Estimating pulsatile ocular blood volume from intraocular pressure, ocular pulse amplitude, and axial length.

The purpose of this study was to develop a method of estimating pulsatile ocular blood volume (POBV) from measurements taken during an ophthalmic exam, including axial length and using a tonometer capable of measuring intraocular pressure (IOP) and ocular pulse amplitude (OPA). Unpublished OPA data from a previous invasive study was used in the derivation, along with central corneal thickness (CCT) and axial length (AL), as well as IOP from the PASCAL dynamic contour tonometer (DCT) and intracameral (ICM) measurements of IOP for 60 cataract patients. Intracameral mean pressure was set to 15, 20, and 35 mmHg (randomized sequence) in the supine position, using a fluid-filled manometer. IOP and OPA measurements were acquired at each manometric setpoint (DCT and ICM simultaneously). In the current study, ocular rigidity (OR) was estimated using a published significant relationship of OR to the natural log of AL in which OR was invasively measured through fluid injection. Friedenwald's original pressure volume relationship was then used to derive the estimated POBV, delivered to the choroid with each heartbeat as a function of OR, systolic IOP (IOPsys), diastolic IOP (IOPdia), and OPA, according to the derived equation POBV = log (IOPsys/IOPdia) / OR. Linear regression analyses were performed comparing OPA to OR and calculated POBV at each of the three manometric setpoints. POBV was also compared to OPA/IOPdia with all data points combined. Significance threshold was p < 0.05. OR estimated from AL showed a significant positive relationship to OPA for both DCT (p < 0.011) and ICM (p < 0.006) at all three manometric pressure setpoints, with a greater slope for lower IOP. Calculated POBV also showed a significant positive relationship to OPA (p < 0.001) at all three setpoints with greater slope at lower IOP, and a significant negative relationship with IOPdia. In the combined analysis, POBV showed a significant positive relationship to OPA/ IOPdia (p < 0.001) in both ICM and DCT measurements with R2 = 0.9685, and R2 = 0.9589, respectively. POBV provides a straight-forward, clinically applicable method to estimate ocular blood supply noninvasively. Higher IOP in combination with lower OPA results in the lowest values of POBV. The simplified ratio, OPA/ IOPdia, may also provide a useful clinical tool for evaluating changes in ocular blood supply in diseases with a vascular component, such as diabetic retinopathy and normal tension glaucoma. Future studies are warranted.

Effects of methylphenidate on impulsive choice and delay aversion in Lewis rats.

Attention-deficit/hyperactivity disorder (ADHD), a common behavioral disorder in children and young adults, is characterized by symptoms of impulsivity, inattention, and hyperactivity. The purpose of this study was to evaluate the Lewis rat strain as a model of ADHD by testing their impulsive choices. Lewis rats were compared to their source strain, the Wistar rat, on an impulsive choice task. Rats completed the tasks on and off methylphenidate, a commonly prescribed medication for ADHD. Off methylphenidate, Lewis rats made more impulsive choices than Wistar rats. Analyses of acquisition of choice behavior suggested that both strains were able to discriminate reward sizes, but Lewis rats still chose the smaller-sooner option more than the larger-later (LL) option when the delays to reward were the same. This may be due to an aversion to the LL lever, which was associated with the longest delays to reward. Higher doses of methylphenidate increased LL choices in Lewis rats but decreased LL choices in Wistar rats. Altogether, these results suggest Lewis rats may be a viable model for ADHD in individuals whose symptoms are characterized by impulsive choices.

The influence of sea ice on the detection of bowhead whale calls.

Bowhead whales (Balaena mysticetus) face threats from diminishing sea ice and increasing anthropogenic activities in the Arctic. Passive acoustic monitoring is the most effective means for monitoring their distribution and population trends, based on the detection of their calls. Passive acoustic monitoring, however, is influenced by the sound propagation environment and ambient noise levels, which impact call detection probability. Modeling and simulations were used to estimate detection probability for bowhead whale frequency-modulated calls in the 80-180 Hz frequency band with and without sea ice cover and under various noise conditions. Sound transmission loss for bowhead calls is substantially greater during ice-covered conditions than during open-water conditions, making call detection ~ 3 times more likely in open-water. Estimates of daily acoustic detection probability were used to compensate acoustic detections for sound propagation and noise effects in two recording datasets in the northeast Chukchi Sea, on the outer shelf and continental slope, collected between 2012 and 2013. The compensated acoustic density suggests a decrease in whale presence with the retreat of sea ice at these recording sites. These results highlight the importance of accounting for effects of the environment on ambient noise and acoustic propagation when interpreting results of passive acoustic monitoring.

