± 2 mmHg, respectively. Compared with baseline, urinary albumin excretion rate was increased by 14% (-17 to 54) in the placebo group and by 11% (-26 to 65) in the irbesartan 150-mg group but was persistently reduced by 47% (24-73) in the irbesartan 300-mg group (P < 0.05). GFR levels increased to baseline values in the placebo group and approached initial levels in irbesartan groups. CONCLUSIONS — Persistent reduction of microalbuminuria after withdrawal of all antihypertensive treatment suggests that high-dose irbesartan treatment confers long-term renoprotective effects. [ABSTRACT FROM AUTHOR]

Presents a study which evaluated the cost-effectiveness of fentanyl transdermal therapeutic system compared with that of sustained release-morphine in the long-term treatment of noncancer pain. Review of related literature; Methodology; Results and discussion.

Background: Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in diabetic patients. We tested whether dual blockade of the renin-angiotensin system (RAS) with both an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) is superior to maximal recommended dose of ACE inhibitor in type 1 diabetic patients with diabetic nephropathy (DN).Methods: We performed a randomized, double-blind, crossover trial with 8 weeks treatment with placebo and irbesartan 300 mg (once daily), added on top of enalapril 40 mg (once daily). We included 24 type 1 patients with DN. At the end of each treatment period, albuminuria, 24-hour blood pressure, and glomerular filtration rate (GFR) were measured.Results: Values on ACE inhibitors + placebo were: albuminuria [mean (95% CI)], 519 (342 to 789) mg/24 hours; blood pressure [mean (SEM)], 131 (3)/74 (1) mm Hg, and GFR [mean (SEM)], 65 (5) mL/min/1.73 m2. Dual blockade of the RAS induced a reduction in albuminuria [mean (95% CI)] of 25% (15, 34) (P < 0.001), a reduction in systolic blood pressure of 8 mm Hg (4, 12) (P = 0.002), and a reduction of 4 mm Hg (2, 7) (P = 0.003) in diastolic blood pressure. GFR and plasma potassium remained unchanged during both treatment regimes. Dual blockade was safe and well tolerated.Conclusion: Dual blockade of the RAS is superior to maximal recommended dose of ACE inhibitors with regard to lowering of albuminuria and blood pressure in type 1 patients with DN. Long-term trials are needed to further establish the role of dual blockade of the RAS in renal and cardiovascular protection. [ABSTRACT FROM AUTHOR]

Objective: Several observational follow-up studies have found that the D allele of the insertion (I)/deletion (D) polymorphism of the ACE gene (ACE/ID) is associated with an increased risk of renal function loss, even during ACE inhibition. Therefore, we investigated the long-term effect of the angiotensin II subtype-1 (AT1) receptor antagonist losartan (100 mg o.d.) on kidney function in II and DD type 1 diabetic patients with diabetic nephropathy.Research Design and Methods: A total of 54 hypertensive type 1 diabetic patients with diabetic nephropathy homozygous for the insertion (n = 26) or the deletion (n = 28) allele were included in the study. After a 4-week washout, the patients received losartan (tablet, 100 mg o.d.) and were followed prospectively with a mean follow-up period of 36 months. Patients and investigators were blinded to ACE genotypes. At baseline, after 2 and 4 months and every 6 months thereafter, glomerular filtration rate (GFR), albuminuria, and 24-h blood pressure were determined.Results: At baseline, GFR, albuminuria, and blood pressure were similar in the two genotype groups, II versus DD: mean (SD), 86 (22) vs. 88 (24) ml. min(-1). 1.73 m(-2); median (interquartile range), 1,134 (598-2,023) vs. 1,451 (893-1,766) mg/24 h; and mean (SD), 156/82 (17/9) vs. 153/80 (17/11) mmHg, respectively. GFR decreased similarly in both genotype groups, versus DD, respectively (P = 0.4): geometric mean (95% CI), 2.9 (2.0-4.2) vs. 3.4 (2.3-5.1) ml. min(-1). year(-1). Albuminuria and arterial blood pressure were significantly reduced during the study; no differences were noted between groups. During follow-up, albuminuria was decreased by 75% (95% CI 59-85) and 73% (56-83) in the II and DD groups, respectively (P < 0.01 vs. baseline). Mean systolic and diastolic blood pressures were 139/74 mmHg (14/8) in both genotype groups during the study (P < 0.01 vs. baseline).Conclusions: In contrast to previous observational studies with ACE inhibitors, long-term treatment with losartan has similar beneficial renoprotective effects on progression of diabetic nephropathy in hypertensive type 1 diabetic patients with ACE II and DD genotypes. [ABSTRACT FROM AUTHOR]

Renoprotective effects of losartan in diabetic nephropathy: Interaction with ACE insertion/deletion genotype? Background. The beneficial short- and long-term renoprotective effects of angiotensin I-converting enzyme (ACE) inhibition are lower in albuminuric diabetic patients homozygous for the deletion compared to the insertion polymorphism of the ACE gene. In an attempt to overcome this interaction, we evaluated the short-term renoprotective effect in diabetic nephropathy of the angiotensin II receptor antagonist losartan in patients homozygous for the insertion or the deletion allele. Methods. Fifty-four hypertensive type 1 diabetic patients with diabetic nephropathy homozygous for the insertion (I; N = 26) or the deletion (D; N = 28) allele of the ACE/ID polymorphism were included. After four weeks of washout, the patients received losartan 50 mg daily followed by 100 mg in two treatment periods each lasting two months. Patients and investigators were blinded to ACE genotypes. At baseline and in the end of the treatment periods, 24-hour blood pressure, albuminuria and glomerular filtration rate values were determined. Results. At baseline, blood pressure, albuminuria and glomerular filtration rate (GFR) values were similar in the two genotype groups [II vs. DD, 1134 (238 to 5302) vs. 1451 (227 to 8129) mg/24 h, median (range); 156/82 (17/9) vs. 153/80 (17/11) mm Hg, mean (SD); and 86 (22) vs. 88 (24) mL/min/1.73 m2 , respectively]. Both doses of losartan significantly lowered blood pressure, albuminuria, and GFR (P < 0.05 vs. baseline). Losartan 100 mg was more effective than 50 mg in reducing albuminuria, 51% (95% CI; 40 to 61) versus 33% (23 to 42), respectively (P < 0.01). No differences in the impact of losartan between the II and DD groups were observed: Losartan 100 mg lowered systolic/diastolic blood pressure by 12/6 and 10/4 mm Hg, whereas albuminuria decreased by 55% (35 to 68) and 46% (28 to 61), in the II and DD groups, respectively (P =... [ABSTRACT FROM AUTHOR]

Studies the glomerular permselectivity in early stages of overt diabetic neuropathy. Development of pathological levels of albuminuria; Neutralization of negatively charged electrostatic barrier within the glomerular capillary wall; Basis of an albumin excretion rate.

