A randomized phase 1/2a trial of ExPEC10V vaccine in adults with a history of UTI.

The safety, reactogenicity, and immunogenicity of 3 doses of ExPEC10V (VAC52416), a vaccine candidate to prevent invasive Escherichia coli disease, were assessed in a phase 1/2a study (NCT03819049). In Cohort 1, ExPEC10V was well tolerated; the high dose was selected as optimal and further characterized in Cohort 2. Cohort 2 comprised a maximum 28-day screening, vaccination (Day 1), double-blind 181-day follow-up, and open-label long-term follow-up until Year 1. Healthy participants (≥60 years) with a history of urinary tract infection (UTI) within 5 years were randomized to receive ExPEC10V or placebo. The primary endpoint evaluated the safety and reactogenicity of ExPEC10V (solicited local and systemic AEs [until Day 15]; unsolicited AEs [until Day 30], SAEs [until Day 181], and immunogenicity [Day 30]) via multiplex electrochemiluminescent (ECL) and multiplex opsonophagocytic assay (MOPA). 416 participants (ExPEC10V, n = 278; placebo, n = 138) were included (mean age [SD], 68.8 [6.52] years; female, 79.6%; White, 96.1%). The incidence of solicited AEs was higher with ExPEC10V (local, 50.0% [n = 139]; systemic, 50.0% [n = 139]) than placebo (15.9% [n = 22]; 38.4% [n = 53]); rates of unsolicited AEs were comparable (ExPEC10V, 28.4% [n = 79]; placebo, 26.1% [n = 36]). No vaccine-related SAEs or deaths were reported. ExPEC10V elicited a robust antibody-mediated immunogenic response across all serotypes with ECL (Day 30 geometric mean fold increase, 2.33-8.18) and demonstrated functional opsonophagocytic killing activity across all measured serotypes (Day 30 geometric mean fold increase, 1.81-9.68). ExPEC10V exhibited an acceptable safety profile and a robust vaccine-induced functional immunogenic response in participants with a history of UTI. Clinical trial registration details: https://clinicaltrials.gov/study/NCT03819049 .

Safety, Reactogenicity, Immunogenicity, and Dose Selection of 10-Valent Extraintestinal Pathogenic Escherichia coli Bioconjugate Vaccine (VAC52416) in Adults Aged 60-85 Years in a Randomized, Multicenter, Interventional, First-in-Human, Phase 1/2a Study.

Background: ExPEC10V is a bioconjugate vaccine containing O-antigen polysaccharides of 10 extraintestinal pathogenic Escherichia coli (ExPEC) serotypes. This phase 1/2a study (NCT03819049) assessed the safety, reactogenicity, and immunogenicity of ExPEC10V (VAC52416) to prevent invasive E coli disease in elderly adults. Methods: The observer-blind, active-controlled design included a 28-day screening, vaccination, 181-day follow-up, and 1-year follow-up. Participants (60-85 years of age) were randomized to ExPEC10V low dose (antigen dose range, 4-8 µg), ExPEC10V medium dose (4-16 µg), or ExPEC10V high dose (8-16 µg); 4-valent ExPEC vaccine (ExPEC4V); or 13-valent pneumococcal conjugate vaccine (PCV13). The incidence of adverse events (AEs; solicited, day 15; unsolicited, day 30; serious AEs, day 181) and immunogenicity (electrochemiluminescent-based assay [ECL] and multiplex opsonophagocytic assay [MOPA]) were assessed. Optimal ExPEC10V dose was determined from safety data through day 30 and an immunogenicity dose selection algorithm based on day 15 ECL and MOPA results. Results: A total of 416 participants were included (median age, 64.0 years; 54.8% female). The incidences of solicited local and systemic AEs were, respectively, 44.2% and 39.4% for low-dose, 52.9% and 46.1% for medium-dose, 57.7% and 45.2% for high-dose ExPEC10V, and 74.1% and 48.1% for PCV13. Five serious AEs, not vaccine related, were reported. The ECL revealed a robust antibody response to ExPEC10V through year 1. Opsonophagocytic killing activity was detected against all but serotype O8; this lack of response against serotype O8 was linked to low assay sensitivity. Based on the totality of data, high-dose ExPEC10V was considered optimal. Conclusions: ExPEC10V was well tolerated and immunogenic in elderly adults against all but serotype O8.

Global Distribution of O Serotypes and Antibiotic Resistance in Extraintestinal Pathogenic Escherichia coli Collected From the Blood of Patients With Bacteremia Across Multiple Surveillance Studies.

