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.

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.

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.

Comparing Nasal End-Tidal Carbon Dioxide Measurement Variation and Agreement While Delivering Pulsed and Continuous Flow Oxygen in Volunteers and Patients.

BACKGROUND: Supplemental oxygen is administered during procedural sedation to prevent hypoxemia. Continuous flow oxygen, the most widespread method, is generally adequate but distorts capnography. Pulsed flow oxygen is novel and ideally will not distort capnography. We have developed a prototype oxygen administration system designed to try to facilitate end-tidal carbon dioxide (ETCO2) measurement. We conducted a volunteer study (ClinicalTrials.gov, NCT02886312) to determine how much nasal ETCO2 measurements vary with oxygen flow rate. We also conducted a clinical study (NCT02962570) to determine the median difference and limits of agreement between ETCO2 measurements made with and without administering oxygen. METHODS: Both studies were conducted at the University of Utah and participants acted as their own control. Inclusion criteria were age 18 years and older with an American Society of Anesthesiologists physical status of I-III. Exclusion criteria included acute respiratory distress syndrome, pneumonia, lung or cardiovascular disease, nasal/bronchial congestion, pregnancy, oxygen saturation measured by pulse oximetry <93%, and a procedure scheduled for <20 minutes. For the volunteer study, pulsed and continuous flow was administered at rates from 2 to 10 L/min using a single sequence of technique and flow. The median absolute deviation from the median value was analyzed for the primary outcome of ETCO2. For the clinical study, ETCO2 measurements (the primary outcome) were collected while administering pulsed and continuous flow at rates between 1 and 5 L/min and were compared to measurements without oxygen flow. Due to institutional review board requirements for patient safety, this study was not randomized. After completing the study, measurements with and without administering oxygen were analyzed to determine median differences and 95% limits of agreement for each administration technique. RESULTS: Thirty volunteers and 60 patients participated in these studies which ended after enrolling the predetermined number of participants. In volunteers, the median absolute deviation for ETCO2 measurements made while administering pulsed flow oxygen (0.89; 25%-75% quantiles: 0.3-1.2) was smaller than while administering continuous flow oxygen (3.93; 25%-75% quantiles: 2.2-6.2). In sedated patients, the median difference was larger during continuous flow oxygen (-6.8 mm Hg; 25%-75% quantiles: -12.5 to -2.1) than during pulsed flow oxygen (0.1 mm Hg; 25%-75% quantiles: -0.5 to 1.5). The 95% limits of agreement were also narrower during pulsed flow oxygen (-2.4 to 4.5 vs -30.5 to 2.4 mm Hg). CONCLUSIONS: We have shown that nasal ETCO2 measurements while administering pulsed flow have little deviation and agree well with measurements made without administering oxygen. We have also demonstrated that ETCO2 measurements during continuous flow oxygen have large deviation and wide limits of agreement when compared with measurements made without administering oxygen.

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 comparison of controlled ventilation with a noninvasive ventilator versus traditional mask ventilation.

After induction, but before intubation, many general anesthesia patients are manually bag-mask ventilated. The objective of this study was to determine the efficacy of bag-mask ventilation (MkV) of an anesthetized patient versus mask ventilation using a noninvasive ventilator (NIV). We hypothesized that feedback-controlled, mask ventilation via NIV is more efficacious and safer. This critical short period of time in the operating room was chosen to compare MkV versus NIV. 30 ASA I-III patients, aged 18-74, presenting for elective surgery under general anesthesia were enrolled in the study. Patients were ventilated first with MkV and then with NIV. One minute of ventilation data was collected for each method. Respiratory inductance plethysmography (RIP) bands around the chest and abdomen were used to measure tidal volumes and breath rates for each method of ventilation. The NIV was set to deliver 10 breaths per minute with 12 cmH2O of pressure support. A non-inferiority test was used to compare MkV and NIV. MkV breaths had an average of 13 breaths and tidal volume of 364 mL (SD 145 mL). NIV resulted in an average of 10 breaths and tidal volume of 552 mL, i.e., 188 mL more than MkV (lower bound of the 95% confidence interval equal to 120 mL). The hypothesis of non-inferiority at the - 100 mL level and the superiority hypothesis at the + 100 mL level was accepted. NIV also resulted in much more consistent ventilation rates (zero variation since it is controlled by the ventilator) when compared to manual ventilation while maintaining safe airway pressures (8 cmH2O EPAP and 20 cmH2O IPAP). Feedback controlled mask ventilation via a NIV is a viable alternative to MkV. It can deliver more optimal tidal volumes with the operator utilizing only one hand. The airway pressures are fixed at safe limits during a period where the goal is to reach a maximal level of oxygenation prior to intubation. Over-ventilation or over-pressurization of the airway is not a concern with NIV since the pressures are maintained well within safe thresholds to avoid injury.

