Initial Laparotomy Versus Peritoneal Drainage in Extremely Low Birthweight Infants With Surgical Necrotizing Enterocolitis or Isolated Intestinal Perforation: A Multicenter Randomized Clinical Trial.

OBJECTIVE: The aim of this study was to determine which initial surgical treatment results in the lowest rate of death or neurodevelopmental impairment (NDI) in premature infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP). SUMMARY BACKGROUND DATA: The impact of initial laparotomy versus peritoneal drainage for NEC or IP on the rate of death or NDI in extremely low birth weight infants is unknown. METHODS: We conducted the largest feasible randomized trial in 20 US centers, comparing initial laparotomy versus peritoneal drainage. The primary outcome was a composite of death or NDI at 18 to 22 months corrected age, analyzed using prespecified frequentist and Bayesian approaches. RESULTS: Of 992 eligible infants, 310 were randomized and 96% had primary outcome assessed. Death or NDI occurred in 69% of infants in the laparotomy group versus 70% with drainage [adjusted relative risk (aRR) 1.0; 95% confidence interval (CI): 0.87-1.14]. A preplanned analysis identified an interaction between preoperative diagnosis and treatment group (P = 0.03). With a preoperative diagnosis of NEC, death or NDI occurred in 69% after laparotomy versus 85% with drainage (aRR 0.81; 95% CI: 0.64-1.04). The Bayesian posterior probability that laparotomy was beneficial (risk difference <0) for a preoperative diagnosis of NEC was 97%. For preoperative diagnosis of IP, death or NDI occurred in 69% after laparotomy versus 63% with drainage (aRR, 1.11; 95% CI: 0.95-1.31); Bayesian probability of benefit with laparotomy = 18%. CONCLUSIONS: There was no overall difference in death or NDI rates at 18 to 22 months corrected age between initial laparotomy versus drainage. However, the preoperative diagnosis of NEC or IP modified the impact of initial treatment.

Clinical and microbiological determinants of severe and fatal outcomes in patients infected with Enterobacteriaceae producing extended-spectrum ß-lactamase.

Although extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae have become a worldwide public health concern, little is known regarding the clinical course of colonized or infected individuals. Our objective was to characterize the determinants of fatal outcomes related to ESBL-producing microorganisms at a large hospital in Paris, France. In 2012-2013, all consecutive patients with clinical samples testing positive for ESBL-producing Enterobacteriaceae at Saint-Antoine Hospital were identified. Patient clinical data were obtained at hospital entry, while information on intensive care unit (ICU) admissions and death were prospectively collected. Risk-factors for fatal 1-year outcomes were assessed using logistic regression. In total, 643/4684 (13%) ESBL-positive samples were observed, corresponding to 516 episodes (n = 206, 40% treated) among 330 patients. Most episodes were nosocomial-related (n = 347/516, 67%) involving Escherichia coli (n = 232/516, 45%) or Klebsiella pneumoniae (n = 164/516, 32%). Empirical antibiotic therapy was adequate in 89/206 (43%) infections, while the median length of hospital stay was 30 days [interquartile range (IQR) = 11-55] and 39/201 (19%) were admitted to the ICU. Overall, 104/241 patients (43%) with available data died within 1 year. In the multivariable analysis, 1-year death was associated with age >80 years (p = 0.01), concomitant comorbidity (p = 0.001), nosocomial-acquired infection (p = 0.002), and being infected rather than colonized (p < 0.001). In this series of patients with identified samples of ESBL-producing Enterobacteriaceae, hospital burden was large and 1-year mortality rates high. Understanding which patients in this setting would benefit from broad-spectrum empirical antibiotic therapy should be further examined.

[News of antibiotic resistance among Gram-negative bacilli in Algeria]. / Actualité de la résistance aux antibiotiques chez les bacilles à Gram négatif en Algérie.

