Characteristics of Patients With Initial Clostridioides difficile Infection (CDI) That Are Associated With Increased Risk of Multiple CDI Recurrences.

Background: Because interventions are available to prevent further recurrence in patients with recurrent Clostridioides difficile infection (rCDI), we identified predictors of multiple rCDI (mrCDI) in adults at the time of presentation with initial CDI (iCDI). Methods: iCDI was defined as a positive C difficile test in any clinical setting during January 2018-August 2019 in a person aged ≥18 years with no known prior positive test. rCDI was defined as a positive test ≥14 days from the previous positive test within 180 days after iCDI; mrCDI was defined as ≥2 rCDI. We performed multivariable logistic regression analysis. Results: Of 18 829 patients with iCDI, 882 (4.7%) had mrCDI; 437 with mrCDI and 7484 without mrCDI had full chart reviews. A higher proportion of patients with mrCDI than without mrCDI were aged ≥65 years (57.2% vs 40.7%; P < .0001) and had healthcare (59.1% vs 46.9%; P < .0001) and antibiotic (77.3% vs 67.3%; P < .0001) exposures in the 12 weeks preceding iCDI. In multivariable analysis, age ≥65 years (adjusted odds ratio [aOR], 1.91; 95% confidence interval [CI], 1.55-2.35), chronic hemodialysis (aOR, 2.28; 95% CI, 1.48-3.51), hospitalization (aOR, 1.64; 95% CI, 1.33-2.01), and nitrofurantoin use (aOR, 1.95; 95% CI, 1.18-3.23) in the 12 weeks preceding iCDI were associated with mrCDI. Conclusions: Patients with iCDI who are older, on hemodialysis, or had recent hospitalization or nitrofurantoin use had increased risk of mrCDI and may benefit from early use of adjunctive therapy to prevent mrCDI. If confirmed, these findings could aid in clinical decision making and interventional study designs.

Potential underreporting of treated patients using a Clostridioides difficile testing algorithm that screens with a nucleic acid amplification test.

OBJECTIVE: Patients tested for Clostridioides difficile infection (CDI) using a 2-step algorithm with a nucleic acid amplification test (NAAT) followed by toxin assay are not reported to the National Healthcare Safety Network as a laboratory-identified CDI event if they are NAAT positive (+)/toxin negative (-). We compared NAAT+/toxin- and NAAT+/toxin+ patients and identified factors associated with CDI treatment among NAAT+/toxin- patients. DESIGN: Retrospective observational study. SETTING: The study was conducted across 36 laboratories at 5 Emerging Infections Program sites. PATIENTS: We defined a CDI case as a positive test detected by this 2-step algorithm during 2018-2020 in a patient aged ≥1 year with no positive test in the previous 8 weeks. METHODS: We used multivariable logistic regression to compare CDI-related complications and recurrence between NAAT+/toxin- and NAAT+/toxin+ cases. We used a mixed-effects logistic model to identify factors associated with treatment in NAAT+/toxin- cases. RESULTS: Of 1,801 cases, 1,252 were NAAT+/toxin-, and 549 were NAAT+/toxin+. CDI treatment was given to 866 (71.5%) of 1,212 NAAT+/toxin- cases versus 510 (95.9%) of 532 NAAT+/toxin+ cases (P < .0001). NAAT+/toxin- status was protective for recurrence (adjusted odds ratio [aOR], 0.65; 95% CI, 0.55-0.77) but not CDI-related complications (aOR, 1.05; 95% CI, 0.87-1.28). Among NAAT+/toxin- cases, white blood cell count ≥15,000/µL (aOR, 1.87; 95% CI, 1.28-2.74), ≥3 unformed stools for ≥1 day (aOR, 1.90; 95% CI, 1.40-2.59), and diagnosis by a laboratory that provided no or neutral interpretive comments (aOR, 3.23; 95% CI, 2.23-4.68) were predictors of CDI treatment. CONCLUSION: Use of this 2-step algorithm likely results in underreporting of some NAAT+/toxin- cases with clinically relevant CDI. Disease severity and laboratory interpretive comments influence treatment decisions for NAAT+/toxin- cases.