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 .

Distinct and opposite profiles of connectivity during self-reference task and rest in youth at clinical high risk for psychosis.

Self-reference is impaired in psychotic disorders such as schizophrenia, associated with disability, and closely related to characteristic patterns of aberrant brain connectivity. However, at present, it is unclear whether self-reference is impacted in pathogenesis of the disorder. Alterations in connectivity during a self-reference task or resting-state in the psychosis risk (i.e., prodromal) period may yield important clues for biomarker development, as well as for novel treatment targets. This study examined a task-based and resting-state functional magnetic resonance imaging in individuals at clinical high risk (CHR) for psychosis (n = 22) and healthy control unaffected peers (n = 20). The self-reference task comprised three task conditions where subjects were asked if an adjective was relevant to themselves (self), a designated other individual (other), or to evaluate the word's spelling (letter). Connectivity analyses examined medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC), regions commonly found in conjunction analyses of self-reference, during both the self-reference task and rest. In task connectivity analyses, CHR individuals exhibited decreased mPFC-PCC connectivity when compared to controls. In resting-state analyses, CHR participants showed greater mPFC-PCC connectivity. Taken together, results suggest that psychosis-like alterations in mPFC-PCC connectivity is present prior to psychosis onset across both task and rest.

Striatal-frontal network activation during voluntary task selection under conditions of monetary reward.

During voluntary task selection, a number of internal and external biases may guide such a choice. However, it is not well understood how reward influences task selection when multiple options are possible. To address this issue, we examined brain activation in a voluntary task-switching paradigm while participants underwent fMRI (n = 19). To reinforce the overall goal to choose the tasks randomly, participants were told of a large bonus that they would receive at the end of the experiment for making random task choices. We also examined how occasional, random rewards influenced both task performance and brain activation. We hypothesized that these transient rewards would increase the value of the just-performed task, and therefore bias participants to choose to repeat the same task on the subsequent trial. Contrary to expectations, transient reward had no consistent behavioral effect on subsequent task choice. Nevertheless, the receipt of such rewards did influence activation in brain regions associated with reward processing as well as those associated with goal-directed control. In addition, reward on a prior trial was found to influence activation during task choice on a subsequent trial, with greater activation in a number of executive function regions compared with no-reward trials. We posit that both the random presentation of transient rewards and the overall task bonus for random task choices together reinforced the goal to choose the tasks randomly, which in turn influenced activation in both reward-related regions and those regions involved in abstract goal processing.

Correction to: Striatal-frontal network activation during voluntary task selection under conditions of monetary reward.

Conflict of interest statement: Although co-author Marie T. Banich is the Editor-in-Chief of Cognitive, Affective, and Behavioral Neuroscience, Stan Floresco served as the action editor for this manuscript.

Evaluation and application of a method for estimating nasal end-tidal O2 fraction while administering supplemental O2.

