Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma.

Background: Combined cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) blockade induces high rates of immune-related adverse events (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination therapy due to irAEs is not known. Patients and methods: We assessed patients who experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade leading to treatment discontinuation at four academic centers. We assessed the safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs. Results: Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (six grade 1-2, seven grade 3-4, and one grade 5 Steven-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% versus 28%, P = 0.01). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2 and 6 grade 3-4). Duration of steroid taper, severity of initial irAEs and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% versus 31%, P = 0.03). Conclusions: Patients who discontinued CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in selected patients.

Automated electrotransformation of Escherichia coli on a digital microfluidic platform using bioactivated magnetic beads.

This paper reports on the use of a digital microfluidic platform to perform multiplex automated genetic engineering (MAGE) cycles on droplets containing Escherichia coli cells. Bioactivated magnetic beads were employed for cell binding, washing, and media exchange in the preparation of electrocompetent cells in the electrowetting-on-dieletric (EWoD) platform. On-cartridge electroporation was used to deliver oligonucleotides into the cells. In addition to the optimization of a magnetic bead-based benchtop protocol for generating and transforming electrocompetent E. coli cells, we report on the implementation of this protocol in a fully automated digital microfluidic platform. Bead-based media exchange and electroporation pulse conditions were optimized on benchtop for transformation frequency to provide initial parameters for microfluidic device trials. Benchtop experiments comparing electrotransformation of free and bead-bound cells are presented. Our results suggest that dielectric shielding intrinsic to bead-bound cells significantly reduces electroporation field exposure efficiency. However, high transformation frequency can be maintained in the presence of magnetic beads through the application of more intense electroporation pulses. As a proof of concept, MAGE cycles were successfully performed on a commercial EWoD cartridge using variations of the optimal magnetic bead-based preparation procedure and pulse conditions determined by the benchtop results. Transformation frequencies up to 22% were achieved on benchtop; this frequency was matched within 1% (21%) by MAGE cycles on the microfluidic device. However, typical frequencies on the device remain lower, averaging 9% with a standard deviation of 9%. The presented results demonstrate the potential of digital microfluidics to perform complex and automated genetic engineering protocols.

Design and fabrication of a window for the gas Cherenkov detector 3.

The gas Cherenkov detector 3 was designed at Los Alamos National Laboratory for use in inertial confinement fusion experiments at both the Omega Laser Facility and the National Ignition Facility. This instrument uses a low-Z gamma-to-electron convertor plate and high pressure gas to convert MeV gammas into UV/visible Cherenkov photons for fast optical detection. This is a follow-on diagnostic from previous versions, with two notable differences: the pressure of the gas is four times higher, and it allows the use of fluorinated gas, requiring metal seals. These changes force significant changes in the window component, having a unique set of requirements and footprint limitations. The selected solution for this component, a sapphire window brazed into a stainless steel flange housing, is described.

Brain connectomics predict response to treatment in social anxiety disorder.

We asked whether brain connectomics can predict response to treatment for a neuropsychiatric disorder better than conventional clinical measures. Pre-treatment resting-state brain functional connectivity and diffusion-weighted structural connectivity were measured in 38 patients with social anxiety disorder (SAD) to predict subsequent treatment response to cognitive behavioral therapy (CBT). We used a priori bilateral anatomical amygdala seed-driven resting connectivity and probabilistic tractography of the right inferior longitudinal fasciculus together with a data-driven multivoxel pattern analysis of whole-brain resting-state connectivity before treatment to predict improvement in social anxiety after CBT. Each connectomic measure improved the prediction of individuals' treatment outcomes significantly better than a clinical measure of initial severity, and combining the multimodal connectomics yielded a fivefold improvement in predicting treatment response. Generalization of the findings was supported by leave-one-out cross-validation. After dividing patients into better or worse responders, logistic regression of connectomic predictors and initial severity combined with leave-one-out cross-validation yielded a categorical prediction of clinical improvement with 81% accuracy, 84% sensitivity and 78% specificity. Connectomics of the human brain, measured by widely available imaging methods, may provide brain-based biomarkers (neuromarkers) supporting precision medicine that better guide patients with neuropsychiatric diseases to optimal available treatments, and thus translate basic neuroimaging into medical practice.