Antibiotic resistance has become a major public health problem in Algeria. Indeed the past decade, we have seen a significant increase in resistance to antibiotics especially in Gram-negative bacilli. Resistance to ß-lactams in enterobacteria is dominated by the production of ESBL CTX-M-3 and CTX-M-15. The strains producing these enzymes are often the cause of potentially serious infections in both hospital and community settings. Identified plasmid cephalosporinases are CMY-2, CMY-12 and DHA-1. The isolation of strains of Enterobacteriaceae and Pseudomonas aeruginosa producing carbapenemases is rare in Algeria. Some Enterobacteriaceae producing OXA-48 or VIM-19 have been reported; so far, only VIM-2 has been identified in P. aeruginosa. However, the situation regarding the strains of Acinetobacter baumannii resistant to carbapenemases seems to be more disturbing. The carbapenemase OXA-23 is the most common and seems to be endemic in the north. The carbapenemase NDM-1 has also been identified. Resistance to aminoglycosides is marked by the identification armA gene associated with blaCTX-M genes in strains of Salmonella sp. Several other resistance genes have been identified sporadically in strains of Enterobacteriaceae, P. aeruginosa and A. baumannii. Resistance genes to fluoroquinolones are more recent identification in Algeria. The most common are the Qnr determinants followed by the bifunctional enzyme AAC[6']-Ib-cr. Resistance to sulfonamides and trimethoprim was also reported in Enterobacteriaceae strains in the west of the country.

In vivo selection of a complex mutant TEM (CMT) from an inhibitor-resistant TEM (IRT) during ceftazidime therapy.

OBJECTIVES: A relapse from Escherichia coli bloodstream infection was observed in a patient with acute leukaemia treated with ceftazidime for 7 days for febrile neutropenia. Whereas the original E. coli isolate was resistant to ß-lactam/ß-lactamase inhibitor combinations (EC1), the relapse E. coli isolate showed a similar phenotype but with resistance extended to ceftazidime (EC2). We investigated the molecular mechanisms of ß-lactam resistance and sought if EC2 could have been selected in vivo from EC1. METHODS: EC1 and EC2 isolates were compared for antibiotic MICs, plasmid content, genotyping, ß-lactamase genes and their environment. Both isolates were conjugated with E. coli JW4111ΔampC and MICs determined for transconjugants. In addition, ceftazidime-resistant mutants were selected in vitro from EC1. RESULTS: EC1 and EC2 showed identical patterns for genotyping and resistance plasmids. PCR sequencing of blaTEM in EC1 showed the mutations M69L and N276D corresponding to TEM-35, also called inhibitor-resistant TEM (IRT)-4. In EC2, the TEM allele showed an additional mutation, R164S, known to confer resistance to ceftazidime. The combination of these three mutations was previously reported in TEM-158, described as the complex mutant TEM (CMT)-9, associated with resistance to ß-lactamase inhibitors and third-generation cephalosporins. In vitro selection of ceftazidime-resistant mutants from EC1 yielded six different CMT alleles, including TEM-158 containing the R164S mutation. CONCLUSIONS: This first known report of in vivo selection of CMT from IRT, reproduced in vitro, shows how the evolution of ß-lactamase enzymes is easily driven by antibiotic pressure, even during a short antibiotic therapy.

[Enterobacteriaceae and beta-lactams : wild susceptibility patterns]. / Entérobactéries et bêta-lactamines : phénotypes de résistance naturelle.

Four susceptibility patterns of wild types of enterobacteria against old beta-lactams including aminopenicillins, carboxypenicillins and first-generation cephalosporins were individualized during the 1980s : susceptible, penicillinase low level, cephalosporinase and a combination of penicillinase and cephalosporinase. Such indirect detection of a mechanism of resistance allowed an interpretative reading for this class of antibiotics. At the present time, seven susceptibility patterns were proposed for this family of gram negative bacilli. Nevertheless, an analysis of results in terms of MICs and diameters of inhibition zone sizes of the main bacterial species of enterobacteria, mainly obtained from the databank of European Committee on Antimicrobial Susceptibility Testing (EUCAST), compared to that observed when overproducing strains were isolated in vivo and in vitro and to the type of beta-lactamase identified and their amino acid sequences conducted to a proposal of five susceptibility patterns. The fifth wild type individualized in several enterobacteria since 2005 is related to the synthesis of various chromosomal extended-spectrum beta-lactamases (ESBL) which hydrolyze many beta-lactams including oxyimino-cephalosporins such as ceftriaxone or cefotaxime. Their expression in a wild strain is characteristic and conducted to our interest for their role as progenitors of the transferable CTM-M types. Otherwise, a medical biologist must consider the possibility of selection of a mutant with a chromosomal overproduced beta-lactamase. But within the same beta-lactam susceptibility pattern such as for Klebsiella pneumoniae and K. oxytoca or Citrobacter amalonaticus, the spectrum of inactivation will be highly variable according to the type of enzyme overproduced. Finally, a nice synergy observed between clavulanic acid and cefotaxime or ceftriaxone or even aztreonam does not mean anytime a transferable ESBL. In some cases according to the result of enterobacterial identification, the epidemiological impact will be very low, because without multidrug resistance (MDR).

