Persistence of Chronic Lymphocytic Leukemia Stem-like Populations under Simultaneous In Vitro Treatment with Curcumin, Fludarabine, and Ibrutinib: Implications for Therapy Resistance.

Leukemic stem cells (LSCs) possess similar characteristics to normal hematopoietic stem cells, including self-renewal capacity, quiescence, ability to initiate leukemia, and drug resistance. These cells play a significant role in leukemia relapse, persisting even after apparent remission. LSCs were first described in 1994 by Lapidot et al. Although they have been extensively studied in acute leukemia, more LSC research is still needed in chronic lymphocytic leukemia (CLL) to understand if reduced apoptosis in mature cells should still be considered as the major cause of this disease. Here, we provide new evidence suggesting the existence of stem-like cell populations in CLL, which may help to understand the disease as well as to develop effective treatments. In this study, we identified a potential leukemic stem cell subpopulation using the tetraploid CLL cell line I83. This subpopulation is characterized by diploid cells that were capable of generating the I83 tetraploid population. Furthermore, we adapted a novel flow cytometry analysis protocol to detect CLL subpopulations with stem cell properties in peripheral blood samples and primary cultures from CLL patients. These cells were identified by their co-expression of CD19 and CD5, characteristic markers of CLL cells. As previously described, increased alkaline phosphatase (ALP) activity is indicative of stemness and pluripotency. Moreover, we used this method to investigate the potential synergistic effect of curcumin in combination with fludarabine and ibrutinib to deplete this subpopulation. Our results confirmed the effectiveness of this ALP-based analysis protocol in detecting and monitoring leukemic stem-like cells in CLL. This analysis also identified limitations in eradicating these populations using in vitro testing. Furthermore, our findings demonstrated that curcumin significantly enhanced the effects of fludarabine and ibrutinib on the leukemic fraction, exhibiting synergistic effects (combination drug index, CDI 0.97 and 0.37, respectively). Our results lend support to the existence of potential stem-like populations in CLL cell lines, and to the idea that curcumin could serve as an effective adjuvant in therapies aimed at eliminating these populations and improving treatment efficacy.

The effect of high-dose, short-term caffeine intake on the renal clearance of calcium, sodium and creatinine in healthy adults.

The consumption of caffeine has been linked to osteoporosis, believed to be due to enhanced bone resorption as a result of increased calcium excretion in the urine. However, the amount of calcium in the urine may not necessarily reflect the true effect of caffeine on calcium clearance. This study therefore examined the impact of high-dose, short-term caffeine intake on renal clearance of calcium, sodium and creatinine in healthy adults. In a double-blind clinical study, participants chewed caffeine (n = 12) or placebo (n = 12) gum for 5 minutes at 2-hour intervals over a 6-hour treatment period (800 mg total caffeine). Caffeine increased renal calcium clearance by 77%. Furthermore, the effect was positively correlated with sodium clearance and urine volume, suggesting that caffeine may act through inhibition of sodium reabsorption in the proximal convoluted tubule. This study confirmed that caffeine does increase renal calcium clearance and fosters further investigation into safe consumption of caffeine.

Development and Comparative Evaluation of Endolysosomal Proximity Labeling-Based Proteomic Methods in Human iPSC-Derived Neurons.

Proximity-based in situ labeling techniques offer a unique way to capture both stable and transient protein-protein and protein-organelle interactions. Combining this technology with mass spectrometry (MS)-based proteomics allows us to obtain snapshots of molecular microenvironments with nanometer resolution, facilitating the discovery of complex and dynamic protein networks. However, a number of technical challenges still exist, such as interferences from endogenously biotinylated proteins and other highly abundant bystanders, how to select the proper controls to minimize false discoveries, and experimental variations among biological/technical replicates. Here, we developed a new method to capture the proteomic microenvironment of the neuronal endolysosomal network by knocking in (KI) an engineered ascorbate peroxidase (APEX) gene to the endogenous locus of lysosome-associated membrane protein 1 (LAMP1). We found that normalizing proximity labeling proteomics data to the endogenously biotinylated protein (PCCA) can greatly reduce variations and enable fair comparisons among different batches of APEX labeling and different APEX probes. We conducted a comparative evaluation between this KI-LAMP1-APEX method and our two overexpression LAMP1-APEX probes, achieving complementary coverage of both known and new lysosomal membrane and lysosomal-interacting proteins in human iPSC-derived neurons. To summarize, this study demonstrated new analytical tools to characterize lysosomal functions and microenvironment in human neurons and filled critical gaps in the field for designing and optimizing proximity labeling proteomic experiments.

Acanthamoeba spp. and Balamuthia mandrillaris leading to fatal granulomatous amebic encephalitis.

