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[Expression of antimicrobial peptide MUC7 in kidneys with pyelonephritis].

BACKGROUND: Mucins are glycoproteins secreted by epithelial cells of various organ systems exerting multiple functions. MG2 as the protein transcript of the MUC7 gene has first been described as secreted by serous salivary glands in the oral cavity. We sought to explore changes of MUC7 expression in the kidney stimulated by bacterial infection of the upper urinary tract. METHODS: We investigated the gene expression of MUC7 by reverse transcriptase-polymerase chain reaction in voided urine specimens from 15 patients with acute pyelonephritis compared to 15 healthy volunteers. Furthermore, the gene and protein expression of MUC7 was studied in 15 renal tissue samples with chronic bacterial pyelonephritis versus 10 normal human kidney samples taken from tumor-bearing organs. RESULTS: MUC7 gene expression was detected in 5 of 15 voided urine samples of patients with pyelonephritis and in 2 samples from 15 healthy volunteers (Fisher's exact test p=0.39). MUC7 gene expression was detected in 7 of 15 tissue samples of kidneys with chronic pyelonephritis and in none of 10 normal renal tissue samples from tumor bearing organs (p=0.02). Immunohistochemical staining with the monoclonal antibody PANH3 revealed protein expression in 6 of the 15 tissue samples with chronic pyelonephritis, but not in normal tissue samples. CONCLUSION: Upregulated MUC7 expression in the urinary tract particularly in renal tubular epithelium can occur under inflammatory conditions. This indicates a putative role of MUC7 as an antimicrobial host defense molecule within the urogenital tract.

Adult↗

[Microproteinuria and enzymuria in fever and pyelonephritis in childhood. A prospective study of 180 children].

In 180 children (87 children belonging to a control group, 68 with fever of non-renal origin, and 25 with pyelonephritis) albumin and immunoglobulin G (markers for glomerular dysfunction), alpha-1-microglobulin and beta-NAG (markers for proximal tubular dysfunction) and apolipoprotein A1 (marker of "postrenal' dysfunction) were measured in second-voided morning urine. In children with fever of non-renal origin, glomerular dysfunction was encountered in 8.8%, tubular dysfunction in 17.6% and mixed glomerular-tubular dysfunction in 14.7% of cases. Among children with pyelonephritis, 28% revealed glomerular dysfunction and 44% mixed glomerular-tubular dysfunction. No case of solitary proximal tubular dysfunction was observed in children with pyelonephritis. There were highly significant differences in presence and expression of glomerular dysfunction between children with fever of non-renal origin and children with pyelonephritis (P < 0.0001), whereas with regard to proximal tubular dysfunction, the differences were only moderately significant (beta-NAG: P < 0.01) or of low significance (alpha-1-microglobulin: P < 0.05). This may indicate that morphologic changes occur during interstitial pyelonephritis due to inflammation of glomeruli, resulting in glomerular dysfunction, while proximal tubular dysfunction may additionally be due to fever-associated function processes.

Acetylglucosaminidase↗

Imaging of acute pyelonephritis in the adult.

The diagnosis of acute pyelonephritis in adults is predominantly made by a combination of typical clinical features of flank pain, high temperature and dysuria combined with urinalysis findings of bacteruria and pyuria. Imaging is generally reserved for patients who have atypical presenting features or in those who fail to respond to conventional therapy. In addition, early imaging may be useful in diabetics or immunocompromised patients. In such patients, imaging may not only aid in making the diagnosis of acute pyelonephritis, but more importantly, it may help identify complications such as abscess formation. In this pictorial review, we discuss the role of modern imaging in acute pyelonephritis and its complications. We discuss the growing role of cross-sectional imaging with computed tomography (CT) and novel magnetic resonance imaging (MRI) techniques that may be used to demonstrate both typical as well as unusual manifestations of acute pyelonephritis and its complications. In addition, conditions such as emphysematous and fungal pyelonephritis are discussed.

Acute Disease↗

Development of kidney scars after acute uncomplicated pyelonephritis: relationship with clinical, laboratory and imaging data at diagnosis.