Role of patient factors in therapy resistance to antiproteinuric intervention in nondiabetic and diabetic nephropathy. Reduction of proteinuria is a prerequisite for successful long-term renoprotection. To investigate whether individual patient factors are determinants of antiproteinuric efficacy, we analyzed individual responses to different modes of antiproteinuric intervention in nondiabetic and diabetic patients, obtained in prior studies comparing the efficacy of various pharmacological regimens. The individual antiproteinuric response to angiotensin-converting enzyme (ACE) inhibition positively correlated to the response to angiotensin type I (AT1) receptor blockade in diabetic (r = 0.67, P < 0.01, N = 16) as well as nondiabetic patients (r = 0.75, P < 0.01, N = 12). This corresponded to the correlations for antihypertensive efficacy between ACE inhibition and AT1 receptor blockade in diabetic (r = 0.73, P < 0.001) as well as nondiabetic patients (r = 0.55, P < 0.05). Remarkably, the antiproteinuric response to ACE inhibition also correlated positively to the antiproteinuric response to indomethacin (r = 0.63, P < 0.05, N = 9). Thus, patients responding favorably to one class of antiproteinuric drugs also respond favorably to other classes of available drugs, supporting a main role for individual patient factors in responsiveness or resistance to antiproteinuric intervention. In the search for strategies to improve response in these high risk patients, combination-treatment (combining different drugs, and combining drugs with dietary measures like sodium and protein restriction), and the use of higher doses may provide more fruitful strategies to optimize renoprotection than shifting to other classes of the available drugs. [ABSTRACT FROM AUTHOR]

Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy. Background. Angiotensin I-converting enzyme (ACE) inhibitors reduce angiotensin II formation and induce bradykinin accumulation. Animal studies suggest that bradykinin may play a role for the effects of ACE inhibition on blood pressure and kidney function. Therefore, we compared the renal and hemodynamic effects of specific intervention in the renin-angiotensin system by blockade of the angiotensin II subtype-1 receptor to the effect of ACE inhibition. Methods. A randomized, double-blind, cross-over trial was performed in 16 type 1 diabetic patients (10 men), age 42 ± 2 years (mean ± sem). The study consisted of five periods, each lasting two months. The patients received losartan 50 mg, losartan 100 mg, enalapril 10 mg, enalapril 20 mg, and placebo in random order. At the end of each period, albuminuria, 24-hour blood pressure, and glomerular filtration rate (GFR) were determined. Results. Both doses of losartan and enalapril reduced albuminuria (P < 0.05) and mean arterial blood pressure (MABP; P < 0.05), whereas GFR remained stable. Albuminuria was reduced by 33% (95% CI, 12 to 51) on losartan 50 mg, 44% (95% CI, 26 to 57) on losartan 100 mg, 45% (95% CI, 23 to 61) on enalapril 10 mg, and 59% (95% CI, 39 to 72) on enalapril 20 mg, and MABP fell by 9 ± 2, 8 ± 2, 6 ± 3, and 11 ± 3 mm Hg (mean ± sem), respectively. No significant differences were found between the effects of losartan 100 mg and enalapril 20 mg. HbA1C and sodium intake remained unchanged throughout the study, whereas a significant rise in serum potassium occurred during ACE inhibition. Conclusion. The angiotensin II subtype 1 receptor antagonist, losartan, reduces albuminuria and MABP similar to the effect of ACE inhibition. These results indicate that the reduction in albuminuria and blood pressure during ACE inhibition is primarily... [ABSTRACT FROM AUTHOR]

Simple Summary: The ringed seal is part of the daily diet for local Inuits in Greenland, and therefore, the contents of trace elements are being monitored bi-annually under the AMAP CORE Programme. In this study Hg, Cd and Se concentrations were measured in ringed seal livers, along with pathological changes in both the liver and the kidneys of the seals. The oldest seals had the highest concentrations of the three trace elements, while the content was the same in both sexes. In more than half of the livers, we found mononuclear cell infiltration (94.7%) and portal cell infiltration (68.4%), while glomerular mesangial deposits (54.1%) were the predominant finding in the kidney. Ringed seals are consumed in Greenland and are therefore included as a key biomonitoring species with the focus on pollution exposure and health effects. Ringed seals in Central West Greenland (Qeqertarsuaq) and in North West Greenland (Qaanaaq) were analyzed for metal concentrations in the liver and histological changes in the liver and kidney. The mean liver concentration of mercury in Qaanaaq was 3.73 ± 5.01 µg/g ww (range: 0.28–23.29 µg/g ww), and the mean cadmium concentration was 7.80 ± 8.95 µg/g ww (range: 0.013–38.79 µg/g ww). For Qeqertarsuaq, the liver concentration of mercury was 1.78 ± 1.70 µg/g ww (range: 0.45–8.00 µg/g ww) and the mean cadmium concentration was 11.58 ± 6.32 µg/g ww (range: 0.11–25.45 µg/g ww). Age had a positive effect on the liver concentrations of metals, while no effect was found for sex or histological changes. The prevalence of histological changes in liver tissue decreased in the following order: random pattern mononuclear cell infiltration (92.1%), portal cell infiltration (68.4%), hepatic intracellular fat (18.4%), portal fibrosis (7.9%), focal hepatic fibrosis (7.9%), bile duct hyperplasia/fibrosis (7.9%) and lipid granuloma (2.6%). For kidney tissue, the prevalence of histological changes decreased in the following order: glomerular mesangial deposits (54.1%) > glomerular basement membrane thickening (45.9%) > THD (40%) > tubular hyaline casts (14.0%) > glomerular atrophy (13.5%) > dilated tubules (13.5%) > glomerular hyper-cellularity (10.8%) > mononuclear cell infiltrations (8.1%). [ABSTRACT FROM AUTHOR]

