Quantified Ataxic Breathing Can Detect Opioid-Induced Respiratory Depression Earlier in Normal Volunteers Infused with Remifentanil.

BACKGROUND: Ataxic breathing (AB) is a well-known manifestation of opioid effects in animals and humans, but is not routinely included in monitoring for opioid-induced respiratory depression (OIRD). We quantified AB in normal volunteers receiving increasing doses of remifentanil. We used a support vector machine (SVM) learning approach with features derived from a modified Poincaré plot. We tested the hypothesis that AB may be found when bradypnea and reduced mental status are not present. METHODS: Twenty-six healthy volunteers (13 female) received escalating target effect-site concentrations of remifentanil with a low baseline dose of propofol to simulate typical breathing patterns in drowsy patients who had received parenteral opioids. We derived respiratory rate (RR) from respiratory inductance plethysmography, mental alertness from the Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S), and AB severity on a 0 to 4 scale (categories ranging from none to severe) from the SVM. The primary outcome measure was sensitivity and specificity for AB to detect OIRD. RESULTS: All respiratory measurements were obtained from unperturbed subjects during steady state in 121 assessments with complete data. The sensitivity of AB for detecting OIRD by the conventional method was 92% and specificity was 28%. As expected, 69 (72%) of the instances not diagnosed as OIRD using conventional measures were observed to have at least moderate AB. CONCLUSIONS: AB was frequently present in the absence of traditionally detected OIRD as defined by reduced mental alertness (MOAA/S score of <4) and bradypnea (RR <8 breaths/min). These results justify the need for future trials to explore replicability with other opioids and clinical utility of AB as an add-on measure in recognizing OIRD.

Participant-derived cell line transcriptomic analyses and mouse studies reveal a role for ZNF335 in plasma cholesterol statin response.

BACKGROUND: Statins lower circulating low-density lipoprotein cholesterol (LDLC) levels and reduce cardiovascular disease risk. Though highly efficacious in general, there is considerable inter-individual variation in statin efficacy that remains largely unexplained. METHODS: To identify novel genes that may modulate statin-induced LDLC lowering, we used RNA-sequencing data from 426 control- and 2 µM simvastatin-treated lymphoblastoid cell lines (LCLs) derived from European and African American ancestry participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial (ClinicalTrials.gov Identifier: NCT00451828). We correlated statin-induced changes in LCL gene expression with plasma LDLC statin response in the corresponding CAP participants. For the most correlated gene identified (ZNF335), we followed up in vivo by comparing plasma cholesterol levels, lipoprotein profiles, and lipid statin response between wild-type mice and carriers of a hypomorphic (partial loss of function) missense mutation in Zfp335 (the mouse homolog of ZNF335). RESULTS: The statin-induced expression changes of 147 human LCL genes were significantly correlated to the plasma LDLC statin responses of the corresponding CAP participants in vivo (FDR = 5%). The two genes with the strongest correlations were zinc finger protein 335 (ZNF335 aka NIF-1, rho = 0.237, FDR-adj p = 0.0085) and CCR4-NOT transcription complex subunit 3 (CNOT3, rho = 0.233, FDR-adj p = 0.0085). Chow-fed mice carrying a hypomorphic missense (R1092W; aka bloto) mutation in Zfp335 had significantly lower non-HDL cholesterol levels than wild-type C57BL/6J mice in a sex combined model (p = 0.04). Furthermore, male (but not female) mice carrying the Zfp335R1092W allele had significantly lower total and HDL cholesterol levels than wild-type mice. In a separate experiment, wild-type mice fed a control diet for 4 weeks and a matched simvastatin diet for an additional 4 weeks had significant statin-induced reductions in non-HDLC (-43 ± 18% and -23 ± 19% for males and females, respectively). Wild-type male (but not female) mice experienced significant reductions in plasma LDL particle concentrations, while male mice carrying Zfp335R1092W allele(s) exhibited a significantly blunted LDL statin response. CONCLUSIONS: Our in vitro and in vivo studies identified ZNF335 as a novel modulator of plasma cholesterol levels and statin response, suggesting that variation in ZNF335 activity could contribute to inter-individual differences in statin clinical efficacy.