Salmonella enterica serotype Gambia with CTX-M-3 and armA resistance markers: nosocomial infections with a fatal outcome.

We report two cases of bacteremia caused by the Salmonella enterica serotype Gambia in our children's hospital, with one fatal outcome. The isolates showed indistinguishable genotypes and infrequent resistance markers: CTX-M-3 extended-spectrum ß-lactamase and armA methyltransferase. This is the first report of S. Gambia exhibiting CTX-M-3 and armA markers involved in serious infections.

Possible importation and subsequent cross-transmission of OXA-48-producing Klebsiella pneumoniae, France, 2010.

We report the possible first patient-to-patient transmission of Klebsiella pneumoniae with decreased susceptibility to imipenem and producing OXA-48, CTX-M15, TEM-1 and OXA-1 in a French hospital.

Extended measures for controlling an outbreak of VIM-1 producing imipenem-resistant Klebsiella pneumoniae in a liver transplant centre in France, 2003-2004.

We report the successful control of an outbreak caused by imipenem-resistant VIM-1-producing Klebsiella pneumoniae (IR-Kp) in France. This outbreak occurred in a care centre for abdominal surgery that includes a 15-bed liver intensive care unit and performs more than 130 liver transplantations per year. The index case was a patient with acute liver failure transferred from a hospital in Greece for urgent liver transplantation who was carrying IR-Kp at admission as revealed by routine culture of a rectal swab. Infection control measures were undertaken and included contact isolation and promotion of hand hygiene with alcohol-based hand rub solution. Nevertheless, secondary IR-Kp cases were identified during the six following months from 3 December 2003 to 2 June 2004. From 2 June to 21 October, extended infection control measures were set up, such as cohorting IR-Kp carriers, contact patients and new patients in distinct sections with dedicated staff, limiting ward admission, and strict control of patient transfer. They led to a rapid control of the outbreak. The global attack rate of the IR-Kp outbreak was 2.5%, 13% in liver transplant patients and 0.4% in the other patients in the care centre (p<0.005). Systematic screening for IR-Kp of all patients admitted to the care centre is still maintained to date and no secondary IR-Kp case has been detected since 2 June 2004.

Genetic context of plasmid-carried blaCMY-2-like genes in Enterobacteriaceae.

Analysis of 15 European clinical Enterobacteriaceae isolates showed that differences in the genetic context of blaCMY-2-like genes reflected the replicon type, usually IncA/C or IncI1. These blaCMY-2 loci may originate from the same ISEcp1-mediated mobilization from the Citrobacter freundii chromosome as structures described in earlier studies.

Mechanisms of carbapenem resistance in non-metallo-beta-lactamase-producing clinical isolates of Pseudomonas aeruginosa from a Tunisian hospital.

AIM OF THE STUDY: An increasing rate of imipenem-resistant Pseudomonas aeruginosa infections has become an important clinical problem in our hospital. The aim of this study is to determine the mechanisms involved in carbapenem resistance. MATERIALS AND METHODS: Ten strains have been randomly selected among 144 clinical isolates of carbapenem-resistant non-metallo-beta-lactamase (MBL)-producing P. aeruginosa. A phenotypic and genotypic study was performed using serotyping, antimicrobial susceptibility, detection of MBL and clonality. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used for the expression of the genes oprD, mexA and mexE and by western blot for the expression of OprM. Sequencing of oprD gene was performed. RESULTS: Five genotypes have been determined by arbitrary primer polymerase chain reaction and seven strains were selected to study the mechanisms involved. The predominant serotype was O12. All isolates exhibited high minimum inhibitory concentration (MICs) to both imipenem and meropenem (MIC ranged from 16 to more than 32 microg/ml) and did not harbor genes encoding MBL as confirmed by PCR. RT-PCR showed a decline in oprD expression with increased expression of mexA compared to PAO1 wild type strain. None of the isolates overexpressed mexE. Western blot analysis of outer membrane showed overproduction of OprM in all isolates. CONCLUSION: Resistance to both imipenem and meropenem of clinical isolates of P. aeruginosa was due to two combined mechanisms: decreased transcription of oprD gene and overproduction of the MexAB-OprM efflux system.