Background: Rapid and accurate detection of pathogens is needed in community-acquired pneumonia (CAP) to enable appropriate antibiotics and to slow the development of antibiotic resistance. We aimed to compare the effect of point-of-care (POC) polymerase chain reaction (PCR) detection of respiratory pathogens added to standard care with standard care only (SCO) on antibiotic prescriptions after acute hospital admission. Methods and findings: We performed a superiority, parallel-group, open-label, multicentre, randomised controlled trial (RCT) in 3 Danish medical emergency departments (EDs) from March 2021 to February 2022. Adults acutely admitted with suspected CAP during the daytime on weekdays were included and randomly assigned (1:1) to POC-PCR (The Biofire FilmArray Pneumonia Panel plus added to standard care) or SCO (routine culture and, if requested by the attending physician, target-specific PCR) analysis of respiratory samples. We randomly assigned 294 patients with successfully collected samples (tracheal secretion 78.4% or expectorated sputum 21.6%) to POC-PCR (n = 148, 50.4%) or SCO (146, 49.6%). Patients and investigators owning the data were blinded to the allocation and test results. Outcome adjudicators and clinical staff at the ED were not blinded to allocation and test results but were together with the statistician, blinded to data management and analysis. Laboratory staff performing standard care analyses was blinded to allocation. The study coordinator was not blinded. Intention-to-treat and per protocol analysis were performed using logistic regression with Huber–White clustered standard errors for the prescription of antibiotic treatment. Loss to follow-up comprises 3 patients in the POC-PCR (2%) and none in the SCO group. Intention-to-treat analysis showed no difference in the primary outcome of prescriptions of no or narrow-spectrum antibiotics at 4 h after admission for the POC-PCR (n = 91, 62.8%) odds ratio (OR) 1.13; (95% confidence interval (CI) [0.96, 1.34] p = 0.134) and SCO (n = 87, 59.6%). Secondary outcomes showed that prescriptions were significantly more targeted at 4-h OR 5.68; (95% CI [2.49, 12.94] p < 0.001) and 48-h OR 4.20; (95% CI [1.87, 9.40] p < 0.001) and more adequate at 48-h OR 2.11; (95% CI [1.23, 3.61] p = 0.006) and on day 5 in the POC-PCR group OR 1.40; (95% CI [1.18, 1.66] p < 0.001). There was no difference between the groups in relation to intensive care unit (ICU) admissions OR 0.54; (95% CI [0.10, 2.91] p = 0.475), readmission within 30 days OR 0.90; (95% CI [0.43, 1.86] p = 0.787), length of stay (LOS) IRR 0.82; (95% CI [0.63, 1.07] p = 0.164), 30 days mortality OR 1.24; (95% CI [0.32, 4.82] p = 0.749), and in-hospital mortality OR 0.98; (95% CI [0.19, 5.06] p = 0.986). Conclusions: In a setting with an already restrictive use of antibiotics, adding POC-PCR to the diagnostic setup did not increase the number of patients treated with narrow-spectrum or without antibiotics. POC-PCR may result in a more targeted and adequate use of antibiotics. A significant study limitation was the concurrent Coronavirus Disease 2019 (COVID-19) pandemic resulting in an unusually low transmission of respiratory virus. Trial registration: ClinicalTrials.gov (NCT04651712). In this multicentre randomised controlled trial, Mariana Bichuette Cartuliares and colleagues evaluate point-of-care multiplex polymerase chain reaction in antibiotic treatment of patients acutely admitted with suspected community-acquired pneumonia in Denmark. Author summary: Why was this study done?: The global rise in antimicrobial resistance fueled by the excessive use and misuse of antibiotics is a major public health concern. Fast and accurate diagnostics is important to counteract this development as it can potentially reduce the use of antibiotics/broad-spectrum antibiotics without sacrificing patient safety. Pneumonia is a common, serious condition where available point-of-care (POC) technology (polymerase chain reaction) allows clinicians to detect possible airway pathogens before treatment decisions are made. What did the researchers do and find?: In this randomised trial of 294 patients admitted with suspected pneumonia, POC did not result in the prescription of less antibiotics or less broad-spectrum antibiotics within 4 h after admission. Based on a subset of patients, the results indicated that more patients in the POC-group were treated with targeted or appropriate antibiotics 48 h and 5 days after admission. Patients in the POC-group had a non-statistically significant reduction in length of hospital stay of approximately 1 day. What do these findings mean?: The use of respiratory POC does not seem to be an effective tool for reducing the use of antibiotics in a setting with a very low level of antimicrobial resistance and already prudent use of antibiotics. The use of respiratory POC may aid to ensure a targeted and/or appropriate treatment in a setting with a restrictive use of antibiotics—and thereby may aid to sustain a restrictive strategy. The concurrent Coronavirus Disease 2019 (COVID-19) pandemic and the unusually low transmission of common respiratory viruses in the period may have affected the results. [ABSTRACT FROM AUTHOR]

The article reports on a case of a pyosalpinx caused by Salmonella Newport. It describes the patient. It presents the findings of histologic diagnosis. It offers treatment options for the disease. Recovery was uncomplicated and it was impossible to trace the origin of the infection. The case shows that genital salmonellosis is possible even in a woman without any preoperatively known risk factors.

Presents a response by Steen Andersen, Jens Bröchner-Mortensen and Hans-Henrik Parving to a letter to the editor about the article on kidney function during and after withdrawal of long-term irbesartan treatment in patients with type 2 diabetes and microalbuminuria.

Investigates the effects of angiotensin II receptor blockade in hypertensive type 1 diabetic patients with diabetic nephropathy homozygous for the insertion or deletion allele of the angiotensin converting enzyme (ACE)/ID polymorphism. Interaction between ACE/ID genotypes and ACE inhibition.