BACKGROUND: Extraintestinal pathogenic Escherichia coli (ExPEC) is the leading cause of bacteremia worldwide, with older populations having increased risk of invasive bacterial disease. Increasing resistance to first-line antibiotics and emergence of multidrug-resistant (MDR) strains represent major treatment challenges. ExPEC O serotypes are key targets for potential multivalent conjugate vaccine development. Therefore, we evaluated the O serotype distribution and antibiotic resistance profiles of ExPEC strains causing bloodstream infections across 4 regions. METHODS: Blood culture isolates from patients aged ≥60 years collected during 5 retrospective E. coli surveillance studies in Europe, North America, Asia-Pacific, and South America (2011-2017) were analyzed. Isolates were O serotyped by agglutination; O genotyping was performed for nontypeable isolates. Antimicrobial susceptibility testing was also conducted. RESULTS: Among 3217 ExPEC blood culture isolates, the most ubiquitous O serotype was O25 (n = 737 [22.9%]), followed by O2, O6, O1, O75, O15, O8, O16, O4, O18, O77 group, O153, O9, O101/O162, O86, and O13 (prevalence of ≥1%). The prevalence of these O serotypes was generally consistent across regions, apart from South America; together, these 16 O serotypes represented 77.6% of all ExPEC bacteremia isolates analyzed. The overall MDR frequency was 10.7%, with limited variation between regions. Within the MDR subset (n = 345), O25 showed a dominant prevalence of 63.2% (n = 218). CONCLUSIONS: Predominant O serotypes among ExPEC bacteremia isolates are widespread across different regions. O25 was the most prevalent O serotype overall and particularly dominant among MDR isolates. These findings may inform the design of multivalent conjugate vaccines that can target the predominant O serotypes associated with invasive ExPEC disease in older adults.

Parental Reading to Infants Improves Language Score: A Rural Family Medicine Intervention.

INTRODUCTION: Both expressive and receptive language development begins early in life. While the benefits of reading to toddlers (over 12 months old) is well-established, benefits of reading to infants (birth to 12 months old) is less established. This study's objective is to determine if consistent reading to infants improves expressive and receptive language development during the first year of life. METHODS: We prospectively randomized infants at a family medicine clinic during their 2-week-old visits and gave them a collection of books. Group A (n = 16) received no instructions, while patients in Group B (n = 18) committed to read 1 book a day. Parents in Group C (n = 18) enrolled after 34 weeks gestation, committed to read 1 book a day, and watch an infant brain development video. We obtained average book counts and both expressive and receptive language testing at standard preventative visits through 12 months. RESULTS: Language scores did not differ between randomized groups. Always reading 7 books per week led to higher expressive, receptive and combined language scores at 9 months than sometimes reading fewer than 7 books per week (P = .025, 0.009 and 0.011 respectively). These differences increased by 12 months (P = .004, 0.002, and 0.003, respectively). Instructing parents to read daily encouraged parents to read more books per week at 4 months (P = .031) and 6 months (P = .049). DISCUSSION: Early, consistent reading demonstrates improved language scores as early as 9 months of age. Setting expectations of minimal daily reading impacted daily reading compliance early in life.

Participant recruitment and retention from vulnerable populations in clinical trials is a matter of trust.

Clinical research sites can struggle with recruiting and retaining vulnerable populations. Vulnerable research participants often have significant trauma histories making traditional approaches to recruitment and retention tenuous. Due to these difficulties, vulnerable populations are often intentionally excluded from clinical research due to the additional time and work involved. While it is important to provide protections for any participant that has decreased autonomy or increased susceptibility to coercion, it is equally important to assure that individuals in vulnerable populations have access to any clinical research that might pertain to them. In addition, the new trends in the drug development industry including early-stage development, risk-identification, preventative care, and disease spread modeling are likely to include health disparate patient populations that have increased probability of vulnerability. In this article we discuss the roots of many vulnerabilities and how to foster trust for more effective recruitment and retention of vulnerable populations.

Intake assessments of salivary cortisol, survey responses, and adverse childhood experiences are associated with recovery success in an abstinence-based treatment program for substance use disorders.

