Texas A&M University at Galveston

1. The diagnosis of asymptomatic bacteriuria should be based on results of culture of a urine specimen collected in a manner that minimizes contamination (A-II) (table 1). Infectious Diseases Society of America—US Public Health Service Grading System for ranking recommendations in clinical guidelines. • For asymptomatic women, bacteriuria is defined as 2 consecutive voided urine specimens with isolation of the same bacterial strain in quantitative counts ⩾105 cfu/mL (B-II). • A single, clean-catch voided urine specimen with 1 bacterial species isolated in a quantitative count ⩾105 cfu/mL identifies bacteriuria in men (B-III). • A single catheterized urine specimen with 1 bacterial species isolated in a quantitative count ⩾102 cfu/mL identifies bacteriuria in women or men (A-II). 2. Pyuria accompanying asymptomatic bacteriuria is not an indication for antimicrobial treatment (A-II). 3. Pregnant women should be screened for bacteriuria by urine culture at least once in early pregnancy, and they should be treated if the results are positive (A-I). • The duration of antimicrobial therapy should be 3–7 days (A-II). • Periodic screening for recurrent bacteriuria should be undertaken following therapy (A-III). • No recommendation can be made for or against repeated screening of culture-negative women in later pregnancy. 4. Screening for and treatment of asymptomatic bacteriuria before transurethral resection of the prostate is recommended (A-I). • An assessment for the presence of bacteriuria should be obtained, so that results will be available to direct antimicrobial therapy prior to the procedure (A-III). • Antimicrobial therapy should be initiated shortly before the procedure (A-II). • Antimicrobial therapy should not be continued after the procedure, unless an indwelling catheter remains in place (B-II). 5. Screening for and treatment of asymptomatic bacteriuria is recommended before other urologic procedures for which mucosal bleeding is anticipated (A-III). 6. Screening for or treatment of asymptomatic bacteriuria is not recommended for the following persons. • Premenopausal, nonpregnant women (A-I). • Diabetic women (A-I). • Older persons living in the community (A-II). • Elderly, institutionalized subjects (A-I). • Persons with spinal cord injury (A-II). • Catheterized patients while the catheter remains in situ (A-I). 7. Antimicrobial treatment of asymptomatic women with catheter-acquired bacteriuria that persists 48 h after indwelling catheter removal may be considered (B-I). 8. No recommendation can be made for screening for or treatment of asymptomatic bacteriuria in renal transplant or other solid organ transplant recipients (C-III). The purpose of this guideline is to provide recommendations for diagnosis and treatment of asymptomatic bacteriuria in adult populations >18 years of age. The recommendations were developed on the basis of a review of published evidence, with the strength of the recommendation and quality of the evidence graded using previously described Infectious Diseases Society of America (IDSA) criteria (table 1) [1]. Recommendations are relevant only for the treatment of asymptomatic bacteriuria and do not address prophylaxis for prevention of symptomatic or asymptomatic urinary infection. This guideline is not meant to replace clinical judgment. Screening of asymptomatic subjects for bacteriuria is appropriate if bacteriuria has adverse outcomes that can be prevented by antimicrobial therapy [2]. Outcomes of interest are short term, such as symptomatic urinary infection (including bacteremia with sepsis or worsening functional status), and longer term, such as progression to chronic kidney disease or hypertension, development of urinary tract cancer, or decreased duration of survival. Treatment of asymptomatic bacteriuria may itself be associated with undesirable outcomes, including subsequent antimicrobial resistance, adverse drug effects, and cost. If treatment of bacteriuria is not beneficial, screening of asymptomatic populations to identify bacteriuria is not indicated, unless performed in a research study to further explore the biology or clinical significance of bacteriuria. Thus, there are 2 topics of interest: whether asymptomatic bacteriuria is associated with adverse outcomes, and whether the interventions of screening and antimicrobial treatment improve these outcomes. “Asymptomatic bacteriuria,” or asymptomatic urinary infection, is isolation of a specified quantitative count of bacteria in an appropriately collected urine specimen obtained from a person without symptoms or signs referable to urinary infection [3]. “Acute uncomplicated urinary tract infection” is a symptomatic bladder infection characterized by frequency, urgency, dysuria, or suprapubic pain in a woman with a normal genitourinary tract, and it is associated with both genetic and behavioral determinants [4]. “Acute nonobstructive pyelonephritis” is a renal infection characterized by costovertebral angle pain and tenderness, often with fever; it occurs in the same population that experiences acute uncomplicated urinary infection. “Complicated urinary tract infection,” which may involve either the bladder or kidneys, is a symptomatic urinary infection in individuals with functional or structural abnormalities of the genitourinary tract [5]. Uncomplicated urinary infection occurs rarely in men, and urinary infection in men is usually considered complicated. A “relapse” is a recurrent urinary tract infection after therapy resulting from persistence of the pretherapy isolate in the urinary tract. “Reinfection” is recurrent urinary tract infection with an organism originating from outside of the urinary tract, either a new bacterial strain or a strain previously isolated that has persisted in the colonizing flora of the gut or vagina [4]. “Pyuria” is the presence of increased numbers of polymorphonuclear leukocytes in the urine and is evidence of an inflammatory response in the urinary tract [6]. The recommendations in this guideline were developed after a review of studies published in English. These were identified through a search of the PubMed database supplemented by review of references of relevant papers to identify additional reports, particularly early studies not accessed through the PubMed search. In addition, experts in urinary infection were asked to identify any additional trials not accessed through review. Clinical studies include prospective, randomized clinical trials; prospective cohort studies; case-control studies; and other descriptive studies. When appropriate, the methodological rigor of studies was evaluated using accepted criteria (e.g., the CONSORT statement [7]). Studies were excluded if the study population was not adequately characterized to assess generalizability, if procedures for patient follow-up or exclusions may have introduced sufficient bias to limit the credibility of observations, or if there were insufficient numbers of patients enrolled to support valid statistical analysis. Asymptomatic bacteriuria is a microbiologic diagnosis determined with a urine specimen that has been collected in a manner to minimize contamination and transported to the laboratory in a timely fashion to limit bacterial growth. The usual quantitative definition is ⩾105 cfu/mL in 2 consecutive urine specimens [3], initially proposed after studies performed in the 1940s and 1950s [8, 9]. In these studies, a bacterial count of ⩾105 cfu/mL in a clean, voided specimen was confirmed by a concomitant count in a catheterized specimen in >95% of subjects in several asymptomatic clinical groups, whereas lower quantitative counts in the voided specimen were not usually confirmed by the catheterized specimen [8]. When the screening of asymptomatic women using multiple voided specimens was evaluated, bacteriuria documented in an initial voided urine specimen was confirmed in a second voided specimen, usually obtained several days later, only 80% of the time. If 2 successive bacteriuric voided specimens had similar positive culture results, a third consecutive specimen also yielded consistent results in 95% of cases [9, 10]. Some studies involving women have used a more restrictive criterion of 3 consecutive voided urine specimens collected over 3 weeks with consistent bacteriologic results [11, 12], whereas other studies have used a more permissive criterion of a single positive urine specimen yielding ⩾105 cfu/mL [13, 14]. Because transient bacteriuria is common in healthy young women [13, 15, 16], the prevalence will be lower if >1 specimen is required for identification of bacteriuria [13]. Microbiologic criteria for diagnosis of asymptomatic bacteriuria in men are not as well validated. The finding of a single voided urine specimen with ⩾105 cfu/mL of an Enterobacteriaceae was reproducible in 98% of asymptomatic ambulatory men when the culture was repeated within 1 week [17]. A voided specimen with the lower quantitative count of ⩾103 cfu/mL was 97% sensitive and 97% specific for identification of bacteriuria in ambulatory men, but most of these patients were symptomatic [18]. If urine specimens are collected using a freshly applied condom catheter and leg bag, however, ⩾105 cfu/mL is the appropriate quantitative criterion, with 90% validity for identifying asymptomatic bacteriuria in the voided specimen, compared with a paired catheterized specimen [19, 20]. With single urine specimens obtained by urethral