Identification of the bacterial etiology of lower respiratory tract infections (LRTI) is crucial to ensure a narrow-spectrum, targeted antibiotic treatment. However, Gram stain and culture results are often difficult to interpret as they depend strongly on sputum sample quality. We aimed to investigate the diagnostic yield of Gram stain and culture from respiratory samples collected by tracheal suction and expiratory technique from adults admitted with suspected community-acquired LRTI (CA-LRTI). In this secondary analysis of a randomized controlled trial, 177 (62%) samples were collected by tracheal suction, and 108 (38%) by expiratory technique. We detected few pathogenic microorganisms, and regardless of sputum quality, there were no significant differences between the sample types. Common pathogens of CA-LRTI were identified by culture in 19 (7%) samples, with a significant difference between patients with or without prior antibiotic treatment (p = 0.007). The clinical value of sputum Gram stain and culture in CA-LRTI is therefore questionable, especially in patients treated with antibiotics. [ABSTRACT FROM AUTHOR]

Role of patient factors in therapy resistance to antiproteinuric intervention in nondiabetic and diabetic nephropathy. Reduction of proteinuria is a prerequisite for successful long-term renoprotection. To investigate whether individual patient factors are determinants of antiproteinuric efficacy, we analyzed individual responses to different modes of antiproteinuric intervention in nondiabetic and diabetic patients, obtained in prior studies comparing the efficacy of various pharmacological regimens. The individual antiproteinuric response to angiotensin-converting enzyme (ACE) inhibition positively correlated to the response to angiotensin type I (AT1) receptor blockade in diabetic ( r = 0.67, P < 0.01, N = 16) as well as nondiabetic patients ( r = 0.75, P < 0.01, N = 12). This corresponded to the correlations for antihypertensive efficacy between ACE inhibition and AT1 receptor blockade in diabetic ( r = 0.73, P < 0.001) as well as nondiabetic patients ( r = 0.55, P < 0.05). Remarkably, the antiproteinuric response to ACE inhibition also correlated positively to the antiproteinuric response to indomethacin ( r = 0.63, P < 0.05, N = 9). Thus, patients responding favorably to one class of antiproteinuric drugs also respond favorably to other classes of available drugs, supporting a main role for individual patient factors in responsiveness or resistance to antiproteinuric intervention. In the search for strategies to improve response in these high risk patients, combination-treatment (combining different drugs, and combining drugs with dietary measures like sodium and protein restriction), and the use of higher doses may provide more fruitful strategies to optimize renoprotection than shifting to other classes of the available drugs. [ABSTRACT FROM AUTHOR]

Microbiological diagnostics of good-quality sputum samples are fundamental for infection control and targeted treatment of lower respiratory tract infections (LRTI). This study aims to compare the expiratory technique and tracheal suction on the quality of sputa from adults acutely hospitalized with suspected LRTI. We performed an open-label, randomized controlled trial. Patients were randomized to sputum sampling by tracheal suction (standard care) or the expiratory technique. The primary outcome was quality of sputum evaluated by microscopy and was analysed in the intention-to-treat population. The secondary outcomes were adverse events and patients experience. In total, 280 patients were assigned to tracheal suction (n = 141, 50.4%) or the expiratory technique (n = 139, 49.6%). Sputum samples were collected from 122 (86.5%) patients with tracheal suction and 67 (48.2%) patients with expiratory technique. Good-quality sputa were obtained more often with tracheal suction than with expiratory technique (odds ratio 1.83 [95% CI 1.05 to 3.19]; p = 0.035). There was no statistical difference in adverse events (IRR 1.21 [95% CI, 0.94 to 1.66]; p = 0.136), but patient experience was better in the expiratory technique group (p < 0.0001). In conclusion, tracheal suction should be considered a routine procedure in emergency departments for patients with suspected LRTI. [ABSTRACT FROM AUTHOR]

Background: Azole resistance complicates treatment of patients with invasive aspergillosis with an increased mortality. Azole resistance in Aspergillus fumigatus is a growing problem and associated with human and environmental azole use. Denmark has a considerable and highly efficient agricultural sector. Following reports on environmental azole resistance in A. fumigatus from Danish patients, the ministry of health requested a prospective national surveillance of azole‐resistant A. fumigatus and particularly that of environmental origin. Objectives: To present the data from the first 2 years of the surveillance programme. Methods: Unique isolates regarded as clinically relevant and any A. fumigatus isolated on a preferred weekday (background samples) were included. EUCAST susceptibility testing was performed and azole‐resistant isolates underwent cyp51A gene sequencing. Results: The azole resistance prevalence was 6.1% (66/1083) at patient level. The TR34/L98H prevalence was 3.6% (39/1083) and included the variants TR34/L98H, TR343/L98H and TR34/L98H/S297T/F495I. Resistance caused by other Cyp51A variants accounted for 1.3% (14/1083) and included G54R, P216S, F219L, G54W, M220I, M220K, M220R, G432S, G448S and Y121F alterations. Non‐Cyp51A‐mediated resistance accounted for 1.2% (13/1083). Proportionally, TR34/L98H, other Cyp51A variants and non‐Cyp51A‐mediated resistance accounted for 59.1% (39/66), 21.2% (14/66) and 19.7% (13/66), respectively, of all resistance. Azole resistance was detected in all five regions in Denmark, and TR34/L98H specifically, in four of five regions during the surveillance period. Conclusion: The azole resistance prevalence does not lead to a change in the initial treatment of aspergillosis at this point, but causes concern and leads to therapeutic challenges in the affected patients. [ABSTRACT FROM AUTHOR]