Development of a Broth Microdilution Method To Characterize Chlorhexidine MICs among Bacteria Collected from 2005 to 2019 at Three U.S. Sites.

Chlorhexidine bathing to prevent transmission of multidrug-resistant organisms has been adopted by many U.S. hospitals, but increasing chlorhexidine use has raised concerns about possible emergence of resistance. We sought to establish a broth microdilution method for determining chlorhexidine MICs and then used the method to evaluate chlorhexidine MICs for bacteria that can cause health care-associated infections. We adapted a broth microdilution method for determining chlorhexidine MICs, poured panels, established quality control ranges, and tested Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae complex isolates collected at three U.S. sites. Chlorhexidine MICs were determined for 535 isolates including 129 S. aureus, 156 E. coli, 142 K. pneumoniae, and 108 E. cloacae complex isolates. The respective MIC distributions for each species ranged from 1 to 8 mg/L (MIC50 = 2 mg/L and MIC90 = 4 mg/L), 1 to 64 mg/L (MIC50 = 2 mg/L and MIC90 = 4 mg/L), 4 to 64 mg/L (MIC50 = 16 mg/L and MIC90 = 32 mg/L), and 1 to >64 mg/L (MIC50 = 16 mg/L and MIC90 = 64 mg/L). We successfully adapted a broth microdilution procedure that several laboratories were able to use to determine the chlorhexidine MICs of bacterial isolates. This method could be used to investigate whether chlorhexidine MICs are increasing. IMPORTANCE Chlorhexidine bathing to prevent transmission of multidrug-resistant organisms and reduce health care-associated infections has been adopted by many hospitals. There is concern about the possible unintended consequences of using this agent widely. One possible unintended consequence is decreased susceptibility to chlorhexidine, but there are not readily available methods to perform this evaluation. We developed a method for chlorhexidine MIC testing that can be used to evaluate for possible unintended consequences.

Volumetric measurement of intracranial meningiomas: a comparison between linear, planimetric, and machine learning with multiparametric voxel-based morphometry methods.

PURPOSE: To compare the accuracy of three volumetric methods in the radiological assessment of meningiomas: linear (ABC/2), planimetric, and multiparametric machine learning-based semiautomated voxel-based morphometry (VBM), and to investigate the relevance of tumor shape in volumetric error. METHODS: Retrospective imaging database analysis at the authors' institutions. We included patients with a confirmed diagnosis of meningioma and preoperative cranial magnetic resonance imaging eligible for volumetric analyses. After tumor segmentation, images underwent automated computation of shape properties such as sphericity, roundness, flatness, and elongation. RESULTS: Sixty-nine patients (85 tumors) were included. Tumor volumes were significantly different using linear (13.82 cm3 [range 0.13-163.74 cm3]), planimetric (11.66 cm3 [range 0.17-196.2 cm3]) and VBM methods (10.24 cm3 [range 0.17-190.32 cm3]) (p < 0.001). Median volume and percentage errors between the planimetric and linear methods and the VBM method were 1.08 cm3 and 11.61%, and 0.23 cm3 and 5.5%, respectively. Planimetry and linear methods overestimated the actual volume in 79% and 63% of the patients, respectively. Correlation studies showed excellent reliability and volumetric agreement between manual- and computer-based methods. Larger and flatter tumors had greater accuracy on planimetry, whereas less rounded tumors contributed negatively to the accuracy of the linear method. CONCLUSION: Semiautomated VBM volumetry for meningiomas is not influenced by tumor shape properties, whereas planimetry and linear methods tend to overestimate tumor volume. Furthermore, it is necessary to consider tumor roundness prior to linear measurement so as to choose the most appropriate method for each patient on an individual basis.

Comparison of the Risk of Recurrent Clostridioides Difficile Infections Among Patients in 2018 Versus 2013.

Among persons with an initial Clostridioides difficile infection (CDI) across 10 US sites in 2018 compared with 2013, 18.3% versus 21.1% had ≥1 recurrent CDI (rCDI) within 180 days. We observed a 16% lower adjusted risk of rCDI in 2018 versus 2013 (P < .0001).

Discovering Precise Temporal Patterns in Large-Scale Neural Recordings through Robust and Interpretable Time Warping.