Necrotizing Enterocolitis and Spontaneous Intestinal Perforation: A Spatiotemporal Case Cluster Analysis.

OBJECTIVE: To expand existing statistical methods to identify clusters of necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) cases in the neonatal intensive care unit. METHODS: In an academic, tertiary referral center, possible NEC or SIP clusters were identified using a binomial distribution scan test. The incidence-density rate (IDR) was calculated as the number of cases per 1,000 patient-days during each possible cluster and compared with the baseline IDR. A structured chart review compared cluster and noncluster cases. Spatial clustering analyzed the physical distribution of cases using the Grimson Test. Repeat analysis included only SIP cases. RESULT: The initial scan identified 3 suspected temporal clusters. IDR comparison confirmed only 1 cluster. Analysis of SIP only cases revealed similar results. Physical proximity was not a significant factor. Chart review of the SIP and NEC cases revealed significant increases during the confirmed cluster of small for gestational age infant births and indomethacin treatment. Chart review of the SIP only cases in the confirmed cluster revealed no significant differences. CONCLUSION: Statistical methods distinguish whether suspected case clusters represent a significant increase in baseline incidence. True clusters warrant detailed investigation including spatial analysis and chart review. This approach may have application in other disease processes and populations.

ß LACTA test performance for detection of extended-spectrum ß-lactamase-producing Gram-negative bacilli directly on bronchial aspirates samples: a validation study.

OBJECTIVES: Incidence of extended-spectrum ß-lactamase-producing Gram-negative bacilli (ESBL-PE-GNB)-related infections is worryingly increasing worldwide. ESBL-PE-GNB detection directly on bronchial aspirate samples (BAS) performed for suspected pneumonia may help save empirical carbapenems. Our objectives were to optimize ß-LACTA™ test (BLT) realization and evaluate BLT performance for ESBL-PE-GNB detection directly on BAS. METHODS: We studied BLT technical optimization using BAS of different matrix types spiked with increasing concentrations of CTX-M-15-producing Klebsiella pneumoniae; in vitro validation of BLT diagnostic performance on 17 ESBL enzymes, belonging to CTX-M, SHV, TEM, OXA, GES, VEB and PER groups; and clinical validation of BLT performance on 126 BAS prospectively collected from seven intensive care units. RESULTS: After optimization, BLT detected with 100% sensitivity the presence of CTX-M-15-producing K. pneumoniae spiked in sterile BAS for inoculums upon two or more GNB per field upon microscopic Gram staining examination (MGSE). The BLT accurately detected the 17 ESBLs tested at 106 CFU/mL and all ESBLs except Pseudomonas aeruginosa-related OXA-14 at 104 CFU/mL. Among the 126 BAS of the validation cohort, 21 (17%) gave positive BLT (ten in BAS positive and 11 in BAS negative on MGSE). All BLT-positive BAS grew with ESBL-PE-GNB, including five hyper-L2-producing Stenotrophomonas maltophilia strains. BLT detected ESBL-PE-GNB directly on clinical BAS positive for GNB on MGSE and/or growing with ≥104 CFU/mL with 100% sensitivity, specificity, and positive and negative predictive values. CONCLUSIONS: BLT is an accurate tool for ESBL-PE-GNB detection directly on BAS. Further studies are needed to evaluate the impact of BLT-guided early antimicrobial de-escalation strategies.

Perioperative management of Parkinson's disease.

INTRODUCTION: Guidelines for the management of Parkinson's disease (PD) patients in the perioperative setting are lacking. Areas covered: Here we review potential problems that may arise when PD patients are undergoing an operation. We also review the literature, where available, and provide our expert opinion and recommendations based on experience. Expert commentary: Elderly patients with PD are especially prone to complications in the perioperative setting. Extreme caution must be used to ensure appropriate medication administration, transition to non-oral agents, if indicated, and early mobilization to achieve rapid recovery after surgery.