catheterization, lower quantitative counts of ⩾102 cfu/mL are consistent with bacteriuria for both men and women [21, 22]. Patients who have chronic kidney disease, who are experiencing diuresis, or who are infected with selected fastidious organisms may have bacteriuria with lower quantitative counts in voided specimens, but the criteria for bacteriuria in such patients are not standardized [23]. Pyuria is evidence of inflammation in the genitourinary tract and is common in subjects with asymptomatic bacteriuria [13, 24–27]. Pyuria is present with asymptomatic bacteriuria in ∼32% of young women [13], 30%–70% of pregnant women [25, 26], 70% of diabetic women [24], 90% of elderly institutionalized patients [27], 90% of hemodialysis patients [28], 30%–75% of bacteriuric patients with short-term catheters in place [29], and 50%–100% of individuals with indwelling catheters in place Pyuria also other inflammatory of the genitourinary tract in patients with urine culture These may be either such as renal and or such as Thus, by the presence of is not sufficient to and the presence or of not symptomatic from asymptomatic urinary infection. The diagnosis of asymptomatic bacteriuria should be based on culture of a urine specimen collected in a manner that minimizes contamination (A-II). • For asymptomatic women, bacteriuria is defined as 2 consecutive voided urine specimens with isolation of the same bacterial strain in quantitative counts of ⩾105 cfu/mL (B-II). • A single, voided urine specimen with 1 bacterial species isolated in a quantitative count of ⩾105 cfu/mL identifies bacteriuria in asymptomatic men (B-III). • A single catheterized urine specimen with 1 bacterial species isolated in a quantitative count of ⩾102 cfu/mL identifies bacteriuria in women or men (A-II). Pyuria accompanying asymptomatic bacteriuria is not an indication for antimicrobial treatment (A-II). Asymptomatic bacteriuria is but the prevalence in populations with and the presence of genitourinary abnormalities (table For healthy women, the prevalence of bacteriuria with from to healthy women years of living in the community The prevalence of bacteriuria young women is associated with was women but only of similar Pregnant and nonpregnant women have a similar prevalence of bacteriuria is more common in diabetic women, with a prevalence of and is usually with duration of and presence of of with of diabetic Asymptomatic bacteriuria is in healthy young men The prevalence in men after the of of and associated with to of men years of who in the community are bacteriuric Diabetic men do not to have an increased prevalence of compared with men of asymptomatic bacteriuria in selected patient with chronic or characterized by urinary or with indwelling urinary have a prevalence of asymptomatic of Patients with short-term indwelling urethral catheters bacteriuria at the of (table Patients with spinal cord injury have a prevalence of whether is by or by and condom Patients hemodialysis have a prevalence of asymptomatic bacteriuria of to of elderly women and of elderly men in are bacteriuric The of these elderly persons have chronic with the prevalence of bacteriuria in the most The clinical assessment of elderly bacteriuric to the presence or of symptoms may be and of or urine by should not be as of symptomatic infection of a indwelling catheter or is associated with bacteriuria of the time. remains the single most common organism isolated from bacteriuric women [11, this for women with acute uncomplicated urinary tract infection. isolated from women with asymptomatic bacteriuria are characterized by are isolated from women with symptomatic infection Enterobacteriaceae as and other organisms (including and are common as For men, are also in to and species with abnormalities of the genitourinary tract, including elderly institutionalized have a of organisms remains the single most common organism isolated from women, but other such as are more common in men and women with a urologic in place usually have which often and such as and The of asymptomatic bacteriuria in nonpregnant women has been described in short-term and prospective cohort studies. In young women, symptomatic urinary infection more in bacteriuric women in women within 1 week after a urine culture of bacteriuric women compared with of women without [13]. The increased of symptomatic infection at 1 after bacteriuria [13]. cohort studies also an increased of symptomatic urinary infection in women identified with asymptomatic bacteriuria at initial screening In a after years of symptomatic urinary infection and at least once in and of women with bacteriuria at and in and of without with bacteriuria at were also more to be bacteriuric at of whether antimicrobial therapy was In 3 prospective studies from and that enrolled women increased was bacteriuric women The of bacteriuria and was not as when the bacteriuric and were and and for other was In a study that enrolled women with a of years there were in the of or chronic kidney disease bacteriuric and women after years of follow-up In study of women initially enrolled at years of the of progression to chronic kidney disease and were similar for bacteriuric and subjects after years women and subjects not with to and after years of follow-up in an study A prospective, randomized bacteriuric women to a of therapy with or The had a lower prevalence of bacteriuria at but not at 1 of symptomatic infection 1 after therapy with a similar in the treatment and These studies support the that women are at an increased for symptomatic urinary infection and are more to have bacteriuria at asymptomatic bacteriuria is not associated with adverse outcomes, such as hypertension, chronic kidney disease, genitourinary cancer, or decreased duration of survival. The of asymptomatic bacteriuria with symptomatic urinary infection is to that both symptomatic and asymptomatic urinary infection, symptomatic infection to asymptomatic bacteriuria. treatment of asymptomatic bacteriuria the of symptomatic infection further of asymptomatic bacteriuria. Screening for and treatment of asymptomatic bacteriuria in nonpregnant women is not (A-I). identified with asymptomatic bacteriuria in early have a increased of pregnancy, compared with women without bacteriuria These women also are more to and to have of clinical trials have that antimicrobial treatment of asymptomatic bacteriuria the of subsequent from to (table of cohort studies and randomized clinical trials also support the that antimicrobial treatment of asymptomatic bacteriuria the of and of these studies were performed early in the antimicrobial with and the most common The and of from multiple studies in screening for and treatment of asymptomatic bacteriuria a of in developed of of screening and treatment for asymptomatic bacteriuria in pregnant women a in of for pregnant women, from to in a and to in a These are consistent with the early of with screening for and treatment of asymptomatic bacteriuria pregnancy. of clinical trials of antimicrobial therapy for the treatment of asymptomatic bacteriuria in pregnancy. In the studies that the of treatment of asymptomatic bacteriuria pregnancy, of antimicrobial therapy usually continued for the duration of the (table A prospective, randomized study of antimicrobial therapy to the of compared with days of or by urine culture screening and if bacteriuria similar outcomes for the 2 treatment A review that there was insufficient evidence to a duration of antimicrobial therapy for pregnant women and treatment Thus, the duration of antimicrobial therapy for treatment of bacteriuria in pregnant women has not been The appropriate screening is a urine culture Screening for has a for identification of bacteriuria in pregnant women The of screening is not well with a urine culture for a single screening specimen at weeks have a of later in (table of this may be prevented with repeated screening is not A single urine obtained for culture at week of was to be in a study An from the of the of that a single screening culture in the was if the prevalence of bacteriuria was and the of in bacteriuric women was Pregnant women should be screened for bacteriuria by urine culture at least once in early pregnancy, and they should be treated if the results are positive (A-I). • The duration of antimicrobial therapy should be 3–7 days (A-III). • Periodic screening for recurrent bacteriuria should be undertaken after therapy (A-III). • No recommendation can be made for or against repeated screening of culture-negative women in the later of pregnancy. cohort studies of diabetic women in of symptomatic urinary infection, or progression to diabetic initially bacteriuric and women at or years of A of therapy or therapy for diabetic women with asymptomatic bacteriuria and continued screening for bacteriuria 3 after a of 3 years of that antimicrobial therapy not or the of symptomatic urinary infection, it the of for urinary infection or other was of progression of diabetic such as in bacteriuric subjects who not antimicrobial Diabetic women who antimicrobial however, had as days of antimicrobial and more adverse antimicrobial Thus, there were for continued screening and treatment of asymptomatic bacteriuria in diabetic women, and there was evidence of Screening for or treatment of asymptomatic bacteriuria in diabetic women is not (A-I). cohort studies of asymptomatic bacteriuria have enrolled both and women These studies adverse outcomes