Evaluation of point-of-care multiplex polymerase chain reaction in guiding antibiotic treatment of patients acutely admitted with suspected community-acquired pneumonia in Denmark: A multicentre randomised controlled trial.

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).

Increase in invasive group A streptococcal infections and emergence of novel, rapidly expanding sub-lineage of the virulent Streptococcus pyogenes M1 clone, Denmark, 2023.

A highly virulent sub-lineage of the Streptococcus pyogenes M1 clone has been rapidly expanding throughout Denmark since late 2022 and now accounts for 30% of the new invasive group A streptococcal infections. We aimed to investigate whether a shift in variant composition can account for the high incidence rates observed over winter 2022/23, or if these are better explained by the impact of COVID-19-related restrictions on population immunity and carriage of group A Streptococcus.

Bacteremia With Anaerobic Bacteria and Association With Colorectal Cancer: A Population-based Cohort Study.

BACKGROUND: There is a well-described association between bacteremia with bovis group streptococci or Clostridium septicum and an increased probability of a colorectal cancer (CRC) diagnosis. We wanted to investigate the existence of a similar association between CRC and bacteremia with other bacteria belonging to the gut microbiota.. METHODS: A population based cohort study in a population about 2 million people including 45 774 bacteremia episodes and 231 387 blood culture negative cases was performed in the Region of Southern Denmark and Region Zealand from 2007-2016. Episodes of bacteremia were combined with the Danish central register for CRC. We performed Cox's regression analysis with hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: The study results confirmed previous findings of an increased risk of a CRC diagnosis after bacteremia with the bovis group streptococci (risk within a year: 4.3%; HR [95% CI]: 8.46 [3.51-20.4]) or C. septicum (20.8%; 76.2 [42.0-138]). Furthermore, Bacteroides ovatus (6.7%; 20.3 [5.04-81.8]), Bacteroides uniformis (5.4%; 16.2 [4.02-65.7]), Clostridium tertium (3.6 %; 13.9 [1.96-99.4]), Fusobacterium spp. (excluding F. necrophorum) (3.0 %; 8.51 [2.73-26.5]), and Gram-positive anaerobic cocci (3.6 %; 10.9 [4.50-26.3]) were also associated with an increased risk of a CRC diagnosis compared to patients with negative blood cultures (0.4%). CONCLUSIONS: Bacteremia with specific gut microbiota anaerobic bacteria is associated with a high risk of a diagnosis of CRC, indicating the need for colorectal workup. Importantly, this strategy also holds the possible additional benefit of detecting adenomas or other premalignant conditions, which were not included in the present study.

Azole resistance in Aspergillus fumigatus. The first 2-year's Data from the Danish National Surveillance Study, 2018-2020.

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, TR34 3 /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.

Serum metabolites predict response to angiotensin II receptor blockers in patients with diabetes mellitus.

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.

Element Concentrations and Histopathology of Liver and Kidney in West Greenland Ringed Seals (Pusa hispida).

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%).

Colorectal cancer and association with anaerobic bacteraemia: a Danish nationwide population-based cohort study.

OBJECTIVES: We aimed to identify specific anaerobic bacteria causing bacteraemia and a subsequent diagnosis of colorectal cancer. METHODS: A nationwide population-based cohort study, which included all episodes of defined specific anaerobic bacteraemia from 2010 (5,534,738 inhabitants) through 2020 (5,822,763 inhabitants) and all cases of colorectal cancer diagnosed from 2010 through 2021 in Denmark. We calculated the incidence and risk of colorectal cancer after bacteraemia with specific anaerobic bacteria using Escherichia coli bacteraemia as reference. RESULTS: Nationwide data on colorectal cancer and specific anaerobic bacteraemia (100% complete, representing 11,124 episodes). The frequencies of colorectal cancer within one year following anaerobic bacteraemia were higher for species, which almost exclusively reside in the colon, such as Phocaeicola vulgatus/dorei (5.5%), Clostridium septicum (24.2%), and Ruminococcus gnavus (4.6%) compared to 0.6% in 50,650 E. coli bacteraemia episodes. Bacteroides spp. had a subhazard ratio for colorectal cancer of 3.9 (95% confidence interval [CI], 3.0 to 5.1) and for Clostridium spp. it was 8.9 (95% CI, 6.7 to 11.8, with C. septicum 50.0 [95% CI, 36.0 to 69.5]) compared to E. coli (reference). CONCLUSION: This nationwide study identified specific colorectal cancer-associated anaerobic bacteria, which almost exclusively reside in the colon. Bacteraemia with these bacteria could be an indicator of colorectal cancer.

Gram Stain and Culture of Sputum Samples Detect Only Few Pathogens in Community-Acquired Lower Respiratory Tract Infections: Secondary Analysis of a Randomized Controlled Trial.

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.

Expiratory Technique versus Tracheal Suction to Obtain Good-Quality Sputum from Patients with Suspected Lower Respiratory Tract Infection: A Randomized Controlled Trial.

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.

Tubular markers do not predict the decline in glomerular filtration rate in type 1 diabetic patients with overt nephropathy.

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 m(2) 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.

Improved Time in Range Over 1 Year Is Associated With Reduced Albuminuria in Individuals With Sensor-Augmented Insulin Pump-Treated Type 1 Diabetes.

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.

Nuclear localization of human DNA mismatch repair protein exonuclease 1 (hEXO1).