This paper describes a method for estimating the oxygen enhanced end-tidal fraction of oxygen (FetOe), the end-tidal fraction of oxygen (FetO2) that is raised by administering supplemental oxygen. The paper has two purposes: the first is to evaluate the method's accuracy on the bench and in volunteers; the second purpose is to demonstrate how to apply the method to compare two techniques of oxygen administration. The method estimates FetOe by analyzing expired oxygen as oxygen washes out of the lung. The method for estimating FetOe was first validated using a bench simulation in which tracheal oxygen was measured directly. Then it was evaluated in 30 healthy volunteers and compared to the bench simulation. Bland-Altman analysis compared calculated and observed FetOe/FetO2 measurements. After the method was evaluated, it was implemented to compare the FetOe obtained when administering oxygen using two different techniques (pulsed and continuous flow). A total of eighteen breath washout conditions were evaluated on the bench. FetOe estimates and tracheal FetO2 had a mean difference of - 0.016 FO2 with 95% limits of agreement from - 0.048 to 0.016 FO2. Thirteen breath washouts per volunteer were analyzed. Extrapolated and observed FetO2 had a mean difference of - 0.001 FO2 with 95% limits of agreement from - 0.006 to 0.004 FO2. Pulsed flow oxygen (PFO) achieved the same FetOe values as continuous flow oxygen (CFO) using 32.1% ± 2.27% (mean ± SD) of the CFO rate. This paper has demonstrated that the method estimates FetO2 enhanced by administering supplemental oxygen with clinically insignificant differences. This paper has also shown that PFO can obtain FetO2 similar to CFO using approximately one-third of the oxygen volume. After evaluating this method, we conclude that the method provides useful estimates of nasal FetO2 enhanced by supplemental oxygen administration.

Novel mandibular advancement bite block with supplemental oxygen to both nasal and oral cavity improves oxygenation during esophagogastroduodenoscopy: a bench comparison.

Drug-induced respiratory depression is a major cause of serious adverse events. Adequate oxygenation is very important during sedated esophagogastroduodenoscopy (EGD). Nasal breathing often shifts to oral breathing during open mouth EGD. A mandibular advancement bite block was developed for EGD using computer-assisted design and three-dimensional printing techniques. The mandible is advanced when using this bite block to facilitate airway opening. The device is composed of an oxygen inlet with one opening directed towards the nostril and another opening directed towards the oral cavity. The aim of this bench study was to compare the inspired oxygen concentration (FiO2) provided by the different nasal cannulas, masks, and bite blocks commonly used in sedated EGD. A manikin head was connected to one side of a two-compartment lung model by a 7.0 mm endotracheal tube with its opening in the nasopharyngeal position. The other compartment was driven by a ventilator to mimic "patient" inspiratory effort. Using this spontaneously breathing lung model, we evaluated five nasal cannulas, two face masks, and four new oral bite blocks at different oxygen flow rates and different mouth opening sizes. The respiratory rate was set at 12/min with a tidal volume of 500 mL and 8/min with a tidal volume of 300 mL. Several Pneuflo resistors of different sizes were used in the mouth of the manikin head to generate different degrees of mouth opening. FiO2 was evaluated continuously via the endotracheal tube. All parameters were evaluated using a Datex anesthesia monitoring system. The mandibular advancement bite block provided the highest FiO2 under the same supplemental oxygen flow. The FiO2 was higher for devices with oxygen flow provided via an oral bite block than that provided via the nasal route. Under the same supplemental oxygen flow, the tidal volume and respiratory rate also played an important role in the FiO2. A low respiratory rate with a smaller tidal volume has a relative high FiO2. The ratio of nasal to oral breathing played an important role in the FiO2 under hypoventilation but less role under normal ventilation. Bite blocks deliver a higher FiO2 during EGD. The ratio of nasal to oral breathing, supplemental oxygen flow, tidal volume, and respiratory rate influenced the FiO2 in most of the supplemental oxygen devices tested, which are often used for conscious sedation in patients undergoing EGD and colonoscopy.

Differential motor and prefrontal cerebello-cortical network development: Evidence from multimodal neuroimaging.