Though the temporal precision of neural computation has been studied intensively, a data-driven determination of this precision remains a fundamental challenge. Reproducible spike patterns may be obscured on single trials by uncontrolled temporal variability in behavior and cognition and may not be time locked to measurable signatures in behavior or local field potentials (LFP). To overcome these challenges, we describe a general-purpose time warping framework that reveals precise spike-time patterns in an unsupervised manner, even when these patterns are decoupled from behavior or are temporally stretched across single trials. We demonstrate this method across diverse systems: cued reaching in nonhuman primates, motor sequence production in rats, and olfaction in mice. This approach flexibly uncovers diverse dynamical firing patterns, including pulsatile responses to behavioral events, LFP-aligned oscillatory spiking, and even unanticipated patterns, such as 7 Hz oscillations in rat motor cortex that are not time locked to measured behaviors or LFP.

The Natural History of Coiled Cerebral Aneurysms Stratified by Modified Raymond-Roy Occlusion Classification.

OBJECTIVE: The natural history and long-term durability of Guglielmi detachable coil (GDC) embolization is still unknown. We hypothesize a stepwise decrease in durability of embolized cerebral aneurysms as stratified by the Modified Raymond-Roy Classification (MRRC). METHODS: First-time GDC-embolized cerebral aneurysms were retrospectively reviewed from 2004 to 2015. Loss of durability (LOD) was defined by change in aneurysm size or patency seen on serial radiographic follow-up. Kaplan-Meier survival analysis was performed to evaluate embolization durability. Multivariate Cox regression modeling was used to assess baseline aneurysm and patient characteristics for their effect on LOD. RESULTS: A total of 427 patients with 443 aneurysms met the inclusion criteria. Overall, 89 (21%) aneurysms met LOD criteria. Grade 1 aneurysms had statistically significantly greater durability than did all other MRRC grades. Grade 3b aneurysms had significantly worse durability than did all other aneurysm grades. There was no difference in durability between grade 2 and 3a aneurysms. Of aneurysms with LOD, 26 (29%) experienced worsening of MRRC grade. Thirty-five (24%) initial MRRC grade 2, 72 (45%) initial MRRC grade 3a, and 6 (22%) initial MRRC grade 3b aneurysms progressed to MRRC grade 1 without retreatment. In our multivariate analysis, only initial MRRC grade was statistically significantly associated with treatment durability (P < 0.001). CONCLUSIONS: MRRC grade is independently associated with first-time GDC-embolized cerebral aneurysm durability. Achieving MRRC grade 1 occlusion outcome is significantly associated with greater long-term GDC durability. Although few aneurysms experience further growth and/or recanalization, most incompletely obliterated aneurysms tend to remain stable over time or even progress to occlusion. Grading scales such as the MRRC are useful for characterizing aneurysm occlusion but may lack sensitivity and specificity for characterizing changes in aneurysm morphology over time.

Early and Late Posttraumatic Epilepsy in the Setting of Traumatic Brain Injury: A Meta-analysis and Review of Antiepileptic Management.

BACKGROUND: Moderate to severe traumatic brain injury confers increased risk of posttraumatic seizures (PTSs). Early PTSs are diagnosed when seizures develop within 7 days after injury, whereas seizures diagnosed as late PTSs occur later. Patients have been treated with phenytoin (PHT) to prevent early PTSs and more recently with levetiracetam (LEV). Various regimens have been tried in patients to prevent late PTSs with variable success. We assessed and compared effectiveness of these drugs on early and late PTS prevention. METHODS: A literature search revealed 120 articles. Data were included if the same factors were compared across studies with identical treatment arms. Random effects models were used for meta-analysis to combine data into an overriding odds ratio (OR) comparing PTS incidence. For early PTSs, PHT was compared with placebo and LEV with PHT. For late PTSs, each drug was compared with placebo. RESULTS: Sixteen studies were included. PHT was associated with decreased odds of early seizures relative to placebo (OR = 0.34, 95% confidence interval [CI] 0.19-0.62). There was no difference in early seizure incidence between LEV and PHT (OR = 0.83, 95% CI 0.33-2.1). Neither LEV (OR = 0.69, 95% CI 0.24-1.96) nor PHT (OR = 0.4, 95% CI 0.1-1.6) was associated with fewer late PTSs than placebo. CONCLUSIONS: New literature is consistent with current guidelines supporting antiepileptic drug administration for prevention of early, but not late, PTSs. With regard to early PTS prevention, LEV and PHT are similarly efficacious, which is consistent with current guidelines. Side-effect profiles favor LEV administration over PHT.

