UMass Memorial Medical Center

OBJECTIVE: The 1987 American College of Rheumatology (ACR; formerly, the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticized for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. METHODS: A joint working group from the ACR and the European League Against Rheumatism developed, in 3 phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease--this being the appropriate current paradigm underlying the disease construct "rheumatoid arthritis." RESULTS: In the new criteria set, classification as "definite RA" is based on the confirmed presence of synovitis in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in 4 domains: number and site of involved joints (score range 0-5), serologic abnormality (score range 0-3), elevated acute-phase response (score range 0-1), and symptom duration (2 levels; range 0-1). CONCLUSION: This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimize the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct "rheumatoid arthritis."

Abstract The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes) 1 . In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

Epidemiologic evidence suggests that cancer incidence is associated with diabetes as well as certain diabetes risk factors and diabetes treatments. This consensus statement of experts assembled jointly by the American Diabetes Association and the American Cancer Society reviews the state of science concerning 1) the association between diabetes and cancer incidence or prognosis, 2) risk factors common to both diabetes and cancer, 3) possible biologic links between diabetes and cancer risk, and 4) whether diabetes treatments influence risk of cancer or cancer prognosis. In addition, key unanswered questions for future research are posed.

BACKGROUND: PATIENTS with rheumatoid arthritis (RA) are at increased risk of developing comorbid conditions. OBJECTIVES: To evaluate the prevalence of comorbidities and compare their management in RA patients from different countries worldwide. STUDY DESIGN: international, cross-sectional. PATIENTS: consecutive RA patients. DATA COLLECTED: demographics, disease characteristics (activity, severity, treatment), comorbidities (cardiovascular, infections, cancer, gastrointestinal, pulmonary, osteoporosis and psychiatric disorders). RESULTS: Of 4586 patients recruited in 17 participating countries, 3920 were analysed (age, 56±13 years; disease duration, 10±9 years (mean±SD); female gender, 82%; DAS28 (Disease Activity Score using 28 joints)-erythrocyte sedimentation rate, 3.7±1.6 (mean±SD); Health Assessment Questionnaire, 1.0±0.7 (mean±SD); past or current methotrexate use, 89%; past or current use of biological agents, 39%. The most frequently associated diseases (past or current) were: depression, 15%; asthma, 6.6%; cardiovascular events (myocardial infarction, stroke), 6%; solid malignancies (excluding basal cell carcinoma), 4.5%; chronic obstructive pulmonary disease, 3.5%. High intercountry variability was observed for both the prevalence of comorbidities and the proportion of subjects complying with recommendations for preventing and managing comorbidities. The systematic evaluation of comorbidities in this study detected abnormalities in vital signs, such as elevated blood pressure in 11.2%, and identified conditions that manifest as laboratory test abnormalities, such as hyperglycaemia in 3.3% and hyperlipidaemia in 8.3%. CONCLUSIONS: Among RA patients, there is a high prevalence of comorbidities and their risk factors. In this multinational sample, variability among countries was wide, not only in prevalence but also in compliance with recommendations for preventing and managing these comorbidities. Systematic measurement of vital signs and laboratory testing detects otherwise unrecognised comorbid conditions.

PURPOSE: Programmed cell death ligand 1 (PD-L1) is an immunomodulatory molecule expressed by antigen-presenting cells and select tumors that engages receptors on T cells to inhibit T-cell immunity. Immunotherapies targeting the PD-1/PD-L1 pathway have shown durable antitumor effects in a subset of patients with solid tumors. PD-L1 can be expressed by Reed-Sternberg cells comprising classical Hodgkin lymphoma (CHL) and by malignant B cells comprising EBV-positive posttransplant lymphoproliferative disorders (PTLD). We sought to determine whether the expression of PD-L1 represents a general strategy of immune evasion among aggressive B-cell lymphomas and virus- and immunodeficiency-associated tumors. EXPERIMENTAL DESIGN: Using novel antibodies and formalin-fixed, paraffin-embedded (FFPE) tissue biopsies, we examined 237 primary tumors for expression of PD-L1. RESULTS: Robust PD-L1 protein expression was found in the majority of nodular sclerosis and mixed cellularity CHL, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich B-cell lymphoma, EBV-positive and -negative PTLD, and EBV-associated diffuse large B-cell lymphoma (DLBCL), plasmablastic lymphoma, extranodal NK/T-cell lymphoma, nasopharyngeal carcinoma, and HHV8-associated primary effusion lymphoma. Within these tumors, PD-L1 was highly expressed by malignant cells and tumor-infiltrating macrophages. In contrast, neither the malignant nor the nonmalignant cells comprising nodular lymphocyte-predominant Hodgkin lymphoma, DLBCL-not otherwise specified, Burkitt lymphoma, and HHV8-associated Kaposi sarcoma expressed detectable PD-L1. CONCLUSION: Certain aggressive B-cell lymphomas and virus- and immunodeficiency-associated malignancies associated with an ineffective T-cell immune response express PD-L1 on tumor cells and infiltrating macrophages. These results identify a group of neoplasms that should be considered for PD-1/PD-L1-directed therapies, and validate methods to detect PD-L1 in FFPE tissue biopsies.

Advances in our understanding of the pathogenesis of RA over the past two decades, particularly the identification of cytokines that promote synovial inflammation (e.g. TNF-α, IL-1 and IL-6), have led to treatment courses that affect the disease process itself, beyond alleviation of symptoms. In turn, emphasis has shifted to intervention early enough in the disease course to prevent the joint destruction that follows inflammation. Accordingly, in 2010 the ACR and the European League Against Rheumatism (EULAR) put forward revised classification criteria emphasizing RA characteristics that emerge early in the disease course, including ACPAs, a biomarker that predicts aggressive disease. These were in contrast with the 1987 ARA criteria, which distinguished established RA patients from those with other forms of arthritis, and identified patients with later disease. The categories of the 2010 ACR/EULAR criteria are grouped into four classifications, with point scores for each: joint symptoms; serology (including RF and/or ACPA); symptom duration, whether <6 weeks or >6 weeks; and acute-phase reactants (CRP and/or ESR). The criteria were developed in a three-phase process, beginning with an analysis of patient cohorts to determine what disease characteristics had persuaded clinicians to initiate MTX therapy, followed by consensus-based decisions and the creation of a scoring system that would predict which patients would go on to develop persistent and/or erosive disease.