While our understanding of cerebellar structural development through adolescence and young adulthood has expanded, we still lack knowledge of the developmental patterns of cerebellar networks during this critical portion of the lifespan. Volume in lateral posterior cerebellar regions associated with cognition and the prefrontal cortex develops more slowly, reaching their peak volume in adulthood, particularly as compared to motor Lobule V. We predicted that resting state functional connectivity of the lateral posterior regions would show a similar pattern of development during adolescence and young adulthood. That is, we expected to see changes over time in Crus I and Crus II connectivity with the cortex, but no changes in Lobule V connectivity. Additionally, we were interested in how structural connectivity changes in cerebello-thalamo-cortical white matter are related to changes in functional connectivity. A sample of 23 individuals between 12 and 21years old underwent neuroimaging scans at baseline and 12months later. Functional networks of Crus I and Crus II showed significant connectivity decreases over 12months, though there were no differences in Lobule V. Furthermore, these functional connectivity changes were correlated with increases in white matter structural integrity in the corresponding cerebello-thalamo-cortical white matter tract. We suggest that these functional network changes are due to both later pruning in the prefrontal cortex as well as further development of the white matter tracts linking these brain regions.

Toward a more sophisticated response representation in theories of medial frontal performance monitoring: The effects of motor similarity and motor asymmetries.

Cognitive control in the posterior medial frontal cortex (pMFC) is formulated in models that emphasize adaptive behavior driven by a computation evaluating the degree of difference between 2 conflicting responses. These functions are manifested by an event-related brain potential component coined the error-related negativity (ERN). We hypothesized that the ERN represents a regulative rather than evaluative pMFC process, exerted over the error motor representation, expediting the execution of a corrective response. We manipulated the motor representations of the error and the correct response to varying degrees. The ERN was greater when 1) the error response was more potent than when the correct response was more potent, 2) more errors were committed, 3) fewer and slower corrections were observed, and 4) the error response shared fewer motor features with the correct response. In their current forms, several prominent models of the pMFC cannot be reconciled with these findings. We suggest that a prepotent, unintended error is prone to reach the manual motor processor responsible for response execution before a nonpotent, intended correct response. In this case, the correct response is a correction and its execution must wait until the error is aborted. The ERN may reflect pMFC activity that aimed to suppress the error.

The neural mechanisms underlying internally and externally guided task selection.

While some prior work suggests that medial prefrontal cortex (MFC) regions mediate freely chosen actions, other work suggests that the lateral frontal pole (LFP) is responsible for control of abstract, internal goals. The present study uses fMRI to determine whether the voluntary selection of a task in pursuit of an overall goal relies on MFC regions or the LFP. To do so, we used a modified voluntary task switching (VTS) paradigm, in which participants choose an individual task to perform on each trial (i.e., a subgoal), under instructions to perform the tasks equally often and in a random order (i.e. the overall goal). In conjunction, we examined patterns of activation in the face of irrelevant, but task-related external stimuli that might nonetheless influence task selection. While there was some evidence that the MFC was involved in voluntary task selection, we found that the LFP and anterior insula (AI) were crucial to task selection in the pursuit of an overall goal. In addition, activation of the LFP and AI increased in the face of environmental stimuli that might serve as an interfering or conflicting external bias on voluntary task choice. These findings suggest that the LFP supports task selection according to abstract, internal goals, and leaves open the possibility that MFC may guide action selection in situations lacking in such top-down biases. As such, the current study represents a critical step towards understanding the neural underpinnings of how tasks are selected voluntarily to enable an overarching goal.

Cerebellar networks in individuals at ultra high-risk of psychosis: impact on postural sway and symptom severity.

