Withholding or withdrawing invasive interventions may not accelerate time to death among dying ICU patients

We considered observational data available from the MIMIC-III open-access ICU database and collected within a study period between year 2002 up to 2011. If a patient had multiple admissions to the ICU during the 30 days before death, only the first stay was analyzed, leading to a final set of 6,436 unique ICU admissions during the study period. We tested two hypotheses: (i) administration of invasive intervention during the ICU stay immediately preceding end-of-life would decrease over the study time period and (ii) time-to-death from ICU admission would also decrease, due to the decrease in invasive intervention administration. To investigate the latter hypothesis, we performed a subgroups analysis by considering patients with lowest and highest severity. To do so, we stratified the patients based on their SAPS I scores, and we considered patients within the first and the third tertiles of the score. We then assessed differences in trends within these groups between years 2002-05 vs. 2008-11. Comparing the period 2002-2005 vs. 2008-2011, we found a reduction in endotracheal ventilation among patients who died within 30 days of ICU admission (120.8 vs. 68.5 hours for the lowest severity patients, p<0.001; 47.7 vs. 46.0 hours for the highest severity patients, p=0.004). This is explained in part by an increase in the use of non-invasive ventilation. Comparing the period 2002-2005 vs. 2008-2011, we found a reduction in the use of vasopressors and inotropes among patients with the lowest severity who died within 30 days of ICU admission (41.8 vs. 36.2 hours, p<0.001) but not among those with the highest severity. Despite a reduction in the use of invasive interventions, we did not find a reduction in the time to death between 2002-2005 vs. 2008-2011 (7.8 days vs. 8.2 days for the lowest severity patients, p=0.32; 2.1 days vs. 2.0 days for the highest severity patients, p=0.74)

Weighted Dirac combs with pure point diffraction

A class of translation bounded complex measures, which have the form of weighted Dirac combs, on locally compact Abelian groups is investigated. Given such a Dirac comb, we are interested in its diffraction spectrum which emerges as the Fourier transform of the autocorrelation measure. We present a sufficient set of conditions to ensure that the diffraction measure is a pure point measure. Simultaneously, we establish a natural link to the theory of the cut and project formalism and to the theory of almost periodic measures. Our conditions are general enough to cover the known theory of model sets, but also to include examples such as the visible lattice points.Comment: 44 pages; several corrections and improvement

Notions and subnotions in information structure

Three dimensions can be distinguished in a cross-linguistic account of information structure. First, there is the definition of the focus constituent, the part of the linguistic expression which is subject to some focus meaning. Second and third, there are the focus meanings and the array of structural devices that encode them. In a given language, the expression of focus is facilitated as well as constrained by the grammar within which the focus devices operate. The prevalence of focus ambiguity, the structural inability to make focus distinctions, will thus vary across languages, and within a language, across focus meanings

Colistin Resistance in Carbapenem-Resistant Klebsiella pneumoniae: Laboratory Detection and Impact on Mortality

Background: Polymyxins including colistin are an important "last-line" treatment for infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKp). Increasing use of colistin has led to resistance to this cationic antimicrobial peptide. Methods: A cohort nested within the Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRACKLE) was constructed of patients with infection, or colonization with CRKp isolates tested for colistin susceptibility during the study period of December, 2011 to October, 2014. Reference colistin resistance determination as performed by broth macrodilution was compared to results from clinical microbiology laboratories (Etest) and to polymyxin resistance testing. Each patient was included once, at the time of their first colistin-tested CRKp positive culture. Time to 30-day in-hospital all-cause mortality was evaluated by Kaplan-Meier curves and Cox proportional hazard modeling. Results: In 246 patients with CRKp, 13% possessed ColR CRKp. ColR was underestimated by Etest (very major error rate = 35%, major error rate = 0.4%). A variety of rep-PCR strain types were encountered in both the ColS and the ColR groups. Carbapenem resistance was mediated primarily by blaKPC-2 (46%) and blaKPC-3 (50%). ColR was associated with increased hazard for in-hospital mortality (aHR 3.48; 95% confidence interval, 1.73-6.57; P < .001). The plasmid-associated ColR genes, mcr-1 and mcr-2 were not detected in any of the ColR CRKp. Conclusions: In this cohort, 13% of patients with CRKp presented with ColR CRKp. The apparent polyclonal nature of the isolates suggests de novo emergence of ColR in this cohort as the primary factor driving ColR. Importantly, mortality was increased in patients with ColR isolates

NDM-5 and OXA-181 Beta-Lactamases, a Significant Threat Continues To Spread in the Americas

