Distinct Origins and Transmission Pathways of blaKPC Enterobacterales across Three U.S. States.

Carbapenem-resistant Enterobacterales (CRE) are among the most concerning antibiotic resistance threats due to high rates of multidrug resistance, transmissibility in health care settings, and high mortality rates. We evaluated the potential for regional genomic surveillance to track the spread of blaKPC-carrying CRE (KPC-CRE) by using isolate collections from health care facilities in three U.S. states. Clinical isolates were collected from Connecticut (2017 to 2018), Minnesota (2012 to 2018), and Tennessee (2016 to 2017) through the U.S. Centers for Disease Control and Prevention's Multi-site Gram-negative Surveillance Initiative (MuGSI) and additional surveillance. KPC-CRE isolates were whole-genome sequenced, yielding 255 isolates from 214 patients across 96 facilities. Case report data on patient comorbidities, facility exposures, and interfacility patient transfer were extracted. We observed that in Connecticut, most KPC-CRE isolates showed evidence of importation from outside the state, with limited local transmission. In Minnesota, cases were mainly from sporadic importation and transmission of blaKPC-carrying Klebsiella pneumoniae ST258, and clonal expansion of blaKPC-carrying Enterobacter hormaechei ST171, primarily at a single focal facility and its satellite facilities. In Tennessee, we observed transmission of diverse strains of blaKPC-carrying Enterobacter and Klesbiella, with evidence that most derived from the local acquisition of blaKPC plasmids circulating in an interconnected regional health care network. Thus, the underlying processes driving KPC-CRE burden can differ substantially across regions and can be discerned through regional genomic surveillance. This study provides proof of concept that integrating genomic data with information on interfacility patient transfers can provide insights into locations and drivers of regional KPC-CRE burden that can enable targeted interventions.

Emotion transmission in peer dyads in middle childhood.

This study investigated emotion transmission among peers during middle childhood. Participants included 202 children (111 males; race: 58% African American, 20% European American, 16% Mixed race, 1% Asian American, and 5% Other; ethnicity: 23% Latino(a) and 77% Not Latino(a); Mincome  = $42,183, SDincome  = $43,889; Mage  = 9.49; English-speaking; from urban and suburban areas of a mid-Atlantic state in the United States). Groups of four same-sex children interacted in round-robin dyads in 5-min tasks during 2015-2017. Emotions (happy, sad, angry, anxious, and neutral) were coded and represented as percentages of 30-s intervals. Analyses assessed whether children's emotion expression in one interval predicted change in partners' emotion expression in the next interval. Findings suggested: (a) escalation of positive and negative emotion [children's positive (negative) emotion predicts an increase in partners' positive (negative) emotion], and (b) de-escalation of positive and negative emotion (children's neutral emotion predicts a decrease in partners' positive or negative emotion). Importantly, de-escalation involved children's display of neutral emotion and not oppositely valenced emotion.

Susceptibility to peer influence in adolescents: Associations between psychophysiology and behavior.

The current study investigated in-the-moment links between adolescents' autonomic nervous system activity and susceptibility to three types of peer influence (indirect, direct, continuing) on two types of behavior (antisocial, prosocial). The sample included 144 racially ethnically diverse adolescents (46% male, 53% female, 1% other; M age  = 16.02 years). We assessed susceptibility to peer influence behaviorally using the Public Goods Game (PGG) while measuring adolescents' mean heart rate (MHR) and pre-ejection period (PEP). Three key findings emerged from bivariate dual latent change score modeling: (1) adolescents whose MHR increased more as they transitioned from playing the PGG alone (pre-influence) to playing while simply observed by peers (indirect influence) displayed more prosocial behavior; (2) adolescents whose PEP activity increased more (greater PEP activity = shorter PEP latency) as they transitioned from indirect influence to being encouraged by peers to engage in antisocial behavior (direct influence) engaged in more antisocial behavior; and (3) adolescents whose PEP activity decreased less as they transitioned from direct influence on prosocial behavior to playing the PGG alone again (continuing influence) displayed more continuing prosocial behavior (marginal effect). The discussion focuses on the role of psychophysiology in understanding adolescents' susceptibility to peer influence.