A primacy code for odor identity.

Humans can identify visual objects independently of view angle and lighting, words independently of volume and pitch, and smells independently of concentration. The computational principles underlying invariant object recognition remain mostly unknown. Here we propose that, in olfaction, a small and relatively stable set comprised of the earliest activated receptors forms a code for concentration-invariant odor identity. One prediction of this "primacy coding" scheme is that decisions based on odor identity can be made solely using early odor-evoked neural activity. Using an optogenetic masking paradigm, we define the sensory integration time necessary for odor identification and demonstrate that animals can use information occurring <100 ms after inhalation onset to identify odors. Using multi-electrode array recordings of odor responses in the olfactory bulb, we find that concentration-invariant units respond earliest and at latencies that are within this behaviorally-defined time window. We propose a computational model demonstrating how such a code can be read by neural circuits of the olfactory system.

Meta-analysis and systematic review of risk factors for shunt dependency after aneurysmal subarachnoid hemorrhage.

OBJECTIVE Aneurysmal subarachnoid hemorrhage (aSAH) may be complicated by hydrocephalus in 6.5%-67% of cases. Some patients with aSAH develop shunt dependency, which is often managed by ventriculoperitoneal shunt placement. The objectives of this study were to review published risk factors for shunt dependency in patients with aSAH, determine the level of evidence for each factor, and calculate the magnitude of each risk factor to better guide patient management. METHODS The authors searched PubMed and MEDLINE databases for Level A and Level B articles published through December 31, 2014, that describe factors affecting shunt dependency after aSAH and performed a systematic review and meta-analysis, stratifying the existing data according to level of evidence. RESULTS On the basis of the results of the meta-analysis, risk factors for shunt dependency included high Fisher grade (OR 7.74, 95% CI 4.47-13.41), acute hydrocephalus (OR 5.67, 95% CI 3.96-8.12), in-hospital complications (OR 4.91, 95% CI 2.79-8.64), presence of intraventricular blood (OR 3.93, 95% CI 2.80-5.52), high Hunt and Hess Scale score (OR 3.25, 95% CI 2.51-4.21), rehemorrhage (OR 2.21, 95% CI 1.24-3.95), posterior circulation location of the aneurysm (OR 1.85, 95% CI 1.35-2.53), and age ≥ 60 years (OR 1.81, 95% CI 1.50-2.19). The only risk factor included in the meta-analysis that did not reach statistical significance was female sex (OR 1.13, 95% CI 0.77-1.65). CONCLUSIONS The authors identified several risk factors for shunt dependency in aSAH patients that help predict which patients are likely to require a permanent shunt. Although some of these risk factors are not independent of each other, this information assists clinicians in identifying at-risk patients and managing their treatment.

Design principles for effective video-based professional development.

BACKGROUND: Most studies of teacher professional development (PD) do not rigorously test impact on teaching practice and student learning. This makes it difficult to define what is truly "effective." The Science Teachers Learning from Lesson Analysis (STeLLA) PD program, in contrast, was studied in a cluster randomized experimental design that examined impact on teaching practice and student learning. The STeLLA video-based PD (VbPD) program demonstrated significant impact, with high effect sizes, on elementary teachers' science teaching practice and their students' learning. Previously published reports provide details about research methods and findings but only broad sketches of the STeLLA program design and implementation. Deeper explorations of the STeLLA design principles can contribute evidence-based knowledge about the features of effective PD and enrich the existing but limited consensus model of effective PD. This article addresses the following questions:What design principles guided the development, implementation, leadership, and scaling up of a video-based PD program that had significant impact on student learning?What do the STeLLA design principles contribute to the existing knowledge base about effective video-based PD? RESULTS: Results from rigorous studies of the STeLLA program are summarized in this paper; details are reported elsewhere and included here as supplementary materials. This article is not a standard research results paper but instead describes the design principles guiding the development, implementation, leadership, and scaling up of the STeLLA VbPD program. CONCLUSIONS: The authors argue that this set of design principles is powerful for four reasons: 1) its demonstrated impact on teaching practice and student learning, 2) its strong theoretical and research foundations, 3) the stability and usefulness of the design principles as implemented in changing contexts over a 10-year period, and 4) the coherence and interconnectedness of the principles. The STeLLA VbPD design principles contribute to the field by empirically supporting and advancing the existing consensus model of effective PD. Further study can build on this effort to strengthen our understanding of effective PD based on evidence of impact on teaching practice and student learning.