Missense variants in SORT1 are associated with LDL-C in an Amish population.

Common noncoding variants at the human 1p13.3 locus associated with SORT1 expression are among those most strongly associated with low-density lipoprotein cholesterol (LDL-C) in human genome-wide association studies. However, validation studies in mice and cell lines have produced variable results regarding the directionality of the effect of SORT1 on LDL-C. This, together with the fact that the 1p13.3 variants are associated with expression of several genes, has raised the question of whether SORT1 is the causal gene at this locus. Using whole exome sequencing in members of an Amish population, we identified coding variants in SORT1 that are associated with increased (rs141749679, K302E) and decreased (rs149456022, Q225H) LDL-C. Further, analysis of plasma lipoprotein particle subclasses by ion mobility in a subset of rs141749679 (K302E) carriers revealed higher levels of large LDL particles compared to noncarriers. In contrast to the effect of these variants in the Amish, the sortilin K302E mutation introduced into a C57BL/6J mouse via CRISPR/Cas9 resulted in decreased non-high-density lipoprotein cholesterol, and the sortilin Q225H mutation did not alter cholesterol levels in mice. This is indicative of different effects of these mutations on cholesterol metabolism in the two species. To our knowledge, this is the first evidence that naturally occurring coding variants in SORT1 are associated with LDL-C, thus supporting SORT1 as the gene responsible for the association of the 1p13.3 locus with LDL-C.

Participant-derived cell line transcriptomic analyses and mouse studies reveal a role for ZNF335 in plasma cholesterol statin response.

Background: Statins lower circulating low-density lipoprotein cholesterol (LDLC) levels and reduce cardiovascular disease risk. Though highly efficacious in general, there is considerable inter-individual variation in statin efficacy that remains largely unexplained. Methods: To identify novel genes that may modulate statin-induced LDLC lowering, we used RNA-sequencing data from 426 control- and 2 µM simvastatin-treated lymphoblastoid cell lines (LCLs) derived from European and African American ancestry participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial (ClinicalTrials.gov Identifier: NCT00451828). We correlated statin-induced changes in LCL gene expression with plasma LDLC statin response in the corresponding CAP participants. For the most correlated gene identified (ZNF335), we followed up in vivo by comparing plasma cholesterol levels, lipoprotein profiles, and lipid statin response between wild-type mice and carriers of a hypomorphic (partial loss of function) missense mutation in Zfp335 (the mouse homolog of ZNF335). Results: The statin-induced expression changes of 147 human LCL genes were significantly correlated to the plasma LDLC statin responses of the corresponding CAP participants in vivo (FDR=5%). The two genes with the strongest correlations were zinc finger protein 335 (ZNF335 aka NIF-1, rho=0.237, FDR-adj p=0.0085) and CCR4-NOT transcription complex subunit 3 (CNOT3, rho=0.233, FDR-adj p=0.0085). Chow-fed mice carrying a hypomorphic missense (R1092W; aka bloto) mutation in Zfp335 had significantly lower non-HDL cholesterol levels than wild type C57BL/6J mice in a sex combined model (p=0.04). Furthermore, male (but not female) mice carrying the Zfp335R1092W allele had significantly lower total and HDL cholesterol levels than wild-type mice. In a separate experiment, wild-type mice fed a control diet for 4 weeks and a matched simvastatin diet for an additional 4 weeks had significant statin-induced reductions in non-HDLC (-43±18% and -23±19% for males and females, respectively). Wild-type male (but not female) mice experienced significant reductions in plasma LDL particle concentrations, while male mice carrying Zfp335R1092W allele(s) exhibited a significantly blunted LDL statin response. Conclusions: Our in vitro and in vivo studies identified ZNF335 as a novel modulator of plasma cholesterol levels and statin response, suggesting that variation in ZNF335 activity could contribute to inter-individual differences in statin clinical efficacy.

Effects of media multitasking frequency on a novel volitional multitasking paradigm.