in women with asymptomatic bacteriuria. A prospective, randomized study of or also enrolled women with a years Thus, these studies that outcomes of bacteriuria and treatment of bacteriuria in healthy women are similar to in nonpregnant A prospective, randomized clinical of antimicrobial treatment for bacteriuria enrolled ambulatory women who in a and a in the prevalence of asymptomatic bacteriuria at but there was in the of symptomatic A prospective cohort study of ambulatory years of for including subjects with adverse outcomes to bacteriuria cohort studies bacteriuria and for men and women at years of follow-up or men and women years years of follow-up screening for and treatment of asymptomatic bacteriuria in persons in the community is not recommended (A-II). randomized clinical trials of antimicrobial therapy or therapy for elderly of have of screening for or treatment of asymptomatic bacteriuria (table was in the of symptomatic infection or in and there were in chronic genitourinary symptoms associated with antimicrobial Treatment of asymptomatic bacteriuria was associated with increased adverse antimicrobial and with organisms of cohort studies similar for with and without bacteriuria women in the men in and women or men in clinical trials of treatment of asymptomatic bacteriuria in elderly Screening for and treatment of asymptomatic bacteriuria in elderly institutionalized of is not recommended (A-I). with spinal cord have a prevalence of and they also a of symptomatic urinary infection When asymptomatic bacteriuria was treated in a cohort of spinal early of bacteriuria after therapy was the usual days of of subjects were bacteriuric by days after of and after a of were bacteriuric by days increased antimicrobial When patients with a of spinal cord injury were for the results of of urine were but only symptomatic of which to antimicrobial treatment In a of symptomatic urinary infection and of bacteriuria were similar recipients of either antimicrobial or for patients with bladder by A prospective, randomized of antimicrobial treatment or treatment of asymptomatic bacteriuria enrolled patients who were treated with and a similar of symptomatic urinary infection an of days of of whether were there have been a of clinical and of results is by short of follow-up and study review and treatment only of symptomatic urinary tract infection in patients with spinal cord Asymptomatic bacteriuria should not be screened for or treated in spinal patients (A-II). 80% of acute patients with short-term indwelling urethral catheters antimicrobial usually for an indication other urinary infection This of antimicrobial assessment of outcomes to treatment of asymptomatic bacteriuria A prospective, cohort study of catheter-acquired 90% of were only 1 infection A case-control study that of bacteriuria with indwelling urethral increased but the for this was not and that antimicrobial therapy not the with A prospective, of treatment of in more of had indwelling urethral catheters in in of 2 weeks after therapy for catheterized subjects and clinical of treatment A prospective, of antimicrobial treatment of asymptomatic bacteriuria 48 h after removal of short-term catheters in women with catheter-acquired bacteriuria microbiologic and clinical outcomes at days in treated women of women randomized to therapy had microbiologic by developed No women in the treatment This study enrolled a selected of women characterized by young and experiencing a short of 3 A prospective, randomized of therapy therapy for bacteriuric patients with indwelling urethral catheters in place and organisms isolated a similar of both treated and patients for weeks of were also but of organisms in the to compared with only in the treatment A prospective, study of consecutive of antimicrobial treatment to bacteriuria in elderly patients with catheters in the of of with compared with the and there was of bacteriuria after often with organisms of Asymptomatic bacteriuria or should not screened for or treated in patients with an indwelling urethral catheter (A-I). • Antimicrobial treatment of asymptomatic women with catheter-acquired bacteriuria that persists 48 h after catheter removal may be Patients with asymptomatic bacteriuria who genitourinary procedures associated with mucosal bleeding have a of bacteremia and occurs in to of bacteriuric patients who transurethral and there is clinical evidence of sepsis in of these persons and prospective, randomized clinical trials support the of antimicrobial treatment in these in bacteriuric men transurethral resection of the In the of was to that of is relevant to other but any with a of mucosal bleeding should be considered a of asymptomatic bacteriuria is not for For of a indwelling catheter is associated with a of and antimicrobial treatment is not The appropriate for of antimicrobial therapy is not well h before the has been this is to be and the for before the of therapy the before or before the procedure is The to a for culture before the procedure and the duration of antimicrobial therapy are also not in clinical In the of an indwelling antimicrobial therapy can be after the procedure When an indwelling catheter remains in place after a it has been recommended by that antimicrobial therapy be continued the catheter is Screening for and treatment of asymptomatic bacteriuria before transurethral resection of the prostate is recommended (A-I). • An assessment for the presence of bacteriuria should be obtained, so results will be available to direct antimicrobial therapy prior to the procedure (A-III). • Antimicrobial therapy should be initiated shortly before the procedure (A-II). • Antimicrobial therapy should not be continued the procedure, unless an indwelling catheter remains in place (B-II). Screening for and treatment of asymptomatic bacteriuria is recommended before other urologic procedures in which mucosal bleeding is anticipated (A-III). studies performed early in the a prevalence of asymptomatic bacteriuria renal transplant in the after in of has introduced of of indwelling urethral and antimicrobial prophylaxis to and other These interventions also both asymptomatic bacteriuria and symptomatic urinary infection studies, including a review and a prospective cohort study have not an asymptomatic bacteriuria and survival. recipients with urinary infection and are also characterized by urologic abnormalities and are identified by of symptomatic urinary infection, bacteriuria Thus, with screening for bacteriuria is to provide a Some experts do screening for at least for the after renal for of renal transplant however, recommendation for screening for bacteriuria Screening for or treatment of bacteriuria has not been evaluated for other solid organ transplant for infection prevention in transplant recipients recommendation for screening for bacteriuria A study of women with and bacteriuria randomized to either antimicrobial therapy or antimicrobial therapy in the to or the of in the 2 studies involving patients have asymptomatic bacteriuria and infection in women, but there was an increased prevalence of bacteriuria men that was with counts clinical outcomes associated with bacteriuria in these populations have not been No recommendation can be made for screening for or treatment of asymptomatic bacteriuria in renal transplant or other solid organ transplant recipients (C-III). Asymptomatic bacteriuria is Pregnant women with asymptomatic bacteriuria are at an increased for adverse outcomes, and these can be prevented with antimicrobial treatment of asymptomatic bacteriuria. Thus, pregnant women should be screened for bacteriuria and treated if results are Asymptomatic bacteriuria is also a for patients who urologic interventions with mucosal and such patients should be treated prior to such For other adult asymptomatic bacteriuria has not been to be persons with bacteriuria are at an increased of symptomatic urinary infection, treatment of asymptomatic bacteriuria not the of symptomatic infection or improve other outcomes. Thus, in populations other for treatment has been documented to be beneficial, screening for or treatment of asymptomatic bacteriuria is not appropriate and should be relevant to asymptomatic bacteriuria further research and in appropriately clinical of the clinical and microbiologic if of in selected such as pregnant The of a second urine specimen to asymptomatic bacteriuria prior to treatment after an initial positive screening specimen in pregnant The duration of antimicrobial therapy for treatment of asymptomatic bacteriuria in pregnant women in appropriate clinical of symptomatic of urinary infection in elderly institutionalized populations with a prevalence of bacteriuria. of asymptomatic bacteriuria in subjects with chronic kidney of the and appropriate of individuals with indwelling urinary other indwelling catheters (e.g., urinary and individuals with asymptomatic bacteriuria with organisms but without indwelling a for or including with or who have solid organ further of the if of asymptomatic bacteriuria. The to duration of and antimicrobial for treatment of bacteriuria prior to genitourinary procedures in further clinical there are clinical of screening for and treatment of bacteriuria prior to a procedure with including and the following individuals for review and in the development of this and was by of has research from has research from and has on the for has been a for and has been a for and on the for and

