Matthew S. Shotwell

The Host Proteins Transportin SR2/TNPO3 and Cyclophilin A Exert Opposing Effects on HIV-1 Uncoating

ABSTRACT Following entry of the HIV-1 core into target cells, productive infection depends on the proper disassembly of the viral capsid (uncoating). Although much is known regarding HIV-1 entry, the actions of host cell proteins that HIV-1 utilizes during early postentry steps are poorly understood. One such factor, transportin SR2 (TRN-SR2)/transportin 3 (TNPO3), promotes infection by HIV-1 and some other lentiviruses, and recent studies have genetically linked TNPO3 dependence of infection to the viral capsid protein (CA). Here we report that purified recombinant TNPO3 stimulates the uncoating of HIV-1 cores in vitro. The stimulatory effect was reduced by RanGTP, a known ligand for transportin family members. Depletion of TNPO3 in target cells rendered HIV-1 less susceptible to inhibition by PF74, a small-molecule HIV-1 inhibitor that induces premature uncoating. In contrast to the case for TNPO3, addition of the CA-binding host protein cyclophilin A (CypA) inhibited HIV-1 uncoating and reduced the stimulatory effect of TNPO3 on uncoating in vitro. In cells in which TNPO3 was depleted, HIV-1 infection was enhanced 4-fold by addition of cyclosporine, indicating that the requirement for TNPO3 in HIV-1 infection is modulated by CypA-CA interactions. Although TNPO3 was localized primarily to the cytoplasm, depletion of TNPO3 from target cells inhibited HIV-1 infection without reducing the accumulation of nuclear proviral DNA, suggesting that TNPO3 facilitates a stage of the virus life cycle subsequent to nuclear entry. Our results suggest that TNPO3 and cyclophilin A facilitate HIV-1 infection by coordinating proper uncoating of the core in target cells.

Improving Pulse Oximetry Pitch Perception with Multisensory Perceptual Training

The pulse oximeter is a critical monitor in anesthesia practice designed to improve patient safety. Here, we present an approach to improve the ability of anesthesiologists to monitor arterial oxygen saturation via pulse oximetry through an audiovisual training process. Fifteen residents’ abilities to detect auditory changes in pulse oximetry were measured before and after perceptual training. Training resulted in a 9% (95% confidence interval, 4%–14%, P = 0.0004, t166 = 3.60) increase in detection accuracy, and a 72-millisecond (95% confidence interval, 40–103 milliseconds, P < 0.0001, t166 = −4.52) speeding of response times in attentionally demanding and noisy conditions that were designed to simulate an operating room. This study illustrates the benefits of multisensory training and sets the stage for further work to better define the role of perceptual training in clinical anesthesiology.

A Systematic Review and Meta-analysis of the Global Burden of Chronic Pain Without Clear Etiology in Low- and Middle-income Countries: Trends in Heterogeneous Data and a Proposal for New Assessment Methods