The effect of media multitasking (e.g., listening to podcasts while studying) on cognitive processes has seen mixed results thus far. To date, the tasks used in the literature to study this phenomenon have been classical paradigms primarily used to examine processes such as working memory. While perfectly valid on their own, these paradigms do not approximate a real-world volitional multitasking environment. To remedy this, as well as attempt to further validate previously found effects in the literature, we designed a novel experimental framework that mimics a desktop computer environment where a "popup" associated with a secondary task would occasionally appear. Participants could choose to attend to the popup, or to ignore it. Attending to the popup would prompt a word stem completion task, while ignoring it would continue the primary math problem verification task. We predicted that individuals who are more impulsive, more frequent media multitaskers, and individuals who prefer to multitask (quantified with the Barratt Impulsiveness Scale, a modified version of the Media Use Questionnaire, and the Multitasking Preference Inventory) would be more distracted by popups, choose to switch tasks more often and more quickly, and be slower to return to the primary task compared to those who media multitask to a lesser degree. We found that as individuals media multitask to a greater extent, they are slower to return to the previous (primary) task set and are slower to complete the primary task overall whether a popup was present or not, among other task performance measures. We found a similar pattern of effects within individuals who prefer to multitask. Our findings suggest that overall, more frequent media multitaskers show a marginal decrease in task performance, as do preferential multitaskers. Attentional impulsivity was not found to influence any task performance measures, but was positively related to a preference for multitasking. While our findings may lack generalizability due to the modifications to the Media Use Questionnaire, and this initial study is statically underpowered, this paradigm is a crucial first step in establishing a more ecologically valid method to study real-world multitasking.

Volatile anesthetic gas concentration sensing using flow sensor fusion for use in Austere settings.

Flow sensors are often sensitive to the presence of volatile anesthetics. However, this sensitivity provides a unique opportunity to combine flow sensors of differing technological principles as an alternative to measuring volatile anesthetic gas concentration, particularly for austere settings. To determine the feasibility of flow sensor fusion for volatile anesthetic concentrations monitoring, eight flow sensors were tested with isoflurane, sevoflurane, and desflurane, ranging in concentrations from 0-4.5%, 0-3.5%, and 0-18%, respectively. Pairs of flow sensors were fit to the volatile anesthetic gas concentration with a leave-one-out cross-validation method to reduce the likelihood of overfitting. Bland-Altman was used for the final evaluation of sensor pair performance. Several sensor pairs yielded limits of agreement comparable to the rated accuracy of a commercial infrared spectrometer. The ultrasonic and orifice-plate flowmeters yielded the most combinations of viable sensor pairs for all three volatile anesthetic gases. Conclusion: Measuring volatile anesthetic gases using flow sensor fusion is a feasible low-cost, low-maintenance alternative to infrared spectroscopy. In this study, testing was done under steady-state conditions in 100% oxygen. Further testing is necessary to ensure sensor fusion performance under conditions that are more reflective of the clinical use case.

OpenSync: An open-source platform for synchronizing multiple measures in neuroscience experiments.

BACKGROUND: The human mind is multimodal. Most behavioral studies rely on century-old measures such as task accuracy and latency. To better understand human behavior and brain functionality, we need to analyze physiological and behavioral signals of various sources. However, it is technically complex and costly to design and implement experiments that record multiple measures. To address this issue, a platform that synchronizes multiple measures is needed. METHOD: This paper introduces an open-source platform named OpenSync, which can be used to synchronize numerous measures in neuroscience experiments. This platform helps to automatically integrate, synchronize and record physiological and behavioral signals (e.g., electroencephalogram (EEG), galvanic skin response (GSR), eye-tracking, body motion, etc.), user input response (e.g., from mouse, keyboard, joystick, etc.), and task-related information (stimulus markers). In this paper, we explain the features of OpenSync and provide two case studies in PsychoPy and Unity. COMPARISON WITH EXISTING TOOLS: Unlike proprietary systems (e.g., iMotions), OpenSync is free and easy to implement, and it can be used inside any open-source experiment design software (e.g., PsychoPy, OpenSesame, Unity, etc., https://pypi.org/project/OpenSync/ and https://github.com/TAMUCogLab/OpenSync). RESULTS: Our experimental results show that the OpenSync platform is able to synchronize multiple measures with microsecond resolution.

Component processes underlying voluntary task selection: Separable contributions of task-set inertia and reconfiguration.