Abstract: Der königliche Komplex in Jelling mit seinen monumentalen Verweisen auf königliche Macht und Christianisierung ist als bedeutender Schlüsselort für die archäologische wie historische Deutung des politischen und religiösen Wandels im skandinavischen Raum am Ende der Wikingerzeit zu verstehen. In den letzten Jahren erfolgte eine Neubewertung der Denkmäler und ihrer Umgebung auf Basis neuer umfangreicher Ausgrabungen und damit auch der in einem Zeitraum von gut zweihundert Jahren akkumulierten Forschungsergebnisse. Diese jüngsten Untersuchungen erlaubten abweichende Deutungen zum bislang bekannten Charakter des Fundplatzes, konnten doch hochinteressante neue strukturelle Elemente erkannt werden, darunter ein von Palisaden umgrenztes Areal mit einer Fläche von 12,5 ha sowie Gebäuden des Trelleborg-Typs, vergleichbar mit den Hauptgebäuden der Ringburgen König Harald Blauzahns. Jene Neuentdeckungen ließen die Historie des Platzes in einem neuen Licht erscheinen, führten aber auch zu veränderten Deutungen der im 10. Jahrhundert nachweisbaren Umwandlungsprozesse im südlichen Skandinavien sowie der Rolle, die Jelling und die hiesigen Könige dabei spielten. Abstract: Le complexe royal de Jelling, avec ses références au pouvoir royal et à la christianisation, forme un site clé dans l'explication archéologique et historique des transformations politiques et religieuses du monde scandinave à la fin de l'époque des Vikings. Ces dernières années, les monuments et leurs alentours ont fait l'objet de nouvelles fouilles extensives, et les données existantes, recueillies au long de deux siècles de recherche sur ce site, ont été réévaluées. Ces investigations ont profondément modifié nos connaissances du caractère de ce complexe, car elles révèlent de nouveaux éléments architecturaux tels qu'une palissade de 12,5 ha et des bâtiments de type Trelleborg comparables aux forteresses circulaires du roi Harald Blaatand («Dent bleue»). Ces découvertes incitent à réinterpréter le développement du site, ce qui a des implications sur la discussion des processus de transformation qui eurent lieu au 10e siècle dans le sud de la Scandinavie et du rôle qu'y jouèrent les rois de Jelling. Abstract: The royal complex at Jelling with its monumental references to royal power and Christianization stands as a key site in the archaeological and historical explanation of the political and religious transformations of the Scandinavian world at the end of the Viking Age. In recent years, the monuments and their surroundings have been subject to renewed, extensive excavations and the existing data from the two-centuries-long research history of the site have been re-evaluated. These investigations have significantly altered our knowledge of the character of the monument complex as they present new structural elements including a 12.5 ha palisade enclosure and buildings of Trelleborg-type comparable to the main buildings of King Harald Bluetooth's ring fortresses. Such findings incite reinterpretations of the development of the site which have implications for the discussion of the transformation processes that took place in 10th-century South Scandinavia and the role which Jelling and the Jelling kings played therein. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- Levels of connective tissue growth factor (CTGF; CCN-2) in plasma are increased in various fibrotic disorders, including diabetic nephropathy. Recently, several articles have reported a strong increase of urinary CTGF excretion (U-CTGF) in patients with diabetic nephropathy. However, these studies addressed too small a number of patients to allow general conclusions to be drawn. Therefore, we evaluated U-CTGF in a large cross-sectional study of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS -- Subjects were 318 type 1 diabetic patients and 29 normoglycemic control subjects. U-CTGF was measured by sandwich enzyme-linked immunosorbent assay. Groups were compared by Kruskal-Wallis and Mann-Whitney analysis. The relation between U-CTGF and markers of diabetic nephropathy was determined by regression analysis. RESULTS -- U-CTGF in patients with diabetic nephropathy (n = 89, median 155 pmol/24 h [interquartile range 96-258]) was significantly higher than in microalbuminuric (n = 79, 100 [65-78]) and normoalbuminuric (n = 150, 85 [48-1271) patients and control subjects (n = 29, 100 [78-1141). U-CTGF correlated with urinary albumin excretion (UAE) (R = 0.31) and glomerular filtration rate (R = -0.38) in patients with diabetic nephropathy. A standardized increase in U-CTGF was associated with diabetic nephropathy (odds ratio 2.3 [95% CI 1.7-3.1]), which was comparable with the odds ratios for diabetic nephropathy of increased HbA[sub 1c] (2.0 [1.5-2.7]), and blood pressure (2.0 [1.5-2.61). CONCLUSIONS -- This is the first large cross-sectional study addressing U-CTGF in human type 1 diabetes. The observed association of U-CTGF with UAE and glomerular filtration rate might reflect a role of CTGF as progression promoter in diabetic nephropathy. [ABSTRACT FROM AUTHOR]

A stability-indicating liquid chromatographic method for the determination of degradation products and impurities in Vagifem®, estradiol vaginal tablets has been developed and validated. Vagifem® is a low dose preparation containing only 25 μg 17β-estradiol in a tablet matrix of 80 mg (a drug to excipient ratio of 1:3200). This paper presents the rationale for the optimization of the sample preparation in order to minimize placebo interference as well as validation data for linearity, accuracy, precision, ruggedness, specificity and limits of detection and quantification. Data shows that the method is suitable for routine analysis of minute amounts of estradiol impurities. [Copyright &y& Elsevier]

OBJECTIVE -- Irbesartan was renoprotective independently of its blood pressure-lowering effect in the Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria (IRMA2) study. However, blood pressure was evaluated by trough office blood pressure (OBP), which may underestimate reductions in 24-h ambulatory blood pressure (ABP). In the present study, we evaluated 24-h blood pressure patterns in a subpopulation of the IRMA2 trial. RESEARCH DESIGN AND METHODS -- Type 2 diabetic patients (n = 43) with persistent microalbuminuria (as determined by repeated overnight measurements of urinary albumin excretion [UAE]) and hypertension who were included in the IRMA2 study at the Steno Diabetes Center were subjected to 24-h ABP (Takeda, TM2420) measurements before and 2 years after randomization to placebo (n = 15), irbesartan 150 mg daily (Irb150; n = 13), or irbesartan 300 mg daily (Irb300; n = 15). RESULTS -- At baseline, the placebo, Irb150, and Irb300 groups were comparable: OBP: 157 ± 15/89 ± 7, 156 ± 15/91 = 11, and 159 ± 16/90 ± 9 mmHg (NS); 24-h ABP: 148 ± 13/83 ± 11, 148 ± 16/82 ± 7 and 147 ± 16/81 ± 10 mmHg (NS); and UAE (geometric mean with 95% CI): 43 (32-57), 46 (30-70), and 59 (42-85) µg/min (NS), respectively. We found that 2 years after randomization, OBP was significantly reduced in all three groups (by 11/7, 13/8, and 13/8 mmHg in the placebo, Irb150, and Irb300 groups, respectively), but that there were no significant differences among groups. Reductions in 24-h ABP were similar in the three groups (11/10, 5/7, and 7/8 mmHg, respectively; NS), as were reductions in day ABP (11/9, 7/7, and 8/9 mmHg, respectively; NS) and night ABP (4/11, 7/7, and 3/3 mmHg, respectively; NS). The reduction in UAE at the end of the study was 0% (-86 to 42), 38% (- 14 to 66), and 73% (59 to 82), respectively (overall, P < 0.01). CONCLUSION -- Irbesartan is renoprotective independently of its beneficial effect in lowering 24-h blood pressure in patients with type 2 diabetes and persistent microalbuminuria. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between treatment-induced change in continuous glucose monitoring (CGM) time in range (TIR) and albuminuria in persons with type 1 diabetes (T1D) treated with sensor-augmented insulin pumps (SAP).Research Design and Methods: Twenty-six out of 55 participants with albuminuria and multiple daily injection therapy (25% females; median 51 [interquartile range 46-63] years of age; glycated hemoglobin A1c (HbA1c) 75 [68-88] mmol/mol [9.0% (8.4-10.4%)]; and urinary albumin-to-creatinine ratio (UACR) 89 [37-250] mg/g) were in a randomized controlled trial assigned to SAP therapy for 1 year. Anthropometrics, CGM data, and blood and urine samples were collected every 3 months.Results: Mean change (95% CI) in percentage of TIR (%TIR) was 13.2% (6.2; 20.2), in HbA1c was -14.4 (-17.4; -10.5) mmol/mol (-1.3% [-1.6; -1.0]), and in UACR was -15% (-38; 17) (all P < 0.05). UACR decreased by 19% (10; 28) per 10% increase in %TIR (P = 0.04), 18% (1; 30) per 10 mmol/mol decrease in HbA1c (P = 0.07), and 31% per 10-mmHg decrease in mean arterial pressure (P < 0.001).Conclusions: In this longitudinal study, treatment-induced increase in %TIR was significantly associated with decrease in albuminuria in T1D. [ABSTRACT FROM AUTHOR]