Improving safety by developing trust with a just culture.

This article presents a simple conceptual road map for implementing a just culture in healthcare settings. The concept of just culture was developed as one of five fundamental elements of a safety culture by psychology professor James Reason in 1997. A just culture requires an unbiased method of judging human error and is designed to develop organisational trust so that adverse medical events (errors) are reported and corrected before they combine with other errors to cause injury or death. To implement a just culture properly so as to increase organisational safety, practitioners must understand its role in enabling the error reporting needed to develop a safety culture. This article reviews these foundational concepts and explores the human causes of errors that a just culture addresses, the psychological importance of a just culture in enabling error reporting and how to implement a just culture in organisations.

Comparative analgesic efficacy and safety of intermittent local anaesthetic epidural bolus for labour: a systematic review and meta-analysis.

BACKGROUND: Continuous epidural infusion (CEI) is commonly used for labour analgesia, but concerns over potential motor block, second-stage labour complications, and ineffective analgesia in late labour have prompted examining intermittent epidural bolus (IEB) as an alternative. However, evidence comparing these modalities is conflicting. The meta-analysis evaluates the analgesic efficacy of CEI vs IEB. METHODS: Databases were searched for trials comparing CEI to IEB for labour analgesia. The two co-primary outcomes were risk of breakthrough pain and difference in area under the curve (AUC) for pain scores during the first 4 h post-epidural initiation. Local anaesthetic consumption, maternal outcomes (i.e. delivery mode, labour duration, and maternal satisfaction), and side-effects of epidural analgesia were also evaluated. Results were pooled using random-effects modelling. Trial sequential analysis (TSA) was used to evaluate evidence reliability. RESULTS: Twenty-seven studies (3133 patients) were analysed. Compared with CEI, IEB decreased risk of breakthrough pain by 38% (risk ratio [95% confidence interval {CI}] of 0.62 [0.48, 0.81]; P=0.0004; I2=47%; 1164 patients) and reduced AUC of pain during the 4 h interval by 32.9% (mean difference [95% CI] of -16.7 mm h-1 [-18.9, -14.4]; P<0.0001; 1638 patients). Intermittent epidural bolus enhanced maternal satisfaction, shortened labour duration, decreased motor block, and reduced local anaesthetic consumption. The difference between the two groups was not statistically significant for epidural side-effects or mode of delivery. The TSA indicated adequate power for reliable inferences. CONCLUSIONS: Intermittent epidural bolus provides improved labour pain control during the first 4 h after epidural initiation with less breakthrough pain. Moderate- to high-quality evidence of intermittent epidural bolus superiority support its use as a safe and effective continuous epidural infusion alternative for labour analgesia.

Microneutralization assay titer correlates analysis in two phase 3 trials of the CYD-TDV tetravalent dengue vaccine in Asia and Latin America.