BACKGROUND: Acute pyelonephritis is a potential cause of kidney scars. AIM: To evaluate the relationship between clinical, laboratory and imaging data and the development of kidney scars in acute pyelonephritis. METHODS: All consecutive patients hospitalized for acute uncomplicated pyelonephritis in our nephrology unit from June 1996 to June 2004 were considered: 58 females, median age 25.6 years (16-52). Diagnosis of pyelonephritis required parenchymal lesions shown by CT or NMR scan. RESULTS: The lesions were bilateral in 17.2% (10/58) patients, unilateral, but multifocal in 81.0% (47/58); at CT or NMR, 65.5% of the lesions were classified as simple, 19% with tendency to colliquation and 15.5% abscessual. The median interval between first symptoms and diagnosis was 5 days (1-25); at referral, only 20.7% had a positive urine culture and 94.8% (55/58) had undergone previous antibiotic treatment. The therapeutic protocol required intravenous therapy for > or = 2 weeks, followed by 2-4 weeks of oral therapy. At 6-8 months, the prevalence of kidney scars was 29.3%. Their development was highly correlated with the type of lesions at diagnosis (highest risk with abscessual lesions; uni- and multivariate analysis). No other clinical or laboratory marker (age, fever, positive cultures, levels of acute phase reactants, interval between onset and diagnosis) was correlated with the outcome (scars). CONCLUSIONS: The type of lesion at diagnosis of acute uncomplicated pyelonephritis is highly correlated with the development of kidney scars. Further studies are needed to test the therapeutic schedules tailored according to the imaging data.

Acute Disease↗

Procalcitonin as a marker of acute pyelonephritis in infants and children.

In the absence of specific symptomatology in children, the early diagnosis of acute pyelonephritis is a challenge, particularly during infancy. In an attempt to differentiate acute pyelonephritis from lower urinary tract infection (UTI), we measured serum procalcitonin (PCT) levels and compared these with other commonly used inflammatory markers. We evaluated the ability of serum PCT levels to predict renal involvement, as assessed by dimercaptosuccinic acid (DMSA) scintigraphy. Serum C-reactive protein (CRP), leukocyte counts, and PCT levels were measured in 64 children admitted for suspected UTI. Renal parenchymal involvement was assessed by (99m)Tc-DMSA scintigraphy in the first 7 days after admission. In acute pyelonephritis, the median PCT level was significantly higher than in the lower UTI group (3.41, range 0.36-12.4 microg/l vs. 0.13, range 0.02-2.15 microg/l, P<0.0001). In these two groups, respectively, median CRP levels were 120 (range 62-249 mg/l) and 74.5 (range 14.5-235 mg/l, P=0.012) and leukocyte counts were 15,910/mm(3) (range 10,200-26,900) and 14,600/mm(3) (range 8,190-26,470, P=0.34). For the prediction of acute pyelonephritis, the sensitivity and specificity of PCT were 94.1% and 89.7%, respectively; CRP had a sensitivity of 100%, but a specificity of 18.5%. We conclude that serum PCT may be an accurate marker for early diagnosis of acute pyelonephritis.

Acute Disease↗

Evaluation of acute pyelonephritis with DMSA scans in children presenting after the age of 5 years.

It is generally believed that infants are more susceptible to development of renal scarring after pyelonephritis than children over 5 years old. This view has led to differences in investigations and treatment according to age. The aim of this prospective study was to assess the occurrence of renal parenchymal lesion in children over 5 years admitted with a first-time symptomatic urinary tract infection (UTI). Between October 2000 and April 2002, 52 children aged over 5 years who were admitted to our department with probable acute pyelonephritis (APN) and a positive urine culture were included in this study. All children received antibiotics for 14 days. During the acute phase of infection, scintigraphy with technetium-99m-labeled dimercaptosuccinic acid (DMSA) and ultrasonography (US) were done. Voiding cystourethrography (VCUG) was performed in all children early in the course of the illness, generally within 5-7 days of hospitalization. When scintigraphy showed renal parenchymal changes, repeat scintigraphy was done after at least 3 months to assess the progression of renal abnormalities. Of the 52 children with a first-time documented pyelonephritis, cortical scintigraphy showed renal lesion in 41 children (78.8%). US was normal in all children with normal renal scintigraphy, while it detected renal abnormalities in 16 of the 41 (39 %) with abnormal scintigraphy (p <0.0001). Topographic analysis of the 165 focal lesions showed that 42.4% were localized to the upper poles, 17.5% to the middle third, and 40% to the lower poles of the kidneys. Repeat scintigraphy showed persistent lesions corresponding to those on the initial scan in nine (28.2%) of the 32 children. Renal lesions had partly regressed in 23 (71.8%) of the patients who underwent repeat scintigraphy. Vesicoureteral reflux was observed in 13.4% of kidneys and renal parenchymal abnormalities were identified in 71.4% and 72.2% of renal units, respectively, with and without reflux ( p >0.05). In conclusion, our data did not confirm the conventional opinion that the risk of renal scarring after pyelonephritis is low in children over the age of 5 years. Our findings suggest that renal scintigraphy may be a more appropriate method of investigation than VCUG for evaluation of the children over 5 years with acute pyelonephritis. Additionally, the frequency of scintigraphic changes is high, and a strategy based exclusively on ultrasound findings would miss about 61% of the abnormal renal units. We recommend that all children, irrespective of age, will benefit from further investigations that might prevent or limit the development of scarring process and renal complications.