BACKGROUND: Connecting patients to treatment for a substance use disorder (SUD) that satisfies their needs is often complicated by confounding factors. A reliable measurement of patients' underlying stress level may be helpful because it often reflects many of the same confounders as their SUD. Whereas cortisol levels reflect physiological responses to stress, patients' cortisol levels during recovery from an SUD may serve as biomarkers for stressors that result in poor treatment outcomes, including early discontinuation of treatment. However, further exploration of the relationship between patients' cortisol levels and their treatment outcomes is needed for this approach to be clinically useful. METHODS: We enrolled participants from an abstinence-based, male-only, residential alcohol and drug recovery program to examine the relationship between salivary cortisol, stress exposure, ACEs, and treatment retention. RESULTS: Participants who remained in the program <90 days had significantly higher initial cortisol levels than those who remained ≥90 days (0.62 ± 0.074 µg/dl vs. 0.36 ± 0.037 µg/dl). Kaplan-Meier curves differed significantly when we grouped participants according to whether their cortisol level was below or above the overall average of 0.49 ± 0.044 µg/dl, with the median numbers of days before discontinuing being 110 and 60, respectively. A Cox proportional hazards model indicated that elevated salivary cortisol (with increases in µg/dl), marital/relationship status, and adverse childhood experiences (ACEs) score correlated significantly with hazards of discontinuing the program (hazard ratios for the three factors were 3.49, 2.39, and 1.50, respectively). DISCUSSION: Cortisol level may predict, at least partially, SUD treatment program retention regardless of individuals' numerous confounding factors or the substance used. If this approach is validated, it could enable providers to consider patients' cortisol levels at the time of admission to treatment to facilitate their retention in treatment and thereby enhance their recovery.

Inclusion of Positive Self-reporting by Mothers of Substance Exposed Neonates Increases the Predictability of NAS Severity Over Toxicology Alone.

OBJECTIVES: The rise in opioid use among pregnant women has resulted in an increase in the incidence of neonatal abstinence syndrome (NAS). Despite the focus on opioid use, prenatal polysubstance exposure is often associated with NAS diagnosis and severity. Drug toxicology screens such as urine drug screens and umbilical cord toxicology are dependent upon the substance, timing, frequency, and dose to detect substances present and can underestimate the neonatal exposure. The aim of this study was to identify the predictability of the consequences of prenatal polysubstance exposure versus opioid only exposure based on toxicology and toxicology plus self-report. METHODS: Neonates > 35 weeks gestation with prenatal opioid exposure were included in this retrospective data analysis. NAS was identified using maternal urine drug screen (UDS) toxicology, self-reported exposure during pregnancy, and neonatal toxicology. Analysis was conducted using Stata 15.1 utilizing McNemar's test, chi-square for categorical outcomes, and Wilcoxon test for numerical outcomes. RESULTS: A statistically significant difference in length of stay and length of treatment with poly-exposed neonates was observed when maternal self-report was considered with toxicology, but not with toxicology alone. This trend was observed for cumulative hospital length of stay as well as length and dose of treatment. CONCLUSIONS FOR PRACTICE: The findings in this report demonstrate that self-report is important for identifying substance of exposure. Three substances in particular that often require a change in treatment paradigm went undetected by toxicology were Gabapentin (20.9% of the population), Heroin (20.5% of the population), and Benzodiazepines (8.5% of the population). A healthy rapport with patients is often critical to effective clinical practice. Women with substance use disorder anticipate negative reactions from healthcare providers. Empathetic interview techniques to facilitate accurate disclosure may be more important to the treatment of the exposed neonate.

Abnormal Presentation of Hypoxic Ischemic Encephalopathy Attributed to Polysubstance Exposure.

BACKGROUND With the increasing prevalence of substance use in pregnancy, the rates of neonatal abstinence syndrome (NAS) are dramatically increasing. There is little information on the use of multiple substances in adults, even less so of polysubstance abuse during pregnancy and the consequences for the fetus as well as the mother. CASE REPORT A newborn male born at 35 weeks presented post-delivery with hips bilaterally dislocated and hyperflexed. The patient's legs fully extended and their shoulders were bilaterally mid-flexed with arms fully extended. This neonate was also reported to have bilateral hearing and vision loss as well as NAS symptoms of high-pitched crying and respiratory distress. During pregnancy the mother in this case study admitted to using buprenorphine, benzodiazepines, gabapentin, and heroin. The consequences of using this combination has not been well studied in pregnancy. CONCLUSIONS The presented case had severe complications, likely due to maternal polysubstance use and poor prenatal care in pregnancy. Clonidine was used to control the NAS symptoms, ranitidine was used to treat the gastroesophageal reflux, and glycopyrronium bromide was used for the neonate's excessive secretions. After delivery, the patient was placed on a nasal noninvasive cannula for respiratory distress and was transferred to a different hospital for treatment of the more serious comorbid conditions.