We previously showed that Month 13 50% plaque reduction neutralization test (PRNT50) neutralizing antibody (nAb) titers against dengue virus (DENV) correlated with vaccine efficacy (VE) of CYD-TDV against symptomatic, virologically-confirmed dengue (VCD) in the CYD14 and CYD15 Phase 3 trials. While PRNT is the gold standard nAb assay, it is time-consuming and costly. We developed a next-generation high-throughput microneutralization (MN) assay and assessed its suitability for immune-correlates analyses and immuno-bridging applications. We analyzed MN and PRNT50 titers measured at baseline and Month 13 in a randomly sampled immunogenicity subset, and at Month 13 in nearly all VCD cases through Month 25. For each serotype, MN and PRNT50 titers showed high correlations, at both baseline and Month 13, with MN yielding a higher frequency of baseline-seronegatives. For both assays, Month 13 titer correlated inversely with VCD risk. Like PRNT50, high Month 13 MN titers were associated with high VE, and estimated VE increased with average Month 13 MN titer. We also studied each assay as a valid surrogate endpoint based on the Prentice criteria, which supported each assay as a valid surrogate for DENV-1 but only partially valid for DENV-2, -3, and -4. In addition, we applied Super-Learner to assess how well demographic, Month 13 MN, and/or Month 13 PRNT50 titers could predict Month 13-25 VCD outcome status; prediction was best when using demographic, MN, and PRNT50 information. We conclude that Month 13 MN titer performs comparably to Month 13 PRNT50 titer as a correlate of risk, correlate of vaccine efficacy, and surrogate endpoint. The MN assay could potentially be used to assess nAb titers in immunogenicity studies, immune-correlates studies, and immuno-bridging applications. Additional research would be needed for assessing the utility of MN titer in correlates analyses of other DENV endpoints and over longer follow-up periods.

Continuous Epidural Hydromorphone Infusion for Post-Cesarean Delivery Analgesia in a Patient on Methadone Maintenance Therapy: A Case Report.

The prevalence of opioid use disorder (OUD) in the United States has more than quadrupled over the past two decades. This patient population presents a number of challenges to clinicians, including difficult pain management after surgical procedures due to the development of opioid tolerance. Significantly greater opioid consumption and pain scores after cesarean delivery have been reported in patients with OUD compared to other obstetric patients. A multi-modal analgesic regimen is generally recommended, but there are few well-established pain management strategies after cesarean delivery specific to patients with OUD. We present the case of a patient with OUD maintained on daily methadone that received a continuous epidural hydromorphone infusion for post-cesarean analgesia, a technique not previously reported in obstetric patients and only rarely described for patients undergoing other surgical procedures. The patient received epidural anesthesia for cesarean delivery, and after surgery, the epidural catheter was left in place for the epidural hydromorphone infusion, initiated at 140 mcg/hr and continued for approximately 40 hrs. This strategy reduced her average daily oral opioid consumption by 97%, reduced self-reported pain scores, shortened the length of hospitalization and improved ability to ambulate compared to her previous cesarean delivery. The use of continuous epidural hydromorphone infusion was effective in this case, and this analgesic technique may also be applicable to other types of surgical procedures with the potential for significant post-operative pain, particularly in patients with OUD.

Cocaine self-administration differentially activates microglia in the mouse brain.

The evidence showing the involvement of microglial activation in the development of drug addiction remain scarce as microglia have not been systematically investigated in self-administered mice, a gold standard rodent model for drug addiction. Here we established the stable cocaine self-administration mice to examine microglial activation levels in various brain regions related to reward circuitry. Immunostaining for Iba1 showed a significant upregulation of intensity in the striatum but not in the medial prefrontal cortex (mPFc), hippocampus or thalamus. Further validation experiments showed that cocaine self-administered mice had significantly increased mRNA expression of ccl2 and IL1ß in the striatum but not the mPFc compared to saline controls. Consistently, we found elevated protein levels of Iba1, CCL2, TLR4 and mature IL1ß in the striatum, not in the mPFc of cocaine-receiving mice. In addition, cocaine-stimulated microglia had modified morphology including a reduced number of intersections, a shortened length and number of processes in the NAc. In summary, our results demonstrated that cocaine mediated microglial activation in a region-specific manner in vivo. These findings indicate that microglia could be activated in the early stage of cocaine addiction directly supporting the rationale that dysregulation on neuroimmune signaling is inherently involved in the development of drug addiction.

Explaining the Immigrant Paradox: The Influence of Acculturation, Enculturation, and Acculturative Stress on Problematic Alcohol Consumption.