Acute Disease↗

Attitude of Belgian pediatricians toward strategy in acute pyelonephritis.

To investigate the attitude of Belgian pediatricians toward the management and treatment of children with suspected acute pyelonephritis, a short letter was sent to all Belgian pediatricians (1,200). It contained a brief description of a clinical case strongly suggestive of acute pyelonephritis followed by a series of questions centered on complementary examinations to be performed, need of hospitalization and treatment. A total of 583 responses were received (49%). In the acute phase, 99% of pediatricians perform urine cultures, 87% blood examinations, and 76% renal ultrasound. Dimercaptosuccinate (DMSA) scintigraphy is performed during the acute phase by 37% and during follow-up by 32% of all pediatricians. A voiding cystogram is requested by 71%. Ambulatory treatment is considered by 30% of responders. Amoxicillin/clavulanic acid (44%) and trimethoprim/sulfonamide (22%) are the most frequently used oral antibiotics. Private pediatricians perform fewer examinations and more frequently consider ambulatory treatment of acute pyelonephritis, compared to pediatricians working in hospitals. Among Belgian pediatricians, attitudes toward the diagnosis and treatment of acute pyelonephritis are heterogeneous. This survey underlines the need for properly documented prospective studies for the evaluation of different treatment modalities in childhood acute pyelonephritis.

Acute Disease↗

Uterine contractions after antibiotic therapy for pyelonephritis in pregnancy.

OBJECTIVE: The purpose of our study was to investigate the pathogenesis of preterm labor in pyelonephritis, we determined the number of uterine contractions occurring in patients with pyelonephritis before and after antibiotic therapy. STUDY DESIGN: We recorded the uterine contractions before and after antibiotic administration in 30 patients with acute pyelonephritis at Lyndon B. Johnson Hospital in Houston. Exclusion criteria were cervical dilatation > or = 4 cm, < 26 weeks' gestation, antibiotics within 7 days, clinical intraamniotic infection, rupture of membranes, or other maternal infection. Statistical analysis was by Kruskal-Wallis analysis of variance and Wilcoxon rank sum tests. RESULTS: The patients averaged eight contractions per hour on admission. The contraction rate significantly increased in hours +1 to +4 after antibiotic administration. The increase in uterine contractility occurred in patients with urinary tract gram-negative isolates. CONCLUSIONS: Pregnant women with pyelonephritis resulting from gram-negative bacteria increase their rate of uterine contractility after antibiotic treatment. This observation may be important in understanding the pathogenesis of preterm labor in pyelonephritis.

Adult↗

Outpatient treatment of pyelonephritis in pregnancy: a randomized controlled trial.

OBJECTIVE: To compare the safety and efficacy of outpatient and inpatient treatment of pyelonephritis in pregnancy. METHODS: We performed a randomized controlled trial of pregnant women with pyelonephritis before 24 weeks' estimated gestational age, comparing inpatient and outpatient treatment. Sixty inpatients received cefazolin intravenously until afebrile for 48 hours, and 60 outpatients received two injections of ceftriaxone intramuscularly. All patients completed a 10-day course of oral cephalexin. We performed a urine culture 5-14 days after completion of therapy. RESULTS: The two groups were similar with respect to age, parity, temperature, estimated gestational age, initial white blood cell count, and incidence of bacteremia. Escherichia coli was the major uropathogen isolated (86% of cultures, 95 of 111). Twelve percent (13 of 111) of bacteria were resistant to cefazolin. Eleven outpatients and 12 inpatients had positive urine cultures after therapy (relative risk 0.9, 95% confidence interval 0.4-1.9). Three patients in each group had recurrent pyelonephritis. We switched six inpatients to gentamicin because of a worsening clinical picture (two) or a prolonged febrile course (four); no outpatients required a change in antibiotic (Fisher exact test, P = .03). One preterm delivery occurred in an inpatient with recurrent pyelonephritis. CONCLUSION: Outpatient antibiotic therapy is effective and safe in selected pregnant women with pyelonephritis.