BACKGROUND: Limited information is available on trends in the incidence of and mortality due to cardiogenic shock complicating acute myocardial infarction. We studied the incidence of cardiogenic shock complicating acute myocardial infarction and in-hospital death rates among patients with this condition in a single community from 1975 through 1997. METHODS: We conducted an observational study of 9076 residents of metropolitan Worcester, Massachusetts, who were hospitalized with confirmed acute myocardial infarction in all local hospitals during 11 one-year periods between 1975 and 1997. Our study included periods before and after the advent of reperfusion therapy. RESULTS: The incidence of cardiogenic shock remained relatively stable over time, averaging 7.1 percent among patients with acute myocardial infarction. The results of a multivariable regression analysis indicated that the patients hospitalized during recent study years were not at a substantially lower risk for shock than patients hospitalized in the mid-to-late 1970s. Patients in whom cardiogenic shock developed had a significantly greater risk of dying during hospitalization (71.7 percent) than those who did not have cardiogenic shock (12.0 percent, P<0.001). A significant trend toward an increase in in-hospital survival among patients with cardiogenic shock in the mid-to-late 1990s was found in crude and adjusted analyses. CONCLUSIONS: Our findings indicate no significant change in the incidence of cardiogenic shock complicating acute myocardial infarction over a 23-year period. However, the short-term survival rate has increased in recent years at the same time as the use of coronary reperfusion strategies has increased.

BACKGROUND: Anemia, which is common in the critically ill, is often treated with red-cell transfusions, which are associated with poor clinical outcomes. We hypothesized that therapy with recombinant human erythropoietin (epoetin alfa) might reduce the need for red-cell transfusions. METHODS: In this prospective, randomized, placebo-controlled trial, we enrolled 1460 medical, surgical, or trauma patients between 48 and 96 hours after admission to the intensive care unit. Epoetin alfa (40,000 U) or placebo was administered weekly, for a maximum of 3 weeks; patients were followed for 140 days. The primary end point was the percentage of patients who received a red-cell transfusion. Secondary end points were the number of red-cell units transfused, mortality, and the change in hemoglobin concentration from baseline. RESULTS: As compared with the use of placebo, epoetin alfa therapy did not result in a decrease in either the number of patients who received a red-cell transfusion (relative risk for the epoetin alfa group vs. the placebo group, 0.95; 95% confidence interval [CI], 0.85 to 1.06) or the mean (+/-SD) number of red-cell units transfused (4.5+/-4.6 units in the epoetin alfa group and 4.3+/-4.8 units in the placebo group, P=0.42). However, the hemoglobin concentration at day 29 increased more in the epoetin alfa group than in the placebo group (1.6+/-2.0 g per deciliter vs. 1.2+/-1.8 g per deciliter, P<0.001). Mortality tended to be lower at day 29 among patients receiving epoetin alfa (adjusted hazard ratio, 0.79; 95% CI, 0.56 to 1.10); this effect was also seen in prespecified analyses in those with a diagnosis of trauma (adjusted hazard ratio, 0.37; 95% CI, 0.19 to 0.72). A similar pattern was seen at day 140 (adjusted hazard ratio, 0.86; 95% CI, 0.65 to 1.13), particularly in those with trauma (adjusted hazard ratio, 0.40; 95% CI, 0.23 to 0.69). As compared with placebo, epoetin alfa was associated with a significant increase in the incidence of thrombotic events (hazard ratio, 1.41; 95% CI, 1.06 to 1.86). CONCLUSIONS: The use of epoetin alfa does not reduce the incidence of red-cell transfusion among critically ill patients, but it may reduce mortality in patients with trauma. Treatment with epoetin alfa is associated with an increase in the incidence of thrombotic events. (ClinicalTrials.gov number, NCT00091910 [ClinicalTrials.gov].).

Single-center studies have reported an association between early (before day 100) cytomegalovirus (CMV) reactivation and decreased incidence of relapse for acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation. To substantiate these preliminary findings, the Center for International Blood and Marrow Transplant Research (CIBMTR) Database was interrogated to analyze the impact of CMV reactivation on hematologic disease relapse in the current era. Data from 9469 patients transplanted with bone marrow or peripheral blood between 2003 and 2010 were analyzed according to 4 disease categories: AML (n = 5310); acute lymphoblastic leukemia (ALL, n = 1883); chronic myeloid leukemia (CML, n = 1079); and myelodysplastic syndrome (MDS, n = 1197). Median time to initial CMV reactivation was 41 days (range, 1-362 days). CMV reactivation had no preventive effect on hematologic disease relapse irrespective of diagnosis. Moreover, CMV reactivation was associated with higher nonrelapse mortality [relative risk [RR] among disease categories ranged from 1.61 to 1.95 and P values from .0002 to <.0001; 95% confidence interval [CI], 1.14-2.61). As a result, CMV reactivation was associated with lower overall survival for AML (RR = 1.27; 95% CI, 1.17-1.38; P <.0001), ALL (RR = 1.46; 95% CI, 1.25-1.71; P <.0001), CML (RR = 1.49; 95% CI, 1.19-1.88; P = .0005), and MDS (RR = 1.31; 95% CI, 1.09-1.57; P = .003). In conclusion, CMV reactivation continues to remain a risk factor for poor posttransplant outcomes and does not seem to confer protection against hematologic disease relapse.

BACKGROUND: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. METHODS: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. RESULTS: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. CONCLUSIONS: Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).