Tetrahydrobiopterin is a critical cofactor for the NO synthases, and in its absence these enzymes become "uncoupled," producing reactive oxygen species (ROSs) rather than NO. In aortas of mice with deoxycorticosterone acetate-salt (DOCA-salt) hypertension, ROS production from NO synthase is markedly increased, and tetrahydrobiopterin oxidation is evident. Using mice deficient in the NADPH oxidase subunit p47(phox) and mice lacking either the endothelial or neuronal NO synthase, we obtained evidence that hypertension produces a cascade involving production of ROSs from the NADPH oxidase leading to oxidation of tetrahydrobiopterin and uncoupling of endothelial NO synthase (eNOS). This decreases NO production and increases ROS production from eNOS. Treatment of mice with oral tetrahydrobiopterin reduces vascular ROS production, increases NO production as determined by electron spin resonance measurements of nitrosyl hemoglobin, and blunts the increase in blood pressure due to DOCA-salt hypertension. Endothelium-dependent vasodilation is only minimally altered in vessels of mice with DOCA-salt hypertension but seems to be mediated by hydrogen peroxide released from uncoupled eNOS, since it is inhibited by catalase. Tetrahydrobiopterin oxidation may represent an important abnormality in hypertension. Treatment strategies that increase tetrahydrobiopterin or prevent its oxidation may prove useful in preventing vascular complications of this common disease.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors are generally prescribed by physicians in doses lower than the large doses that have been shown to reduce morbidity and mortality in patients with heart failure. It is unclear, however, if low doses and high doses of ACE inhibitors have similar benefits. METHODS AND RESULTS: We randomly assigned 3164 patients with New York Heart Association class II to IV heart failure and an ejection fraction < or = 30% to double-blind treatment with either low doses (2.5 to 5.0 mg daily, n=1596) or high doses (32.5 to 35 mg daily, n=1568) of the ACE inhibitor, lisinopril, for 39 to 58 months, while background therapy for heart failure was continued. When compared with the low-dose group, patients in the high-dose group had a nonsignificant 8% lower risk of death (P=0.128) but a significant 12% lower risk of death or hospitalization for any reason (P=0.002) and 24% fewer hospitalizations for heart failure (P=0.002). Dizziness and renal insufficiency was observed more frequently in the high-dose group, but the 2 groups were similar in the number of patients requiring discontinuation of the study medication. Conclusions-These findings indicate that patients with heart failure should not generally be maintained on very low doses of an ACE inhibitor (unless these are the only doses that can be tolerated) and suggest that the difference in efficacy between intermediate and high doses of an ACE inhibitor (if any) is likely to be very small.