For the first time in > 30 years of routine sampling under the Arctic Monitoring and Assessment Program, a parasite was found in the liver of ringed seals (Phoca hispida) collected near Qaanaaq (Thule), Northwest Greenland, in 2008 and 2014. Concerns regarding changes to parasite occurrence, possibly related to climate change and bioaccumulation of immunomodulating anthropogenic pollutants, spurred further investigations into parasite characterization, and implications for wildlife health and seal hunters. Microscopic, molecular, and morphometric analyses are presented herein. Of 40 seals, 6 (15%) were infected, and 5 of 6 of these seals had severe infections. The parasite was identified morphologically as Orthosplanchnus arcticus Odhner, 1905 (Trematoda; Digenea: Brachycladiidae). Macro- and microscopic pathologic study indicated mild-to-severe biliary hyperplasia associated, stasis associated, and fibrosis associated with trematode infections. Molecular analysis of the trematode confirmed its classification within the Brachycladiidae using sequencing and comparing Internal Transcribed Spacer-1, mitochondrial-NADH Dehydrogenase 3, 18S ribosomal DNA, and Cyclooxygenase-1 regions. This is the first ever report of O. arcticus in ringed seals from Qaanaaq and is one of the most northern records of this parasite. We found significant liver pathology in severely infected seals, but its effects on health of seals in this population are unknown. Host-specificity and the lifecycle of O. arcticus are unknown, but transmission may involve subsistence and commercially harvested Arctic fish species. Further work is needed to answer these questions. Surveying parasites in Arctic wildlife is important in order to assess potential effects on wildlife and human health (i.e., zoonoses). [ABSTRACT FROM AUTHOR]

Background: Individual patients show a large variability in albuminuria response to angiotensin receptor blockers (ARB). Identifying novel biomarkers that predict ARB response may help tailor therapy. We aimed to discover and validate a serum metabolite classifier that predicts albuminuria response to ARBs in patients with diabetes mellitus and micro- or macroalbuminuria.Methods: Liquid chromatography-tandem mass spectrometry metabolomics was performed on serum samples. Data from patients with type 2 diabetes and microalbuminuria (n = 49) treated with irbesartan 300 mg/day were used for discovery. LASSO and ridge regression were performed to develop the classifier. Improvement in albuminuria response prediction was assessed by calculating differences in R(2) between a reference model of clinical parameters and a model with clinical parameters and the classifier. The classifier was externally validated in patients with type 1 diabetes and macroalbuminuria (n = 50) treated with losartan 100 mg/day. Molecular process analysis was performed to link metabolites to molecular mechanisms contributing to ARB response.Results: In discovery, median change in urinary albumin excretion (UAE) was -42 % [Q1-Q3: -69 to -8]. The classifier, consisting of 21 metabolites, was significantly associated with UAE response to irbesartan (p < 0.001) and improved prediction of UAE response on top of the clinical reference model (R(2) increase from 0.10 to 0.70; p < 0.001). In external validation, median change in UAE was -43 % [Q1-Q35: -63 to -23]. The classifier improved prediction of UAE response to losartan (R(2) increase from 0.20 to 0.59; p < 0.001). Specifically ADMA impacting eNOS activity appears to be a relevant factor in ARB response.Conclusions: A serum metabolite classifier was discovered and externally validated to significantly improve prediction of albuminuria response to ARBs in diabetes mellitus. [ABSTRACT FROM AUTHOR]

Aims: To investigate the relationship between arterial stiffness and insulin treatment mode [continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI)] in type 1 diabetes patients. Methods: Cross-sectional study, from 2009 to 2011, including 601 Caucasian type 1 diabetes patients, 58 and 543 treated with CSII and MDI, respectively. Arterial stiffness was measured as pulse wave velocity (PWV) (SphygmoCor, AtCor Medical). Adjustment included gender, age, diabetes duration, HbA, heart rate, mean arterial pressure, P-creatinine, urinary albumin excretion rate (UAER), smoking, total daily insulin dose, antihypertensive treatment, previous cardiovascular disease (CVD), total cholesterol and statin treatment. Albuminuria was UAER ≥30 mg/24-h, and CVD included myocardial infarction, revascularization, peripheral arterial disease and stroke. Results: CSII- versus MDI-treated patients were 48 versus 57 % men, 51 ± 11 versus 54 ± 13 years old (mean ± SD), had 33 ± 12 versus 32 ± 16 years diabetes duration and HbA 7.8 ± 0.9 % (62 ± 10 mmol/mol) versus 8.0 ± 1.2 % (64 ± 13 mmol/mol) ( P ≥ 0.08 for all). PWV was lower in CSII- versus MDI-treated patients (9.3 ± 2.8 vs. 10.4 ± 3.4 m/s; P = 0.016). In fully adjusted analysis, CSII treatment was significantly ( P = 0.038) associated with lower PWV, whereas HbA-level was not ( P = 0.93). Conclusions: In type 1 diabetes patients, CSII treatment was associated with lower arterial stiffness independent of other risk factors, while HbA was not. Although glucose variability was not assessed, our results suggest that glucose variability and not HbA-level affect arterial stiffness. This needs confirmation in randomised prospective studies. [ABSTRACT FROM AUTHOR]