BACKGROUND: The global burden of chronic pain is projected to be large and growing, in concert with the burden of noncommunicable diseases. This is the first systematic review and meta-analysis of the prevalence of chronic pain without clear etiology in general, elderly, and working populations of low- and middle-income countries (LMICs). METHODS: We collected and reported data using Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, excluding acute pain or pain associated with a concurrent medical condition. One hundred nineteen publications in 28 LMICs were identified for systematic review; the 68 reports that focused on general adult populations (GP), elderly general populations (EGP), or workers (W) were evaluated using mixed-effects regression meta-analysis. RESULTS: Average chronic pain prevalence is reported as a percentage of the population, with 95% confidence interval for each pain type and population (GP, EGP, and W; NA is equal to not available): unspecified chronic pain (34[26–42], 62[41–81], and NA); low back pain (21[15–27], 28[16–42], and 52[26–77]); headache (42[27–58], 30[19–43], and 51[13–88]); chronic daily headache (5[3–7], 5[1–12], and 10[0–33]); chronic migraine (GP 12[6–19]); chronic tension type headache (GP 8[3–15]); musculoskeletal pain (25[19–33], 44[28–62], and 79[60–94]); joint pain (14[11–18], 34[16–54], and NA); chronic pelvic/prostatitis pain (GP 4[0–14]); temporomandibular disorder (35[4–78], 8[0–24], and NA); abdominal pain (EGP 17[6–32]); fibromyalgia (Combined GP, EGP, W 6[5–7]); and widespread pain (7[1–18], 19[8–32], and NA). Chronic low back pain and musculoskeletal pain were 2.50 (1.21–4.10) and 3.11 (2.13–4.37) times more prevalent among W, relative to a GP. Musculoskeletal, joint, and unspecified pain were 1.74 (1.03–2.69), 2.36 (1.09–4.02), and 1.83 (1.13–2.65) times more prevalent among the EGP, relative to a GP. There was significant heterogeneity among studies for all pain types (I 2 > 90%). CONCLUSIONS: Chronic pain is prevalent in LMICs, and where there was sufficient evidence, generally more prevalent in EGP and W. This meta-analysis reveals the spectrum of chronic pain without clear etiology in LMICs. Steps should be taken to reduce heterogeneity in the assessment of global chronic pain. Possible actions may include standardization of chronic pain definition, widespread adoption of validated questionnaires across cultures, attention to inequitably burdened populations, and inclusion of queries regarding known associations of chronic pain with social and psychological factors that, in combination, increase the global burden of noncommunicable disease and disability.

Nitrous Oxide During Labor: Maternal Satisfaction Does Not Depend Exclusively on Analgesic Effectiveness.

BACKGROUND: Evidence on the analgesic effectiveness of nitrous oxide for labor pain is limited. Even fewer studies have looked at patient satisfaction. Although nitrous oxide appears less effective than neuraxial analgesia, it is unclear whether labor analgesic effectiveness is the most important factor in patient satisfaction. We sought to compare the relationship between analgesic effectiveness and patient satisfaction with analgesia in women who delivered vaginally using nitrous oxide, neuraxial analgesia (epidural or combined spinal-epidural [CSE]), or both (neuraxial after a trial of nitrous oxide). METHODS: A standardized survey was recorded on the first postpartum day for all women who received anesthetic care for labor and delivery. Data were queried for women who delivered vaginally with nitrous oxide and/or neuraxial labor analgesia over a 34-month period in 2011 to 2014. Parturients with complete data for analgesia quality and patient satisfaction were included. Analgesia and satisfaction scores were grouped into 8 to 10 high, 5 to 7 intermediate, and 0 to 4 low. These scores were compared with the use of ordinal logistic regression across 3 groups: nitrous oxide alone, epidural or CSE alone, or nitrous oxide followed by neuraxial (epidural or CSE) analgesia. RESULTS: A total of 6507 women received anesthesia care and delivered vaginally. Complete data were available for 6242 (96%) women; 5261 (81%) chose neuraxial analgesia and 1246 (19%) chose nitrous oxide. Of the latter, 753 (60%) went on to deliver with nitrous oxide alone, and 493 (40%) switched to neuraxial analgesia. Most parturients who received neuraxial analgesia (>90%) reported high analgesic effectiveness. Those who used nitrous oxide alone experienced variable analgesic effectiveness, with only one-half reporting high effectiveness. Among all women who reported poor analgesia effectiveness (0−4; n = 257), those who received nitrous oxide alone were more likely to report high satisfaction (8−10) than women who received epidural analgesia alone (OR 2.5; 95% CI 1.4–4.5; P = .002). Women who reported moderate analgesia (5−7) and received nitrous oxide only were more likely to report high satisfaction compared with the other groups. Among women who reported a high level of analgesic effectiveness, satisfaction with anesthesia was high and not different among groups. CONCLUSIONS: Patients who received nitrous oxide alone were as likely to express satisfaction with anesthesia care as those who received neuraxial analgesia, even though they were less likely to report excellent analgesia. Although pain relief contributes to the satisfaction with labor analgesia care, our results suggest that analgesia is not the only contributor to maternal satisfaction.