Global increases in atmospheric CO2 and temperature are associated with changes in ocean chemistry and circulation, altering light and nutrient regimes. Resulting changes in phytoplankton community structure are expected to have a cascading effect on primary and export production, food web dynamics and the structure of the marine food web as well the biogeochemical cycling of carbon and bio-limiting elements in the sea. A review of current literature indicates cell size and elemental stoichiometry often respond predictably to abiotic conditions and follow biophysical rules that link environmental conditions to growth rates, and growth rates to food web interactions, and consequently to the biogeochemical cycling of elements. This suggests that cell size and elemental stoichiometry are promising ecophysiological traits for modelling and tracking changes in phytoplankton community structure in response to climate change. In turn, these changes are expected to have further impacts on phytoplankton community structure through as yet poorly understood secondary processes associated with trophic dynamics.

The formation of the Isthmus of Panama stands as one of the greatest natural events of the Cenozoic, driving profound biotic transformations on land and in the oceans. Some recent studies suggest that the Isthmus formed many millions of years earlier than the widely recognized age of approximately 3 million years ago (Ma), a result that if true would revolutionize our understanding of environmental, ecological, and evolutionary change across the Americas. To bring clarity to the question of when the Isthmus of Panama formed, we provide an exhaustive review and reanalysis of geological, paleontological, and molecular records. These independent lines of evidence converge upon a cohesive narrative of gradually emerging land and constricting seaways, with formation of the Isthmus of Panama sensu stricto around 2.8 Ma. The evidence used to support an older isthmus is inconclusive, and we caution against the uncritical acceptance of an isthmus before the Pliocene.