[Beta-lactamases of Gram negative bacteria: never-ending clockwork!]. / Beta-lactamases de bacilles à Gram négatif: le mouvement perpétuel!

The acquired resistance against the wide-spectrum and highly stable beta-lactams including third-generation cephalosporins (3GC) and carbapenems is constinuously increasing and widespead with the discovery of various plasmid-encoded, or genes cassette or integrons coding for a novel beta-lactamase, always a major mechanism of resistance. To explain resistance against 3GC, with the continuing story with TEM and SHV mutated enzymes, several types of ESBL (class A) emerge the CTX-M type, at least CTX-M-40, but also other non predominant types intitled BES, GES, PLA, PER, VEB. The wider resistance including 3GC, cephamycins and beta-lactamase inhibitor is correlated to synthesis of transferable cephalosporinases (class C) usually located in the chromosome but mobilized from Enterobacter spp., Citrobacter freundii, Hafnia alvei, Morganella morganii, Aeromonas caviae. Such genes encoded the following types: ACC-1, ACT-1, CFE-1, CMY group, DHA-1, FOX group, MIR-1, MOX-1. Finally the resistance against carbapemens e.g. imipenem originally restricted to Pseudomonas aeruginosa, then to Acinetobacter baumannii and finally to enterobacteria is related to production of novel enzymes (classes B, D and A) denominated IMP, VIM SME, GIM, OXA, KPC. A striking exemple of evolution towards more and more resistance is given by Salmonella, even from animal origins, a great threat fo public health. So far it appears necessary to perform molecular approaches to identify such enzymatic production. Finally because the absence of real new drugs, the discovery of some progenitors of the gene beta-lactamase, a strict control of beta-lactam antibiotics must be provide not only in medecine or veterinary field but also in agriculture, including aquaculture for example.

Genital tract actinomycosis caused by Actimyces israëlii.

We report a case of actinomycosis caused by actinomyces israelii, related to the removal of intrauterine device (IUD). Diagnosing actinomycosis is difficult but should be considered in the event of any acute abdominal problems in a woman carrying an IUD. All abdominal organs may be affected. Even with a disseminated infection, the combination of appropriate antibiotic therapy (penicillin G) and surgery ensures a full recovery in most cases.

Molecular detection of CTX-M-15-type ß-lactamases in Escherichia coli strains from Senegal.

We aimed to detect the extended-spectrum ß-lactamases (ESBLs) secreted by clinical strains of Escherichia coli at Fann University Hospital in Dakar and to characterize them molecularly. We identified 32 isolates producing ESBLs. The CTX-M-15 gene was the most frequently detected ESBL gene, detected in 90.63% of the isolates studied.

Nonoperative treatment of acute appendicitis in children: A feasibility study.

PURPOSE: Nonoperative treatment of acute appendicitis appears to be feasible in adults. It is unclear whether the same is true for children. METHODS: Children 5-18 years with <48 h symptoms of acute appendicitis were offered nonoperative treatment: 2 doses of piperacillin IV, then ampicillin/clavulanate ×1 week. Treatment failure (worsening on therapy) and recurrence (after completion of therapy) were noted. Patients who declined enrollment were asked to participate as controls. Cost-utility analysis was performed using Pediatric Quality of Life Scale (PedsQL®) to calculate quality-adjusted life month (QALM) for study and control patients. RESULTS: Twenty-four patients agreed to undergo nonoperative management, and 50 acted as controls. At a mean follow-up of 14 months, three of the 24 failed on therapy, and 2/21 returned with recurrent appendicitis at 43 and 52 days, respectively. Two patients elected to undergo an interval appendectomy despite absence of symptoms. Appendectomy-free rate at one year was therefore 71% (C.I. 50-87%). No patient developed perforation or other complications. Cost-utility analysis shows a 0.007-0.03 QALM increase and a $1359 savings from $4130 to $2771 per nonoperatively treated patient. CONCLUSION: Despite occasional late recurrences, antibiotic-only treatment of early appendicitis in children is feasible, safe, cost-effective and is experienced more favorably by patients and parents.

Patient-centered outcomes research in appendicitis in children: Bridging the knowledge gap.