Human exonuclease 1 (hEXO1) is implicated in DNA mismatch repair (MMR) and mutations in hEXO1 may be associated with hereditary nonpolyposis colorectal cancer (HNPCC). Since the subcellular localization of MMR proteins is essential for proper MMR function, we characterized possible nuclear localization signals (NLSs) in hEXO1. Using fluorescent fusion proteins, we show that the sequence 418KRPR421, which exhibit strong homology to other monopartite NLS sequences, is responsible for correct nuclear localization of hEXO1. This NLS sequence is located in a region that is also required for hEXO1 interaction with hMLH1 and we show that defective nuclear localization of hEXO1 mutant proteins could be rescued by hMLH1 or hMSH2. Both hEXO1 and hMLH1 form complexes with the nuclear import factors importin beta/alpha1,3,7 whereas hMSH2 specifically recognizes importin beta/alpha3. Taken together, we infer that hEXO1, hMLH1 and hMSH2 form complexes and are imported to the nucleus together, and that redundant NLS import signals in the proteins may safeguard nuclear import and thereby MMR activity.

Does the nutrition profile of vitamins, fatty acids and microelements counteract the negative impact from organohalogen pollutants on bone mineral density in Greenland sledge dogs (Canis familiaris)?

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 BMD(femur) or BMD(vertebrae) 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 BMD(femur), BMD(vertebrae) 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.

Urinary connective tissue growth factor excretion correlates with clinical markers of renal disease in a large population of type 1 diabetic patients with diabetic nephropathy.

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 [48-127]) patients and control subjects (n = 29, 100 [78-114]). 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(1c) (2.0 [1.5-2.7]), and blood pressure (2.0 [1.5-2.6]). 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.

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 (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. 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.

Breakthrough pain in malignant and non-malignant diseases: a review of prevalence, characteristics and mechanisms.

Breakthrough pain or transient worsening of pain in patients with an ongoing steady pain is a well known feature in cancer pain patients, but it is also seen in non-malignant pain conditions with involvement of nerves, muscles, bones or viscera. Continuous and intermittent pain seems to be a general feature of these different pain conditions, and this raises the possibility of one or several common mechanisms underlying breakthrough pain in malignant and non-malignant disorders. Although the mechanisms of spontaneous ongoing pain and intermittent flares of pain (BTP) may be difficult to separate, we suggest that peripheral and/or central sensitization (hyperexcitability) may play a major role in many causes of BTP. Mechanical stimuli (e.g. micro-fractures) changes in chemical environments and release of tumour growth factors may initiate sensitization both peripherally and centrally. It is suggested that sensitization could be the common denominator of BTP in malignant and non-malignant pain.

Kidney function during and after withdrawal of long-term irbesartan treatment in patients with type 2 diabetes and microalbuminuria.

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 double-masked 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 GFR were 1.3 +/- 0.7, 1.2 +/- 0.7, and 1.0 +/- 0.8 ml. min(-1). 1.73 m(-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(-1). 1.73 m(-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.

Comparative effects of Irbesartan on ambulatory and office blood pressure: a substudy of ambulatory blood pressure from the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria study.

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.

Long-term renoprotective effects of losartan in diabetic nephropathy: interaction with ACE insertion/deletion genotype?

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.

Effect of Sensor-Augmented Pump Treatment Versus Multiple Daily Injections on Albuminuria: A 1-Year Randomized Study.

CONTEXT: The effect of glycemic control on persisting albuminuria remains unclear. Insulin delivery and glucose variability may be important. OBJECTIVE: This study aimed to investigate the effect of 1-year treatment with sensor-augmented insulin pump (SAP) or multiple daily injections (MDIs) on albuminuria. DESIGN, PATIENTS, AND METHODS: This was a randomized controlled open-label parallel trial composed of 60 patients with type 1 diabetes with a history of albuminuria and on stable renin-angiotensin system inhibition, were randomly assigned to SAP or MDI. Urine albumin creatinine ratio (UACR) was measured in three urine samples at all visits. Glucose variability and glomerular filtration rate ((51)Cr-EDTA-GFR) were measured at beginning and study end. Using linear mixed model, change in UACR between groups was analyzed as intention to treat. MAIN OUTCOME MEASURE: Change in UACR was measured. RESULTS: Fifty-five patients (SAP, n = 26; MDI, n = 29) completed the study. Diabetes duration (mean ± SD, 33 ± 12 y), UACR (geometric mean, 99 mg/g; interquartile range, 37-233 mg/g), (51)Cr-EDTA-GFR (94 ± 22 mL/min/1.73m(2)), glycosylated hemoglobin (HbA1c) (9.0 ± 1.1%), glucose variability (calculated as SD), 4.0 ± 1.0 mmol/l; no-group differences (P ≥ .06 for all). After 1 year, change in UACR was mean, -13%; 95% confidence interval, -39 to 22 with SAP vs mean, 30%; 95% CI, -12 to 92% on MDI treatment (unadjusted P = .051; adjusted for HbA1c, P = .04). HbA1c decreased 1.3 ± 1.0 vs 0.6 ± 1.0% (P = .013), glucose variability decreased 0.9 ± 1.1 vs 0.3 ± 1.0 mmol/L (P = .04), and (51)Cr-EDTA-GFR declined 5.6 ± 9.6 vs 3.4 ± 13 mL/min/1.73m(2) (P = .50) with SAP vs MDI treatment. There were no changes in blood pressure (P ≥ .27). CONCLUSION: SAP treatment reduced UACR in a randomized controlled trial in type 1 diabetes patients with a history of albuminuria on stable renin-angiotensin system inhibition. Significance was reached after adjustment. SAP treatment reduced HbA1c and glucose variability (calculated as SD).