Introduction Enterobacter sakazakii was originally designated as yellow-pigmented variant of Enterobacter cloacae until 1980 when it was introduced as a new species based on differences between E. sakazakii and E. cloacae in DNA-DNA hybridization, biochemical reactions, the production of yellow-pigmented colonies, and antibiotic susceptibility (12). It is a motile peritrichous, Gram-negative rod and its normal habitat is unclear. Muytjens and Kollee (26) could not isolate E. sakazakii from environmental sources such as surface water, soil, mud, rotting wood, grain, bird dung, rodents, domestic animals, cattle, and raw cow’s milk. Most of the E. sakazakii strains described in the literature have been isolated from clinical sources. Although its epidemiology and reservoir are unknown, intrinsically and extrinsically contaminated dried infant formula has been implicated as the source of outbreaks and sporadic cases of E. sakazakii infections and colonization among neonates (4,9,26,28,31). E. sakazakii is a rare cause of infections but has been known to cause sepsis and meningitis, particularly among neonates and infants (1,3,4,6,9,15,19,20,22,25,28,29,30,31,36–38,40). The first 2 known cases of E. sakazakii neonatal meningitis were reported by Urmenyi and Franklin (38) in 1961; it was then still classified as the pigmented strain of E. cloacae. The case-fatality rate of neonatal E. sakazakii infections has been reported to be as high as 50%, with half of the previously reported patients dying within 1 week of diagnosis. Neonatal meningitis caused by E. sakazakii has a propensity to result in cerebral abscess or infarction with cyst formation with severe neurologic impairment. There were only 4 reported cases of E. sakazakii infections among adults: 3 bacteremias of which 2 were due to urosepsis, and 1 osteomyelitis (10,16,18,32). To better delineate the clinical characteristics and outcomes of E. sakazakii infection, we report 5 cases of E. sakazakii infections in 1 child and 4 adults, and review the literature on this subject. Methods We reviewed all cultures positive for E. sakazakii from January 1995 to December 1996. The charts of patients with E. sakazakii infections at the University of Massachusetts Medical Center were abstracted for demographic data, underlying diseases, surgical procedures, type of infections, presence of ventilators and central lines, susceptibility testings, antimicrobial therapy, and outcome. We then reviewed the English-language literature from 1960 to 1999 with the use of MEDLINE (National Library of Medicine, Bethesda, MD). To broaden the search for E. sakazakii infections, the key words Enterobacteriaceae, Enterobacter, Enterobacter sakazakii infection, and Enterobacter infection were used. Available data regarding the clinical manifestations, treatment, and outcome are summarized. Abstracts of foreign-language literature with English translation were perused for cases of E. sakazakii infections through the same period. E. sakazakii was identified by the Vitek System and also by conventional biochemicals for Enterobacteriaceae (11). Susceptibility testings were determined by broth microdilution procedures. Epidemiology Review of the microbiology data showed that from 1994 through 1999, 3.6% (range, 2.2%-4.3%) of the blood stream infections at our institution were related to Enterobacter species. E. sakazakii was the etiologic agent only in fiscal year 1996 and accounted for 0.4% of all blood stream infection. With the exception of isolation of E. sakazakii in the sputa and blood of the patients in this report from January 1995 through December 1996, E. sakazakii has not been isolated from other clinical specimens at our institution. There was no clustering noted in this period. The 5 E. sakazakii infections reported were scattered throughout the 2-year period. Case Reports From January 1995 to December 1996, 5 cases of nosocomial E. sakazakii infections involving 1 child and 4 adults were observed. The infections included 3 bloodstream and 2 respiratory infections. The bloodstream infections were due to a central line, biliary source, and abdominal infection. Three patients had malignancies: embryonic rhabdomyosarcoma, tonsillar carcinoma, and Klatskin tumor. Two of these patients underwent chemotherapy and 1 was neutropenic when bacteremic with E. sakazakii. Two patients recovered and 3 died;E. sakazakii bacteremia contributed to 2 of the deaths. Case 1 A 3-year-old boy with embryonic rhabdomyosarcoma of the prostate metastatic to the temporal lobe underwent radiation therapy and 6 cycles of chemotherapy through a Broviac catheter for a period of 4 months. The patient was admitted for fever and neutropenia with an absolute neutrophil count of 100/mm3. On admission, blood cultures were positive for E. sakazakii and Serratia marcescens. The line was removed. E. sakazakii was resistant to cefazolin, intermediately sensitive to ampicillin, but sensitive to cefotaxime, gentamicin, and trimethoprim-sulfamethoxazole. The patient was begun on nafcillin and ceftazidime, which were changed to gentamicin and cefotaxime, and upon discharge he was given gentamicin and ceftriaxone for a total of 15 days. He became afebrile on day 5 and subsequent blood cultures were negative. Case 2 A 39-year-old man underwent resection of tonsillar carcinoma a year ago and received chemotherapy for metastatic disease. He was admitted for placement of gastrostomy tube and subsequently required emergent tracheostomy. His chest X-ray showed bibasilar bronchopneumonia consistent with aspiration pneumonitis. His sputum was purulent and grew E. sakazakii and Staphylococcus aureus. E. sakazakii was resistant to cefazolin and ampicillin and sensitive to cefotaxime, ceftazidime, genta-micin, and trimethoprim-sulfamethoxazole. He was given ceftazidime and clindamycin for 5 days followed by cefuroxime axetil and clindamycin via the gastrostomy tube for another 2 days. He recovered and his follow-up chest X-ray was free of infiltrates. Case 3 A 73-year-old woman was admitted for evaluation of painless jaundice. Endoscopic retrograde cholangiographic pancreatogram revealed stricture of hepatic duct that was relieved by stent placement. She had an exploratory laparotomy with resection of the common bile duct and hepatojejunostomy. The common bile duct revealed a Klatskin tumor. Her postoperative course was complicated by hypotension, hypoxemia, and renal failure. Cholangiogram showed occlusion of the left hepatic duct, with bile drainage growing E. sakazakii, Serratia marcescens, and enterococci. Blood cultures were positive for E. sakazakii. E. sakazakii was resistant to cefazolin, ampicillin, cefotaxime, ceftazidime, piperacillin-tazobactam, gentamicin, and ofloxacin, and was sensitive to amikacin, imipenem-cilastatin, and trimethoprim-sulfamethoxazole. She was given piperacillin-tazobactam for 3 days and 1 dose of gentamicin and switched to imipenem on the fourth day when she died from biliary sepsis. Case 4 An 82-year-old woman underwent emergent abdominal aortic aneurysmal repair. Her course was complicated by abdominal compartment syndrome with massively swollen viscera, acute respiratory distress syndrome, fever, metabolic acidosis, and oliguria. Nine days postoperatively her blood cultures were positive for E. sakazakii, which was resistant to cefazolin, cefuroxime, and ampicillin, and was sensitive to cefotaxime, piperacillin/tazobactam, gentamicin, ofloxacin, and trimethoprim-sulfamethoxazole. She was treated with ofloxacin and on the second day piperacillin/tazobactam was added, but she died on the sixth day. Case 5 A 76-year-old woman was found unresponsive and was intubated before being brought to the emergency room. She underwent emergent surgery for cecal volvulus with resection of the cecum. She remained intubated and developed Candida albicans bloodstream infection for which she was given amphotericin B. Three weeks postoperatively her chest X-ray showed an infiltrate and her purulent sputum grew E. sakazakii and S. aureus. There were 2 strains of E. sakazakii: the first strain was sensitive only to the aminoglycosides, quinolones, and trimethoprimsulfamethoxazole, while the second strain was susceptible only to the aminoglycosides and trimethoprim-sulfamethoxazole. She was initially treated with tobramycin and ceftazidime, and on the second day ceftazidime was discontinued and ofloxacin was added for a total of 10 days. Her course was complicated by hypotension requiring pressors and development of intraabdominal abscess requiring drainage. She expired 1 month after surgery. Comment: Cases 2 and 5 were patients with evidence of pneumonia with isolation of S. aureus and E. sakazakii. E. sakazakii might not be the causative agent for their infections. Susceptibility Testing These E. sakazakii isolates were uniformly resistant to ampicillin, cefazolin, and extended spectrum penicillins, and were not uniformly susceptible to the third-generation cephalosporins or the quinolones. They were uniformly susceptible to the aminoglycosides and trimethoprim-sulfamethoxazole. Literature Review Findings in the literature and our own cases of infections due to E. sakazakii in neonates, infants, children, and adults are summarized in Tables 1 and 2. Cases of colonization with E. sakazakii described in the outbreaks in neonates by Arseni’s group (3) are excluded. In addition, we excluded 1 case of E. sakazakii meningitis mentioned by Lecour et al (22), 2 cases of bacteremia from the M. D. Anderson Cancer Center reported by Bodey et al (5), and 2 cases of E. sakazakii bacteremia reported by Ansari et al (2), since no clinical details were given. One case of bacteremia in an infant who later developed a brain abscess was reported twice (14,15) and therefore was counted once. One case of E. sakazakii bacteremia reported by Chow et al (8) was excluded since there was no clinical information. Emery and Weymouth (10) mentioned 6 patients with clinical isolates of E. sakazakii but did not describe the types of infection with the exception of 1 patient with extended spectrum betalactamase producing E. sakazakii. This patient was included as 1 of the adult cases. Varaldo and colleagues (39) reported on the distribution and antibiotic susceptibility of extraintestinal clinical isolates of Enterobacteriaceae. Twelve of these isolates were E. sakazakii, of which 8 were from urine, 1 from genital secretion, 2 from respiratory secretion, and 1 from spinal fluid; however, there was no clinical information and therefore these were excluded.TABLE 1: Enterobacter sakazakii infections in neonates, infants, and childrenTABLE 1: ContinuedTABLE 1: ContinuedTABLE 1: ContinuedTABLE 2: Enterobacter sakazakii infections in adultsE. sakazakii infections among neonates, infants, and children In the literature there were 31 cases of E. sakazakii infections affecting neonates, infants, and children with sufficient clinical information to be included. Almost all cases were nosocomial and quite a few cases were associated with contaminated powdered milk or infant formula. The ages of these neonates, infants, and children with E. sakazakii infections ranged from 3 days to 4 years with half of them ≤1 week of age, and close to three-quarters being <1 month of age. Twenty-one patients presented with meningitis, 12 of whom also had concomitant E. sakazakii bacteremia, 7 with bacteremia alone, 1 with urinary tract infection, 1 with diarrheal illness, and 1 with infected dermoid cyst. Fifty-five percent of the neonates with birth weight available had weights ≤2,500 g. Seventy-five percent were either premature infants or had peripartum complications. Seizures were described in 9 of the 21 patients (43%) with meningitis. Pneumoencephalogram was performed on Patient 3 (see Table 1) and showed cysts in the ventricles; craniectomy revealed abscess. Computerized tomography (CT) of the head was first mentioned in a report from Kleiman et al (20). All CTs revealed abnormalities: cystic changes were most common, followed by abscesses or fluid collections, dilated ventricles, and infarctions. Persistently positive cerebral spinal fluid (CSF) cultures on treatment were noted in 5 of the patients with meningitis as late as day 40 of illness. Three of the 7 patients with bacteremia had diarrhea or bloody diarrhea, and necrotizing enterocolitis was mentioned in 2 of the patients with concomitant meningitis and bacteremia. These were the patients whose infection might be related to contaminated infant formulas. Susceptibility testing when available showed that E. sakazakii was usually sensitive to ampicillin, the aminoglycosides, chloramphenicol, and the third-generation cephalosporins. The neonates and infants were treated with a variety of antibiotics. Before 1985, patients with E. sakazakii infections were frequently treated with ampicillin, gentamicin and/or chloramphenicol. After 1985, the third-generation cephalosporins were commonly used in conjunction with ampicillin and gentamicin. The overall case-fatality rate for E. sakazakii infections among neonates and infants was 33%. Patients with meningitis had a case-fatality rate of 45%, and there was 1 death among patients with bacteremia without meningitis. E. sakazakii infections caused a higher case-fatality rate among premature or low-birth weight infants than full-term or infants with birth weight ≥2,500 g (50% versus 30%). The case-fatality rate among patients with meningitis before the use of third-generation cephalosporins was 62%; with the introduction of third-generation cephalosporins, it was 14%. Nine of the 11 patients with meningitis who survived the infection had follow-ups, all had hydrocephalus, some form of developmental delay, and neurologic sequelae. Autopsy reports were mentioned in 5 patients with meningitis. Pathologic findings showed evidence of meningoencephalitis or cerebral necrotic hemorrhage inflammation caused by massive invasion by Gram-negative bacilli. As mentioned previously, a few patients developed E. sakazakii bacteremia in the setting of contaminated infant formula. Bacteremia tended to affect low-birth weight and premature infants. Only 1 of the 7 patients with E. sakazakii bacteremia died. E. sakazakii infections among adults In contrast to the 31 cases of infection in neonates, infants, and children, there were only 4 reported cases of E. sakazakii infections in adults: 3 with bacteremia, 2 of which were secondary to urosepsis, and 1 with osteomyelitis of the foot, which was also coinfected with Staphylococcus epidermidis and Enterococcus species (10,16,18,32). Two of our patients presented with pneumonia and 2 with bacteremia. All patients were in their sixth decade of life with the exception of 1 of our patients (Case 2) who was 39 years of age. Two of the 4 patients from the literature and 2 of our patients with E. sakazakii infections had neoplasm. The other patients had serious underlying conditions that are ultimately fatal. Most adult cases were nosocomial. Among the adult patients, third-generation cephalosporins and the quinolones were frequently used for treatment of E. sakazakii infections. Three patients reported in the literature survived their infections, 3 of our patients died. Susceptibility testing Antibiotic susceptibility testing results were available for some of the isolates reported in the literature. E. sakazakii was susceptible to ampicillin, tetracycline, chloramphenicol, gentamicin, and the third-generation cephalosporins, which is in contrast to our strains with uniform resistance to ampicillin and variable resistance to the other beta-lactams including the third-generation cephalosporins. Discussion E. sakazakii infections continue to be rare but are more common among neonates and infants than adults. Among neonates and infants, E. sakazakii has a propensity to cause meningitis resulting in ventriculitis, brain abscess or cyst formation, and late development of hydrocephalus requiring ventricular-peritoneal (VP) shunt. Other Gram-negative bacilli with a propensity to cause neonatal brain abscess are Citrobacter diversus and Escherichia coli(13,21). Using DNA-DNA hybridization techniques, strains of E. sakazakii have shown a 50% relationship to C. diversus(12). Mortality and morbidity of E. sakazakii meningitis is high with virtually all patients recovering from central nervous system infections suffering from developmental delay mentally and/or physically. The majority of the adults with E. sakazakii infections had underlying diseases and notably 4 out of 8 adults had malignancies. However there has not been a known case of meningitis. Muytjens and van de Repe (27) performed comparative in vitro susceptibilities of 8 Enterobacter species including E. sakazakii. Their results showed that resistance to ampicillin or inhibition by a high concentration of cephalothin was likely to exclude E. sakazakii, and they further suggested that this could be used to eliminate additional steps in the identification of E. sakazakii. Indeed the isolates gleaned from the literature were uniformly sensitive to ampicillin. However, in contrast, our isolates were all resistant to ampicillin and some of the broad-spectrum beta-lactams as well. Burwen and colleagues (7) tested 3,992 Enterobacter isolates and found that 36% were resistant to ceftazidime. Resistance increased significantly during the 1987–1991 period and was more common among isolates from patients in intensive care units, urinary tract or bloodstream infection sites, and teaching hospitals. The prevalence of resistance among isolates of Enterobacter to beta-lactams, trimethoprim-sulfamethoxazole, and quinolones, in general, increases with the size of the hospital, reflecting possible selective antibiotic pressure on the development of resistance among the Enterobacter. Although the authors did not specify what proportion of the Enterobacter tested was E. sakazakii, the overall increasing trend of antibiotic resistance among all Enterobacter species may well explain the increased antibiotic resistance that was observed among our clinical E. sakazakii isolates. Before the introduction of the third-generation cephalosporins, E. sakazakii meningitis was treated with ampicillin and gentamicin or ampicillin and chlor-amphenicol. Of the 13 cases treated before the availability of third-generation cephalosporins, 8 patients (62%) died. Seven cases were treated with a third-generation cephalosporin in combination with ampicillin plus or minus gentamicin, all survived with 1 person dead within hours and there was no outcome information on another patient (Patient 29). It would seem that the outcome of E. sakazakii meningitis improved with the availability of the third-generation cephalosporins. Enterobacter species are among those Gram-negative bacteria most likely to produce beta-lactamases capable of inactivating broad-spectrum penicillins and cephalosporins (8,10). With increasing antibiotics resistance being observed among Enterobacter species, the use of carbapenems, or the newer cephalosporins, such as cefepime, in combination with a second agent should be considered and susceptibility testing done. Sanders and colleagues (35) did not note emergence of resistance to cefepime when they treated a variety of infections caused by multiply-resistant species with this and of the infections were However of the infections the central nervous emergence of resistance to cefepime during treatment of bacteremia and hepatic abscess due to E. in a patient who underwent has been reported The this report the use of cefepime in patients with infections such as pneumonia or abscess caused by strains of Enterobacter species. The further suggested that of susceptibility testing should be when Enterobacter infections due to strains with This would to the emergence of with resistance to ceftazidime and a higher concentration to cefepime still within the of this is the to to should be susceptibility data that Enterobacter species sensitive to the aminoglycosides and and these may be as a second agent the of aminoglycosides the central nervous system may their use to or and colleagues reported their own for the treatment of Enterobacter meningitis and reviewed the literature. They found that all patients treated with were to of those who received resistance to cephalosporins developed in for which these were days the of the antibiotics. E. sakazakii has a propensity to the central nervous system of neonates and infants and frequently the development of cysts or head should be considered on in the of patients with isolation of E. sakazakii from the blood or Although some authors reported from fluid from the cysts or abscesses the aspiration after weeks of antibiotic and isolated E. sakazakii from fluid from the abscess on the day of after than a week of antibiotics and a at 2 weeks A follow-up should be the first not cystic since new findings such as hydrocephalus may and/or of fluid may be in when there was no fluid in the The findings of this are by the that the literature search was to in The Enterobacteriaceae and Enterobacter species were in that describe Enterobacter, of these did not additional cases of E. sakazakii infection. English from foreign-language literature were perused for E. sakazakii infections from through 1999, at 5 cases were Two of these were in premature and there was no of the ages for the other One infant had meningitis with cerebral and and the a premature had Of the 3 patients, 2 had E. sakazakii isolated from and a from an Enterobacter sakazakii cause serious infections among the and the It to be more common among neonates and infants than adults. for the central nervous system in neonates and infants a Among neonates and infants, E. sakazakii has a propensity to cause meningitis resulting in ventriculitis, brain abscess or cyst formation, and development of hydrocephalus requiring ventricular-peritoneal shunt. tomography of the head is therefore in patients with E. sakazakii meningitis. Mortality and morbidity of E. sakazakii meningitis is and virtually all patients recovering from the central nervous system infection and developmental The case-fatality rate among patients with meningitis treated with the third-generation cephalosporins. Most adults with E. sakazakii infection had serious underlying diseases and 50% of the adults with the infection had malignancies. However there has been a known case of meningitis. antibiotic resistance among Enterobacter species should to the or the newer cephalosporins in combination with a second agent such as an data that may be a agent in the treatment of infections caused by the Enterobacter species, in of the production of capable of inactivating the cephalosporins and The and for the cases.