ABSTRACT Among Gram-negative bacteria, carbapenem-resistant infections pose a serious and life-threatening challenge. Here, the CRACKLE network reports a sentinel detection and characterization of a carbapenem-resistant Klebsiella pneumoniae ST147 isolate harboring bla NDM-5 and bla OXA-181 from a young man who underwent abdominal surgery in India. bla NDM-5 was located on an IncFII plasmid of ≈90 kb, whereas bla OXA-181 was chromosomally encoded. Resistome and genome analysis demonstrated multiple copies of the transposable element IS 26 and a “hot-spot region” in the IncFII plasmid

Restrictions and extensions of semibounded operators

We study restriction and extension theory for semibounded Hermitian operators in the Hardy space of analytic functions on the disk D. Starting with the operator zd/dz, we show that, for every choice of a closed subset F in T=bd(D) of measure zero, there is a densely defined Hermitian restriction of zd/dz corresponding to boundary functions vanishing on F. For every such restriction operator, we classify all its selfadjoint extension, and for each we present a complete spectral picture. We prove that different sets F with the same cardinality can lead to quite different boundary-value problems, inequivalent selfadjoint extension operators, and quite different spectral configurations. As a tool in our analysis, we prove that the von Neumann deficiency spaces, for a fixed set F, have a natural presentation as reproducing kernel Hilbert spaces, with a Hurwitz zeta-function, restricted to FxF, as reproducing kernel.Comment: 63 pages, 11 figure

The Antimicrobial Scrub Contamination and Transmission (ASCOT) Trial: A Three-Arm, Blinded, Randomized Controlled Trial With Crossover Design to Determine the Efficacy of Antimicrobial-Impregnated Scrubs in Preventing Healthcare Provider Contamination

OBJECTIVE To determine whether antimicrobial-impregnated textiles decrease the acquisition of pathogens by healthcare provider (HCP) clothing. DESIGN We completed a 3-arm randomized controlled trial to test the efficacy of 2 types of antimicrobial-impregnated clothing compared to standard HCP clothing. Cultures were obtained from each nurse participant, the healthcare environment, and patients during each shift. The primary outcome was the change in total contamination on nurse scrubs, measured as the sum of colony-forming units (CFU) of bacteria. PARTICIPANTS AND SETTING Nurses working in medical and surgical ICUs in a 936-bed tertiary-care hospital. INTERVENTION Nurse subjects wore standard cotton-polyester surgical scrubs (control), scrubs that contained a complex element compound with a silver-alloy embedded in its fibers (Scrub 1), or scrubs impregnated with an organosilane-based quaternary ammonium and a hydrophobic fluoroacrylate copolymer emulsion (Scrub 2). Nurse participants were blinded to scrub type and randomly participated in all 3 arms during 3 consecutive 12-hour shifts in the intensive care unit. RESULTS In total, 40 nurses were enrolled and completed 3 shifts. Analyses of 2,919 cultures from the environment and 2,185 from HCP clothing showed that scrub type was not associated with a change in HCP clothing contamination ( P =.70). Mean difference estimates were 0.118 for the Scrub 1 arm (95% confidence interval [CI], −0.206 to 0.441; P =.48) and 0.009 for the Scrub 2 rm (95% CI, −0.323 to 0.342; P =.96) compared to the control. HCP became newly contaminated with important pathogens during 19 of the 120 shifts (16%). CONCLUSIONS Antimicrobial-impregnated scrubs were not effective at reducing HCP contamination. However, the environment is an important source of HCP clothing contamination. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT 02645214 Infect Control Hosp Epidemiol 2017;38:1147–115

Genomic and Transcriptomic Analyses of Colistin-Resistant Clinical Isolates of Klebsiella pneumoniae Reveal Multiple Pathways of Resistance

ABSTRACT The emergence of multidrug-resistant (MDR) Klebsiella pneumoniae has resulted in a more frequent reliance on treatment using colistin. However, resistance to colistin (Col r ) is increasingly reported from clinical settings. The genetic mechanisms that lead to Col r in K. pneumoniae are not fully characterized. Using a combination of genome sequencing and transcriptional profiling by RNA sequencing (RNA-Seq) analysis, distinct genetic mechanisms were found among nine Col r clinical isolates. Col r was related to mutations in three different genes in K. pneumoniae strains, with distinct impacts on gene expression. Upregulation of the pmrH operon encoding 4-amino-4-deoxy- l -arabinose (Ara4N) modification of lipid A was found in all Col r strains. Alteration of the mgrB gene was observed in six strains. One strain had a mutation in phoQ . Common among these seven strains was elevated expression of phoPQ and unaltered expression of pmrCAB , which is involved in phosphoethanolamine addition to lipopolysaccharide (LPS). In two strains, separate mutations were found in a previously uncharacterized histidine kinase gene that is part of a two-component regulatory system (TCRS) now designated crrAB . In these strains, expression of pmrCAB , crrAB , and an adjacent glycosyltransferase gene, but not that of phoPQ , was elevated. Complementation with the wild-type allele restored colistin susceptibility in both strains. The crrAB genes are present in most K. pneumoniae genomes, but not in Escherichia coli . Additional upregulated genes in all strains include those involved in cation transport and maintenance of membrane integrity. Because the crrAB genes are present in only some strains, Col r mechanisms may be dependent on the genetic background