Acanthamoeba spp. and Balamuthia mandrillaris are free-living amebae known to cause disseminated and fatal central nervous system dysfunction which manifests as granulomatous amebic encephalitis (GAE) with exceedingly rare frequency. We report two lethal cases of infection with free-living amebae: an acute case of Acanthamoeba spp. infection in an immunocompromised female and a subacute case of B. mandrillaris in a Hispanic male. The Acanthamoeba spp. infection presented with an atypical lesion in the thalamus that caused rapid deterioration of the patient while the case of B. mandrillaris had a prolonged clinical course with multifocal lesions beginning in the frontal lobe. Cerebrospinal fluid results were non-specific in both cases, however, post-mortem histology demonstrated the presence of trophozoites along a perivascular distribution of necrosis and infiltrate composed primarily of neutrophils. In addition to detailing the clinical presentations of these infrequent amebic infections, we offer insight into the difficulties surrounding their diagnoses in order to aid the clinician in accurate and timely identification.

Tales from the Trips: A Qualitative Study of Timely Recognition, Treatment, and Transfer of Emergency Department Patients with Acute Ischemic Stroke.

BACKGROUND AND OBJECTIVES: Acute Ischemic stroke (AIS) is a time-sensitive emergency and patients frequently present to, and are transferred from emergency departments (EDs). We sought to evaluate potential factors, particularly organizational, that may influence the timeliness of interfacility transfer for ED patients with AIS. METHODS: We conducted semistructured interviews at 3 EDs that routinely transfer AIS patients. A structured interview guide was developed and piloted prior to use. Staff were asked about perceived facilitators and barriers to timely and high quality emergency care for patients with AIS who require transfer. Each interview was audio recorded, transcribed, coded, and analyzed using an iterative inductive-deductive approach to build a list of themes and subthemes, and identify supporting quotes. RESULTS: We interviewed 45 ED staff (administrative staff, nurses, and physicians) involved in acute stroke care. We identified 4 major themes influencing the execution of interfacility transfers of AIS patients: (1) processes, (2) historical experiences; (3) communication; and (4) resources. Pre-existing protocols that standardized processes (eg, autoacceptance protocols) and reduced unnecessary communication, combined with direct communication with the neurology team at the comprehensive stroke center, and the flexibility and availability of human and physical resources (eg, staff and equipment) were commonly cited as facilitators. Lack of communication of clinical and operational outcomes back to transferring ED staff was viewed as a lost opportunity for process improvement, interorganization relationship building, and professional satisfaction. CONCLUSIONS: ED staff view the interfacility transfer of AIS patients as highly complex with multiple opportunities for delay. Coordination through the use of protocols and communication pre- and post-transfer represented opportunities to facilitate transfers. Staff and clinicians at transferring facilities identified multiple opportunities to enhance existing processes and ongoing communication quality among facilities involved in the acute management of patients with AIS.

Rabies response, One Health and more-than-human considerations in Indigenous communities in northern Australia.

Australia is currently canine rabies free; however, the spread of rabies in eastern Indonesia poses an increasing risk to northern Australia. Domestic dogs are numerous in East Arnhem Land (EAL) and the Northern Peninsular Area (NPA), usually unrestrained and living in close relationships with humans. The response to any rabies outbreak on Australian territory will focus on dog vaccination, controlling dog movements and depopulation. A One Health approach to zoonotic disease control should seek to co-promote human and animal health, whilst also seeking to accommodate the preferences of affected communities. We report on 5 collaborative workshops and 28 semi-structured interviews conducted between January 2017 and June 2018 with: (i) EAL and NPA community members; (ii) Indigenous Rangers in EAL and NPA; and (iii) residents of Cairns, the local regional centre. Storyboard methodologies were used to work with participants and explore what rabies response measures they thought were justified or unacceptable, why they held these views, and what other steps they believed needed to be taken. Key findings include that the capacity of the NPA and EAL communities to contribute/adapt to a biosecurity response is limited by structural disadvantage including poor infrastructure (such as lockable premises and intact fences) and appropriate information, dominant cultural norms and food security concerns. Dogs and dingoes can have great cultural and social importance; key interventions might be accommodated within cultural beliefs and long-standing norms of dog management if sufficient effort is made to adapt interventions to local contexts and community preferences. Adopting such a 'strengths-based' approach mandates that the communities at greatest risk need help to prepare for and develop strategies to manage a biosecurity response to a rabies incursion. This would include listening to individual and community concerns and attending to the educational and infrastructural needs for supporting different groups to respond appropriately.

Feasibility and assessment of outcome measures for yoga as self-care for minorities with arthritis: a pilot study.