Black carbon (BC), the product of incomplete combustion of fossil fuels and biomass (called elemental carbon (EC) in atmospheric sciences), was quantified in 12 different materials by 17 laboratories from different disciplines, using seven different methods. The materials were divided into three classes: (1) potentially interfering materials, (2) laboratory‐produced BC‐rich materials, and (3) BC‐containing environmental matrices (from soil, water, sediment, and atmosphere). This is the first comprehensive intercomparison of this type (multimethod, multilab, and multisample), focusing mainly on methods used for soil and sediment BC studies. Results for the potentially interfering materials (which by definition contained no fire‐derived organic carbon) highlighted situations where individual methods may overestimate BC concentrations. Results for the BC‐rich materials (one soot and two chars) showed that some of the methods identified most of the carbon in all three materials as BC, whereas other methods identified only soot carbon as BC. The different methods also gave widely different BC contents for the environmental matrices. However, these variations could be understood in the light of the findings for the other two groups of materials, i.e., that some methods incorrectly identify non‐BC carbon as BC, and that the detection efficiency of each technique varies across the BC continuum. We found that atmospheric BC quantification methods are not ideal for soil and sediment studies as in their methodology these incorporate the definition of BC as light‐absorbing material irrespective of its origin, leading to biases when applied to terrestrial and sedimentary materials. This study shows that any attempt to merge data generated via different methods must consider the different, operationally defined analytical windows of the BC continuum detected by each technique, as well as the limitations and potential biases of each technique. A major goal of this ring trial was to provide a basis on which to choose between the different BC quantification methods in soil and sediment studies. In this paper we summarize the advantages and disadvantages of each method. In future studies, we strongly recommend the evaluation of all methods analyzing for BC in soils and sediments against the set of BC reference materials analyzed here.

We present an extension of the Minimum Information about any (x) Sequence (MIxS) standard for reporting sequences of uncultivated virus genomes. Minimum Information about an Uncultivated Virus Genome (MIUViG) standards were developed within the Genomic Standards Consortium framework and include virus origin, genome quality, genome annotation, taxonomic classification, biogeographic distribution and in silico host prediction. Community-wide adoption of MIUViG standards, which complement the Minimum Information about a Single Amplified Genome (MISAG) and Metagenome-Assembled Genome (MIMAG) standards for uncultivated bacteria and archaea, will improve the reporting of uncultivated virus genomes in public databases. In turn, this should enable more robust comparative studies and a systematic exploration of the global virosphere.

ADVERTISEMENT RETURN TO ISSUEPREVArticleAromaticity as a Cornerstone of Heterocyclic ChemistryAlexandru T. Balaban, Daniela C. Oniciu, and Alan R. KatritzkyView Author Information Texas A&M University at Galveston, 5007 Avenue U, Galveston, Texas 77551 Esperion Therapeutics (a Division of Pfizer Global Research and Development), 3621 South State Street, Ann Arbor, Michigan 48108 Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200 Cite this: Chem. Rev. 2004, 104, 5, 2777–2812Publication Date (Web):April 17, 2004Publication History Received9 October 2003Published online17 April 2004Published inissue 1 May 2004https://pubs.acs.org/doi/10.1021/cr0306790https://doi.org/10.1021/cr0306790research-articleACS PublicationsCopyright © 2004 American Chemical SocietyRequest reuse permissionsArticle Views9861Altmetric-Citations628LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Aromatic compounds,Aromaticity,Energy,Heterocyclic compounds,Reaction products Get e-Alerts

With trauma, sepsis, cancer, or uremia, animals or patients experience accelerated degradation of muscle protein in the ATP-ubiquitin-proteasome (Ub-P'some) system. The initial step in myofibrillar proteolysis is unknown because this proteolytic system does not break down actomyosin complexes or myofibrils, even though it degrades monomeric actin or myosin. Since cytokines or insulin resistance are common in catabolic states and will activate caspases, we examined whether caspase-3 would break down actomyosin. We found that recombinant caspase-3 cleaves actomyosin, producing a characteristic, approximately 14-kDa actin fragment and other proteins that are degraded by the Ub-P'some. In fact, limited actomyosin cleavage by caspase-3 yields a 125% increase in protein degradation by the Ub-P'some system. Serum deprivation of L6 muscle cells stimulates actin cleavage and proteolysis; insulin blocks these responses by a mechanism requiring PI3K. Cleaved actin fragments are present in muscles of rats with muscle atrophy from diabetes or chronic uremia. Accumulation of actin fragments and the rate of proteolysis in muscle stimulated by diabetes are suppressed by a caspase-3 inhibitor. Thus, in catabolic conditions, an initial step resulting in loss of muscle protein is activation of caspase-3, yielding proteins that are degraded by the Ub-P'some system. Therapeutic strategies could be designed to prevent these events.

This communication presents an 11-center prospective randomized trial using the artificial dermis invented by Burke and Yannas. Patients with life-threatening burns who underwent primary excision and grafting within 7 days of injury had comparable sites randomized to receive either the artificial dermis (study site) or the investigator's usual skin grafting material (control site). Control materials were autograft, allograft, xenograft, or a synthetic dressing. Epidermal grafts were applied to the study site during a second operation, and surviving patients were followed for 1 year after grafting. One hundred thirty-nine sites on 106 patients were studied. Mean burn size was 46.5 +/- 15% mean total body surface (TBSA). Overall mortality was 13%, and mean hospital stay was 68 +/- 45 days. Median artificial dermis take was 80% compared with 95% for all comparative sites, but the take was equivalent to that of all nonautograft control materials. Results with the artificial dermis improved slightly as the investigators became more familiar with the material. Donor site thickness for the study site averaged .006'' +/- .002'' compared to .013'' +/- .018'' for control (p less than .0001) and the epidermal donor site healed an average of 4 days sooner (10 +/- 6 vs. 14 +/- 8 days) (p less than .0001). As the wounds matured during the first year, both patients and surgeons felt that both sites became more comparable in appearance and function. At the completion of the study, there was less hypertrophic scarring of the artificial dermis, and more patients preferred the artificial dermis to the control graft. Artificial dermis with an epidermal graft provides a permanent cover that is at least as satisfactory as currently available skin grafting techniques, and uses donor grafts that are thinner and donor sites that heal faster.