Risk associations between HLA-DPB1 T-cell epitope matching and outcome of unrelated hematopoietic cell transplantation are independent of HLA-DPA1.

HLA-DP antigens are beta-alpha heterodimers encoded by polymorphic HLA-DPB1 and -DPA1 alleles, respectively, in strong linkage disequilibrium (LD) with each other. Non-permissive unrelated donor (UD)-recipient HLA-DPB1 mismatches across three different T-cell epitope (TCE) groups are associated with increased mortality after hematopoietic SCT (HCT), but the role of HLA-DPA1 is unclear. We studied 1281 onco-hematologic patients after 10/10 HLA-matched UD-HCT facilitated by the National Marrow Donor Program. Non-permissive mismatches defined solely by HLA-DPB1 TCE groups were associated with significantly higher risks of TRM compared to permissive mismatches (hazard ratio (HR) 1.30, confidence interval (CI) 1.06-1.53; P=0.009) or allele matches. Moreover, non-permissive HLA-DPB1 TCE group mismatches in the graft versus host (GvH) direction significantly decreased the risk of relapse compared to permissive mismatches (HR 0.55, CI 0.37-0.80; P=0.002) or allele matches. Splitting each group into HLA-DPA1*02:01 positive or negative, in frequent LD with HLA-DPB1 alleles from two of the three TCE groups, or into HLA-DPA1 matched or mismatched, did not significantly alter the observed risk associations. Our findings suggest that the effects of clinically non-permissive HLA-DPB1 TCE group mismatches are independent of HLA-DPA1, and that selection of donors with non-permissive DPB1 TCE mismatches in GvH direction might provide some protection from disease recurrence.

Evaluation of a digital microfluidic real-time PCR platform to detect DNA of Candida albicans in blood.

Species of Candida frequently cause life-threatening infections in neonates, transplant and intensive care unit (ICU) patients, and others with compromised host defenses. The successful management of systemic candidiasis depends upon early, rapid diagnosis. Blood cultures are the standard diagnostic method, but identification requires days and less than half of the patients are positive. These limitations may be eliminated by using real-time polymerase chain reaction (PCR) to detect Candida DNA in the blood specimens of patients at risk. Here, we optimized a PCR protocol to detect 5-10 yeasts in low volumes of simulated and clinical specimens. We also used a mouse model of systemic candidiasis and determined that candidemia is optimally detectable during the first few days after infection. However, PCR tests are often costly, labor-intensive, and inconvenient for routine use. To address these obstacles, we evaluated the innovative microfluidic real-time PCR platform (Advanced Liquid Logic, Inc.), which has the potential for full automation and rapid turnaround. Eleven and nine of 16 specimens from individual patients with culture-proven candidemia tested positive for C. albicans DNA by conventional and microfluidic real-time PCR, respectively, for a combined sensitivity of 94%. The microfluidic platform offers a significant technical advance in the detection of microbial DNA in clinical specimens.

Translating the use of an enriched environment poststroke from bench to bedside: study design and protocol used to test the feasibility of environmental enrichment on stroke patients in rehabilitation.

RATIONALE: Environmental enrichment, a paradigm investigated extensively in animal models, is an intervention, which by design facilitates motor, sensory, social, and cognitive activity. It has been shown to improve poststroke motor and cognitive function in animal models of stroke. This is the first study to attempt to translate this intervention from the laboratory to the clinical setting. AIMS: The overall aim of this pilot study is to test the feasibility of using environmental enrichment with stroke patients in a rehabilitation setting. The aim is to enrich the environment of stroke survivors in a rehabilitation ward and measure changes in their activity (physical, cognitive, and social activity). DESIGN: Prospective nonrandomized block design intervention study. STUDY: In the control phase we will determine the change in activity levels of patients treated in a usual rehabilitation environment over time. In the intervention phase structured observational techniques (behavioural mapping) will be used to quantify the change in activity levels of patients exposed to environmental enrichment. OUTCOMES: The primary outcome is change in activity level. Additional data collected on entry to and exit from the study will include: cognitive function using a battery of cognitive tests, general function using the Functional Independence Measure, mood using the Patient Health Questionnaire 9 and boredom using the Stroke Rehabilitation Boredom Survey. Quality of life will be assessed using the Assessment of Quality of Life 1 month postdischarge from rehabilitation. Australian New Zealand Clinical Trials Registry# ACTRN12611000629932.