The present study explored the Immigrant Paradox (IP), generational differences in problematic alcohol use (alcohol consumption and alcohol-related consequences), among immigrants and US born groups from a number of ethnic minority backgrounds. Our approach separates group differences in problematic alcohol consumption in a counterfactual manner for immigrants and the US born to answer the following counterfactual question: "What would problematic alcohol use levels be for the US born had they been exposed to the alcohol use generation (or protective) processes of immigrants and vice versa?" Multidimensional measures of enculturation (involvement with heritage culture), acculturation (involvement with US culture), acculturative stress, and demographic covariates were used to statistically explain these differences. The sample consisted of Asian American (n = 1,153), Black American (n = 833), and Latinx (n = 1,376) college students from 30 universities. Results indicated significant generational differences in mean levels of alcohol consumption but not alcohol-related consequences. Differences in measured characteristics (endowments) marginally explained differences between immigrants and the US born. On the other hand, endowments significantly explained generational differences and represented an increase in alcohol consumption among immigrants if they had the endowments of the U.S. born. Results are discussed in light of cultural and social factors that contribute to the IP.

On the use of nonparametric tests for comparing immunological Reverse Cumulative distribution curves (RCDCs).

Reverse Cumulative Distribution Curves (RCDCs) have proven to be a useful tool in summarizing immune response profiles in vaccine studies since their introduction by Reed, Meade, and Steinhoff (RMS) (1995). They are able to display virtually all of the treatment data and characterize summary statistics such as means or even their confidence intervals (CIs) that might be obscure. RMS mentioned their similarity to survival curves often used to summarize time-to-event data which are usually not normally distributed. The RCDCs, while intuitively pleasing and useful, contain important properties which allow for more powerful statistical applications. In this paper, we will suggest several widely used rank-based tests to compare the curves in the context of vaccine studies. These rank-based tests allow for comparisons between treatments, for stratified analyses, weighted analyses, and other modifications that make them the alternative of parametric analyses without the normality assumptions. Clinical trial identification: NCT01712984 and NCT01230957.

Predictors of complications following retroperitoneoscopic total and partial nephrectomy.

INTRODUCTION: Recent reports in the literature suggest an increased risk of complications with retroperitoneal as opposed to transperitoneal approach to partial nephrectomy (PN) and total nephrectomy (TN). We are a large unit performing predominantly retroperitoneoscopic PN and TN. We aim to review our outcomes and perform analysis to elucidate the predictors of complications following the retroperitoneal approach for extirpative kidney surgery. METHODS: We performed a single center retrospective review of children undergoing MIMS TN and PN between 2005 and 2015. Variables were tested for association with outcomes using Chi2 and Spearman's Rho correlation. RESULTS: We performed 173 MIMS nephrectomies, 119 total and 54 partial. Median age and weight were 5 years (6 months to 18 years) and 24.9 kg (7.7 to 85 kg) and operative time 147 min. There were 4 conversions and 17 postoperative complications. 19.6% children required further surgery, including 8 completion stumpectomies. Retroperitoneal approach did not have increased risk compared to transperitoneal for need of further surgery. Partial nephrectomy was not associated with higher rate of intraoperative complication or LOS. Predictors of intraoperative complication were vessel closure technique. Associations with need for further surgery were: ESRF, contralateral disease, bladder dysfunction, presence of PD catheter, and need for concomitant procedure. CONCLUSION: Our conversion rate (1.9%) and need for further surgery (13.1%) following the retroperitoneal approach to the kidney are favorable to the literature. Need for reoperation is often associated with the underlying diagnosis and the natural sequelae of the disease process. LEVEL OF EVIDENCE: IV.

Characteristics of the cerebrospinal fluid pressure waveform and craniospinal compliance in idiopathic intracranial hypertension subjects.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a condition of abnormally high intracranial pressure with an unknown etiology. The objective of this study is to characterize craniospinal compliance and measure the cerebrospinal fluid (CSF) pressure waveform as CSF is passively drained during a diagnostic and therapeutic lumbar puncture (LP) in IIH. METHODS: Eighteen subjects who met the Modified Dandy Criteria, including papilledema and visual field loss, received an ultrasound guided LP where CSF pressure (CSFP) was recorded at each increment of CSF removal. Joinpoint regression models were used to calculate compliance from CSF pressure and the corresponding volume removed at each increment for each subject. Twelve subjects had their CSFP waveform recorded with an electronic transducer. Body mass index, mean CSFP, and cerebral perfusion pressure (CPP) were also calculated. T-tests were used to compare measurements, and correlations were performed between parameters. RESULTS: Cerebrospinal fluid pressure, CSFP pulse amplitude (CPA), and CPP were found to be significantly different (p < 0.05) before and after the LP. CSFP and CPA decreased after the LP, while CPP increased. The craniospinal compliance significantly increased (p < 0.05) post-LP. CPA and CSFP were significantly positively correlated. CONCLUSIONS: Both low craniospinal compliance (at high CSFP) and high craniospinal compliance (at low CSFP) regions were determined. The CSFP waveform morphology in IIH was characterized and CPA was found to be positively correlated to the magnitude of CSFP. Future studies will investigate how craniospinal compliance may correlate to symptoms and/or response to therapy in IIH subjects.