Neonatal Opioid Withdrawal Syndrome: A Developmental Care Approach.

Tens of thousands of infants are impacted yearly by prenatal opioid exposure. The term neonatal opioid withdrawal syndrome (NOWS) is now replacing the more familiar term neonatal abstinence syndrome (NAS). Ongoing debate continues related to standard regimens for treatment of this oftentimes perplexing condition. Historically, treatment has focused on pharmacologic interventions. However, there is limited research that points to nonpharmacologic methods of treatment as viable options, whether alone or in addition to pharmacologic interventions. This article, utilizing a review of pertinent literature, outlines the physical aspects of NOWS, including its pathophysiology and the resulting physical clinical signs. In addition, we present an overview of how age-appropriate, nonpharmacologic interventions, centered on developmental care, may be a valuable approach to organize and prioritize routine care for these infants, their families, and the health care team facing the challenges of NOWS. Finally, the need for further research to better define evidence-based standards of care for these infants and their families is discussed.

History of postpartum depression as a contributor to the severity of NAS.

Currently, there are no clinical tools available to accurately predict the severity of neonatal withdrawal. Studies of non-exposed neonates suggest that maternal depression and anxiety are predictive of negative short and long-term neonatal outcomes, but research is lacking in the addicted population. We studied of 109 pregnant women in medication-assisted treatment (MAT) and their neonates to determine if psychiatric conditions co-occurring with Substance Use Disorder (SUD) contributed to the severity of neonatal withdrawal. The need for pharmacological intervention, Finnegan scores, length of methadone treatment, and length of hospital stay were used to assess withdrawal severity. Categorical variables were analyzed in Stata14 using Chi Square and continuous variables were analyzed using Wilcoxon Rank Sum. Among the 110 neonates whose outcomes were reviewed, a maternal history of Postpartum Depression (PPD) was found to be correlated with increased severity of withdrawal. The neonates born to mothers with past diagnoses of PPD had more consecutive days of high Finnegan scores (95% confidence interval [CI], P = 0.003), longer length of treatment (95% CI, P = 0.006), and length of hospital stay (95% CI, P = 0.014). There was no apparent relationship between NAS severity and other psychiatric disorders. In a study of pregnant women with SUD and their neonates, we uncovered a relationship between the severity of NAS and maternal history of PPD. Our findings demonstrate that further research into these deleterious outcomes is warranted. Until then, we suggest collection of maternal history of PPD and careful screening for new cases in the SUD population.

Novel Withdrawal Symptoms of a Neonate Prenatally Exposed to a Fentanyl Analog.

Neonatal abstinence syndrome (NAS) is a withdrawal syndrome observed in neonates exposed to drugs in utero, typically opioids, which is associated with symptoms affecting the central and autonomic nervous systems and the gastrointestinal system. West Virginia, particularly the southeastern region of the state, has remarkably higher rates of NAS than similar communities. Our facility is increasingly faced with complex cases of NAS caused by in utero exposure to multiple substances. We present a case report of a neonate born to a 25-year-old mother enrolled in a medication-assisted treatment program for substance use disorder who was noncompliant in prenatal care, using multiple substances throughout the pregnancy, including gabapentin and fentanyl. After birth, the neonate began to exhibit unusual withdrawal symptoms including arching, tongue thrusting, and irregular eye movements, which are typically associated with in utero gabapentin exposure. The parents denied consent to treat with gabapentin, the suggested management for these symptoms; thus, a treatment protocol for methadone and clonidine were followed. This case exemplifies the medical and social complexities involved in treating polysubstance exposure-associated NAS.

Development and Qualification of an Opsonophagocytic Killing Assay To Assess Immunogenicity of a Bioconjugated Escherichia coli Vaccine.