Osteoarthritis (OA) is a degenerative joint disease, and the mechanism of its pathogenesis is poorly understood. Recent human genetic association studies showed that mutations in the Frzb gene predispose patients to OA, suggesting that the Wnt/beta-catenin signaling may be the key pathway to the development of OA. However, direct genetic evidence for beta-catenin in this disease has not been reported. Because tissue-specific activation of the beta-catenin gene (targeted by Col2a1-Cre) is embryonic lethal, we specifically activated the beta-catenin gene in articular chondrocytes in adult mice by generating beta-catenin conditional activation (cAct) mice through breeding of beta-catenin(fx(Ex3)/fx(Ex3)) mice with Col2a1-CreER(T2) transgenic mice. Deletion of exon 3 of the beta-catenin gene results in the production of a stabilized fusion beta-catenin protein that is resistant to phosphorylation by GSK-3beta. In this study, tamoxifen was administered to the 3- and 6-mo-old Col2a1-CreER(T2);beta-catenin(fx(Ex3)/wt) mice, and tissues were harvested for histologic analysis 2 mo after tamoxifen induction. Overexpression of beta-catenin protein was detected by immunostaining in articular cartilage tissues of beta-catenin cAct mice. In 5-mo-old beta-catenin cAct mice, reduction of Safranin O and Alcian blue staining in articular cartilage tissue and reduced articular cartilage area were observed. In 8-mo-old beta-catenin cAct mice, cell cloning, surface fibrillation, vertical clefting, and chondrophyte/osteophyte formation were observed. Complete loss of articular cartilage layers and the formation of new woven bone in the subchondral bone area were also found in beta-catenin cAct mice. Expression of chondrocyte marker genes, such as aggrecan, Mmp-9, Mmp-13, Alp, Oc, and colX, was significantly increased (3- to 6-fold) in articular chondrocytes derived from beta-catenin cAct mice. Bmp2 but not Bmp4 expression was also significantly upregulated (6-fold increase) in these cells. In addition, we also observed overexpression of beta-catenin protein in the knee joint samples from patients with OA. These findings indicate that activation of beta-catenin signaling in articular chondrocytes in adult mice leads to the premature chondrocyte differentiation and the development of an OA-like phenotype. This study provides direct and definitive evidence about the role of beta-catenin in the development of OA.