Evaluation of the innate immunostimulatory potential of originator and non-originator copies of insulin glargine in an in vitro human immune model.

BACKGROUND: The manufacture of insulin analogs requires sophisticated production procedures which can lead to differences in the structure, purity, and/or other physiochemical properties of resultant products that can affect their biologic activity. Here, we sought to compare originator and non-originator copies of insulin glargine for innate immune activity and mechanisms leading to differences in these response profiles in an in vitro model of human immunity. METHODS: An endothelial/dendritic cell-based innate immune model was used to study antigen-presenting cell activation, cytokine secretion, and insulin receptor signalling pathways induced by originator and non-originator insulin glargine products. Mechanistic studies included signalling pathway blockade with specific inhibitors, analysis of the products in a Toll-like receptor reporter cell line assay, and natural insulin removal from the products by immunopurification. FINDINGS: All insulin glargine products elicited at least a minor innate immune response comparable to natural human insulin, but some lots of a non-originator copy product induced the elevated secretion of the cytokines, IL-8 and IL-6. In studies aimed at addressing the mechanisms leading to differential cytokine production by these products, we found (1) the inflammatory response was not mediated by bacterial contaminants, (2) the innate response was driven by the native insulin receptor through the MAPK pathway, and (3) the removal of insulin glargine significantly reduced their capacity to induce innate activity. No evidence of product aggregates was detected, though the presence of some high molecular weight proteins argues for the presence of insulin glargine dimers or others contaminants in these products. CONCLUSION: The data presented here suggests some non-originator insulin glargine product lots drive heightened in vitro human innate activity and provides preliminary evidence that changes in the biochemical composition of non-originator insulin glargine products (dimers, impurities) might be responsible for their greater immunostimulatory potential.

Neutralizing Antibody Correlates Analysis of Tetravalent Dengue Vaccine Efficacy Trials in Asia and Latin America.

Background: In the CYD14 and CYD15 Phase 3 trials of the CYD-TDV dengue vaccine, estimated vaccine efficacy (VE) against symptomatic, virologically confirmed dengue (VCD) occurring between months 13 and 25 was 56.5% and 60.8%, respectively. Methods: Neutralizing antibody titers to the 4 dengue serotypes in the CYD-TDV vaccine insert were measured at month 13 in a randomly sampled immunogenicity subcohort and in all VCD cases through month 25 (2848 vaccine, 1574 placebo) and studied for their association with VCD and with the level of VE to prevent VCD. Results: For each trial and serotype, vaccinees with higher month 13 titer to the serotype had significantly lower risk of VCD with that serotype (hazard ratios, 0.19-0.43 per 10-fold increase). Moreover, for each trial, vaccinees with higher month 13 average titer to the 4 serotypes had significantly higher VE against VCD of any serotype (P < .001). Conclusions: Neutralizing antibody titers postdose 3 correlate with CYD-TDV VE to prevent dengue. High titers associate with high VE for all serotypes, baseline serostatus groups, age groups, and both trials. However, lowest titers do not fully correspond to zero VE, indicating that other factors influence VE.

Surreptitious sympatry: Exploring the ecological and genetic separation of two sibling species.