The role of anxiety sensitivity in sleep disturbance in panic disorder.

Previous research has demonstrated that individuals with panic disorder (PD) report significant sleep disturbances, although the mechanism of this disturbance is not clear. Patients with PD tend to report abnormally high levels of anxiety sensitivity (AS). Because higher AS involves increases in attention and fearfulness about anxiety and associated physical sensations, which in turn may cause excessive psychological and physiologic arousal, we hypothesized that amongst individuals with PD, higher AS would be associated with sleep disruption, particularly in the form of increased sleep latency. As expected, PD was associated with poorer sleep as measured by the Global Pittsburgh Sleep Quality Index (PSQI) compared to controls and AS was significantly associated with longer sleep latency. Our data suggest that sleep disturbance, and in particular sleep latency, in PD may be partly due to high levels of AS, which can be targeted with cognitive-behavioral therapeutic strategies.

Metropolitan-rural divide for stroke outcomes: do stroke units make a difference?

BACKGROUND: Stroke care across Australian hospitals is variable. The impact on health outcomes, in particular levels of disability for patients in rural areas, is unclear. The aim of this study was to determine whether geographic location and access to stroke units are associated with differences in health outcomes in patients with acute stroke. METHODS: Retrospective cohort study of consecutive eligible admissions from 32 hospitals (12 rural) in New South Wales between 2003 and 2007. Health status measured at discharge included level of independence (modified Rankin score: mRS) and frequency of severe complications during hospitalization. Multivariable analyses included adjustment for patient casemix and clustering. RESULTS: Among 2254 eligible patients, 55% were treated in metropolitan hospitals. Stroke unit treatment varied significantly (rural 3%; metropolitan 77%). Age, gender and stroke type did not differ by location (mean age 74, 50% female). After adjusting for age, gender, ethnicity, important risk factors and validated stroke prognostic variables, patients treated in rural hospitals had a greater odds of dying during hospitalization compared with those treated in metropolitan hospitals (adjusted odds ratio (aOR) 1.46, 95% confidence interval (CI) 1.03-2.05). There were no differences in mortality or frequency of severe complications between patients treated in rural and metropolitan hospitals when we adjusted for access to stroke units (aOR 1.00, 95% CI 0.62-1.61). Nevertheless, patients treated in rural hospitals were more dependent (mRS 3-5) at discharge (aOR 1.82, 95% CI 1.23-2.70) despite adjusting for stroke unit status. CONCLUSION: Patients with stroke treated in rural hospitals have poorer health outcomes, especially if not managed in stroke units.

Stroke rehab down under: can Rupert Murdoch, Crocodile Dundee, and an Aboriginal elder expect the same services and care?

Australia is the world's sixth largest country, has a relatively small population of 21.5 million, and a blended (public and private) health system. In this article, we explain the stroke rehabilitation infrastructure including consumer organisations, research networks, data collection systems, and registries. This represents a complex but fledgling set of organisations showing great promise for coordination of care and research. The article goes on to expose the inequalities in service provision by describing the paths of stroke survivors in three settings - in the city, in the country, and in remote settings. The complexities and difficulties in treating indigenous stroke survivors are described in a culturally sensitive narrative. The article then discusses the outcomes of the first Australian audit of post acute stroke services completed in December 2008, which describes the journeys of 2,119 stroke survivors at 68 rehabilitation units throughout Australia's 6 states and 2 territories. It demonstrates an average length of stay of 26 days, with 18% of survivors requiring nursing home or other supported accommodation. The article concludes with future directions for stroke rehabilitation in Australia, which include hyperacute rehabilitation trials, studies in 7-days-a-week rehabilitation, and the potential use of robotics.

