St. John Hospital & Medical Center

BACKGROUND: Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥ 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2) or a decline of ≥ 50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.).

BACKGROUND: Indications for cardiac-resynchronization therapy (CRT) in patients with heart failure include a prolonged QRS interval (> or =120 msec), in addition to other functional criteria. Some patients with narrow QRS complexes have echocardiographic evidence of left ventricular mechanical dyssynchrony and may also benefit from CRT. METHODS: We enrolled 172 patients who had a standard indication for an implantable cardioverter-defibrillator. Patients received the CRT device and were randomly assigned to the CRT group or to a control group (no CRT) for 6 months. The primary end point was the proportion of patients with an increase in peak oxygen consumption of at least 1.0 ml per kilogram of body weight per minute during cardiopulmonary exercise testing at 6 months. RESULTS: At 6 months, the CRT group and the control group did not differ significantly in the proportion of patients with the primary end point (46% and 41%, respectively). In a prespecified subgroup with a QRS interval of 120 msec or more, the peak oxygen consumption increased in the CRT group (P=0.02), but it was unchanged in a subgroup with a QRS interval of less than 120 msec (P=0.45). There were 24 heart-failure events requiring intravenous therapy in 14 patients in the CRT group (16.1%) and 41 events in 19 patients in the control group (22.3%), but the difference was not significant. CONCLUSIONS: CRT did not improve peak oxygen consumption in patients with moderate-to-severe heart failure, providing evidence that patients with heart failure and narrow QRS intervals may not benefit from CRT. (ClinicalTrials.gov number, NCT00132977 [ClinicalTrials.gov].).

BACKGROUND: Chronic right ventricular pacing has been reported to promote cardiac dyssynchrony. The PAVE trial prospectively compared chronic biventricular pacing to right ventricular pacing in patients undergoing ablation of the AV node for management of atrial fibrillation with rapid ventricular rates. METHODS AND RESULTS: One hundred and eighty-four patients requiring AV node ablation were randomized to receive a biventricular pacing system (n = 103) or a right ventricular pacing system (n = 81). The study endpoints were change in the 6-minute hallway walk test, quality of life, and left ventricular ejection fraction. Patient characteristics were similar (64% male; age: 69 +/- 10 years, ejection fraction: 0.46 +/- 0.16; 83%, NYHA Class II or III). At 6 months postablation, patients treated with cardiac resynchronization had a significant improvement in 6-minute walk distance, (31%) above baseline (82.9 +/- 94.7 m), compared to patients receiving right ventricular pacing, (24%) above baseline (61.2 +/- 90.0 m) (P = 0.04). There were no significant differences in the quality-of-life parameters. At 6 months postablation, the ejection fraction in the biventricular group (0.46 +/- 0.13) was significantly greater in comparison to patients receiving right ventricular pacing (0.41 +/- 0.13, P = 0.03). Patients with an ejection fraction <or=45% or with NYHA Class II/III symptoms receiving a biventricular pacemaker appear to have a greater improvement in 6-minute walk distance compared to patients with normal systolic function or Class I symptoms. CONCLUSION: For patients undergoing AV node ablation for atrial fibrillation, biventricular pacing provides a significant improvement in the 6-minute hallway walk test and ejection fraction compared to right ventricular pacing. These beneficial effects of cardiac resynchronization appear to be greater in patients with impaired systolic function or with symptomatic heart failure.