A Prospective Observational Study of the Epidemiology, Management, and Outcomes of Skin and Soft Tissue Infections Due to Carbapenem-Resistant Enterobacteriaceae

Abstract Background: This study was performed to characterize the epidemiology, management, and outcomes of skin and soft tissue infection (SSTI) and colonization due to carbapenem-resistant Enterobacteriaceae (CRE). Methods: Patients from the Consortium on Resistance Against Carbapenem in Klebsiella and Other Enterobacteriaceae (CRACKLE-1) from December 24, 2011 to October 1, 2014 with wound cultures positive for CRE were included in the study. Predictors of surgical intervention were analyzed. Molecular typing of isolates was performed using repetitive extragenic palindromic polymerase chain reaction (PCR). Carbapenemase genes were detected using PCR. Results: One hundred forty-two patients were included: 62 had SSTI (44%) and 56% were colonized. Mean age was 61 years, and 48% were male: median Charlson score was 3 (interquartile range, 1–5). Forty-eight percent of patients were admitted from long-term care facilities (LTCFs), and 31% were from the community. Two strain types (ST258A and ST258B) were identified (73% of 45 tested). Carbapenemase genes were detected in 40 of 45 isolates (blaKPC-3 [47%], blaKPC-2 [42%]). Sixty-eight patients (48%) underwent surgical intervention, 63% of whom had SSTI. Patients admitted from LTCFs were less likely to undergo surgical intervention (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.18–0.71). In multivariable analysis, among patients with SSTI, those admitted from LTCFs were less likely to undergo debridement (OR, 0.18; 95% CI, 0.04–0.93). Conclusions: Patients admitted from LTCFs with CRE SSTI were less likely to undergo surgical intervention. Sixteen percent of the patients died, and approximately 50% of survivors required more intensive care upon discharge. These findings suggest a unique, impactful syndrome within the CRE infection spectrum. Further studies are needed to assess the role of surgical debridement in management of CRE-SSTI, particularly among LTCF residents

Surveillance of Carbapenem-Resistant Klebsiella pneumoniae: Tracking Molecular Epidemiology and Outcomes through a Regional Network

ABSTRACT Carbapenem resistance in Gram-negative bacteria is on the rise in the United States. A regional network was established to study microbiological and genetic determinants of clinical outcomes in hospitalized patients with carbapenem-resistant (CR) Klebsiella pneumoniae in a prospective, multicenter, observational study. To this end, predefined clinical characteristics and outcomes were recorded and K. pneumoniae isolates were analyzed for strain typing and resistance mechanism determination. In a 14-month period, 251 patients were included. While most of the patients were admitted from long-term care settings, 28% of them were admitted from home. Hospitalizations were prolonged and complicated. Nonsusceptibility to colistin and tigecycline occurred in isolates from 7 and 45% of the patients, respectively. Most of the CR K. pneumoniae isolates belonged to repetitive extragenic palindromic PCR (rep-PCR) types A and B (both sequence type 258) and carried either bla KPC-2 (48%) or bla KPC-3 (51%). One isolate tested positive for bla NDM-1 , a sentinel discovery in this region. Important differences between strain types were noted; rep-PCR type B strains were associated with bla KPC-3 (odds ratio [OR], 294; 95% confidence interval [CI], 58 to 2,552; P < 0.001), gentamicin nonsusceptibility (OR, 24; 95% CI, 8.39 to 79.38; P < 0.001), amikacin susceptibility (OR, 11.0; 95% CI, 3.21 to 42.42; P < 0.001), tigecycline nonsusceptibility (OR, 5.34; 95% CI, 1.30 to 36.41; P = 0.018), a shorter length of stay (OR, 0.98; 95% CI, 0.95 to 1.00; P = 0.043), and admission from a skilled-nursing facility (OR, 3.09; 95% CI, 1.26 to 8.08; P = 0.013). Our analysis shows that (i) CR K. pneumoniae is seen primarily in the elderly long-term care population and that (ii) regional monitoring of CR K. pneumoniae reveals insights into molecular characteristics. This work highlights the crucial role of ongoing surveillance of carbapenem resistance determinants