Most theories describing the cognitive processes underlying task switching allow for contributions of active task-set reconfiguration and task set inertia. Manipulations of the Cue-to-Stimulus-Interval (CSI) are generally thought to influence task set reconfiguration, while Response-to-Cue (RCI) manipulations are thought to influence task set inertia. Together, these intervals compose the Response-to-Stimulus (RSI) interval. However, these theories do not adequately account for voluntary task switching, because a participant can theoretically prepare for an upcoming trial at any point. We used drift diffusion models to examine the contributions of reconfiguration and task set inertia to performance in single- and double-registrant-registrant voluntary task switching. In both paradigms, RSI length moderated nondecision time, suggesting both switch-specific and general preparation prior to cue presentation. In only the double-registrant registrant paradigm, RSI length additionally moderated task set inertia and CSI length affected general (but not switch-specific) preparation. The effects of cue timing (CSI length) depended upon required response to the cue. Future work should attempt to corroborate our findings regarding switch-specific and general preparation effects of interval lengths using EEG.

Direct Optoelectronic Imaging of 2D Semiconductor-3D Metal Buried Interfaces.

The semiconductor-metal junction is one of the most critical factors for high-performance electronic devices. In two-dimensional (2D) semiconductor devices, minimizing the voltage drop at this junction is particularly challenging and important. Despite numerous studies concerning contact resistance in 2D semiconductors, the exact nature of the buried interface under a three-dimensional (3D) metal remains unclear. Herein, we report the direct measurement of electrical and optical responses of 2D semiconductor-metal buried interfaces using a recently developed metal-assisted transfer technique to expose the buried interface, which is then directly investigated using scanning probe techniques. We characterize the spatially varying electronic and optical properties of this buried interface with <20 nm resolution. To be specific, potential, conductance, and photoluminescence at the buried metal/MoS2 interface are correlated as a function of a variety of metal deposition conditions as well as the type of metal contacts. We observe that direct evaporation of Au on MoS2 induces a large strain of ∼5% in the MoS2 which, coupled with charge transfer, leads to degenerate doping of the MoS2 underneath the contact. These factors lead to improvement of contact resistance to record values of 138 kΩ µm, as measured using local conductance probes. This approach was adopted to characterize MoS2-In/Au alloy interfaces, demonstrating contact resistance as low as 63 kΩ µm. Our results highlight that the MoS2/metal interface is sensitive to device fabrication methods and provide a universal strategy to characterize buried contact interfaces involving 2D semiconductors.

Preliminary effects of prefrontal tDCS on dopamine-mediated behavior and psychophysiology.

The ability to manipulate dopamine in vivo through non-invasive, reversible mechanisms has the potential to impact clinical, translational, and basic research. Recent PET studies have demonstrated increased dopamine release in the striatum after bifrontal transcranial direct current stimulation (tDCS). We sought to extend this work by examining whether bifrontal tDCS could demonstrate an effect on behavioral and physiological correlates of subcortical dopamine activity. We conducted a preliminary between-subjects study (n = 30) with active and sham tDCS and used spontaneous eye blink rate (EBR), facial attractiveness ratings, and greyscales orienting bias as indirect proxies for dopamine functioning. The initial design and analyses were pre-registered (https://osf.io/gmnpc). Stimulation did not significantly affect any of the three measures, though effect sizes were often moderately large and were all in the predicted directions. Additional exploratory analyses suggested that stimulation's effect on EBR might depend on pre-stimulation dopamine levels. Our results suggest that larger samples than those that are standard in tDCS literature should be used to assess the effect of tDCS on dopamine using indirect measures. Further, exploratory results add to a growing body of work demonstrating the importance of accounting for individual differences in tDCS response.

Cerebellar and prefrontal-cortical engagement during higher-order rule learning in older adulthood.