Previously published guidelines are available that provide comprehensive recommendations for detecting and preventing healthcare-associated infections (HAIs). The intent of this document is to highlight practical recommendations in a concise format designed to assist acute care hospitals in implementing and prioritizing their central line-associated bloodstream infection (CLABSI) prevention efforts. This document updates "Strategies to Prevent Central Line-Associated Bloodstream Infections in Acute Care Hospitals," 1 published in 2008. This expert guidance document is sponsored by the Society for Healthcare Epidemiology of America (SHEA) and is the product of a collaborative effort led by SHEA, the Infectious Diseases Society of America (IDSA), the American Hospital Association (AHA), the Association for Professionals in Infection Control and Epidemiology (APIC), and The Joint Commission, with major contributions from representatives of a number of organizations and societies with content expertise. The list of endorsing and supporting organizations is presented in the introduction to the 2014 updates. 2 section 2: background-strategies to detect clabsi I. Surveillance protocol and definition of CLABSIs A. Use consistent surveillance methods and definitions to allow comparison to benchmark data. B. Refer to the National Healthcare Safety Network (NHSN) Manual: Patient Safety Component Protocol for information on the appropriate surveillance methodology, including information about blood specimen collection, and for surveillance definitions of CLABSIs. The relevant sections of the manual are "Identifying Healthcare-Associated Infections (HAI) in NHSN," "Device-Associated Module: Methodology," and "Device-Associated Module: Central Line-Associated Bloodstream Infection (CLABSI) Event." 31 1. Recent data suggest that interrater reliability using NHSN definitions is lower than expected. 32-34 This may also affect the reliability of public reporting. Additionally, the NHSN surveillance definition for CLABSI is different from the clinical definition for catheterrelated bloodstream infection. 35 section 3: background-strategies to prevent clabsi I. Existing guidelines and recommendations A. Several governmental, public health, and professional organizations have published evidence-based guidelines and/or implementation aids regarding the prevention of CLABSI, including the following: 1. The Healthcare Infection Control Practices Advisory Committee (HICPAC), Centers for Disease Control and Prevention 36,37 2. The Institute for Healthcare Improvement 38 3. The Agency for Healthcare Research and Quality 39 4. The American Pediatric Surgical Association Outcomes and Clinical Trials Committee 40 5. The Joint Commission 41 6. APIC 42 7. The Infusion Nurses Society 43 B. The recommendations in this document focus on CVCs unless noted otherwise. These recommendations 1. Are not stratified on the basis of catheter type (eg, tunneled, implanted, cuffed, noncuffed catheter, and dialysis catheter) and 2. May not be applicable for prevention of bloodstream infections with other intravascular devices. II. Infrastructure requirements include the following: A. An adequately staffed infection prevention and control program responsible for identifying patients who meet the surveillance definition for CLABSI. B. Information technology to collect and calculate catheter-days as a denominator when computing rates of CLABSI and patient-days to allow calculation of CVC utilization. Catheter-days from information systems should be validated against a manual method, with a margin of error no greater than .%5 C. Resources to provide appropriate education and training. D. Adequate laboratory support for timely processing of specimens and reporting of results.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer related deaths in the world with an estimated number of 1.8 million new cases and about 881,000 deaths worldwide in 2018. The epidemiology of CRC varies significantly between different regions in the world as well as between different age, gender and racial groups. Multiple factors are involved in this variation, including risk factor exposure, demographic variations in addition to genetic susceptibility and genetic mutations and their effect on the prognosis and treatment response. In this mini-review, we discuss the recent epidemiological trend including the incidence and mortality of colorectal cancer worldwide and the factors affecting these trends.

BACKGROUND: The neurochemical and biological effects of antidepressant medications have become better defined over the last decade. When the anti-depressant bupropion was introduced in the United States in 1989, the specific pharmacologic basis of its clinical effects was uncertain. Research conducted over the past decade has significantly advanced the understanding of the neuropharmacology of bupropion and has demonstrated a novel mechanism of antidepressant activity. This article discusses the mechanism of action of bupropion and relates the drug's neuropharmacologic effects to its clinical efficacy and tolerability profiles. DATA SOURCES: Data were obtained via the MEDLINE database in an English-language search spanning the period 1965 to May 2002 and using the search terms bupropion, bupropion SR, and antidepressants, as well as from the manufacturer's bupropion databases. CONCLUSIONS: The preclinical and clinical data show that bupropion acts via dual inhibition of norepinephrine and dopamine reuptake and is devoid of clinically significant serotonergic effects or direct effects on postsynaptic receptors. Dual norepinephrine and dopamine reuptake inhibition is associated with a unique clinical profile. Bupropion has demonstrated efficacy comparable to that of other antidepressants. However, because bupropion is a selective norepinephrine and dopamine reuptake inhibitor with no serotonergic activity, common antidepressant-associated side effects, such as sexual dysfunction, weight gain, and sedation, are not associated with bupropion therapy.