Nightmares among Cambodian refugees: the breaching of concentric ontological security.

This article explores the nightmares of Cambodian refugees in a cultural context, and the role of nightmares in the trauma ontology of this population, including their role in generating post-traumatic stress disorder (PTSD). Among Cambodian refugees attending a psychiatric clinic, we found that having a nightmare was strongly associated with having PTSD (chi(2) = 61.7, P < 0.001, odds ratio = 126); that nightmares caused much distress upon awakening, including panic attacks, fear of bodily dysfunction, flashbacks and difficulty returning to sleep; that nightmare content was frequently related to traumatic events; that nightmares resulted in a decrease in the sense of "concentric ontology security" (i.e., in an increased sense of physical and spiritual vulnerability in a culture that conceives of the self in terms of concentric, protective layers), including fears of being attacked by ghosts; and that nightmares frequently led to the performance of specific practices and rituals aiming to extrude and repel attacking forces and to create "protective layers." Cases are presented to illustrate these findings. The Discussion considers some treatment implications of the study.

Broad spectrum of cytokine abnormalities in panic disorder and posttraumatic stress disorder.

BACKGROUND: Proinflammatory cytokines have been reported to be elevated in individuals experiencing chronic stress as well as in those with major depressive disorder. Much less is known about cytokines in anxiety disorders such as posttraumatic stress disorder (PTSD) and panic disorder (PD). We hypothesized that PD and PTSD would be associated with a generalized proinflammatory cytokine signature. METHOD: We utilized Luminex technology to examine 20 cytokines and chemokines in serum from 48 well-characterized individuals with a primary DSM-IV PD or PTSD diagnosis, and 48 age- and gender-matched healthy controls. We conservatively employed a Bonferroni correction for multiple testing (alpha=.05/20=.0025). RESULTS: Individuals with primary PTSD or PD had significantly elevated median peripheral cytokine levels for 18 of 20 different cytokines compared to age- and gender-matched healthy controls (all P<.0025). To assess for the presence of a generalized proinflammatory state, we also examined the proportion of subjects with detectable levels of at least six of nine common proinflammatory cytokines and chemokines (IL-6, IL-1alpha, IL-1beta, IL-8, MCP-1, MIP-1alpha, Eotaxin, GM-CSF, and IFN-alpha). For men and women, 87% of anxiety patients had six or more detectable levels of these proinflammatory cytokines, compared with only 25% of controls (Fisher's Exact Test (FET) P=.000). Confirmatory analysis of the subset of individuals without current psychiatric medication use or comorbid depression was of comparable significance. CONCLUSIONS: These findings suggest that a generalized inflammatory state may be present in individuals with PD or PTSD.

A detailed examination of cytokine abnormalities in Major Depressive Disorder.

Recent technological advances offer an opportunity to further elucidate the complex cytokine network in Major Depressive Disorder (MDD). Twenty cytokines were simultaneously assessed in 49 individuals with MDD and 49 age and gender matched controls. Multiple pro-inflammatory and two anti-inflammatory cytokines were significantly elevated in the MDD sample, including an antidepressant naïve subset. These data support a generalized chronic inflammatory state in MDD, and implicate additional cytokines and chemokines previously linked to cardiovascular disease.

Will insomnia treatments produce overall cost savings to commercial managed-care plans? A predictive analysis in the United States.