A comprehensive review of cerebral oximetry in cardiac surgery.

BACKGROUND: Patients who undergo cardiac surgery are at increased risk of stroke, postoperative cognitive decline, and delirium. These neurocognitive complications have led to increased costs, intensive care unit stays, morbidity, and mortality. As a result, there is a significant push to mitigate any neurological complications in cardiac surgery patients. Near-infrared spectroscopy to measure regional cerebral oxygen saturations has gained consideration due to its noninvasive and user-friendly nature. Cerebral oximetry desaturations during cardiac surgery have been linked to an array of adverse clinical outcomes. However, the most effective intraoperative interventions to protect this vulnerable patient population have yet to be ascertained. AIM OF STUDY: To provide a comprehensive summary of the intraoperative management for cerebral oximetry desaturations during cardiac surgery. The review highlights clinical outcomes from cerebral oximetry use to quantify the importance of identifying cerebral desaturations during cardiac surgery. The review then interrogates possible interventions for cerebral oximetry desaturations in an effort to determine which interventions are most efficacious and to enlighten possible areas for further research. METHODS: A narrative review of randomized controlled trials, observational studies, and systematic reviews with metanalyses was performed through August 2021. RESULTS: There is significant heterogeneity among patient populations for which cerebral oximetry monitoring has been studied in cardiac surgery. Further, the definition of a clinically significant cerebral desaturation and the assessment of neurocognitive outcomes varied substantially across studies. As a result, metanalysis is challenging and few conclusions can be drawn. Cerebral oximetry use during cardiac surgery has not been associated with improvements in neurocognitive outcomes, morbidity, or mortality to date. The evidence to support a particular intervention for an acute desaturation is equivocal. CONCLUSIONS: Future research is needed to quantify a clinically significant cerebral desaturation and to determine which interventions for an acute desaturation effectively improve clinical outcomes.

An integrated program of computer-presented and physical cognitive training exercises for children with attention-deficit/hyperactivity disorder.

BACKGROUND: This study integrated an experimental medicine approach and a randomized cross-over clinical trial design following CONSORT recommendations to evaluate a cognitive training (CT) intervention for attention deficit hyperactivity disorder (ADHD). The experimental medicine approach was adopted because of documented pathophysiological heterogeneity within the diagnosis of ADHD. The cross-over design was adopted to provide the intervention for all participants and make maximum use of data. METHODS: Children (n = 93, mean age 7.3 +/- 1.1 years) with or sub-threshold for ADHD were randomly assigned to CT exercises over 15 weeks, before or after 15 weeks of treatment-as-usual (TAU). Fifteen dropped out of the CT/TAU group and 12 out of the TAU/CT group, leaving 66 for cross-over analysis. Seven in the CT/TAU group completed CT before dropping out making 73 available for experimental medicine analyses. Attention, response inhibition, and working memory were assessed before and after CT and TAU. RESULTS: Children were more likely to improve with CT than TAU (27/66 v. 13/66, McNemar p = 0.02). Consistent with the experimental medicine hypotheses, responders improved on all tests of executive function (p = 0.009-0.01) while non-responders improved on none (p = 0.27-0.81). The degree of clinical improvement was predicted by baseline and change scores in focused attention and working memory (p = 0.008). The response rate was higher in inattentive and combined subtypes than hyperactive-impulsive subtype (p = 0.003). CONCLUSIONS: Targeting cognitive dysfunction decreases clinical symptoms in proportion to improvement in cognition. Inattentive and combined subtypes were more likely to respond, consistent with targeted pathology and clinically relevant heterogeneity within ADHD.

Respiratory sinus arrhythmia as a moderator of early maltreatment effects on later externalizing problems.

Physiological regulation may interact with early experiences such as maltreatment to increase risk for behavior problems. In the current study, we investigate the role of parasympathetic nervous system regulation (respiratory sinus arrhythmia [RSA] at rest and in response to a frustration task) as a moderator of the association between early risk for maltreatment (i.e., involvement with Child Protective Services; CPS) and externalizing behavior problems in middle childhood. CPS involvement was associated with elevated externalizing problems, but only among children with average to high RSA at rest and average to high RSA withdrawal in response to frustration. Effects appeared to be specific to CPS involvement as the association between cumulative risk (i.e., nonmaltreatment experiences of early adversity) and externalizing problems was not significantly moderated by RSA activity. These findings are consistent with the theoretical idea that the consequences of early maltreatment for later externalizing behavior problems depend on children's biological regulation abilities.