PURPOSE: Patient-centered outcomes research (PCOR) aims to give patients a better understanding of the treatment options to enable optimal decision-making. As nonoperative alternatives are now being evaluated in children for acute appendicitis, we surveyed patients and their families regarding their knowledge of appendicitis and evaluated whether providing basic medical information would affect their perception of the disease and allow them to more rationally consider the treatment alternatives. METHODS: Families of children aged 5-18 presenting to the Emergency Department with suspected appendicitis were recruited for a tablet-based interactive educational survey. One hundred subjects (caregivers and patients ≥ 15 years) were questioned before and after an education session about their understanding of appendicitis, including questions on three hypothetical treatment options: urgent appendectomy, antibiotics alone, or initial antibiotics followed by elective appendectomy. Subjects were clearly informed that urgent appendectomy is currently the standard of care. RESULTS: Only 14% of respondents correctly identified the mortality rate of appendicitis (17 deaths/year according to the 2010 US census) when compared with other extremely rare causes of death. Fifty-four and 31% thought it was more common than death from lightning (40/year) and hunting-associated deaths (44/year), respectively. Eighty-two percent of respondents believed it "likely" or "very likely" that the appendix would rupture if operation was at all delayed, and 81% believed that rupture of the appendix would rapidly lead to severe complications and death. In univariate analysis, this perception was significantly more prevalent for mothers (odds ratio, (OR) 5.19, confidence interval (CI) 1.33-21.15), and subjects who knew at least one friend or relative who had a negative experience with appendicitis (OR 5.53, CI 1.40-25.47). Following education, these perceptions changed significantly (53% still believed that immediate operation was necessary, and 47% believed perforation led to great morbidity and potential mortality, P<0.001). In a survey of potential appendicitis treatment options, urgent appendectomy was considered a "good" or "very good" option by 74% of subjects, compared with 68% for antibiotics only without appendectomy and 49% for initial antibiotic therapy followed by elective outpatient appendectomy. CONCLUSION: There was a striking knowledge gap in the participant perception of appendicitis. Appropriate education can correct anecdotally supported misconceptions. Adequate education may empower patients to make better-informed decisions about their medical care and may be important for future studies in alternative treatments for appendicitis in children.

Is there a role for routine preoperative endoscopic retrograde cholangiopancreatography for suspected choledocholithiasis in children?

HYPOTHESIS: Endoscopic retrograde cholangiopancreatography (ERCP) is frequently used preoperatively in adult patients with suspected choledocholithiasis. Cholelithiasis occurs much less often in children, and the indications for ERCP are not established. We hypothesized that the natural history of choledocholithiasis in children is spontaneous passage of stones through the papilla and that these children can be managed without routine preoperative ERCP. DESIGN: Retrospective analysis of patients treated over a 10-year period. SETTING: Tertiary care children's hospital. PATIENTS: All patients with cholecystectomy for biliary disease. INTERVENTIONS: Cholecystectomy; intraoperative cholangiography for suspected choledocholithiasis: hyperbilirubinemia, gallstone pancreatitis, and ultrasonographic evidence of common bile duct dilation or common bile duct stones; and postoperative ERCP for symptomatic choledocholithiasis: pain and jaundice. MAIN OUTCOME MEASURES: Incidence and complications of choledocholithiasis and frequency of ERCP. RESULTS: One hundred patients (63 females) were studied. Indications included acute cholecystitis (10%), chronic cholecystitis (59%), gallstone pancreatitis (26%), and choledocholithiasis (5%). An intraoperative cholangiography was performed in 45 patients, and common bile duct stones were identified in 13. Expectant management of asymptomatic common bile duct stones was associated with sonographic resolution within 1 week. One patient with intraoperative cholangiography-proven choledocholithiasis required ERCP for symptoms 24 hours after operation. One additional patient, who did not undergo intraoperative cholangiography, developed symptomatic choledocholithiasis and required ERCP. There were no choledocholithiasis- or ERCP-related complications. CONCLUSIONS: This study suggests that choledocholithiasis occurs frequently in children and that spontaneous passage of common bile duct stones is common. This could explain the relatively high incidence of gallstone pancreatitis. Conservative management of choledocholithiasis is successful in the majority of patients. Routine preoperative or postoperative ERCP is usually not indicated.