IMPORTANCE: Since 2000, the incidence and severity of Clostridium difficile infection (CDI) have increased. OBJECTIVE: To review current evidence regarding best practices for the diagnosis and treatment of CDI in adults (age ≥ 18 years). EVIDENCE REVIEW: Ovid MEDLINE and Cochrane databases were searched using keywords relevant to the diagnosis and treatment of CDI in adults. Articles published between January 1978 and October 31, 2014, were selected for inclusion based on targeted keyword searches, manual review of bibliographies, and whether the article was a guideline, systematic review, or meta-analysis published within the past 10 years. Of 4682 articles initially identified, 196 were selected for full review. Of these, the most pertinent 116 articles were included. Clinical trials, large observational studies, and more recently published articles were prioritized in the selection process. FINDINGS: Laboratory testing cannot distinguish between asymptomatic colonization and symptomatic infection with C difficile. Diagnostic approaches are complex due to the availability of multiple testing strategies. Multistep algorithms using polymerase chain reaction (PCR) for the toxin gene(s) or single-step PCR on liquid stool samples have the best test performance characteristics (for multistep: sensitivity was 0.68-1.00 and specificity was 0.92-1.00; and for single step: sensitivity was 0.86-0.92 and specificity was 0.94-0.97). Vancomycin and metronidazole are first-line therapies for most patients, although treatment failures have been associated with metronidazole in severe or complicated cases of CDI. Recent data demonstrate clinical success rates of 66.3% for metronidazole vs 78.5% for vancomycin for severe CDI. Newer therapies show promising results, including fidaxomicin (similar clinical cure rates to vancomycin, with lower recurrence rates for fidaxomicin, 15.4% vs vancomycin, 25.3%; P = .005) and fecal microbiota transplantation (response rates of 83%-94% for recurrent CDI). CONCLUSIONS AND RELEVANCE: Diagnostic testing for CDI should be performed only in symptomatic patients. Treatment strategies should be based on disease severity, history of prior CDI, and the individual patient's risk of recurrence. Vancomycin is the treatment of choice for severe or complicated CDI, with or without adjunctive therapies. Metronidazole is appropriate for mild disease. Fidaxomicin is a therapeutic option for patients with recurrent CDI or a high risk of recurrence. Fecal microbiota transplantation is associated with symptom resolution of recurrent CDI but its role in primary and severe CDI is not established.

BACKGROUND: Catheter-associated urinary tract infections (CAUTI) are costly, common and often preventable by reducing unnecessary urinary catheter (UC) use. METHODS: To summarise interventions to reduce UC use and CAUTIs, we updated a prior systematic review (through October 2012), and a meta-analysis regarding interventions prompting UC removal by reminders or stop orders. A narrative review summarises other CAUTI prevention strategies including aseptic insertion, catheter maintenance, antimicrobial UCs, and bladder bundle implementation. RESULTS: 30 studies were identified and summarised with interventions to prompt removal of UCs, with potential for inclusion in the meta-analyses. By meta-analysis (11 studies), the rate of CAUTI (episodes per 1000 catheter-days) was reduced by 53% (rate ratio 0.47; 95% CI 0.30 to 0.64, p<0.001) using a reminder or stop order, with five studies also including interventions to decrease initial UC placement. The pooled (nine studies) standardised mean difference (SMD) in catheterisation duration (days) was -1.06 overall (p=0.065) including a statistically significant decrease in stop-order studies (SMD -0.37; p<0.001) but not in reminder studies (SMD, -1.54; p=0.071). No significant harm from catheter removal strategies is supported. Limited research is available regarding the impact of UC insertion and maintenance technique. A recent randomised controlled trial indicates antimicrobial catheters provide no significant benefit in preventing symptomatic CAUTIs. CONCLUSIONS: UC reminders and stop orders appear to reduce CAUTI rates and should be used to improve patient safety. Several evidence-based guidelines have evaluated CAUTI preventive strategies as well as emerging evidence regarding intervention bundles. Implementation strategies are important because reducing UC use involves changing well-established habits.