The Calpain Gene is Correlated With Metal-on-Metal Hip Replacement Failures.

BACKGROUND: Metal-on-metal (MOM) total hip arthroplasty is associated with unacceptable failure rates secondary to metal ion reactions. Efforts to identify which patients will go on to failure have been limited; recently, there has been a suggestion for a potential genetic basis for the increased risk of revision in MOM hip replacements (MOMHRs). The purpose of this study is to determine whether certain immunologic genotypes are predictive of the need for revision in patients with MOM total hip implants. METHODS: This is a case-control study of all patients undergoing primary MOMHR between September 2002 and January 2012 with a minimum of 5-year follow-up. Our investigational "case" cohort was comprised of patients who underwent revision for MOMHR for a reason other than infection. A single-nucleotide polymorphism (SNP) array analysis was performed to identify a potential genetic basis for failure. RESULTS: Thirty-two patients (15 case and 17 control) were included in our analysis. All patients in the revision group had a chief complain of pain; revision patients were more likely to have a posterior approach (P = .01) and larger head size (P = .04) than nonrevision patients. No patient or implant characteristics were independently associated with revision in a multivariate analysis. Patients with SNP kgp9316441 were identified as having an increased odds of revision for MOM failure (P < .001). CONCLUSION: This study identified an SNP, kgp9316441, encoding proteins associated with inflammation and macrophage activation. This SNP was associated with significantly increased odds of revision for MOMHR. Future studies are warranted to validate this gene target both in vitro and in vivo. LEVEL OF EVIDENCE: III.

Temporal and Genotypic Associations of Sporadic Norovirus Gastroenteritis and Reported Norovirus Outbreaks in Middle Tennessee, 2012-2016.

BACKGROUND: In the United States, surveillance of norovirus gastroenteritis is largely restricted to outbreaks, limiting our knowledge of the contribution of sporadic illness to the overall impact on reported outbreaks. Understanding norovirus transmission dynamics is vital for improving preventive measures, including norovirus vaccine development. METHODS: We analyzed seasonal patterns and genotypic distribution between sporadic pediatric norovirus cases and reported norovirus outbreaks in middle Tennessee. Sporadic cases were ascertained via the New Vaccine Surveillance Network in a single county, while reported norovirus outbreaks from 7 middle Tennessee counties were included in the study. We investigated the predictive value of sporadic cases on outbreaks using a 2-state discrete Markov model. RESULTS: Between December 2012 and June 2016, there were 755 pediatric sporadic norovirus cases and 45 reported outbreaks. Almost half (42.2%) of outbreaks occurred in long-term care facilities. Most sporadic cases (74.9%) and reported outbreaks (86.8%) occurred between November and April. Peak sporadic norovirus activity was often contemporaneous with outbreak occurrence. Among both sporadic cases and outbreaks, GII genogroup noroviruses were most prevalent (90.1% and 83.3%), with GII.4 being the dominant genotype (39.0% and 52.8%). The predictive model suggested that the 3-day moving average of sporadic cases was positively associated with the probability of an outbreak occurring. CONCLUSIONS: Despite the demographic differences between the surveillance populations, the seasonal and genotypic associations between sporadic cases and outbreaks are suggestive of contemporaneous community transmission. Public health agencies may use this knowledge to expand surveillance and identify target populations for interventions, including future vaccines.

Return to racing after surgical management of third carpal bone slab fractures in thoroughbred and standardbred racehorses.