Despite known deficits in postural control in patients with schizophrenia, this domain has not been investigated in youth at ultra high-risk (UHR) for psychosis. This is particularly relevant as postural control implicates dysfunction in the cerebellum-a region implicated in cognitive dysmetria conceptions of schizophrenia but poorly understood in the prodrome. Here, we extended our understanding of movement abnormalities in UHR individuals to include postural control, and have linked these deficits to both symptom severity and cerebello-cortical network connectivity. UHR and healthy control participants completed an instrumentally based balance task to quantify postural control along with a resting state brain imaging scan to investigate cerebellar networks. We also quantified positive and negative symptom severity with structured clinical interviews. The UHR group showed overall increased postural sway and decreased cerebello-cortical resting state connectivity, relative to controls. The decreased cerebello-cortical connectivity was seen across multiple networks. Postural sway was also correlated with cerebellar connectivity in this population and uniquely positively correlated with the severity of negative symptoms. Finally, symptom severity was also associated with cerebellar connectivity. Together, our results point to a potential deficit in sensory integration as an underlying contributor to the increased postural sway, and provide evidence of cerebellar abnormalities in UHR individuals. These results extend our understanding of the motor abnormalities of UHR individuals beyond striatum-based dyskinesias to include postural control and sensory integration deficits, and implicate the cerebellum as a distinct neural substrate preceding the onset of psychosis. Taken together, our results extend the cognitive dysmetria framework to UHR populations.

Using the entropy of tracheal sounds to detect apnea during sedation in healthy nonobese volunteers.

BACKGROUND: Undetected apnea can lead to severe hypoxia, bradycardia, and cardiac arrest. Tracheal sounds entropy has been proved to be a robust method for estimating respiratory flow, thus maybe a more reliable way to detect obstructive and central apnea during sedation. METHODS: A secondary analysis of a previous pharmacodynamics study was conducted. Twenty volunteers received propofol and remifentinal until they became unresponsive to the insertion of a bougie into the esophagus. Respiratory flow rate and tracheal sounds were recorded using a pneumotachometer and a microphone. The logarithm of the tracheal sound Shannon entropy (Log-E) was calculated to estimate flow rate. An adaptive Log-E threshold was used to distinguish between the presence of normal breath and apnea. Apnea detected from tracheal sounds was compared to the apnea detected from respiratory flow rate. RESULTS: The volunteers stopped breathing for 15 s or longer (apnea) 322 times during the 12.9-h study. Apnea was correctly detected 310 times from both the tracheal sounds and the respiratory flow. Periods of apnea were not detected by the tracheal sounds 12 times. The absence of tracheal sounds was falsely detected as apnea 89 times. Normal breathing was detected correctly 1,196 times. The acoustic method detected obstructive and central apnea in sedated volunteers with 95% sensitivity and 92% specificity. CONCLUSIONS: We found that the entropy of the acoustic signal from a microphone placed over the trachea may reliably provide an early warning of the onset of obstructive and central apnea in volunteers under sedation.

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.

Changes in lipoprotein subfraction concentration and composition in healthy individuals treated with the CETP inhibitor anacetrapib.

We investigated the effects of the cholesteryl ester (CE) transfer protein inhibitor anacetrapib (ANA) on plasma lipids, lipoprotein subfraction concentrations, and lipoprotein composition in 30 healthy individuals. Participants (n = 30) were randomized to ANA 20 mg/day, 150 mg/day, or placebo for 2 weeks. Changes in concentration of lipoprotein subfractions were assessed using ion mobility, and compositional analyses were performed on fractions separated by density gradient ultracentrifugation. ANA 150 mg/day versus placebo resulted in significant decreases in LDL-cholesterol (26%) and apo B (29%) and increases in HDL-cholesterol (82%). Concentrations of medium and small VLDL, large intermediate density lipoprotein (IDL), and medium and small LDL (LDL2a, 2b, and 3a) decreased whereas levels of very small and dense LDL4b were increased. There was enrichment of triglycerides and reduction of CE in VLDL, IDL, and the densest LDL fraction. Levels of large buoyant HDL particles were substantially increased, and there was enrichment of CE, apo AI, and apoCIII, but not apoAII or apoE, in the mid-HDL density range. Changes in lipoprotein subfraction concentrations and composition with ANA 20 mg/day were similar to those for ANA 150 mg/day but were generally smaller in magnitude. The impact of these changes on cardiovascular risk remains to be determined.