CONTEXT: Despite the growing popularity of bariatric surgery, there remain concerns about perioperative safety and variation in outcomes across hospitals. OBJECTIVE: To assess complication rates of different bariatric procedures and variability in rates of serious complications across hospitals and according to procedure volume and center of excellence (COE) status. DESIGN, SETTING, AND PATIENTS: Involving 25 hospitals and 62 surgeons statewide, the Michigan Bariatric Surgery Collaborative (MBSC) administers an externally audited, prospective clinical registry. We evaluated short-term morbidity in 15,275 Michigan patients undergoing 1 of 3 common bariatric procedures between 2006 and 2009. We used multilevel regression models to assess variation in risk-adjusted complication rates across hospitals and the effects of procedure volume and COE designation (by the American College of Surgeons or American Society for Metabolic and Bariatric Surgery) status. MAIN OUTCOME MEASURE: Complications occurring within 30 days of surgery. RESULTS: Overall, 7.3% of patients experienced perioperative complications, most of which were wound problems and other minor complications. Serious complications were most common after gastric bypass (3.6%; 95% confidence interval [CI], 3.2%-4.0%), followed by sleeve gastrectomy (2.2%; 95% CI, 1.2%-3.2%), and laparoscopic adjustable gastric band (0.9%; 95% CI, 0.6%-1.1%) procedures (P < .001). Mortality occurred in 0.04% (95% CI, 0.001%-0.13%) of laparoscopic adjustable gastric band, 0 sleeve gastrectomy, and 0.14% (95% CI, 0.08%-0.25%) of the gastric bypass patients. After adjustment for patient characteristics and procedure mix, rates of serious complications varied from 1.6% (95% CI, 1.3-2.0) to 3.5% (95% CI, 2.4-5.0) (risk difference, 1.9; 95% CI, 0.08-3.7) across hospitals. Average annual procedure volume was inversely associated with rates of serious complications at both the hospital level (< 150 cases, 4.1%; 95% CI, 3.0%-5.1%; 150-299 cases, 2.7%; 95% CI, 2.2-3.2; and > or = 300 cases, 2.3%; 95% CI, 2.0%-2.6%; P = .003) and surgeon level (< 100 cases, 3.8%; 95% CI, 3.2%-4.5%; 100-249 cases, 2.4%; 95% CI, 2.1%-2.8%; > or = 250 cases, 1.9%; 95% CI, 1.4%-2.3%; P = .001). Adjusted rates of serious complications were similar in COE and non-COE hospitals (COE, 2.7%; 95% CI, 2.5%-3.1%; non-COE, 2.0%; 95% CI, 1.5%-2.4%; P = .41). CONCLUSIONS: The frequency of serious complications among patients undergoing bariatric surgery in Michigan was relatively low. Rates of serious complications are inversely associated with hospital and surgeon procedure volume, but unrelated to COE accreditation by professional organizations.

Acinetobacter baumannii remains an important and difficult-to-treat pathogen whose resistance patterns result in significant challenges for the clinician. Despite the prevalence and interest in A. baumannii infections, there is relatively limited well-controlled scientific data to help the clinician select optimal empirical and subsequent targeted therapy for a variety of infections. We will review the currently available antimicrobial agents and discuss the clinical data supporting the use of the various agents.

At a crucial time with rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant globally, the United States Food and Drug Administration has issued an emergency use authorization for 2 oral antivirals, molnupiravir (in persons aged ≥18 years) and nirmatrelvir-ritonavir (Paxlovid) (in persons aged ≥12 years weighing ≥40 kg), for the outpatient treatment of patients with mild to moderate coronavirus disease 2019 (COVID-19) who are at risk for progression. Molnupiravir is a nucleoside analogue, whereas nirmatrelvir is a SARS-CoV-2 main protease inhibitor, and ritonavir is a human immunodeficiency virus type 1 protease inhibitor. Drug interactions are a major concern for nirmatrelvir-ritonavir. Nirmatrelvir-ritonavir demonstrated a greater risk reduction in hospitalization and death than molnupiravir compared to placebo. Both drugs need to be started within 5 days of symptoms onset and given for 5 days' duration. This article reviews the 2 oral COVID-19 antiviral drugs including the mechanisms of action, antiviral activity, pharmacokinetics, drug interactions, clinical experience including trials, adverse events, recommended indications, and formulary considerations.