OBJECTIVE: To determine the prognosis for racing of horses surgically treated for slab fractures of the third carpal bone (C3). STUDY DESIGN: Retrospective case study. ANIMALS: Horses (n = 125) surgically treated for C3 slab fractures. METHODS: Medical records of horses surgically treated for dorsal or sagittal C3 fractures were reviewed for age, sex, breed, limb, fracture type, degree of cartilage damage, and surgical treatment. Radiographs were evaluated to determine fracture depth, width, and displacement. Osteophytes, C3 lysis, and fragmentation were scored. Racing performance was obtained from online databases. Univariable and multivariable analyses were used to determine associations between independent variables and outcomes. RESULTS: Fifty-four (43%) horses raced postoperatively. Among thoroughbreds, 35% (30/86) with dorsal fractures and 63% (17/27) with sagittal fractures raced postoperatively. Among standardbreds, 77% (10/13) with dorsal fractures and 0% (0/2) with sagittal fractures raced postoperatively. Fracture displacement, C3 lysis, and cartilage damage affected the likelihood of racing postoperatively. Placement of 3.5-mm screws vs 4.5-mm screws and the placement of fewer screws were associated with improved likelihood of racing. CONCLUSION: The prognosis for postoperative racing of thoroughbreds with dorsal C3 fractures was less favorable than that previously reported. Concurrent joint pathology, such as cartilage damage at time of surgery, affected the ability of the horse to race postoperatively. CLINICAL SIGNIFICANCE: Although internal fixation of C3 slab fractures is required to restore joint congruity, return to racing should be expected in only 42% of thoroughbreds and 67% of standardbreds.

Implementation Evaluation of the Mother-Child Education Program Among Refugee and Other Vulnerable Communities in Lebanon.

Despite the knowledge that quality early childhood development programs, including those that target parental knowledge and behaviors, are essential for ameliorating the negative effects of early-life adversity, robust analyses of their implementation and impact in highly vulnerable settings are scarce. To address this knowledge gap, we conducted a pilot wait-list randomized controlled trial (RCT) to assess the impact and the process of implementing and evaluating the Mother-Child Education Program (MOCEP) among refugee families and one low-income community in Beirut, Lebanon. This paper focuses on the analysis of MOCEP's implementation (i.e., key enablers of and barriers to the application and evaluation of the program). Our analysis suggests that, despite multiple challenges, implementation and robust evaluations of early childhood parenting programs in fragile contexts are feasible and urgently needed. This study illustrates how implementation evaluations are a key component of RCTs and crucial to identifying strategies to optimize program uptake and maximize impact.

The simultaneous assessment of and relations between children's sympathetic and parasympathetic psychophysiology and their reactive and proactive aggression.

The goal of the current study was to examine the link between children's psychophysiology and aggression when both constructs were assessed simultaneously in scenarios designed to provide the opportunity to aggress for either a reactive reason or a proactive reason. Both sympathetic nervous system (SNS) activity (skin conductance) and parasympathetic nervous system (PNS) activity (respiratory sinus arrhythmia or RSA), as well as their interaction, were included as physiological measures. Participants were 35 5th-grade children who were placed in two virtual-peer scenarios; one scenario provided the opportunity to aggress in response to peer provocation (i.e., reactive aggression) and the other scenario provided the opportunity to aggress for instrumental gain (i.e., proactive aggression). Both skin conductance and RSA were assessed at the time that children were given the opportunity to aggress; this simultaneous assessment of psychophysiology and aggression allowed for an examination of in-the-moment relations between the two constructs. For the reactive scenario, RSA moderated the in-the-moment relation between skin conductance and aggression such that the association was positive at low RSA but negative at high RSA. For the proactive scenario, skin conductance negatively predicted aggression in-the-moment, and RSA positively predicted aggression in-the-moment, but their interaction was not a significant predictor of aggression. Theoretical implications for reactive and proactive aggression and underlying physiological processes are discussed.

Calcium Signaling throughout the Toxoplasma gondii Lytic Cycle: A STUDY USING GENETICALLY ENCODED CALCIUM INDICATORS.

Toxoplasma gondii is an obligate intracellular parasite that invades host cells, creating a parasitophorous vacuole where it communicates with the host cell cytosol through the parasitophorous vacuole membrane. The lytic cycle of the parasite starts with its exit from the host cell followed by gliding motility, conoid extrusion, attachment, and invasion of another host cell. Here, we report that Ca(2+) oscillations occur in the cytosol of the parasite during egress, gliding, and invasion, which are critical steps of the lytic cycle. Extracellular Ca(2+) enhances each one of these processes. We used tachyzoite clonal lines expressing genetically encoded calcium indicators combined with host cells expressing transiently expressed calcium indicators of different colors, and we measured Ca(2+) changes in both parasites and host simultaneously during egress. We demonstrated a link between cytosolic Ca(2+) oscillations in the host and in the parasite. Our approach also allowed us to measure two new features of motile parasites, which were enhanced by Ca(2+) influx. This is the first study showing, in real time, Ca(2+) signals preceding egress and their direct link with motility, an essential virulence trait.