The global burden of disease caused by extraintestinal pathogenic Escherichia coli (ExPEC) is increasing as the prevalence of multidrug-resistant strains rises. A multivalent ExPEC O-antigen bioconjugate vaccine could have a substantial impact in preventing bacteremia and urinary tract infections. Development of an ExPEC vaccine requires a readout to assess the functionality of antibodies. We developed an opsonophagocytic killing assay (OPA) for four ExPEC serotypes (serotypes O1A, O2, O6A, and O25B) based on methods established for pneumococcal conjugate vaccines. The performance of the assay was assessed with human serum by computing the precision, linearity, trueness, total error, working range, and specificity. Serotypes O1A and O6A met the acceptance criteria for precision (coefficient of variation for repeatability and intermediate precision, ≤50%), linearity (90% confidence interval of the slope of each strain, 0.80, 1.25), trueness (relative bias range, -30% to 30%), and total error (total error range, -65% to 183%) at five serum concentrations and serotypes O2 and O25B met the acceptance criteria at four concentrations (the lowest concentration for serotypes O2 and O25B did not meet the system suitability test of maximum killing of ≥85% of E. coli cells). All serotypes met the acceptance criteria for specificity (opsonization index value reductions of ≤20% for heterologous serum preadsorption and ≥70% for homologous serum preadsorption). The assay working range was defined on the basis of the lowest and highest concentrations at which the assay jointly fulfilled the target acceptance criteria for linearity, precision, and accuracy. An OPA suitable for multiple E. coli serotypes has been developed, qualified, and used to assess the immunogenicity of a 4-valent E. coli bioconjugate vaccine (ExPEC4V) administered to humans.

Safety, immunogenicity, and preliminary clinical efficacy of a vaccine against extraintestinal pathogenic Escherichia coli in women with a history of recurrent urinary tract infection: a randomised, single-blind, placebo-controlled phase 1b trial.

BACKGROUND: Escherichia coli infections are increasing worldwide in community and hospital settings. The E coli O-antigen is a promising vaccine target. We aimed to assess the safety and immunogenicity of a bioconjugate vaccine containing the O-antigens of four E coli serotypes (ExPEC4V). METHODS: In this multicentre phase 1b, first-in-human, single-blind, placebo-controlled trial, we randomly assigned (1:1) healthy adult women with a history of recurrent urinary tract infection (UTI) to receive a single injection of either intramuscular ExPEC4V or placebo. The primary outcome was the incidence of adverse events among vaccine and placebo recipients throughout the study. Secondary outcomes included immunogenicity and antibody functionality, and the incidence of UTIs caused by E coli vaccine serotypes in each group. This study is registered with ClinicalTrials.gov, number NCT02289794. FINDINGS: Between Jan 20, 2014, and Aug 27, 2014, 93 women received target-dose ExPEC4V and 95 received placebo. The vaccine was well tolerated: no vaccine-related serious adverse events occurred. Overall, 56 (60%) target-dose vaccines and 47 (49%) placebo recipients experienced at least one adverse event that was possibly, probably, or certainly related to injection. Vaccination induced significant IgG responses for all serotypes: at day 30 compared with baseline, O1A titres were 4·6 times higher, O2 titres were 9·4 times higher, O6A titres were 4·9 times higher, and O25B titres were 5·9 times higher (overall p<0·0001). Immune responses persisted at 270 days but were lower than those at 30 days. Opsonophagocytic killing activity showed antibody functionality. No reduction in the incidence of UTIs with 103 or more colony-forming units per mL of vaccine-serotype E coli was noted in the vaccine compared with the placebo group (0·149 mean episodes vs 0·146 mean episodes; p=0·522). In post-hoc exploratory analyses of UTIs with higher bacterial counts (≥105 colony-forming units per mL), the number of vaccine serotype UTIs did not differ significantly between groups (0·046 mean episodes in the vaccine group vs 0·110 mean episodes in the placebo group; p=0·074). However, significantly fewer UTIs caused by E coli of any serotype were noted in the vaccine group compared with the placebo group (0·207 mean episodes vs 0·463 mean episodes; p=0·002). INTERPRETATION: This tetravalent E coli bioconjugate vaccine candidate was well tolerated and elicited functional antibody responses against all vaccine serotypes. Phase 2 studies have been initiated to confirm these findings. FUNDING: GlycoVaxyn, Janssen Vaccines.

An Atypical Withdrawal Syndrome in Neonates Prenatally Exposed to Gabapentin and Opioids.

We report a retrospective case series of 19 infants exposed to both opioids and gabapentin prenatally. We describe a unique behavioral phenotype in 15 of these infants and report a treatment strategy.

Effectiveness of public deliberation methods for gathering input on issues in healthcare: Results from a randomized trial.