OBJECTIVE: Research indicates that insomnia may contribute significantly to healthcare costs; however, information on the effects of treatments on costs has not been thoroughly published. This study presents predictive models that forecast, from the perspective of commercial managed care, the effects of insomnia medications in reducing overall medical costs. The main objectives of this study were to predict the level of cost savings associated with insomnia treatments, illustrate the variation in outcomes given underlying model assumptions, and assist managed-care policy-makers with the evaluation of medications routinely administered for insomnia. METHODS: Data on four primary-efficacy measures: wake after sleep onset (WASO), sleep efficiency (SE), sleep onset latency (SOL) and total sleep time (TST) were abstracted from published clinical trial data for eszopiclone, indiplon, low-dose trazodone, ramelteon, zaleplon, zolpidem and zolpidem extended-release. Change in per-patient per-year (PPPY) healthcare costs in a single claims database was calculated for subjects taking zolpidem, zaleplon and low-dose trazodone using generalized linear model (GLM) techniques, controlling for baseline demographics and baseline costs. Change in costs for emerging insomnia medications was forecasted by imputing efficacy values for these drugs into the regressions. RESULTS: Using the accepted efficacy measure, WASO, zolpidem extended-release had the overall forecasted savings of -$1253 (CI: -$1404 to -$1404) PPPY compared to remaining treatments, whereas ramelteon cost an additional $348 (-$1280 to $584) PPPY. In three out of four cost-efficacy models, zolpidem extended-release had higher mean forecasted PPPY savings. CONCLUSION: This study examined cost effects of existing and emerging insomnia medications using models integrating clinical literature and medical claims within a statistical framework. The use of a single database may limit generalizability and models only address a 1-year period. Results suggest treatments can offer health plans direct cost savings, with amounts sensitive to variable and efficacy measures, potentially limited by those variables available in the claims database. Compared to other evaluated treatments, zolpidem extended-release produced consistently higher predicted cost savings.

Prospective 12-month course of bipolar disorder in out-patients with and without comorbid anxiety disorders.

BACKGROUND: The impact of anxiety disorders has not been well delineated in prospective studies of bipolar disorder. AIMS: To examine the association between anxiety and course of bipolar disorder, as defined by mood episodes, quality of life and role functioning. METHOD: A thousand thousand out-patients with bipolar disorder were followed prospectively for 1 year. RESULTS: A current comorbid anxiety disorder (present in 31.9% of participants) was associated with fewer days well, a lower likelihood of timely recovery from depression, risk of earlier relapse, lower quality of life and diminished role function over I year of prospective study. The negative impact was greater with multiple anxiety disorders. CONCLUSIONS: Anxiety disorders, including those present during relative euthymia, predicted a poorer bipolar course. The detrimental effects of anxiety were not simply a feature of mood state. Treatment studies targeting anxiety disorders will help to clarify the nature of the impact of anxiety on bipolar course.

Assessment of posttraumatic stress disorder in Cambodian refugees using the Clinician-Administered PTSD Scale: psychometric properties and symptom severity.

Posttraumatic stress disorder (PTSD) symptoms were assessed by using the Clinician-Administered PTSD Scale (CAPS) in a consecutive sample of Cambodian refugees attending a psychiatric clinic in the United States. Psychometric properties of the translated CAPS and severity of PTSD-related symptoms were examined. The CAPS demonstrated adequate psychometric properties, including coefficient alpha (.92) and item-total correlations (.48-.85). Of the sample 56% (101/179) met Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria for current PTSD. Those patients who met criteria for current PTSD had significantly higher CAPS total scores (M = 65.3, SD = 18.1) than those who did not meet the criteria (M = 13.9, SD = 16.7).

Olfactory-triggered panic attacks among Cambodian refugees attending a psychiatric clinic.

Olfactory panic attacks have not been systematically assessed in a psychiatric population by any previous studies. Among Cambodian refugees attending a psychiatric clinic, the present investigation determines the following: (a) 1-month current prevalence of olfactory-triggered panic attacks, (b) associated psychopathology (Hopkins Symptom Checklist and the Structured Clinical Interview for DSM-IV-diagnosed posttraumatic stress disorder [PTSD]), and (c) frequency in events of olfactory panic of catastrophic cognitions (Panic Attack Cognitions Scale [PACQ]) and flashbacks (Clinician-Administered PTSD flashback scale). Forty-five percent of 100 consecutive psychiatric patients were found to have suffered an olfactory-triggered panic attack in the previous month; having current olfactory panic attacks was highly correlated with psychopathology (e.g., to PTSD diagnosis: and chi(2)=50.0; df=1; p<.001); and during olfactory-triggered panic attacks, catastrophic cognitions and flashbacks were common. Possible mechanisms for generation of high rates of olfactory-triggered panic attacks in this population are discussed (the "traumatic memory/catastrophic cognitions/interoceptive conditioning/escalating arousal" or "TCIE" model of panic generation) as are treatment implications.