Climate change is having profound impacts on animal populations, and shifts in geographic range are predicted in response. Shifts that result in range overlap between previously allopatric congeneric species may have consequences for biodiversity through interspecific competition, hybridization, and genetic introgression. Harbor seals (Phoca vitulina) and spotted seals (Phoca largha) are parapatric sibling species and areas of co-occurrence at the edges of their range, such as Bristol Bay, Alaska, offer a unique opportunity to explore ecological separation and discuss potential consequences of increased range overlap resulting from retreating sea ice. Using telemetry and genetic data from 14 harbor seals and six spotted seals, we explored the ecological and genetic separation of the two species by comparing their utilization distributions, distance from haul-out, dive behavior (e.g., depth, duration, focus), and evidence of hybridization. Firstly, we show that harbor and spotted seals, which cannot be visually distinguished definitively in all cases, haul-out together side by side in Bristol Bay from late summer to early winter. Secondly, we observed subtle rather than pronounced differences in ranging patterns and dive behavior during this period. Thirdly, most spotted seals in this study remained close to shore in contrast to what is known of the species in more northern areas, and lastly, we did not find any evidence of hybridization. The lack of distinct ecological separation in this area of sympatry suggests that interspecific competition could play an important role in the persistence of these species, particularly if range overlap will increase as a result of climate-induced range shifts and loss of spotted seal pagophilic breeding habitat. Our results also highlight the added complexities in monitoring these species in areas of suspected overlap, as they cannot easily be distinguished without genetic analysis. Predicted climate-induced environmental change will likely influence the spatial and temporal extent of overlap in these two sibling species. Ultimately, this may alter the balance between current isolating mechanisms with consequences for species integrity and fitness.

From Bad to Worse: Paraganglioma Diagnosis during Induction of Labor for Coexisting Preeclampsia.

Pheochromocytomas and extra-adrenal paragangliomas are catecholamine-secreting tumors that rarely occur in pregnancy. The diagnosis of these tumors in pregnancy can be challenging given that many of the signs and symptoms are commonly attributed to preeclampsia or other more common diagnoses. Early diagnosis and appropriate management are essential in optimizing maternal and fetal outcomes. We report a rare case of a catecholamine-secreting tumor in which diagnosis occurring at the time labor was being induced for concomitant preeclampsia with severe features. Her initial presentation in hypertensive crisis with other symptoms led to diagnostic workup for secondary causes of hypertension and led to eventual diagnosis of paraganglioma. Obtaining this diagnosis prior to delivery was essential, as this led to prompt multidisciplinary care, changed the course of her clinical management, and ultimately enabled good maternal and fetal outcomes. This case highlights the importance of maintaining a high index of suspicion for secondary causes of hypertension and in obstetric patients and providing timely multidisciplinary care.

Leveraging constraints and biotelemetry data to pinpoint repetitively used spatial features.

Satellite telemetry devices collect valuable information concerning the sites visited by animals, including the location of central places like dens, nests, rookeries, or haul-outs. Existing methods for estimating the location of central places from telemetry data require user-specified thresholds and ignore common nuances like measurement error. We present a fully model-based approach for locating central places from telemetry data that accounts for multiple sources of uncertainty and uses all of the available locational data. Our general framework consists of an observation model to account for large telemetry measurement error and animal movement, and a highly flexible mixture model specified using a Dirichlet process to identify the location of central places. We also quantify temporal patterns in central place use by incorporating ancillary behavioral data into the model; however, our framework is also suitable when no such behavioral data exist. We apply the model to a simulated data set as proof of concept. We then illustrate our framework by analyzing an Argos satellite telemetry data set on harbor seals (Phoca vitulina) in the Gulf of Alaska, a species that exhibits fidelity to terrestrial haul-out sites.

A Rare Case of C2 Sensory Blockade with Preserved Phrenic Nerve Function in an Obstetric Patient.

High neuraxial blockade is a serious complication in obstetric patients and requires prompt recognition and management in order to optimize patient outcomes. In cases of high neuroblockade, patients may present with significant hypotension, dyspnea, agitation, difficulty speaking or inability to speak, or even loss of consciousness. We report the unusual presentation of an obstetric patient that remained hemodynamically stable and had the preserved ability to initiate breaths despite sensory blockade up to C2. The presence of differential motor and sensory block documented in this case helped enable the patient to be managed with noninvasive ventilatory support until the high blockade regressed and we are not aware of any other similar reports in literature.