BACKGROUND: Catheter-associated urinary tract infection (UTI) is a common device-associated infection in hospitals. Both technical factors--appropriate catheter use, aseptic insertion, and proper maintenance--and socioadaptive factors, such as cultural and behavioral changes in hospital units, are important in preventing catheter-associated UTI. METHODS: The national Comprehensive Unit-based Safety Program, funded by the Agency for Healthcare Research and Quality, aimed to reduce catheter-associated UTI in intensive care units (ICUs) and non-ICUs. The main program features were dissemination of information to sponsor organizations and hospitals, data collection, and guidance on key technical and socioadaptive factors in the prevention of catheter-associated UTI. Data on catheter use and catheter-associated UTI rates were collected during three phases: baseline (3 months), implementation (2 months), and sustainability (12 months). Multilevel negative binomial models were used to assess changes in catheter use and catheter-associated UTI rates. RESULTS: Data were obtained from 926 units (59.7% were non-ICUs, and 40.3% were ICUs) in 603 hospitals in 32 states, the District of Columbia, and Puerto Rico. The unadjusted catheter-associated UTI rate decreased overall from 2.82 to 2.19 infections per 1000 catheter-days. In an adjusted analysis, catheter-associated UTI rates decreased from 2.40 to 2.05 infections per 1000 catheter-days (incidence rate ratio, 0.86; 95% confidence interval [CI], 0.76 to 0.96; P=0.009). Among non-ICUs, catheter use decreased from 20.1% to 18.8% (incidence rate ratio, 0.93; 95% CI, 0.90 to 0.96; P<0.001) and catheter-associated UTI rates decreased from 2.28 to 1.54 infections per 1000 catheter-days (incidence rate ratio, 0.68; 95% CI, 0.56 to 0.82; P<0.001). Catheter use and catheter-associated UTI rates were largely unchanged in ICUs. Tests for heterogeneity (ICU vs. non-ICU) were significant for catheter use (P=0.004) and catheter-associated UTI rates (P=0.001). CONCLUSIONS: A national prevention program appears to reduce catheter use and catheter-associated UTI rates in non-ICUs. (Funded by the Agency for Healthcare Research and Quality.).

BACKGROUND AND OBJECTIVES: Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, regulates iron metabolism, and reduces hepcidin, was evaluated in this phase 2b study for safety, efficacy, optimal dose, and dose frequency in patients with nondialysis CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The 145 patients with nondialysis CKD and hemoglobin ≤10.5 g/dl were randomized into one of six cohorts of approximately 24 patients each with varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (two and three times weekly) followed by hemoglobin maintenance with roxadustat one to three times weekly. Treatment duration was 16 or 24 weeks. Intravenous iron was prohibited. The primary end point was the proportion of patients achieving hemoglobin increase of ≥1.0 g/dl from baseline and hemoglobin of ≥11.0 g/dl by week 17 (16 weeks of treatment). Secondary analyses included mean hemoglobin change from baseline, iron utilization, and serum lipids. Safety was evaluated by frequency/severity of adverse events. RESULTS: Of the 145 patients enrolled, 143 were evaluable for efficacy. Overall, 92% of patients achieved hemoglobin response. Higher compared with lower starting doses led to earlier achievement of hemoglobin response. Roxadustat-induced hemoglobin increases were independent of baseline C-reactive protein levels and iron repletion status. Overall, over the first 16 treatment weeks, hepcidin levels decreased by 16.9% (P=0.004), reticulocyte hemoglobin content was maintained, and hemoglobin increased by a mean (±SD) of 1.83 (±0.09) g/dl (P<0.001). Overall mean total cholesterol level was reduced by a mean (±SD) of 26 (±30) mg/dl (P<0.001) after 8 weeks of therapy, independent of the use of statins or other lipid-lowering agents. No drug-related serious adverse events were reported. CONCLUSIONS: In patients with nondialysis CKD who were anemic, various starting dose regimens of roxadustat were well tolerated and achieved anemia correction with reduced serum hepcidin levels. After anemia correction, hemoglobin was maintained by roxadustat at various dose frequencies without intravenous iron supplementation.