Certainty and mortality prediction in critically ill children.

OBJECTIVES: The objective of this study is to investigate the relationship between a physician's subjective mortality prediction and the level of confidence with which that mortality prediction is made. DESIGN AND PARTICIPANTS: The study is a prospective cohort of patients less than 18 years of age admitted to a tertiary Paediatric Intensive Care Unit (ICU) at a University Children's Hospital with a minimum length of ICU stay of 10 h. Paediatric ICU attending physicians and fellows provided mortality risk predictions and the level of confidence associated with these predictions on consecutive patients at the time of multidisciplinary rounds within 24 hours of admission to the paediatric ICU. Median confidence levels were compared across different ranges of mortality risk predictions. RESULTS: Data were collected on 642 of 713 eligible patients (36 deaths, 5.6%). Mortality predictions greater than 5% and less than 95% were made with significantly less confidence than those predictions <5% and >95%. Experience was associated with greater confidence in prognostication. CONCLUSIONS: We conclude that a physician's subjective mortality prediction may be dependent on the level of confidence in the prognosis; that is, a physician less confident in his or her prognosis is more likely to state an intermediate survival prediction. Measuring the level of confidence associated with mortality risk predictions (or any prognostic assessment) may therefore be important because different levels of confidence may translate into differences in a physician's therapeutic plans and their assessment of the patient's future.

Hematopoietic stem cell donor registry strategies for assigning search determinants and matching relationships.

Registries and cord blood banks around the world collect and store the HLA types of volunteers in order to identify matched unrelated donors for patients requiring hematopoietic stem cell transplantation. This task is complicated by the many formats in which HLA types are provided by the testing laboratories (types obtained by serology vs by DNA-based methods; high vs intermediate vs low resolution) and by the need to identify which of these diverse types are most likely to match the HLA assignments of a searching patient as closely as possible. Conversion of the assignments to 'search determinants' may be included within the algorithm used to select and prioritize a list of potentially suitable donors, either as an aid to matching or as a tool to optimize the performance of comparisons within large data files. The strategies used by registries to create search determinants are described. A set of search determinants, utilized by the National Marrow Donor Program, is provided as an example and is intended to initiate further discussion aimed at understanding the process used by each registry with the possibility of developing a standard process among registries worldwide.

Personality and symptom sensitivity predictors of alprazolam withdrawal in panic disorder.

BACKGROUND: Discontinuation of benzodiazepine (BZ) treatment results in a well-characterized withdrawal syndrome in 40-50% of anxious patients. While numerous studies have established the role of BZ dose, treatment duration, half-life, potency, rate of withdrawal and severity of underling anxiety disorder in predicting severity of withdrawal symptoms, fewer studies have examined the role of psychological and personality factors. METHOD: In 123 panic disorder patients undergoing gradual tapered discontinuation of alprazolam in conjunction with pre-treatment with carbamazepine or placebo, the relationship between measures of 'symptom sensitivity' and 'harm avoidance', and severity of withdrawal symptoms measured as peak severity of symptoms, time before taper needed to be slowed due to symptoms, and ability to complete taper, was examined. RESULTS: After controlling for the less substantial effects of dose, treatment duration, pre-taper anxiety and panic attack frequency, measures of symptom sensitivity and harm avoidance accounted for an additional 3-6% of withdrawal variance. CONCLUSIONS: These results show an effect of symptom sensitivity and harm avoidance on BZ withdrawal symptoms, comparable to prior findings linking dependent personality characteristics to withdrawal severity. Failure to show the expected effect on ability to complete taper may be due to either the more symptomatic nature of the patients in this study.