Ca2+ Regulation of Trypanosoma brucei Phosphoinositide Phospholipase C.

We characterized a phosphoinositide phospholipase C (PI-PLC) from the procyclic form (PCF) of Trypanosoma brucei. The protein contains a domain organization characteristic of typical PI-PLCs, such as X and Y catalytic domains, an EF-hand calcium-binding motif, and a C2 domain, but it lacks a pleckstrin homology (PH) domain. In addition, the T. brucei PI-PLC (TbPI-PLC) contains an N-terminal myristoylation consensus sequence found only in trypanosomatid PI-PLCs. A peptide containing this N-terminal domain fused to green fluorescent protein (GFP) was targeted to the plasma membrane. TbPI-PLC enzymatic activity was stimulated by Ca(2+) concentrations below the cytosolic levels in the parasite, suggesting that the enzyme is constitutively active. TbPI-PLC hydrolyzes both phosphatidylinositol (PI) and phosphatidylinositol 4,5-bisphosphate (PIP2), with a higher affinity for PIP2. We found that modification of a single amino acid in the EF-hand motif greatly affected the protein's Ca(2+) sensitivity and substrate preference, demonstrating the role of this motif in Ca(2+) regulation of TbPI-PLC. Endogenous TbPI-PLC localizes to intracellular vesicles and might be using an intracellular source of PIP2. Knockdown of TbPI-PLC expression by RNA interference (RNAi) did not result in growth inhibition, although enzymatic activity was still present in parasites, resulting in hydrolysis of PIP2 and a contribution to the inositol 1,4,5-trisphosphate (IP3)/diacylglycerol (DAG) pathway.

The Importance of Both Individual Differences and Dyadic Processes in Children's Emotion Expression.

Although children display strong individual differences in emotion expression, they also engage in emotional synchrony or reciprocity with interaction partners. To understand this paradox between trait-like and dyadic influences, the goal of the current study was to investigate children's emotion expression using a Social Relations Model (SRM) approach. Playgroups consisting typically of four same-sex unfamiliar nine-year-old children (N = 202) interacted in a round-robin format (6 dyads per group). Each dyad completed two 5-minute tasks, a challenging frustration task and a cooperative planning task. Observers coded children's emotions during the tasks (happy, sad, angry, anxious, neutral) on a second-by-second basis. SRM analyses provided substantial evidence of both the trait-like nature of children's emotion expression (through significant effects for actor variance, multivariate actor-actor correlations, and multivariate intrapersonal correlations) and the dyadic nature of their emotion expression (through significant effects for partner variance, relationship variance, dyadic reciprocity correlations, and multivariate interpersonal correlations).

Concurrent transmission of multiple carbapenemases in a long-term acute-care hospital.

OBJECTIVE: We investigated concurrent outbreaks of Pseudomonas aeruginosa carrying blaVIM (VIM-CRPA) and Enterobacterales carrying blaKPC (KPC-CRE) at a long-term acute-care hospital (LTACH A). METHODS: We defined an incident case as the first detection of blaKPC or blaVIM from a patient's clinical cultures or colonization screening test. We reviewed medical records and performed infection control assessments, colonization screening, environmental sampling, and molecular characterization of carbapenemase-producing organisms from clinical and environmental sources by pulsed-field gel electrophoresis (PFGE) and whole-genome sequencing. RESULTS: From July 2017 to December 2018, 76 incident cases were identified from 69 case patients: 51 had blaKPC, 11 had blaVIM, and 7 had blaVIM and blaKPC. Also, blaKPC were identified from 7 Enterobacterales, and all blaVIM were P. aeruginosa. We observed gaps in hand hygiene, and we recovered KPC-CRE and VIM-CRPA from drains and toilets. We identified 4 KPC alleles and 2 VIM alleles; 2 KPC alleles were located on plasmids that were identified across multiple Enterobacterales and in both clinical and environmental isolates. CONCLUSIONS: Our response to a single patient colonized with VIM-CRPA and KPC-CRE identified concurrent CPO outbreaks at LTACH A. Epidemiologic and genomic investigations indicated that the observed diversity was due to a combination of multiple introductions of VIM-CRPA and KPC-CRE and to the transfer of carbapenemase genes across different bacteria species and strains. Improved infection control, including interventions that minimized potential spread from wastewater premise plumbing, stopped transmission.