To date most aging research has focused on cortical systems and networks, ignoring the cerebellum which has been implicated in both cognitive and motor function. Critically, older adults (OA) show marked differences in cerebellar volume and functional networks, suggesting it may play a key role in the behavioral differences observed in advanced age. OA may be less able to recruit cerebellar resources due to network and structural differences. Here, 26 young adults (YA) and 25 OA performed a second-order learning task, known to activate the cerebellum in the fMRI environment. Behavioral results indicated that YA performed significantly better and learned more quickly compared to OA. Functional imaging detailed robust parietal and cerebellar activity during learning (compared to control) blocks within each group. OA showed increased activity (relative to YA) in the left inferior parietal lobe in response to instruction cues during learning (compared to control); whereas, YA showed increased activity (relative to OA) in the left anterior cingulate to feedback cues during learning, potentially explaining age-related performance differences. Visual interpretation of effect size maps showed more bilateral posterior cerebellar activation in OA compared to YA during learning blocks, but early learning showed widespread cerebellar activation in YA compared to OA. There were qualitatively large age-related differences in cerebellar recruitment in terms of effect sizes, yet no statistical difference. These findings serve to further elucidate age-related differences and similarities in cerebellar and cortical brain function and implicate the cerebellum and its networks as regions of interest in aging research.

Efficient sampling for polynomial chaos-based uncertainty quantification and sensitivity analysis using weighted approximate Fekete points.

Performing uncertainty quantification (UQ) and sensitivity analysis (SA) is vital when developing a patient-specific physiological model because it can quantify model output uncertainty and estimate the effect of each of the model's input parameters on the mathematical model. By providing this information, UQ and SA act as diagnostic tools to evaluate model fidelity and compare model characteristics with expert knowledge and real world observation. Computational efficiency is an important part of UQ and SA methods and thus optimization is an active area of research. In this work, we investigate a new efficient sampling method for least-squares polynomial approximation, weighted approximate Fekete points (WAFP). We analyze the performance of this method by demonstrating its utility in stochastic analysis of a cardiovascular model that estimates changes in oxyhemoglobin saturation response. Polynomial chaos (PC) expansion using WAFP produced results similar to the more standard Monte Carlo in quantifying uncertainty and identifying the most influential model inputs (including input interactions) when modeling oxyhemoglobin saturation, PC expansion using WAFP was far more efficient. These findings show the usefulness of using WAFP based PC expansion to quantify uncertainty and analyze sensitivity of a oxyhemoglobin dissociation response model. Applying these techniques could help analyze the fidelity of other relevant models in preparation for clinical application.

Longitudinal Assessment and Functional Neuroimaging of Movement Variability Reveal Novel Insights Into Motor Dysfunction in Clinical High Risk for Psychosis.

Motor dysfunction in youth at clinical high risk (CHR) for psychosis is thought to reflect abnormal neurodevelopment within cortical-subcortical motor circuits and may be important for understanding clinical trajectories of CHR individuals. However, to date, our perspective of brain-behavior relationships has been informed solely by cross-sectional correlational studies linking behavior in the lab to brain structure or respective resting-state network connectivity. Here, we assess movement dysfunction from 2 perspectives: study 1 investigates the longitudinal progression of handwriting variability and positive symptoms in a sample of 91 CHR and healthy controls during a 12-month follow-up and study 2 involves a multiband functional magnetic resonance imaging task exploring the relationship between power grip force stability and motor network brain activation in a subset of participants. In study 1, we found that greater handwriting variability was a stable feature of CHR participants who experienced worse symptom progression. Study 2 results showed that CHR individuals had greater variability in their grip force and greater variability was related to decreased activation in the associative cortico-striatal network compared to controls. Motor variability may be a stable marker of vulnerability for psychosis risk and possible indicator of a vulnerable cortico-striatal brain network functioning in CHR participants, although the effects of antipsychotic medication should be considered.

Adolescents at clinical high risk for psychosis show qualitatively altered patterns of activation during rule learning.