Bayesian Outlier Detection with Dirichlet Process Mixtures

We introduce a Bayesian inference mechanism for outlier detection using the augmented Dirichlet process mixture. Outliers are detected by forming a maximum a posteriori (MAP) estimate of the data partition. Observations that comprise small or singleton clusters in the estimated partition are considered out- liers. We ofier a novel interpretation of the Dirichlet process precision parameter, and demonstrate its utility in outlier detection problems. The precision parameter is used to form an outlier detection criterion based on the Bayes factor for an outlier partition versus a class of partitions with fewer or no outliers. We further introduce a computational method for MAP estimation that is free of posterior sampling, and guaranteed to flnd a MAP estimate in flnite time. The novel meth- ods are compared with several established strategies in a yeast microarray time series.

Regional anesthesia, time to hospital discharge, and in-hospital mortality: a propensity score matched analysis.

Background and Objectives The anesthetic technique used during surgery can affect postoperative length of stay and outcomes, even after controlling for other clinically important factors. This study evaluated the impact of regional anesthesia (RA) compared with general anesthesia (GA) on the amount of time between leaving the operating room and hospital discharge and the odds of in-hospital mortality. Methods Surgical patients admitted after surgery, who received RA, were matched to patients who received GA by propensity score in a 1:4 ratio. We measured the association between anesthetic technique and time to hospital discharge using Kaplan-Meier methods. In-hospital mortality was analyzed using a generalized estimating equation logistic regression model. Results A total of 5870 inpatient surgical cases were analyzed; 1174 cases received RA and 4696 cases received GA. The median time to hospital discharge among patients who received RA was 67.6 hours compared with 71.9 hours among patients who received GA (P < 0.0001). A total of 86 cases died in the hospital after surgery; 7 were in the RA cohort and 79 were in the GA cohort. Receiving RA during surgery was associated with 64% lesser odds of dying in the hospital (odds ratio, 0.36; 95% confidence interval, 0.16–0.75), when adjusting for the number of postoperative days spent in the hospital. Conclusions The study data provide evidence that median time to discharge is shorter when RA is used instead of GA, controlling for other clinically important factors. Additionally, RA use during surgery was associated with a decrease in in-hospital mortality. When an appropriate option, RA may facilitate faster hospital discharge and improve patient outcomes.

Elevated Serum Osmolality and Total Water Deficit Indicate Impaired Hydration Status in Residents of Long-Term Care Facilities Regardless of Low or High Body Mass Index.

BACKGROUND Dehydration is typically associated with underweight and malnutrition in long-term care (LTC) settings. Evidence is lacking regarding the influence of the rising prevalence of overweight and obesity on risk factors, prevalence, and presentation of dehydration. OBJECTIVE The aim of this study was to objectively assess hydration status and the adequacy of total water intake, and determine relationships between hydration status, total water intake, and body mass index (BMI) in LTC residents. DESIGN A cross-sectional analysis of baseline data was performed. PARTICIPANTS AND SETTING Baseline data from 247 subjects recruited from eight community-based LTC facilities participating in two randomized trials comparing nutrient and cost-efficacy of between-meal snacks vs oral nutrition supplements (ONS). MAIN OUTCOMES Hydration status was assessed by serum osmolality concentration and total water intakes were quantified by weighed food, beverage, water, and ONS intake. STATISTICAL ANALYSES Simple and multiple linear regression methods were applied. RESULTS Forty-nine (38.3%) subjects were dehydrated (>300 mOsm/kg) and another 39 (30.5%) had impending dehydration (295 to 300 mOsm/kg). The variance in serum osmolality was significantly accounted for by blood urea nitrogen level, mental status score, and having diabetes (R(2)=0.46; P<0.001). Total water intake averaged 1,147.2±433.1 mL/day. Thus, 96% to 100% of subjects did not meet estimated requirements, with a deficit range of 700 to 1,800 mL/day. The variance in total water intake was significantly accounted for by type of liquid beverages (thin vs thick), type of ONS, total energy intake, total activities of daily living dependence, sex, and BMI (R(2)=0.56; P<0.001). CONCLUSIONS Dehydration and inadequate total water intake is prevalent in LTC residents across all BMI categories. Type of liquid beverages, type of ONS, and type of between-meal snacks are factors that could be targeted for nutrition interventions designed to prevent or reverse dehydration.