BACKGROUND: Microbiologic cultures, the current gold standard diagnostic method for invasive Candida infections, have low specificity and take up to 2-5 days to grow. We present the results of the first extensive multicenter clinical trial of a new nanodiagnostic approach, T2 magnetic resonance (T2MR), for diagnosis of candidemia. METHODS: Blood specimens were collected from 1801 hospitalized patients who had a blood culture ordered for routine standard of care; 250 of them were manually supplemented with concentrations from <1 to 100 colony-forming units (CFUs)/mL for 5 different Candida species. RESULTS: T2MR demonstrated an overall specificity per assay of 99.4% (95% confidence interval [CI], 99.1%-99.6%) with a mean time to negative result of 4.2 ± 0.9 hours. Subanalysis yielded a specificity of 98.9% (95% CI, 98.3%-99.4%) for Candida albicans/Candida tropicalis, 99.3% (95% CI, 98.7%-99.6%) for Candida parapsilosis, and 99.9% (95% CI, 99.7%-100.0%) for Candida krusei/Candida glabrata. The overall sensitivity was found to be 91.1% (95% CI, 86.9%-94.2%) with a mean time of 4.4 ± 1.0 hours for detection and species identification. The subgroup analysis showed a sensitivity of 92.3% (95% CI, 85.4%-96.6%) for C. albicans/C. tropicalis, 94.2% (95% CI, 84.1%-98.8%) for C. parapsilosis, and 88.1% (95% CI, 80.2%-93.7%) for C. krusei/C. glabrata. The limit of detection was 1 CFU/mL for C. tropicalis and C. krusei, 2 CFU/mL for C. albicans and C. glabrata, and 3 CFU/mL for C. parapsilosis. The negative predictive value was estimated to range from 99.5% to 99.0% in a study population with 5% and 10% prevalence of candidemia, respectively. CONCLUSIONS: T2MR is the first fully automated technology that directly analyzes whole blood specimens to identify species without the need for prior isolation of Candida species, and represents a breakthrough shift into a new era of molecular diagnostics. CLINICAL TRIALS REGISTRATION: NCT01752166.