Administration, Oral↗

Computerized tomography and acute pyelonephritis in children. A clinical correlation.

The clinical records and computerized tomography (CT) scans of 14 patients who presented with pyelonephritis to the Children's Hospital of Buffalo between 1976-1985 have been reviewed. The CT findings were as follows: multifocal pyelonephritis (6), lobar nephronia (6), focal pyelonephritis (2). All patients were treated with intravenous antibiotics, and none was surgically drained. Significant underlying diseases were present in 8 patients: diabetes (6), von Gierke disease (1), hepatorenal syndrome (1). The diabetic children tended to have focal disease. Ten voiding cystourethrograms were performed and only four demonstrated reflux. All children became afebrile within a few days. Lobar nephronia was as clinically responsive as pyelonephritis to antibiotic therapy. Urine cultures were most often positive, although there was 1 patient in each category with negative cultures. Blood cultures were rarely positive in any group. Gram negative organisms predominated. CT scanning in children with clinical acute pyelonephritis reveals three major imaging patterns. While distinct radiographically, they behave in a similar clinical manner. Lobar nephronia does not imply a worse clinical prognosis. Intravenous antibiotic therapy alone was adequate for all patients.

Child↗

Endoscopic management of vesicoureteral reflux in women presenting with pyelonephritis.

PURPOSE: Vesicoureteral reflux is not usually considered a major cofactor in acute pyelonephritis in women. However, there is a subset of individuals in whom reflux must be considered in the evaluation of acute pyelonephritis. We sought to evaluate the effectiveness of endoscopic treatment for vesicoureteral reflux in this subset of patients. MATERIALS AND METHODS: We retrospectively reviewed the records of 13 female patients presenting with clinical pyelonephritis between 2001 and 2005. All of these patients had either a history of vesicoureteral reflux in childhood or a family history of reflux, or had previously undergone surgery for reflux. All patients underwent voiding cystourethrogram and dimercapto-succinic acid renal scan as part of the evaluation. RESULTS: Of the 13 individuals evaluated 9 had vesicoureteral reflux. Of these patients 5 had been operated on previously for vesicoureteral reflux, 2 had a strong family history of reflux and 2 had reflux as a child with documented resolution. Six of the 9 patients with reflux exhibited renal scarring on dimercapto-succinic acid renal scintigraphy. Endoscopic correction of reflux was done in all 9 patients and was successful in 8, as shown on voiding cystourethrogram at 3 months postoperatively. One patient required a second procedure, which was successful. Only 1 patient has had a subsequent episode of clinical pyelonephritis, and voiding cystourethrogram following treatment again revealed resolution of reflux. CONCLUSIONS: There is a subset of women presenting with acute pyelonephritis in whom vesicoureteral reflux is a risk factor. When documented, vesicoureteral reflux can be managed effectively with endoscopic treatment.

Adolescent↗

Virulence characteristics and DNA fingerprints of Escherichia coli isolated from women with acute uncomplicated pyelonephritis.

PURPOSE: Previous studies indicated that acute pyelonephritis in infants is initiated by the dominance of uropathogenic strains in fecal flora. Such pathogenic evidence, however, is still lacking for adult women. In this study, the validity of a fecal-perineal-urethral hypothesis in acute uncomplicated pyelonephritis of adult women was assessed at a genetic level. MATERIALS AND METHODS: A total of 1,200 Escherichia coli isolates from the urine and rectal swab of 12 adult women with acute uncomplicated pyelonephritis were examined. The clonality of the urinary and fecal isolates was evaluated by genotyping of 6 urovirulence determinants and pulsed-field gel electrophoresis. Furthermore, urovirulence genotypes were examined in E. coli isolates from the rectal swab of 30 normal healthy women (mean 26.7 isolates per person). RESULTS: The E. coli strains causing pyelonephritis were present in the rectal swab in 10 of 12 patients and were a predominant fecal clone in 9 cases. Also, P-fimbriated strains dominated in the fecal flora in 10 of 30 normal healthy women. CONCLUSIONS: The clonal identity of the urinary and fecal strains in acute pyelonephritis clearly supports the fecal-perineal-urethral hypothesis.