Simulation-based Assessment of the Management of Critical Events by Board-certified Anesthesiologists.

Background: We sought to determine whether mannequin-based simulation can reliably characterize how board-certified anesthesiologists manage simulated medical emergencies. Our primary focus was to identify gaps in performance and to establish psychometric properties of the assessment methods. Methods: A total of 263 consenting board-certified anesthesiologists participating in existing simulation-based maintenance of certification courses at one of eight simulation centers were video recorded performing simulated emergency scenarios. Each participated in two 20-min, standardized, high-fidelity simulated medical crisis scenarios, once each as primary anesthesiologist and first responder. Via a Delphi technique, an independent panel of expert anesthesiologists identified critical performance elements for each scenario. Trained, blinded anesthesiologists rated video recordings using standardized rating tools. Measures included the percentage of critical performance elements observed and holistic (one to nine ordinal scale) ratings of participant’s technical and nontechnical performance. Raters also judged whether the performance was at a level expected of a board-certified anesthesiologist. Results: Rater reliability for most measures was good. In 284 simulated emergencies, participants were rated as successfully completing 81% (interquartile range, 75 to 90%) of the critical performance elements. The median rating of both technical and nontechnical holistic performance was five, distributed across the nine-point scale. Approximately one-quarter of participants received low holistic ratings (i.e., three or less). Higher-rated performances were associated with younger age but not with previous simulation experience or other individual characteristics. Calling for help was associated with better individual and team performance. Conclusions: Standardized simulation-based assessment identified performance gaps informing opportunities for improvement. If a substantial proportion of experienced anesthesiologists struggle with managing medical emergencies, continuing medical education activities should be reevaluated.

The Impact of Family Visitation on Feeding Assistance Quality in Nursing Homes

The purpose of this study was to determine: (a) the frequency of family visitation during mealtime and (b) whether the presence of family during meals had an impact on the quality of feeding assistance care and resident intake. Participants included 74 nursing home residents from two Veterans Affairs (VA) and four community facilities in one geographic region. Mealtime periods in which family was present were compared with mealtime periods when family was not present for the same resident. Results showed that family visitation was infrequent during mealtime; however, feeding assistance time was significantly higher when visitors were present. Despite the increase in assistance time, there was not a significant difference in intake. Strategies that encourage the involvement of family in mealtime assistance may have additional benefits not directly associated with meal consumption, including providing family members with meaningful activity during a visit and enhancing residents’ quality of life and well-being.

The Quality of Feeding Assistance Care Practices for Long-Term Care Veterans: Implications for Quality Improvement Efforts

The primary purpose of this study was to determine the quality of feeding assistance care and identify areas in need of improvement for a sample of long-term care veterans. A secondary purpose was to compare these findings with the results of previous studies in community facilities to determine ways in which the VA sample might differ. A repeated measures observational study was conducted in two VA facilities with 200 long-stay residents. Research staff conducted standardized observations during and between meals for 3 months. There was a trend for better feeding assistance care quality during meals in the VA sample, but there were still multiple aspects of care in need of improvement both during and between meals. Higher licensed nurse staffing levels in the VA should enable effective supervision and management, but observation-based measures of care quality are necessary for accurate information about daily feeding assistance care provision.