BACKGROUND: Tight blood glucose control has been correlated with a reduction in diabetes complications. Adherence to antidiabetic medications is crucial to achieving blood glucose control. OBJECTIVE: To assess the relationship between good glucose control [glycosylated hemoglobin (HbA1c) levels] and adherence to prescribed treatment in patients on a stable medication regimen for type 2 diabetes. METHODS: The Morisky survey, a 4-item questionnaire that predicts patient medication-taking behavior, was used to assess adherence in 301 patients. The relationship of HbA1c to Morisky score was evaluated, controlling for other variables related to patient demographics and clinical characteristics. Data were analyzed using a general linear model on log (HbA1c). RESULTS: Unadjusted mean HbA1c values (capped at 14.0%) for patients with Morisky scores of 0 or 1, 2, 3, and 4 were 8.92%, 8.67%, 7.74%, and 7.60%, respectively. Of all patients, 13.0%, 14.0%, 24.3%, and 48.8% had scores of 0 or 1, 2, 3, and 4, respectively. Good adherence (Morisky score > or = 3) was associated with a 10% lower total HbA1c (p = 0.0003) adjusted for all other factors in the model. Duration of diabetes (5-10 y) and presence of diabetes complications were also significantly associated with HbA1c (p = 0.026 and 0.002, respectively). Adherence was poor in 27% of patients. CONCLUSIONS: This study found that patients with a higher score on the Morisky scale had a lower associated HbA1c measurement. The Morisky score may be an efficient tool for identifying patients with poor medication-taking behavior who can then be targeted for directed adherence counseling services.

BACKGROUND: Sepsis is a common condition encountered by emergency and critical care physicians, with significant costs, both economic and human. Myocardial dysfunction in sepsis is a well-recognized but poorly understood phenomenon. There is an extensive body of literature on this subject, yet results are conflicting and no objective definition of septic cardiomyopathy exists, representing a critical knowledge gap. OBJECTIVES: In this article, we review the pathophysiology of septic cardiomyopathy, covering the effects of key inflammatory mediators on both the heart and the peripheral vasculature, highlighting the interconnectedness of these two systems. We focus on the extant literature on echocardiographic and laboratory assessment of the heart in sepsis, highlighting gaps therein and suggesting avenues for future research. Implications for treatment are briefly discussed. CONCLUSIONS: As a result of conflicting data, echocardiographic measures of left ventricular (systolic or diastolic) or right ventricular function cannot currently provide reliable prognostic information in patients with sepsis. Natriuretic peptides and cardiac troponins are of similarly unclear utility. Heterogeneous classification of illness, treatment variability, and lack of formal diagnostic criteria for septic cardiomyopathy contribute to the conflicting results. Development of formal diagnostic criteria, and use thereof in future studies, may help elucidate the link between cardiac performance and outcomes in patients with sepsis.

OBJECTIVE: Münchausen by proxy syndrome (MBPS) is a form of child abuse in which a parent fabricates or produces illness in a child. Although the medical consequences of MBPS have been well described, there is no detailed published account of what it was like to grow up in a family where the mother systematically induced serious illness. This article describes one victim's childhood experiences. METHODS: The medical history was obtained from a review of the original medical records, notes from the primary physician, discussions with two physicians who provided treatment, and several meetings with the victim and the victim's therapist. RESULTS: This article chronicles the actual experiences of an MBPS victim through 8 years of medical abuse at the hands of her mother, reveals the victim's account of what happened to her, describes what her family was like, details the long-term consequences on emotional and physical development, identifies the factors that influence recovery, and details the impact on family relationships. CONCLUSIONS: Child maltreatment and MBPS need to be part of the differential diagnosis when the clinical picture is atypical or does not appear medically plausible. The consequences of MBPS are psychological and physical and impact the entire family. Suggestions to assist heath care providers recognize, assess, and report cases of suspected MBPS are provided.

BackgroundRoxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that promotes erythropoiesis through increasing endogenous erythropoietin, improving iron regulation, and reducing hepcidin.Study DesignPhase 2, randomized (3:1), open-label, active-comparator, safety and efficacy study.Setting & ParticipantsPatients with stable end-stage renal disease treated with hemodialysis who previously had hemoglobin (Hb) levels maintained with epoetin alfa.InterventionPart 1: 6-week dose-ranging study in 54 individuals of thrice-weekly oral roxadustat doses versus continuation of intravenous epoetin alfa. Part 2: 19-week treatment in 90 individuals in 6 cohorts with various starting doses and adjustment rules (1.0-2.0 mg/kg or tiered weight based) in individuals with a range of epoetin alfa responsiveness. Intravenous iron was prohibited.OutcomesPrimary end point was Hb level response, defined as end-of-treatment Hb level change (ΔHb) of −0.5 g/dL or greater from baseline (part 1) and as mean Hb level ≥ 11.0 g/dL during the last 4 treatment weeks (part 2).MeasurementsHepcidin, iron parameters, cholesterol, and plasma erythropoietin (the latter in a subset).ResultsBaseline epoetin alfa doses were 138.3 ± 51.3 (SD) and 136.3 ± 47.7 U/kg/wk in part 1 and 152.8 ± 80.6 and 173.4 ± 83.7 U/kg/wk in part 2, in individuals randomly assigned to roxadustat and epoetin alfa, respectively. Hb level responder rates in part 1 were 79% in pooled roxadustat 1.5 to 2.0 mg/kg compared to 33% in the epoetin alfa control arm (P = 0.03). Hepcidin level reduction was greater at roxadustat 2.0 mg/kg versus epoetin alfa (P < 0.05). In part 2, the average roxadustat dose requirement for Hb level maintenance was ∼1.7 mg/kg. The least-squares-mean ΔHb in roxadustat-treated individuals was comparable to that in epoetin alfa–treated individuals (about −0.5 g/dL) and the least-squares-mean difference in ΔHb between both treatment arms was −0.03 (95% CI, −0.39 to 0.33) g/dL (mixed effect model-repeated measure). Roxadustat significantly reduced mean total cholesterol levels, not observed with epoetin alfa. No safety concerns were raised.LimitationsShort treatment duration and small sample size.ConclusionsIn this phase 2 study of anemia therapy in patients with end-stage renal disease on maintenance hemodialysis therapy, roxadustat was well tolerated and effectively maintained Hb levels. Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that promotes erythropoiesis through increasing endogenous erythropoietin, improving iron regulation, and reducing hepcidin. Phase 2, randomized (3:1), open-label, active-comparator, safety and efficacy study. Patients with stable end-stage renal disease treated with hemodialysis who previously had hemoglobin (Hb) levels maintained with epoetin alfa. Part 1: 6-week dose-ranging study in 54 individuals of thrice-weekly oral roxadustat doses versus continuation of intravenous epoetin alfa. Part 2: 19-week treatment in 90 individuals in 6 cohorts with various starting doses and adjustment rules (1.0-2.0 mg/kg or tiered weight based) in individuals with a range of epoetin alfa responsiveness. Intravenous iron was prohibited. Primary end point was Hb level response, defined as end-of-treatment Hb level change (ΔHb) of −0.5 g/dL or greater from baseline (part 1) and as mean Hb level ≥ 11.0 g/dL during the last 4 treatment weeks (part 2). Hepcidin, iron parameters, cholesterol, and plasma erythropoietin (the latter in a subset). Baseline epoetin alfa doses were 138.3 ± 51.3 (SD) and 136.3 ± 47.7 U/kg/wk in part 1 and 152.8 ± 80.6 and 173.4 ± 83.7 U/kg/wk in part 2, in individuals randomly assigned to roxadustat and epoetin alfa, respectively. Hb level responder rates in part 1 were 79% in pooled roxadustat 1.5 to 2.0 mg/kg compared to 33% in the epoetin alfa control arm (P = 0.03). Hepcidin level reduction was greater at roxadustat 2.0 mg/kg versus epoetin alfa (P < 0.05). In part 2, the average roxadustat dose requirement for Hb level maintenance was ∼1.7 mg/kg. The least-squares-mean ΔHb in roxadustat-treated individuals was comparable to that in epoetin alfa–treated individuals (about −0.5 g/dL) and the least-squares-mean difference in ΔHb between both treatment arms was −0.03 (95% CI, −0.39 to 0.33) g/dL (mixed effect model-repeated measure). Roxadustat significantly reduced mean total cholesterol levels, not observed with epoetin alfa. No safety concerns were raised. Short treatment duration and small sample size. In this phase 2 study of anemia therapy in patients with end-stage renal disease on maintenance hemodialysis therapy, roxadustat was well tolerated and effectively maintained Hb levels.