Sustained glucocorticoid exposure recruits cortico-limbic CRH signaling to modulate endocannabinoid function.

Sustained exposure to stress or corticosteroids is known to cause changes in brain endocannabinoid (eCB) signaling, such that tissue contents of the eCBs N-arachidonylethanolamine (AEA) are generally reduced while 2-arachidonoylglycerol (2-AG) levels increase. These changes in eCB signaling are important for many of the aspects of chronic stress, such as anxiety, reward sensitivity and stress adaptation, yet the mechanisms mediating these changes are not fully understood. We have recently found that the stress-related neuropeptide corticotropin-releasing hormone (CRH), acting through the CRH type 1 receptor (CRHR1), can reduce AEA content by increasing its hydrolysis by the enzyme fatty acid amide hydrolase (FAAH) as well as increase 2-AG contents. As extra-hypothalamic CRH is upregulated by chronic corticosteroid or stress exposure, we hypothesized that increased CRH signaling through CRHR1 contributes to the effects of chronic corticosteroid exposure on the eCB system within the amygdala and prefrontal cortex. Male rats were exposed to 7 days of systemic corticosterone capsules, with or without concurrent exposure to a CRHR1 antagonist, after which we examined eCB content. Consistent with previous studies in the amygdala, sustained corticosterone exposure increases CRH mRNA in the prefrontal cortex. As was shown previously, FAAH activity was increased and AEA contents were reduced within the amygdala and prefrontal cortex following chronic corticosterone exposure. Chronic corticosterone exposure also elevated 2-AG content in the prefrontal cortex but not the amygdala. These corticosteroid-driven changes were all blocked by systemic CRHR1 antagonism. Consistent with these data indicating sustained increases in CRH signaling can mediate the effects of chronic elevations in corticosteroids, CRH overexpressing mice also exhibited increased FAAH-mediated AEA hydrolysis in the amygdala and prefrontal cortex compared to wild type. CRH overexpression increased 2-AG content in the amygdala, but not the prefrontal cortex. These data indicate that chronic elevations in CRH signaling, as is seen following exposure to chronic elevations in corticosterone or stress, drive persistent changes in eCB function. As reductions in AEA signaling mediate the effects of CRH and chronic stress on anxiety, these data provide a mechanism linking these processes.

Dysregulated hypothalamic-pituitary-adrenal axis function contributes to altered endocrine and neurobehavioral responses to acute stress.

Organisms react to environmental challenges by activating a coordinated set of brain-body responses known as the stress response. These physiological and behavioral countermeasures are, in large part, regulated by the neuroendocrine hypothalamic-pituitary-adrenal (HPA) axis. Normal functioning of the HPA axis ensures that an organism responds appropriately to altered environmental demands, representing an essential system to promote survival. Over the past several decades, increasing evidence supports the hypothesis that disruption of the HPA axis can lead to dysregulated stress response phenotypes, exacting a physiological cost on the organism commonly referred to as allostatic load. Furthermore, it has been recognized that high allostatic load can contribute to increased vulnerability of the organism to further challenges. This observation leads to the notion that disrupted HPA function and resulting inappropriate responses to stressors may underlie many neuropsychiatric disorders, including depression and anxiety. In the present set of studies, we investigate the role of both the normally functioning and disrupted HPA axis in the endocrine, neural, and behavioral responses to acute stress. Using a model of non-invasive chronic corticosterone treatment in mice, we show that dysregulating the normal function of the HPA leads to a mismatch between the hormonal and neural response to acute stress, resulting in abnormal behavioral coping strategies. We believe this model can be leveraged to tease apart the mechanisms by which altered HPA function contributes to neurobehavioral dysregulation in response to acute stress.