Abstract: Context: Breakthrough pain is common in patients with cancer and is a significant cause of morbidity in this group of patients. Objectives: The aim of this study was to characterize breakthrough pain in a diverse population of cancer patients. Methods: The study involved 1000 cancer patients from 13 European countries. Patients were screened for breakthrough pain using a recommended diagnostic algorithm and then questioned about the characteristics and management of their pain. Results: Of the 1000 patients, 44% reported incident pain, 41.5% spontaneous pain, and 14.5% a combination. The median number of episodes was three a day. The median time to peak intensity was 10 minutes, with the median for patients with incident pain being five minutes (P < 0.001). The median duration of untreated episodes was 60 minutes, with the median for patients with incident pain being 45 minutes (P = 0.001). Eight hundred six patients stated that pain stopped them doing something, 66 that it sometimes stopped them doing something, and only 107 that it did not interfere with their activities. Patients with incident pain reported more interference with walking ability and normal work, whereas patients with spontaneous pain reported more interference with mood and sleep. As well, 65.5% of patients could identify an intervention that improved their pain (29.5%, pharmacological; 23%, nonpharmacological; 12%, combination). Regarding medications, 980 patients were receiving an opioid to treat their pain, although only 191 patients were receiving a transmucosal fentanyl product licensed for the treatment of breakthrough pain. Conclusion: Breakthrough cancer pain is an extremely heterogeneous condition. [Copyright &y& Elsevier]

Abstract: The implementation of Fuel Cell (FC) systems in transportation systems, as aircrafts, requires some better understanding and mastering of the new generator behaviours in low temperature environments. To this end, a PEMFC stack is tested and characterised in a climatic chamber. The impacts of the low temperatures over different FC operation and start-up conditions are estimated using a specific test bench developed in-lab. Some descriptions concerning the test facilities and the experimental set-up are given in the paper, as well as some information about the test procedures applied. Some examples of test results are shown and analysed. The experiments are derived from aircraft requirements and are related with different scenarios of airplane operation. Finally, some assessments concerning the FC system behaviour in low temperature conditions are made, especially with regard to the constraints to be encountered by the next embedded FC generators. [Copyright &y& Elsevier]

Abstract: Arctic seals are known to accumulate relatively high concentrations of potential toxic heavy metals in their vital organs, such as livers and kidneys, as well as in their central nervous system. We therefore decided to determine whether mercury, copper, cadmium and zinc levels in liver, kidney and brain tissues of three Arctic seal species were associated with the intracellular metal-binding protein metallothionein (MT) as a sign of toxic exposure. Samples from four ringed (Phoca hispida), five harp (P . groenlandica) and five hooded (Cystophora cristata) seals taken during field trips to Central West Greenland (Godhavn) and the Barents Sea in the spring of 1999 were used for the present study. In all three seal species concentrations of mercury, zinc and copper were highest in the liver, except for cadmium which was highest in the kidneys. Metal concentrations increased significantly in the order: ringed seal

Abstract: The implementation of fuel cells (FC) in transportation systems, as airplanes, requires some better understanding and mastering of their mechanical behaviours in vibrating environments. To this end, a FC stack is tested on a vibrating platform and characterised on the three geometric axes of the equipment. The impacts over the stack assembly of sine excitations with different frequencies and magnitudes are estimated using various accelerometers placed on different locations of the FC surface. Leak checks are also performed in order to verify that no malfunctions occur in the stack. In this first part, some descriptions concerning the test facilities and the experimental setup are given, as well as some information about the mechanical test procedure applied. Some frequency – acceleration diagrams resulting from the experiments are shown and analysed. Finally, some assessments concerning the stack behaviour in vibrating conditions are made. [Copyright &y& Elsevier]

Abstract: There is a great need for understanding the impact from dietary OHCs (organohalogen compounds) on bone mineral composition – and thereby osteoporosis – in especially arctic wildlife such as polar bears (Ursus maritimus) as well as humans. For that purpose, we measured BMD (bone mineral density) by DXA scanning (g/cm−2) in 15 age and weight normalized sledge dog (Canis familiaris) bitches and their 26 pups divided into a control group (n =26) given 50–200 g/day clean pork (Suis scrofa) fat and a treated group (n =15) given 50–200 g/day OHC polluted minke whale (Balaenoptera acutorostrata) blubber as main lipid sources. The results showed that BMD increased significantly with age (linear regression: p <0.0001, r 2 =0.83, n =41) while no sex difference was found in the F-generation (two-way ANOVA: all p >0.3). No differences in BMDfemur or BMDvertebrae between exposed and control individuals in the bitch generation were found (linear mixed effect model: both p >0.38). Likewise, no difference between exposed and control subadults and juveniles in the F-generation was found (two-way ANOVA: all p >0.33). Correlation analyses between BMDfemur, BMDvertebrae and groups of OHCs, respectively, did not show any statistically significant relationships nor a clear or decreasing trend (Pearson''s: p: 0.07–0.78; r: −0.2–0.59; n: 10–18). As the groups were similar regarding genetics, age and sex are the only factors that can explain this observation. Either the pollutants did not have an impact on BMD using the present time frame and OHC concentrations (threshold levels not reached), or the difference in food composition (mainly vitamins and n3 fatty acids) conceal the potential OHC impact on BMD. Such information is important when evaluating the positive and negative health consequences from eating polluted marine species. [Copyright &y& Elsevier]