CKD is a major risk factor for ESRD, cardiovascular disease, and premature death. Whether dietary sodium and potassium intake affect CKD progression remains unclear. We prospectively studied the association of urinary sodium and potassium excretion with CKD progression and all-cause mortality among 3939 patients with CKD in the Chronic Renal Insufficiency Cohort Study. Urinary sodium and potassium excretion were measured using three 24-hour urine specimens, and CKD progression was defined as incident ESRD or halving of eGFR. During follow-up, 939 CKD progression events and 540 deaths occurred. Compared with the lowest quartile of urinary sodium excretion (<116.8 mmol/24 h), hazard ratios (95% confidence intervals) for the highest quartile of urinary sodium excretion (≥194.6 mmol/24 h) were 1.54 (1.23 to 1.92) for CKD progression, 1.45 (1.08 to 1.95) for all-cause mortality, and 1.43 (1.18 to 1.73) for the composite outcome of CKD progression and all-cause mortality after adjusting for multiple covariates, including baseline eGFR. Additionally, compared with the lowest quartile of urinary potassium excretion (<39.4 mmol/24 h), hazard ratios for the highest quartile of urinary potassium excretion (≥67.1 mmol/24 h) were 1.59 (1.25 to 2.03) for CKD progression, 0.98 (0.71 to 1.35) for all-cause mortality, and 1.42 (1.15 to 1.74) for the composite outcome. These data indicate that high urinary sodium and potassium excretion are associated with increased risk of CKD progression. Clinical trials are warranted to test the effect of sodium and potassium reduction on CKD progression.

Posaconazole is a triazole antifungal agent with a spectrum of activity that includes Candida and Cryptococcus species, many molds, and some endemic fungi. Posaconazole has received US Food and Drug Administration approval for the treatment of oropharyngeal candidiasis, including infections refractory to itraconazole and/or fluconazole. It is also approved as prophylaxis for invasive Aspergillus and Candida infections in patients aged >or=13 years who are at high risk of developing these infections, in adult and adolescent hematopoietic stem cell transplant recipients with graft-versus-host disease, and in persons with hematologic malignancies and prolonged neutropenia due to chemotherapy, who are at high risk of developing these infections. Approval for additional indications is being sought. Limited clinical experience suggests efficacy for the treatment of infections due to Zygomycetes and as salvage therapy for patients with invasive aspergillosis and coccidioidomycosis. Currently available only as an oral suspension, posaconazole, which has been well tolerated, requires administration with food or a nutritional supplement to assure adequate bioavailability. Posaconazole is predominantly eliminated in the feces, where it appears as unchanged drug. Metabolism, mostly glucuronidation, plays only a minor role in its elimination, as does renal clearance; as a consequence, dose adjustment is not required in the presence of renal or hepatic insufficiency. Although not a substrate of hepatic CYP450 3A4, posaconazole inhibits this enzyme and thus has the potential for significant pharmacokinetic interactions with drugs metabolized by this isoform. Its use in combination with CYP450 substrates that prolong the QTc interval is contraindicated, as is its use with ergot alkaloids; administration of posaconazole with other substrates and/or inducers of this enzyme system requires caution. Posaconazole is both a substrate and inhibitor of P-glycoprotein. Currently, the major roles for posaconazole in clinical practice are as prophylaxis for neutropenic patients with significant risk of infection with filamentous fungi and as therapy for zygomycoses. It may also have a role in the treatment of other filamentous fungal and some yeast infections, but assessment of its overall place in antifungal therapy awaits the availability of further clinical experience.

BACKGROUND: Aortic pulse wave velocity (PWV) is a measure of arterial stiffness and has proved useful in predicting cardiovascular morbidity and mortality in several populations of patients, including the healthy elderly, hypertensives and those with end-stage renal disease receiving hemodialysis. Little data exist characterizing aortic stiffness in patients with chronic kidney disease (CKD) who are not receiving dialysis, and in particular the effect of reduced kidney function on aortic PWV. METHODS: We performed measurements of aortic PWV in a cross-sectional cohort of participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study to determine factors which predict increased aortic PWV in CKD. RESULTS: PWV measurements were obtained in 2,564 participants. The tertiles of aortic PWV (adjusted for waist circumference) were <7.7 m/s, 7.7-10.2 m/s, and >10.2 m/s with an overall mean (+/- s.d.) value of 9.48 +/- 3.03 m/s (95% confidence interval = 9.35-9.61 m/s). Multivariable regression identified significant independent positive associations of age, blood glucose concentrations, race, waist circumference, mean arterial blood pressure, gender, and presence of diabetes with aortic PWV and a significant negative association with the level of kidney function. CONCLUSIONS: The large size of this unique cohort, and the targeted enrollment of CKD participants provides an ideal situation to study the role of reduced kidney function as a determinant of arterial stiffness. Arterial stiffness may be a significant component of the enhanced cardiovascular risk associated with kidney failure.