Anatomic, hematologic, and biochemical features of C57BL/6NCrl mice maintained on chronic oral corticosterone.

Metabolic syndrome is a condition that typically includes central obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension. Disruption of the hypothalamic-pituitary-adrenal axis, a regulator of corticosterone secretion, occurs in some cases of metabolic syndrome and obesity, and Cushing hypercortisolemia is associated with obesity and metabolic disorders. We therefore assessed anatomic and clinical pathology in C57BL/6NCrl mice to evaluate the effects of chronic corticosterone in the drinking water at doses of 25, 50, and 100 µg/mL for 25 d. Treated mice developed obesity, glucose intolerance, electrolyte aberrations, and dyslipidemia that were dose-dependent and most severe in the 100-mu;g/mL treatment group. To evaluate return to normal function, additional C57BL/6NCrl mice received corticosterone-free water for 2 wk after the 25-d treatment period. According to results of gross examination, mice appeared to recover within days of exogenous corticosterone withdrawal; however, adrenal gland vacuolation and protein, lipid, and electrolyte abnormalities persisted. Together, these findings support chronic corticosterone exposure through the drinking water as a potentially useful, noninvasive method to induce some features of metabolic syndrome.

Fungal infections and antifungal prophylaxis in pediatric cardiac extracorporeal life support.

OBJECTIVE: Infections acquired by children during extracorporeal membrane oxygenation (ECMO) increase mortality. Our aim was to evaluate the effectiveness of prophylactic fluconazole on the incidence of fungal infections and to assess whether hospital-acquired fungal infection is associated with increased in-hospital mortality in pediatric cardiac patients requiring ECMO. METHODS: We retrospectively reviewed a prospectively maintained database and collected data on all hospital-acquired infections in patients supported for cardiac indications at a tertiary children's hospital from 1989 to 2008. RESULTS: ECMO was deployed 801 times in 767 patients. After exclusion criteria were applied, 261 pediatric patients supported for cardiac indications were studied. Fungal infection (blood, urine, or surgical site) occurred in 12% (31/261) of patients, 9 (7%) of 127 patients receiving fluconazole prophylaxis versus 22 (16.4%) of 134 without antifungal prophylaxis (P = .02). Using a multivariable logistic regression model, the absence of fluconazole prophylaxis was associated with an increased risk of fungal infection (odds ratio [OR] = 2.8; 95% confidence intervals [CI], 1.2, 6.7; P = .016). In a multivariable logistic regression model for in-hospital mortality, the presence of fungal infection was associated with increased odds (OR = 3.8; 95% CI, 1.5, 9.6; P = .005) of in-hospital mortality among cardiac patients requiring ECMO, and the absence of antifungal prophylaxis showed a trend toward the same (OR = 1.6; 95% CI, 0.96, 2.8; P = .072). CONCLUSIONS: Children with cardiac disease supported with ECMO who acquire fungal infections have increased mortality. Routine fluconazole prophylaxis is associated with lower rates of fungal infections in these patients.

Assessing students' ability to trace matter in dynamic systems in cell biology.

College-level biology courses contain many complex processes that are often taught and learned as detailed narratives. These processes can be better understood by perceiving them as dynamic systems that are governed by common fundamental principles. Conservation of matter is such a principle, and thus tracing matter is an essential step in learning to reason about biological processes. We present here multiple-choice questions that measure students' ability and inclination to trace matter through photosynthesis and cellular respiration. Data associated with each question come from students in a large undergraduate biology course that was undergoing a shift in instructional strategy toward making fundamental principles (such as tracing matter) a central theme. We also present findings from interviews with students in the course. Our data indicate that 1) many students are not using tracing matter as a tool to reason about biological processes, 2) students have particular difficulties tracing matter between systems and have a persistent tendency to interconvert matter and energy, and 3) instructional changes seem to be effective in promoting application of the tracing matter principle. Using these items as diagnostic tools allows instructors to be proactive in addressing students' misconceptions and ineffective reasoning.