Objective: Irbesartan was renoprotective independently of its blood pressure-lowering effect in the Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria (IRMA2) study. However, blood pressure was evaluated by trough office blood pressure (OBP), which may underestimate reductions in 24-h ambulatory blood pressure (ABP). In the present study, we evaluated 24-h blood pressure patterns in a subpopulation of the IRMA2 trial.Research Design and Methods: Type 2 diabetic patients (n = 43) with persistent microalbuminuria (as determined by repeated overnight measurements of urinary albumin excretion [UAE]) and hypertension who were included in the IRMA2 study at the Steno Diabetes Center were subjected to 24-h ABP (Takeda, TM2420) measurements before and 2 years after randomization to placebo (n = 15), irbesartan 150 mg daily (Irb150; n = 13), or irbesartan 300 mg daily (Irb300; n = 15).Results: At baseline, the placebo, Irb150, and Irb300 groups were comparable: OBP: 157 +/- 15/89 +/- 7, 156 +/-15/91 +/- 11, and 159 +/- 16/90 +/- 9 mmHg (NS); 24-h ABP: 148 +/- 13/83 +/- 11, 148 +/- 16/82 +/- 7 and 147 +/- 16/81 +/- 10 mmHg (NS); and UAE (geometric mean with 95% CI): 43 (32-57), 46 (30-70), and 59 (42-85) micro g/min (NS), respectively. We found that 2 years after randomization, OBP was significantly reduced in all three groups (by 11/7, 13/8, and 13/8 mmHg in the placebo, Irb150, and Irb300 groups, respectively), but that there were no significant differences among groups. Reductions in 24-h ABP were similar in the three groups (11/10, 5/7, and 7/8 mmHg, respectively; NS), as were reductions in day ABP (11/9, 7/7, and 8/9 mmHg, respectively; NS) and night ABP (4/11, 7/7, and 3/3 mmHg, respectively; NS). The reduction in UAE at the end of the study was 0% (-86 to 42), 38% (-14 to 66), and 73% (59 to 82), respectively (overall, P < 0.01).Conclusion: Irbesartan is renoprotective independently of its beneficial effect in lowering 24-h blood pressure in patients with type 2 diabetes and persistent microalbuminuria. [ABSTRACT FROM AUTHOR]

Presents several studies on kidney dialysis. Analysis of the effectiveness of catheter-restricted filling with gentamicin and citrate in preventing catheter-related infections in hemodialysis patients; Aspects of hepatitis C infection in patient with end-stage renal disease; Effects of comorbid conditions on the outcomes of patients undergoing peritoneal dialysis; Prevalence of gastrointestinal complaints; Risk factors for hip fracture in hemodialysis patients.

Objective: To investigate the association between treatment induced change in continuous glucose monitored (CGM) time in range (TIR) and microalbuminuria in persons with type 1 diabetes (T1D) treated with sensor-augmented pumps (SAP). Methods: In an open labelled controlled trial, 60 participants with T1D treated with multiple daily injections (MDI) and history of albuminuria were randomised to MDI- or SAP-therapy for 1 year. During the study, the SAP group wore a CGM (Enlite®, Medtronic). The MDI group wore blinded CGMs (Ipro2®, Medtronic) for 6 days at baseline and study end. Anthropometrics, CGM data, blood and urine samples were collected at 0, 1, 3, 6, 9, and 12-month visits. Based on CGM data collected between each visit, the percentage of time spent within 3.9-10.0 mmol/l (%TIR) was calculated. Urine albumin creatinine ratio (UACR) was measured in 3 samples at all visits. Only CGM data for the SAP group were included in the analysis. A linear mixed model with a participant-specific random intercept was used to analyse the effect of %TIR during 1 year after start of SAP on UACR, adjusting for changes in mean arterial pressure (MAP), HbA1c and body mass index. Results: Twenty-six participants were assigned to the SAP group and had a baseline median (interquartile range) age of 51.5 (45.9; 62.1) years, HbA1c of 66 (58; 77) mmol/mol, UACR of 78.8 (37; 205) mg/g and 51Cr-EDTA-GFR 85.0 (73.0; 96.5) ml/min/1.73m2. From baseline to study end, the mean improvement (95% CI) in %TIR was 11.3 (6.0; 16.6) %, HbA1C was -14.4 (-17.5; -11.2) mmol/mol and UACR was -13 (-33; -22) %; all p<0.001. HbA1c decreased with 4.7 mmol/mol per 10% increase in %TIR (p<0.001). The UACR decreased with 13% per 10% increase in %TIR (p=0.038), with 15% per 10 mmol/mol decrease in HbA1c (p=0.071), and with 31 % per 10 mmHg decrease in MAP (p<0.001). Conclusion: In this longitudinal study, treatment induced increase in CGM-derived %TIR were significantly associated with decrease in albuminuria in T1D. Disclosure: A. Ranjan: None. S. Rosenlund: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. T.W. Hansen: None. P. Rossing: Advisory Panel; Self; Sanofi. Consultant; Self; Astellas Pharma Inc., AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Eli Lilly and Company. Stock/Shareholder; Self; Novo Nordisk A/S. S. Andersen: None. K. Nørgaard: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Medtronic, Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk Inc. Funding: Novo Nordisk Foundation (NNF17SA0031406); Medtronic A/S [ABSTRACT FROM AUTHOR]

Background: Microalbuminuria and hypertension are risk factors for diabetic nephropathy. Blockade of the renin–angiotensin system slows the progression to diabetic nephropathy in patients with type 1 diabetes, but similar data are lacking for hypertensive patients with type 2 diabetes. We evaluated the renoprotective effect of the angiotensin-II–receptor antagonist irbesartan in hypertensive patients with type 2 diabetes and microalbuminuria. Methods: A total of 590 hypertensive patients with type 2 diabetes and microalbuminuria were enrolled in this multinational, randomized, double-blind, placebo-controlled study of irbesartan, at a dose of either 150 mg daily or 300 mg daily, and were followed for two years. The primary outcome was the time to the onset of diabetic nephropathy, defined by persistent albuminuria in overnight specimens, with a urinary albumin excretion rate that was greater than 200 μg per minute and at least 30 percent higher than the base-line level. Results: The base-line characteristics in the three groups were similar. Ten of the 194 patients in the 300-mg group (5.2 percent) and 19 of the 195 patients in the 150-mg group (9.7 percent) reached the primary end point, as compared with 30 of the 201 patients in the placebo group (14.9 percent) (hazard ratios, 0.30 [95 percent confidence interval, 0.14 to 0.61; P<0.001] and 0.61 [95 percent confidence interval, 0.34 to 1.08; P=0.08] for the two irbesartan groups, respectively). The average blood pressure during the course of the study was 144/83 mm Hg in the placebo group, 143/83 mm Hg in the 150-mg group, and 141/83 mm Hg in the 300-mg group (P=0.004 for the comparison of systolic blood pressure between the placebo group and the combined irbesartan groups). Serious adverse events were less frequent among the patients treated with irbesartan (P=0.02). Conclusions: Irbesartan is renoprotective independently of its blood-pressure–lowering effect in patients with type 2 diabetes and microalbuminuria. (N Engl J Med 2001;345:870-8.) [ABSTRACT FROM AUTHOR]