BACKGROUND: The ability to flexibly apply rules to novel situations is a critical aspect of adaptive human behavior. While executive function deficits are known to appear early in the course of psychosis, it is unclear which specific facets are affected. Identifying whether rule learning is impacted at the early stages of psychosis is necessary for truly understanding the etiology of psychosis and may be critical for designing novel treatments. Therefore, we examined rule learning in healthy adolescents and those meeting criteria for clinical high risk (CHR) for psychosis. METHODS: 24 control and 22 CHR adolescents underwent rapid, high-resolution fMRI while performing a paradigm which required them to apply novel or practiced task rules. RESULTS: Previous work has suggested that practiced rules rely on rostrolateral prefrontal cortex (RLPFC) during rule encoding and dorsolateral prefrontal cortex (DLPFC) during task performance, while novel rules show the opposite pattern. We failed to replicate this finding, with greater activity for novel rules during performance. Comparing the HC and CHR group, there were no statistically significant effects, but an effect size analysis found that the CHR group showed less activation during encoding and greater activation during performance. This suggests the CHR group may use less efficient reactive control to retrieve task rules at the time of task performance, rather than proactively during rule encoding. CONCLUSIONS: These findings suggest that flexibility is qualitatively altered in the clinical high risk state, however, more data is needed to determine whether these deficits predict disease progression.

Creativity on demand - Hacking into creative problem solving.

How can creative problem solving be enhanced? The paper identifies and examines modulatory approaches from the cognitive and neuroscientific literature that have been made to make creative problem solving better. We review neuromodulatory approaches of both global and local effects. Through a 2-process model of creative problem solving that involves both automatic and controlled processes, we demonstrate how these approaches could be used and what potential they may have for enhancing creative problem solving. We conclude that direct neuromodulation will be best used in unison with behavioral manipulations of cognition, and that better understanding of these manipulations should inform and guide research on direct neuromodulatory procedures.

An Automated Algorithm Incorporating Poincaré Analysis Can Quantify the Severity of Opioid-Induced Ataxic Breathing.

BACKGROUND: Opioid-induced respiratory depression (OIRD) is traditionally recognized by assessment of respiratory rate, arterial oxygen saturation, end-tidal CO2, and mental status. Although an irregular or ataxic breathing pattern is widely recognized as a manifestation of opioid effects, there is no standardized method for assessing ataxic breathing severity. The purpose of this study was to explore using a machine-learning algorithm for quantifying the severity of opioid-induced ataxic breathing. We hypothesized that domain experts would have high interrater agreement with each other and that a machine-learning algorithm would have high interrater agreement with the domain experts for ataxic breathing severity assessment. METHODS: We administered target-controlled infusions of propofol and remifentanil to 26 healthy volunteers to simulate light sleep and OIRD. Respiration data were collected from respiratory inductance plethysmography (RIP) bands and an intranasal pressure transducer. Three domain experts quantified the severity of ataxic breathing in accordance with a visual scoring template. The Krippendorff alpha, which reports the extent of interrater agreement among N raters, was used to assess agreement among the 3 domain experts. A multiclass support vector machine (SVM) was trained on a subset of the domain expert-labeled data and then used to quantify ataxic breathing severity on the remaining data. The Vanbelle kappa was used to assess the interrater agreement of the machine-learning algorithm with the grouped domain experts. The Vanbelle kappa expands on the Krippendorff alpha by isolating a single rater-in this case, the machine-learning algorithm-and comparing it to a group of raters. Acceptance criteria for both statistical measures were set at >0.8. The SVM was trained and tested using 2 sensor inputs for the breath marks: RIP and intranasal pressure. RESULTS: Krippendorff alpha was 0.93 (95% confidence interval [CI], 0.91-0.95) for the 3 domain experts. Vanbelle kappa was 0.98 (95% CI, 0.96-0.99) for the RIP SVM and 0.96 (0.92-0.98) for the intranasal pressure SVM compared to the domain experts. CONCLUSIONS: We concluded it may be feasible for a machine-learning algorithm to quantify ataxic breathing severity in a manner consistent with a panel of domain experts. This methodology may be helpful in conjunction with traditional measures to identify patients experiencing OIRD.

A procedure for determining subject-specific pulse oxygen saturation response.