BACKGROUND: Although a role for resection of solitary metastases from renal cell carcinoma (RCC) has been described, the utility of surgery in patients with multiple sites of disease has been less well defined. The authors report the survival of patients who underwent complete metastasectomy for multiple RCC metastases. METHODS: The authors identified 887 patients who underwent nephrectomy for RCC between 1976 and 2006 who developed multiple metastatic lesions. The impact of complete metastasectomy on survival was evaluated controlling for the timing, location, and number of metastases and for patient performance status. RESULTS: Of 887 patients, 125 (14%) underwent complete surgical resection of all metastases. Complete metastasectomy was associated with a significant prolongation of median cancer-specific survival (CSS) (4.8 years vs 1.3 years; P < .001). Patients who had lung-only metastases had a 5-year CSS rate of 73.6% with complete resection versus 19% without complete resection (P < .001). A survival advantage from complete metastasectomy also was observed among patients with multiple, nonlung-only metastases, who had a 5-year CSS rate of 32.5% with complete resection versus 12.4% without complete resection (P < .001). Complete resection remained predictive of improved CSS for patients who had ≥ 3 metastatic lesions (P < .001) and for patients who had synchronous (P < .001) and asynchronous (P = .002) multiple metastases. Moreover, on multivariate analysis, the absence of complete metastasectomy was associated significantly with an increased risk of death from RCC (hazard ratio, 2.91; 95% confidence interval, 2.17-3.90; P < .001). CONCLUSIONS: The current results indicated that complete resection of multiple RCC metastases may be associated with long-term survival and should be considered when technically feasible in appropriate surgical candidates.