During latest Quaternary glaciation, the Black Sea became a giant freshwater lake. The surface of this lake drew down to levels more than 100 m below its outlet. When the Mediterranean rose to the Bosporus sill at 7,150 yr BP1, saltwater poured through this spillway to refill the lake and submerge, catastrophically, more than 100,000 km2 of its exposed continental shelf. The permanent drowning of a vast terrestrial landscape may possibly have accelerated the dispersal of early neolithic foragers and farmers into the interior of Europe at that time.

BACKGROUND: Safe and effective antiviral agents are needed to prevent infection with influenza A and B virus. Oseltamivir (GS4104), which can be administered orally, is the prodrug of GS4071, a potent and selective inhibitor of influenzavirus neuraminidases. We studied the use of oseltamivir for long-term prophylaxis against influenza in two placebo-controlled, double-blind trials at different U.S. sites during the winter of 1997-1998. METHODS: We randomly assigned 1559 healthy, nonimmunized adults 18 to 65 years old to receive either oral oseltamivir (75 mg given once or twice daily, for a total daily dose of 75 or 150 mg) or placebo for six weeks during a peak period of local influenzavirus activity. The primary end point with respect to efficacy was laboratory-confirmed influenza-like illness (defined as a temperature of at least 37.2 degrees C accompanied by at least one respiratory and at least one systemic symptom). RESULTS: In the two studies combined, the risk of influenza among subjects assigned to either once-daily or twice-daily oseltamivir (1.2 percent and 1.3 percent, respectively) was lower than that among subjects assigned to placebo (4.8 percent; P<0.001 and P=0.001 for the comparison with once-daily and twice-daily oseltamivir, respectively). The protective efficacy of oseltamivir in the two active-treatment groups combined was 74 percent (95 percent confidence interval, 53 to 88 percent) at all the sites combined and 82 percent (95 percent confidence interval, 60 to 93 percent) at sites in Virginia, where the rate of influenza infection was higher than the overall rate. For culture-proved influenza, the rate of protective efficacy in the two oseltamivir groups combined was 87 percent (95 percent confidence interval, 65 to 96 percent). The rate of laboratory-confirmed influenza infection was lower with oseltamivir than with placebo (5.3 percent vs. 10.6 percent, P<0.001). Oseltamivir was well tolerated but was associated with a greater frequency of nausea (12.1 percent and 14.6 percent in the once-daily and twice-daily groups, respectively) and vomiting (2.5 percent and 2.7 percent, respectively) than was placebo (nausea, 7.1 percent; vomiting, 0.8 percent). However, the frequency of premature discontinuation of drug or placebo was similar among the three groups (3.1 to 4.0 percent). CONCLUSIONS: Oseltamivir administered daily for six weeks by the oral route is safe and effective for the prevention of influenza.

At present, the limited existence of fossil fuels and the environmental issues over greenhouse gas emissions have been directly affected to the transition from conventional vehicles to electric vehicles (EVs). In fact, the electrification of transportation system and the growing demand of EVs have prompted recent researchers to investigate the optimal location of electric vehicle charging stations (EVCSs). However, there are numerous challenges would face when implementing EVs at large scale. For instance, underdeveloped EVCSs infrastructure, optimal EVCS locations, and charge scheduling in EVCSs. In addition, the most fundamental EV questions, such as EV cost and range, could be partly answered only by a well-developed EVCS infrastructure. According to the literature, the researchers have been followed different types of approaches, objective functions, constraints for problem formulation. Moreover, according to the approaches, objective functions, constraints, EV load modeling, uncertainty, vehicle to grid strategy, integration of distributed generation, charging types, optimization techniques, and sensitivity analysis are reviewed for the recent research articles. Furthermore, optimization techniques for optimal solution are also reviewed in this article. In addition, the EV load impact on the distribution network, environmental impacts and economic impact are discussed.

The carbon balance of peatlands is predicted to shift from a sink to a source this century. However, peatland ecosystems are still omitted from the main Earth system models that are used for future climate change projections, and they are not considered in integrated assessment models that are used in impact and mitigation studies. By using evidence synthesized from the literature and an expert elicitation, we define and quantify the leading drivers of change that have impacted peatland carbon stocks during the Holocene and predict their effect during this century and in the far future. We also identify uncertainties and knowledge gaps in the scientific community and provide insight towards better integration of peatlands into modelling frameworks. Given the importance of the contribution by peatlands to the global carbon cycle, this study shows that peatland science is a critical research area and that we still have a long way to go to fully understand the peatland–carbon–climate nexus. Peatlands are impacted by climate and land-use changes, with feedback to warming by acting as either sources or sinks of carbon. Expert elicitation combined with literature review reveals key drivers of change that alter peatland carbon dynamics, with implications for improving models.

A comprehensive seafloor biomass and abundance database has been constructed from 24 oceanographic institutions worldwide within the Census of Marine Life (CoML) field projects. The machine-learning algorithm, Random Forests, was employed to model and predict seafloor standing stocks from surface primary production, water-column integrated and export particulate organic matter (POM), seafloor relief, and bottom water properties. The predictive models explain 63% to 88% of stock variance among the major size groups. Individual and composite maps of predicted global seafloor biomass and abundance are generated for bacteria, meiofauna, macrofauna, and megafauna (invertebrates and fishes). Patterns of benthic standing stocks were positive functions of surface primary production and delivery of the particulate organic carbon (POC) flux to the seafloor. At a regional scale, the census maps illustrate that integrated biomass is highest at the poles, on continental margins associated with coastal upwelling and with broad zones associated with equatorial divergence. Lowest values are consistently encountered on the central abyssal plains of major ocean basins The shift of biomass dominance groups with depth is shown to be affected by the decrease in average body size rather than abundance, presumably due to decrease in quantity and quality of food supply. This biomass census and associated maps are vital components of mechanistic deep-sea food web models and global carbon cycling, and as such provide fundamental information that can be incorporated into evidence-based management.