Gender and Autism Program: A novel clinical service model for gender-diverse/transgender autistic youth and young adults.

Objective: Situated in Children's National Hospital (CNH)'s Neuropsychology Division, the Gender and Autism Program (GAP) is the first clinical service dedicated to the needs of autistic gender-diverse/transgender youth. This study describes GAP clinical assessment profiles and presents a multi-perspective programmatic review of GAP evaluation services. Method: Seventy-five consecutive gender- and neuropsychologically-informed GAP evaluations were analyzed, including demographics, gender and autism characterization, and primary domains evaluated. Three program-based Delphi studies were conducted and identify: clinician priorities and challenges in providing care, program administrator lessons learned and ongoing barriers, and considerations adapting this model for a rural academic medical center. Results: Nearly two-thirds of referrals were transfeminine. Most youth had existing autism diagnoses; of those undiagnosed, three-quarters were found to be autistic. Five goals of evaluations were identified: Mental health was always assessed, and most evaluations also assessed gender-related needs in the context of autism neurodiversity. Neuropsychological characterization of strengths and challenges informed personalized accommodations to support youth gender-related self-advocacy. Clinicians emphasized frequent youth safety concerns. Administrators emphasized the need for specialized training for working with families. Components for adaptation of the GAP in a rural academic medical center were identified. Conclusions: Since its founding, the GAP has proven a sustainable neuropsychology-based service with consistent referral flow and insurance authorizations. Capturing staff perspectives through rigorous Delphi methods, and addressing the GAP's feasibility and replicability, this study provides a road map for replicating this service. We also highlight GAP training of specialist clinicians, fundamental to addressing the desperate shortage of providers in this field.

Population-based study reveals new risk-stratification biomarker panel for Barrett's esophagus.

BACKGROUND & AIMS: The risk of progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) is low and difficult to calculate. Accurate tools to determine risk are needed to optimize surveillance and intervention. We assessed the ability of candidate biomarkers to predict which cases of BE will progress to EAC or high-grade dysplasia and identified those that can be measured in formalin-fixed tissues. METHODS: We analyzed data from a nested case-control study performed using the population-based Northern Ireland BE Register (1993-2005). Cases who progressed to EAC (n = 89) or high-grade dysplasia ≥ 6 months after diagnosis with BE were matched to controls (nonprogressors, n = 291), for age, sex, and year of BE diagnosis. Established biomarkers (abnormal DNA content, p53, and cyclin A expression) and new biomarkers (levels of sialyl Lewis(a), Lewis(x), and Aspergillus oryzae lectin [AOL] and binding of wheat germ agglutinin) were assessed in paraffin-embedded tissue samples from patients with a first diagnosis of BE. Conditional logistic regression analysis was applied to assess odds of progression for patients with dysplastic and nondysplastic BE, based on biomarker status. RESULTS: Low-grade dysplasia and all biomarkers tested, other than Lewis(x), were associated with risk of EAC or high-grade dysplasia. In backward selection, a panel comprising low-grade dysplasia, abnormal DNA ploidy, and AOL most accurately identified progressors and nonprogressors. The adjusted odds ratio for progression of patients with BE with low-grade dysplasia was 3.74 (95% confidence interval, 2.43-5.79) for each additional biomarker and the risk increased by 2.99 for each additional factor (95% confidence interval, 1.72-5.20) in patients without dysplasia. CONCLUSIONS: Low-grade dysplasia, abnormal DNA ploidy, and AOL can be used to identify patients with BE most likely to develop EAC or high-grade dysplasia.