Background: Endovascular treatment with mechanical thrombectomy (MT) is beneficial for patients with acute stroke suffering a large-vessel occlusion, although treatment efficacy is highly time-dependent. We hypothesized that interhospital transfer to endovascular-capable centers would result in treatment delays and worse clinical outcomes compared with direct presentation. Methods: STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) was a prospective, multicenter, observational, single-arm study of real-world MT for acute stroke because of anterior-circulation large-vessel occlusion performed at 55 sites over 2 years, including 1000 patients with severe stroke and treated within 8 hours. Patients underwent MT with or without intravenous tissue plasminogen activator and were admitted to endovascular-capable centers via either interhospital transfer or direct presentation. The primary clinical outcome was functional independence (modified Rankin Score 0–2) at 90 days. We assessed (1) real-world time metrics of stroke care delivery, (2) outcome differences between direct and transfer patients undergoing MT, and (3) the potential impact of local hospital bypass. Results: A total of 984 patients were analyzed. Median onset-to-revascularization time was 202.0 minutes for direct versus 311.5 minutes for transfer patients ( P &lt;0.001). Clinical outcomes were better in the direct group, with 60.0% (299/498) achieving functional independence compared with 52.2% (213/408) in the transfer group (odds ratio, 1.38; 95% confidence interval, 1.06–1.79; P =0.02). Likewise, excellent outcome (modified Rankin Score 0–1) was achieved in 47.4% (236/498) of direct patients versus 38.0% (155/408) of transfer patients (odds ratio, 1.47; 95% confidence interval, 1.13–1.92; P =0.005). Mortality did not differ between the 2 groups (15.1% for direct, 13.7% for transfer; P =0.55). Intravenous tissue plasminogen activator did not impact outcomes. Hypothetical bypass modeling for all transferred patients suggested that intravenous tissue plasminogen activator would be delayed by 12 minutes, but MT would be performed 91 minutes sooner if patients were routed directly to endovascular-capable centers. If bypass is limited to a 20-mile radius from onset, then intravenous tissue plasminogen activator would be delayed by 7 minutes and MT performed 94 minutes earlier. Conclusions: In this large, real-world study, interhospital transfer was associated with significant treatment delays and lower chance of good outcome. Strategies to facilitate more rapid identification of large-vessel occlusion and direct routing to endovascular-capable centers for patients with severe stroke may improve outcomes. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02239640.

BACKGROUND: Multiple lines of evidence indicate a strong genetic contribution to autism spectrum disorders (ASDs). Current guidelines for clinical genetic testing recommend a G-banded karyotype to detect chromosomal abnormalities and fragile X DNA testing, but guidelines for chromosomal microarray analysis have not been established. PATIENTS AND METHODS: A cohort of 933 patients received clinical genetic testing for a diagnosis of ASD between January 2006 and December 2008. Clinical genetic testing included G-banded karyotype, fragile X testing, and chromosomal microarray (CMA) to test for submicroscopic genomic deletions and duplications. Diagnostic yield of clinically significant genetic changes was compared. RESULTS: Karyotype yielded abnormal results in 19 of 852 patients (2.23% [95% confidence interval (CI): 1.73%-2.73%]), fragile X testing was abnormal in 4 of 861 (0.46% [95% CI: 0.36%-0.56%]), and CMA identified deletions or duplications in 154 of 848 patients (18.2% [95% CI: 14.76%-21.64%]). CMA results for 59 of 848 patients (7.0% [95% CI: 5.5%-8.5%]) were considered abnormal, which includes variants associated with known genomic disorders or variants of possible significance. CMA results were normal in 10 of 852 patients (1.2%) with abnormal karyotype due to balanced rearrangements or unidentified marker chromosome. CMA with whole-genome coverage and CMA with targeted genomic regions detected clinically relevant copy-number changes in 7.3% (51 of 697) and 5.3% (8 of 151) of patients, respectively, both higher than karyotype. With the exception of recurrent deletion and duplication of chromosome 16p11.2 and 15q13.2q13.3, most copy-number changes were unique or identified in only a small subset of patients. CONCLUSIONS: CMA had the highest detection rate among clinically available genetic tests for patients with ASD. Interpretation of microarray data is complicated by the presence of both novel and recurrent copy-number variants of unknown significance. Despite these limitations, CMA should be considered as part of the initial diagnostic evaluation of patients with ASD.