Acute Disease↗

Evaluation of 99mtechnetium-dimercapto-succinic acid renal scans in experimental acute pyelonephritis in piglets.

We evaluated the sensitivity and specificity of 99mtechnetium-dimercapto-succinic acid renal scans in the detection and localization of experimental acute pyelonephritis in piglets. To create pyelonephritis vesicoureteral reflux of infected urine was surgically induced in 22 piglets. Nine animals were evaluated with a dimercapto-succinic acid renal scan at 1 week and 13 at 2 weeks. Autopsy and histopathological examination of the kidneys were performed subsequently. The location and extent of the inflammatory response found on histopathological examination were compared to dimercapto-succinic acid renal scan findings in a blinded fashion. Of the 22 kidneys subjected to vesicoureteral reflux 15 had positive histopathological findings of acute pyelonephritis, including 13 detected by the dimercapto-succinic acid renal scan findings. The 2 kidneys in which inflammation was not detected had only minimal grade I lesions and were grossly normal. There were no false positive scans in any of these kidneys. The sensitivity of the scan for detection of acute pyelonephritis in the kidneys subjected to reflux was 87 per cent and the specificity was 100 per cent. Furthermore, in these same kidneys the dimercapto-succinic acid renal scan findings correctly predicted the presence or absence of individual pyelonephritic lesions in 62 of 66 poles for an over-all agreement rate of 94 per cent. Thus, dimercapto-succinic acid renal cortical imaging is a highly sensitive and reliable imaging modality to detect and localize experimental acute pyelonephritis in piglets.

Acute Disease↗

Treatment of pyelonephritis in adults.

Although prescribing an antibiotic for the treatment of pyelonephritis seems to be a relatively easy task, a close look at the available data is disturbing. Optimal therapies for the different clinical syndromes of pyelonephritis have not yet been defined. The high failure rate suggests that in pyelonephritis (bacteria protected in the medulla) as well as in bacterial endocarditis (bacteria sequestered in vegetations) and in infections in neutropenic patients (host defenses not necessarily operating in conjunction with antibiotics), it may be necessary to maintain bactericidal levels at the site of infection (infected medulla) to achieve cure. Pharmacodynamic studies suggest that TMP/SMX, quinolones, and aminoglycosides, which penetrate well the infected renal parenchyma and are not impaired by the local inflammatory process, should, with the exception of pyelonephritis in pregnancy, be preferred to beta-lactams as first-choice agents for the therapy of gram-negative pyelonephritis.

Acute Disease↗

Aerobactin-mediated uptake of iron by strains of Escherichia coli causing acute pyelonephritis and bacteraemia.

A total of 285 strains of Escherichia coli isolated from children and women with acute non-obstructive pyelonephritis and from patients with bacteraemia as well as 120 faecal strains of E. coli from healthy children and adults were examined for aerobactin-mediated uptake of iron. The incidence of aerobactin-positive strains was significantly more in isolates from children with acute pyelonephritis (81%) than in faecal isolates from healthy children (50%, P less than 0.01). It was also higher in isolates of E. coli from women with acute pyelonephritis (72%) compared with faecal isolates from healthy adults (42%, P less than 0.001). Of the E. coli strains causing bacteraemia, 55% were aerobactin-positive. A significant correlation was found between the presence of aerobactin and expression of P-fimbriae in strains of E. coli isolated from children with acute pyelonephritis (P less than 0.01) and in isolates from bacteraemic patients (P less than 0.001). These results indicate that the presence of an aerobactin-mediated system of iron uptake may be an important virulence factor in strains of E. coli that cause ascending pyelonephritis.

Acute Disease↗

The therapeutic response of cephalosporin-treated E. coli pyelonephritis of the rat, in relation to variations of the infection model.