UNLABELLED: Public deliberation elicits informed perspectives on complex issues that are values-laden and lack technical solutions. This Deliberative Methods Demonstration examined the effectiveness of public deliberation for obtaining informed public input regarding the role of medical evidence in U.S. healthcare. We conducted a 5-arm randomized controlled trial, assigning participants to one of four deliberative methods or to a reading materials only (RMO) control group. The four deliberative methods reflected important differences in implementation, including length of the deliberative process and mode of interaction. The project convened 76 groups between August and November 2012 in four U.S. LOCATIONS: Chicago, IL; Sacramento, CA; Silver Spring, MD; and Durham, NC, capturing a sociodemographically diverse sample with specific attention to ensuring inclusion of Hispanic, African-American, and elderly participants. Of 1774 people recruited, 75% participated: 961 took part in a deliberative method and 377 participants comprised the RMO control group. To assess effectiveness of the deliberative methods overall and of individual methods, we evaluated whether mean pre-post changes on a knowledge and attitude survey were statistically different from the RMO control using ANCOVA. In addition, we calculated mean scores capturing participant views of the impact and value of deliberation. Participating in deliberation increased participants' knowledge of evidence and comparative effectiveness research and shifted participants' attitudes regarding the role of evidence in decision-making. When comparing each deliberative method to the RMO control group, all four deliberative methods resulted in statistically significant change on at least one knowledge or attitude measure. These findings were underscored by self-reports that the experience affected participants' opinions. Public deliberation offers unique potential for those seeking informed input on complex, values-laden topics affecting broad public constituencies.

Evaluation of clonality and carbapenem resistance mechanisms among Acinetobacter baumannii-Acinetobacter calcoaceticus complex and Enterobacteriaceae isolates collected in European and Mediterranean countries and detection of two novel ß-lactamases, GES-22 and VIM-35.

We evaluated doripenem-resistant Acinetobacter baumannii-Acinetobacter calcoaceticus complex (ACB; n = 411) and Enterobacteriaceae (n = 92) isolates collected from patients from 14 European and Mediterranean countries during 2009 to 2011 for the presence of carbapenemase-encoding genes and clonality. Following susceptibility testing, carbapenem-resistant (doripenem MIC, >2 µg/ml) isolates were screened for carbapenemases. New ß-lactamase genes were expressed in a common background and susceptibility was tested. Class 1 integrons were sequenced. Clonality was evaluated by pulsed-field gel electrophoresis and multilocus sequence typing (Pasteur scheme). Relative expression of ß-lactam intrinsic resistance mechanisms was determined for carbapenemase-negative Enterobacteriaceae. ACB and Enterobacteriaceae displayed 58.9 and 0.9% doripenem resistance, respectively. bla(OXA-23), bla(OXA-58), and bla(OXA-24/OXA-40) were detected among 277, 77, and 29 ACB, respectively (in 8, 6, and 5 countries). Ten Turkish isolates carried bla(GES-11) or bla(GES-22). GES-22 (G243A and M169L mutations in GES-1) had an extended-spectrum ß-lactamase profile. A total of 33 clusters of ≥ 2 ACB isolates were observed, and 227 isolates belonged to sequence type 2/international clone II. Other international clones were limited to Turkey and Israel. Doripenem-resistant Enterobacteriaceae increased significantly (0.7 to 1.6%), and 15 blaKPC-2- and 22 blaKPC-3-carrying isolates, mostly belonging to clonal complexes 11 and 258, were observed. Enterobacteriaceae isolates producing OXA-48 (n = 16; in Turkey and Italy), VIM-1 (n = 10; in Greece, Poland, and Spain), VIM-26 (n = 1; in Greece), and IMP-19, VIM-4, and the novel VIM-35 (n = 1 each from Poland) were detected. VIM-35 had one substitution compared to VIM-1 (A235T) and a similar susceptibility profile. One or more resistance mechanisms were identified in 4/6 carbapenemase-negative Enterobacteriaceae. This broad evaluation confirms results from country-specific surveys and shows a highly diverse population of carbapenemase-producing ACB and Enterobacteriaceae in Europe and Mediterranean countries.

Reconfigurable mosaic annular arrays.

Mosaic annular arrays (MAA) based on reconfigurable array (RA) transducer electronics assemblies are presented as a potential solution for future highly integrated ultrasonic transducer subsystems. Advantages of MAAs include excellent beam quality and depth of field resulting from superior elevational focus compared with 1-D electronically scanned arrays, as well as potentially reduced cost, size, and power consumption resulting from the use of a limited number of beamforming channels for processing a large number of subelements. Specific design tradeoffs for these highly integrated arrays are discussed in terms of array specifications for center frequency, element pitch, and electronic switch-on resistance. Large-area RAs essentially function as RC delay lines. Efficient architectures which take into account RC delay effects are presented. Architectures for integration of the transducer and electronics layers of large-area array implementations are reviewed.