Locomotor activity by diving marine mammals is accomplished while breath-holding and often exceeds predicted aerobic capacities. Video sequences of freely diving seals and whales wearing submersible cameras reveal a behavioral strategy that improves energetic efficiency in these animals. Prolonged gliding (greater than 78% descent duration) occurred during dives exceeding 80 meters in depth. Gliding was attributed to buoyancy changes with lung compression at depth. By modifying locomotor patterns to take advantage of these physical changes, Weddell seals realized a 9.2 to 59.6% reduction in diving energetic costs. This energy-conserving strategy allows marine mammals to increase aerobic dive duration and achieve remarkable depths despite limited oxygen availability when submerged.

A frequent conclusion based on study of individual records from the so-called Medieval Warm Period (∼1000-1300 A.D.) is that the present warmth of the 20 th century is not unusual and therefore cannot be taken as an indication of forced climate change from greenhouse gas emissions. This conclusion is not supported by published composites of Northern Hemisphere climate change, but the conclusions of such syntheses are often either ignored or challenged. In this paper, we revisit the controversy by incorporating additional time series not used in earlier hemispheric compilations. Another difference is that the present reconstruction uses records that are only 900–1000 years long, thereby, avoiding the potential problem of uncertainties introduced by using different numbers of records at different times. Despite clear evidence for Medieval warmth greater than present in some individual records, the new hemispheric composite supports the principal conclusion of earlier hemispheric reconstructions and, furthermore, indicates that maximum Medieval warmth was restricted to two-three 20–30 year intervals, with composite values during these times being only comparable to the mid-20 th century warm time interval. Failure to substantiate hemispheric warmth greater than the present consistently occurs in composites because there are significant offsets in timing of warmth in different regions; ignoring these offsets can lead to serious errors concerning inferences about the magnitude of Medieval warmth and its relevance to interpretation of late 20 th century warming.

The ability of engineered black carbons (or biochars) to resist abiotic and, or biotic degradation (herein referred to as recalcitrance) is crucial to their successful deployment as a soil carbon sequestration strategy. A new recalcitrance index, the R(50), for assessing biochar quality for carbon sequestration is proposed. The R(50) is based on the relative thermal stability of a given biochar to that of graphite and was developed and evaluated with a variety of biochars (n = 59), and soot-like black carbons. Comparison of R(50), with biochar physicochemical properties and biochar-C mineralization revealed the existence of a quantifiable relationship between R(50) and biochar recalcitrance. As presented here, the R(50) is immediately applicable to pre-land application screening of biochars into Class A (R(50) ≥ 0.70), Class B (0.50 ≤ R(50) < 0.70) or Class C (R(50) < 0.50) recalcitrance/carbon sequestration classes. Class A and Class C biochars would have carbon sequestration potential comparable to soot/graphite and uncharred plant biomass, respectively, whereas Class B biochars would have intermediate carbon sequestration potential. We believe that the coupling of the R(50), to an index-based degradation, and an economic model could provide a suitable framework in which to comprehensively assess soil carbon sequestration in biochars.

Abstract A regional haze with daily PM2.5 (fine particulate matters with diameters less than 2.5 µm) exceeding 500 µg/m3 lasted for several days in January 2013 over North China, offering an opportunity to evaluate models. Observations show that inorganic aerosols (sulfate, nitrate, and ammonium) are the largest contributor to PM2.5 during the haze period, while sulfate shows the largest enhancement ratio of 5.4 from the clean to haze period. The nested‐grid GEOS‐Chem model reproduces the distribution of PM2.5 and simulates up to 364 µg/m3 of daily maximum PM2.5. Yet on average, the model is a factor of 3 and 4 lower in PM2.5 and fails to capture the large sulfate enhancement from the clean to haze period. A doubling of SO2 emissions over North China, along with daily meteorology corrections, would be required to reconcile model results with surface SO2 observations, but it is not sufficient to explain the model discrepancy in sulfate. Heterogeneous uptake of SO2 on deliquesced aerosols is proposed as an additional source of sulfate under high‐relative humidity conditions during the haze period. Parameterizing this process in the model improves the simulated spatial distribution and results in a 70% increase of sulfate enhancement ratio and a 120% increase in sulfate fraction in PM2.5. Combined adjustments in emissions, meteorology, and sulfate chemistry lead to higher sulfate by a factor of 3 and 50% higher PM2.5, significantly reducing the model's low bias during the haze.

Most of the carbon fixed in primary production is rapidly cycled and remineralized, leaving behind various forms of organic carbon that contribute to a vast reservoir of nonliving organic matter in seawater. Most of this carbon resides in dissolved molecules of varying bioavailability and reactivity, and aspects of the cycling of this carbon remain an enigma. The size-reactivity continuum model provides a conceptual framework for understanding the mechanisms governing the formation and mineralization of this carbon. In the seawater bioassay experiments that served as the original basis for this model, investigators observed that larger size classes of organic matter were more bioavailable and more rapidly remineralized by microbes than were smaller size classes. Studies of the chemical composition and radiocarbon content of marine organic matter have further indicated that the complexity and age of organic matter increase with decreasing molecular size. Biodegradation processes appear to shape the size distribution of organic matter and the nature of the small dissolved molecules that persist in the ocean.