BACKGROUND: A report from a high-volume single center indicated a survival benefit of receiving a kidney transplant from an HLA-incompatible live donor as compared with remaining on the waiting list, whether or not a kidney from a deceased donor was received. The generalizability of that finding is unclear. METHODS: In a 22-center study, we estimated the survival benefit for 1025 recipients of kidney transplants from HLA-incompatible live donors who were matched with controls who remained on the waiting list or received a transplant from a deceased donor (waiting-list-or-transplant control group) and controls who remained on the waiting list but did not receive a transplant (waiting-list-only control group). We analyzed the data with and without patients from the highest-volume center in the study. RESULTS: Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year (95.0%, vs. 94.0% for the waiting-list-or-transplant control group and 89.6% for the waiting-list-only control group), 3 years (91.7% vs. 83.6% and 72.7%, respectively), 5 years (86.0% vs. 74.4% and 59.2%), and 8 years (76.5% vs. 62.9% and 43.9%) (P<0.001 for all comparisons with the two control groups). The survival benefit was significant at 8 years across all levels of donor-specific antibody: 89.2% for recipients of kidney transplants from incompatible live donors who had a positive Luminex assay for anti-HLA antibody but a negative flow-cytometric cross-match versus 65.0% for the waiting-list-or-transplant control group and 47.1% for the waiting-list-only control group; 76.3% for recipients with a positive flow-cytometric cross-match but a negative cytotoxic cross-match versus 63.3% and 43.0% in the two control groups, respectively; and 71.0% for recipients with a positive cytotoxic cross-match versus 61.5% and 43.7%, respectively. The findings did not change when patients from the highest-volume center were excluded. CONCLUSIONS: This multicenter study validated single-center evidence that patients who received kidney transplants from HLA-incompatible live donors had a substantial survival benefit as compared with patients who did not undergo transplantation and those who waited for transplants from deceased donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

PURPOSE Limitations of the paclitaxel-doxorubicin-cisplatin (TAP) regimen in the treatment of endometrial cancer include tolerability and cumbersome scheduling. The Gynecologic Oncology Group studied carboplatin plus paclitaxel (TC) as a noninferior alternative to TAP. METHODS GOG0209 was a phase III, randomized, noninferiority, open-label trial. Inclusion criteria were stage III, stage IV, and recurrent endometrial cancers; performance status 0-2; and adequate renal, hepatic, and marrow function. Prior radiotherapy and/or hormonal therapy were permitted, but chemotherapy, including radiosensitization, was not. Patients were treated with doxorubicin 45 mg/m 2 and cisplatin 50 mg/m 2 (day 1), followed by paclitaxel 160 mg/m 2 (day 2) with granulocyte colony-stimulating factor or paclitaxel 175 mg/m 2 and carboplatin area under the curve 6 (day 1) every 21 days for seven cycles. The primary endpoint was overall survival (OS; modified intention to treat). Progression-free survival (PFS), health-related quality of life (HRQoL), and toxicity were secondary endpoints. RESULTS From 2003 to 2009, 1,381 women were enrolled. Noninferiority of TC to TAP was concluded for OS (median, 37 v 41 months, respectively; hazard ratio [HR], 1.002; 90% CI, 0.9 to 1.12), and PFS (median, 13 v 14 months; HR, 1.032; 90% CI, 0.93 to 1.15). Neutropenic fever was reported in 7% of patients receiving TAP and 6% of those receiving TC. Grade &gt; 2 sensory neuropathy was recorded in 26% of patients receiving TAP and 20% receiving TC ( P = .40). More grade ≥ 3 thrombocytopenia (23% v 12%), vomiting (7% v 4%), diarrhea (6% v 2%), and metabolic (14% v 8%) toxicities were reported with TAP. Neutropenia (52% v 80%) was more common with TC. Small HRQoL differences favored TC. CONCLUSION With demonstrated noninferiority to TAP, TC is the global first-line standard for advanced endometrial cancer.

Fournier gangrene is a rapidly progressing necrotizing fasciitis involving the perineal, perianal, or genital regions and constitutes a true surgical emergency with a potentially high mortality rate. Although the diagnosis of Fournier gangrene is often made clinically, emergency computed tomography (CT) can lead to early diagnosis with accurate assessment of disease extent. CT not only helps evaluate the perineal structures that can become involved by Fournier gangrene, but also helps assess the retroperitoneum, to which the disease can spread. Findings at CT include asymmetric fascial thickening, subcutaneous emphysema, fluid collections, and abscess formation. Subcutaneous emphysema is the hallmark of Fournier gangrene but is not seen in all cases. Compared with radiography and ultrasonography, CT provides a higher specificity for the diagnosis of Fournier gangrene and superior evaluation of disease extent; however, diagnosis and evaluation can also be performed with these other modalities. The administration of broad-spectrum antibiotics and aggressive surgical débridement of the nonviable tissue are both essential for successful treatment. An awareness of the CT features of Fournier gangrene is imperative for prompt diagnosis and effective treatment planning.

Few metabolites can claim a more central and versatile role in cell metabolism than acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is produced during nutrient catabolism to fuel the tricarboxylic acid cycle and is the essential building block for fatty acid and isoprenoid biosynthesis. It also functions as a signalling metabolite as the substrate for lysine acetylation reactions, enabling the modulation of protein functions in response to acetyl-CoA availability. Recent years have seen exciting advances in our understanding of acetyl-CoA metabolism in normal physiology and in cancer, buoyed by new mouse models, in vivo stable-isotope tracing approaches and improved methods for measuring acetyl-CoA, including in specific subcellular compartments. Efforts to target acetyl-CoA metabolic enzymes are also advancing, with one therapeutic agent targeting acetyl-CoA synthesis receiving approval from the US Food and Drug Administration. In this Review, we give an overview of the regulation and cancer relevance of major metabolic pathways in which acetyl-CoA participates. We further discuss recent advances in understanding acetyl-CoA metabolism in normal tissues and tumours and the potential for targeting these pathways therapeutically. We conclude with a commentary on emerging nodes of acetyl-CoA metabolism that may impact cancer biology. Acetyl coenzyme A (acetyl-CoA) is a key metabolite in carbohydrate and lipid metabolism and plays a role in signalling through protein acetylation, and the dysregulation of these pathways is a hallmark of various cancers. In this Review, Guertin and Wellen give an overview of acetyl-CoA metabolism in health and in cancer and discuss emerging therapeutic strategies for targeting metabolic pathways involving acetyl-CoA.