The oxyhemoglobin dissociation curve describes the relationship between the partial pressure of oxygen and the percent of hemoglobin saturated with oxygen and varies with chemical and physical factors that differ for every patient. If variability could be determined, patient-specific oxygen therapy could be administered. We have developed a procedure for characterizing variations in the oxygen dissociation curve. The purpose of this study was to validate this procedure in surgical patients. The procedure uses an automated system to alter oxygen therapy during surgery, within safe operational levels, and fit to Hill's equation non-invasive measurements of end-tidal oxygen and peripheral pulse oxygen saturation. The best-fit parameters for the Hill equation, estimated by iterative least squares, provide an apparent dissociation curve, meaningful of the patient-specific pulse oximeter response. Thirty-nine patients participated in this study. Using patient-specific parameter values increases correlation when compared with standard values. The procedure improved the model fit of patient saturation values significantly in 19 patients. This paper has demonstrated a procedure for determining patient-specific pulse oximeter response. This procedure determined best-fit parameters resulting in a significantly improved fit when compared with standard values. These best-fit parameters increased the coefficient of determination R2 in all cases. Graphical Abstract This patient-specific procedure improves fit significantly compared to standard estimates.

Age Differences in the Subcomponents of Executive Functioning.

OBJECTIVES: Across the life span, deficits in executive functioning (EF) are associated with poor behavioral control and failure to achieve goals. Though EF is often discussed as one broad construct, a prominent model of EF suggests that it is composed of three subdomains: inhibition, set shifting, and updating. These subdomains are seen in both younger (YA) and older adults (OA), with performance deficits across subdomains in OA. Therefore, our goal was to investigate whether subdomains of EF might be differentially affected by age, and how these differences may relate to broader global age differences in EF. METHODS: To assess these age differences, we conducted a meta-analysis at multiple levels, including task level, subdomain level, and of global EF. Based on previous work, we hypothesized that there would be overall differences in EF in OA. RESULTS: Using 1,268 effect sizes from 401 articles, we found overall differences in EF with age. Results suggested that differences in performance are not uniform, such that variability in age effects emerged at the task level, and updating was not as affected by age as other subdomains. DISCUSSION: These findings advance our understanding of age differences in EF, and stand to inform early detection of EF decline.

A comparison of ventilation with a non-invasive ventilator versus standard O2 with a nasal cannula for colonoscopy with moderate sedation using propofol.

The aim of this study was to test the effects of CPAP on moderately sedated patients undergoing colonoscopy. Our hypothesis was that CPAP can reduce the incidence and duration of obstructive apnea and hemoglobin oxygen desaturation in patients undergoing procedural sedation for colonoscopy. Two groups of consenting adult patients scheduled to undergo routine colonoscopy procedures and sedated with propofol and fentanyl were monitored in this study: control and intervention. Patients in the intervention group were connected via a facemask to a ventilator that delivered supplemental oxygen (100%) through a standard air-cushion mask. The mask had a built-in leak to facilitate CO2 clearance during CPAP. Patients in the control group received 2-10 L/min of oxygen via nasal cannula or non-rebreather mask. Subjects in the control group were collected in a prior study and used as historical controls. The primary outcome measures were the number of apneic events and the cumulative duration of apneic events. An apneic event was defined as a period longer than 10 s without respiration. The secondary outcome was the area under the curve (AUC) for the arterial oxygen saturation less than 90% versus time during sedative and analgesic administration (time (s) below threshold multiplied by percent below threshold). A desaturation event was defined as a period of time during which arterial oxygen saturation was less than 90%. 29 patients were enrolled in the intervention group and 156 patients were previously enrolled in the control group as part of an earlier study. The median number of apneic events in the control group was 7 compared to 0 in the intervention group. The intervention group experienced apnea less than 1% of the total procedure time compared to 17% in the control group (p < 0.001). There were no desaturation events observed in the 29 patients in the intervention group. In contrast, 27 out of 156 patients in the control group experienced a desaturation event. Average AUC of patients in the control group was 70%-s (time (s) * oxygen saturation below < 90%) (95% CI 32.34-108.60%) whereas the average AUC in intervention group patients was 0%-s (% time (s) * oxygen saturation < 90%) (95% CI 0-0%), p = 0.01. This preliminary study found that CPAP via a tight-fitting mask may be an effective tool to reduce the incidence and duration of obstructive apneic events as well as hemoglobin oxygen desaturation during lower endoscopy procedures that use propofol and fentanyl for sedation.Clinical Trial Registration ClinicalTrials.gov ID: NCT02623270. https://clinicaltrials.gov/ct2/show/NCT02623270 .