In the E. coli pyelonephritis, induced in female Wistar rats by retrograde infection (high pressure reflux), we investigated the influence of 1) the time of commencement of therapy, 2) the renal bacterial counts, i.e. the inflammatory activity of the pyelonephritis after endovesical instillation of cultures with different bacterial concentrations, and 3) the level of infection resistance of the experimental animal strain on the therapeutic response of the model infection with single doses of cefoxitin (150 mg/ml) and cefotaxime (5 mg/ml). Early commencement of therapy post inoculation was therapeutically advantageous provided the intrarenal multiplication of the infective organisms was not delayed or the initial bacterial concentrations were not too high. The mild form of pyelonephritis with lower renal bacterial concentrations and poor inflammatory activity after endovesical instillation of a low inoculum (10(4) cfu/ml) was less amenable to treatment than the inflammatory active pyelonephritis with high renal bacterial counts, using a high inoculum (10(7) cfu/ml). High renal bacterial counts after retrograde inoculation of an E. coli culture of 10(8) cfu/ml resulted in significant reduction of bacterial counts 48, 72 and 96 h post infectionem, with i.m. application of cefoxitin 12 h prior. For Wistar rat strain Bor:WIST, which showed a stronger infection resistance with lower renal bacterial concentrations and a stronger tendency to spontaneous healing, application of a single dose of cefotaxime (5 mg/ml) was therapeutically ineffective, whereas, in contrast, with Han: WIST rats the acute phase of E. coli pyelonephritis could be treated effectively.

Animals↗

Management of acute pyelonephritis in an emergency department observation unit.

STUDY OBJECTIVES: To determine whether moderately to severely ill patients with acute pyelonephritis can be treated successfully on an outpatient basis, and whether any aspect of history, physical examination, or initial laboratory data predicts failure of outpatient therapy and the need for hospitalization. DESIGN: Retrospective chart review of all patients with a diagnosis of acute pyelonephritis seen during a three-year period. SETTING: Emergency department observation unit of an urban teaching hospital serving residents of the city and county of Denver. TYPE OF PARTICIPANTS: Women between the ages of 15 and 50 with symptoms, physical examination, and initial laboratory data consistent with a diagnosis of pyelonephritis. INTERVENTIONS: Patients received IV antibiotics, rehydration, analgesics, and antiemetics in an observation unit for up to 12 hours, when they were either admitted to the hospital or discharged home on oral antibiotics. MEASUREMENTS AND MAIN RESULTS: Sixty-three of 87 patients (72%) with acute pyelonephritis were managed successfully as outpatients, nine (22%) were hospitalized directly from the observation unit because they were considered to be too ill to go home, and five (6%) returned with persistent symptoms after ED therapy and were hospitalized. No clinical or laboratory variable predicted success or failure of ED observation unit therapy at the time of initial presentation. CONCLUSION: In selected patients, the observation unit may be used to initiate therapy for acute pyelonephritis. Those with an adequate clinical response to initial treatment may be discharged on oral antibiotic therapy with appropriate follow-up.

Adolescent↗

Acute pyelonephritis in US hospitals in 1997: hospitalization and in-hospital mortality.

PURPOSE: To describe the 1997 incidence of hospitalization for acute pyelonephritis in the US and the risk factors for in-hospital mortality associated with acute pyelonephritis. METHODS: Cases were defined as those with ICD9-CM codes corresponding to acute pyelonephritis in the 1997 Health Care Cost and Utilization Project (HCUP) Nationwide Inpatient Sample (NIS). Frequencies and calculations were weighted to produce either national or state estimates. Hospitalization rates were calculated using 1997 US Census Bureau population projections for the denominator. RESULTS: Females were almost five times as likely as males to be hospitalized for acute pyelonephritis (11.7/10,000 vs. 2.4/10,000), but males had higher mortality rates (16.5/1000 vs. 7.3/1000); 30% greater after adjustment. Hospitalization and in-hospital mortality rates increased with age, but not with diabetes. Mortality rates increased with number of procedures, diagnoses and having a major diagnostic category other than disorders of the kidney and urinary tract. Persons living in zip codes with lower median incomes were also at higher risk of mortality. There was little variation in mortality by hospital size, ownership, location or teaching status. CONCLUSION: In hospital mortality for pyelonephritis was associated with patient rather than hospital characteristics suggesting uniform application of standard care across hospitals and populations.

Acute Disease↗