BACKGROUND: While there is a growing interest in the therapeutic benefits of yoga, minority populations with arthritis tend to be under-represented in the research. Additionally, there is an absence of guidance in the literature regarding the use of multicultural teams and sociocultural health beliefs, when designing yoga studies for a racially diverse population with arthritis. This pilot study examined the feasibility of offering yoga as a self-care modality to an urban, bilingual, minority population with osteoarthritis (OA) or rheumatoid arthritis (RA), in the Washington, DC area. METHODS: The primary objective of the study was to assess the feasibility of offering an 8-week, bilingual yoga intervention adapted for arthritis to a convenience sample of primarily Hispanic and Black/African-American adults. A racially diverse interdisciplinary research team was assembled to design a study to facilitate recruitment and retention. The second objective identified outcome measures to operationalize potential facilitators and barriers to self-care and self-efficacy. The third objective determined the feasibility of using computer-assisted self-interview (CASI) for data collection. RESULTS: Enrolled participants (n = 30) were mostly female (93%), Spanish speaking (69%), and diagnosed with RA (88.5%). Feasibility was evaluated using practicality, acceptability, adaptation, and expansion of an arthritis-adapted yoga intervention, modified for this population. Recruitment (51%) and participation (60%) rates were similar to previous research and clinical experience with the study population. Of those enrolled, 18 started the intervention. For adherence, 12 out of 18 (67%) participants completed the intervention. All (100%), who completed the intervention, continued to practice yoga 3 months after completing the study. Using nonparametric tests, selected outcome measures showed a measurable change post-intervention suggesting appropriate use in future studies. An in-person computerized questionnaire was determined to be a feasible method of data collection. CONCLUSIONS: Findings from this pilot study confirm the feasibility of offering yoga to this racially/ethnically diverse population with arthritis. This article provides recruitment/retention rates, outcome measures with error rates, and data collection recommendations for a previously under-represented population. Suggestions include allocating resources for translation and using a multicultural design to facilitate recruitment and retention. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01617421.

Lessons Learned From the Development and Parameterization of a Computer Simulation Model to Evaluate Task Modification for Health Care Providers.

Computer simulation is a highly advantageous method for understanding and improving health care operations with a wide variety of possible applications. Most computer simulation studies in emergency medicine have sought to improve allocation of resources to meet demand or to assess the impact of hospital and other system policies on emergency department (ED) throughput. These models have enabled essential discoveries that can be used to improve the general structure and functioning of EDs. Theoretically, computer simulation could also be used to examine the impact of adding or modifying specific provider tasks. Doing so involves a number of unique considerations, particularly in the complex environment of acute care settings. In this paper, we describe conceptual advances and lessons learned during the design, parameterization, and validation of a computer simulation model constructed to evaluate changes in ED provider activity. We illustrate these concepts using examples from a study focused on the operational effects of HIV screening implementation in the ED. Presentation of our experience should emphasize the potential for application of computer simulation to study changes in health care provider activity and facilitate the progress of future investigators in this field.

Scalable Production of iPSC-Derived Human Neurons to Identify Tau-Lowering Compounds by High-Content Screening.

Lowering total tau levels is an attractive therapeutic strategy for Alzheimer's disease and other tauopathies. High-throughput screening in neurons derived from human induced pluripotent stem cells (iPSCs) is a powerful tool to identify tau-targeted therapeutics. However, such screens have been hampered by heterogeneous neuronal production, high cost and low yield, and multi-step differentiation procedures. We engineered an isogenic iPSC line that harbors an inducible neurogenin 2 transgene, a transcription factor that rapidly converts iPSCs to neurons, integrated at the AAVS1 locus. Using a simplified two-step protocol, we differentiated these iPSCs into cortical glutamatergic neurons with minimal well-to-well variability. We developed a robust high-content screening assay to identify tau-lowering compounds in LOPAC and identified adrenergic receptors agonists as a class of compounds that reduce endogenous human tau. These techniques enable the use of human neurons for high-throughput screening of drugs to treat neurodegenerative disease.

A qualitative approach exploring the acceptability of yoga for minorities living with arthritis: 'Where are the people who look like me?'

OBJECTIVES: To examine the acceptability of yoga research tailored to recruit and retain a minority population (both English and Spanish speaking) with arthritis. Yoga research for arthritis often underrepresents minorities and acceptability for this population has not previously been investigated. DESIGN: Acceptability was evaluated using retention, adherence, journals, and semi-structured exit interviews from twelve participants with osteoarthritis or rheumatoid arthritis undergoing an 8-week yoga intervention. Journal quotes were analyzed using content analysis techniques. NVivo software was used to organize transcripts and assemble themes. Two methods of triangulation (data and investigator) were used to overcome potential bias from a single-perspective interpretation. Exit interview comments were content analyzed using a card sort method. The study was designed with a cultural infrastructure including a multicultural research team, translators, and bilingual materials and classes, to facilitate trust and acceptability for primarily Hispanic and Black/African-American adults. SETTING: Washington, D.C. metropolitan area, USA. RESULTS: On average participants attended 10 of 16 classes, with home practice 2-3days a week. All who completed were still practicing yoga three-months later. Qualitative narrative analysis identified major themes related to facilitating factors and barriers for yoga practice, self-efficacy, and support. Participant comments indicated that offering an arthritis-based yoga intervention and using a culturally congruent research design was found to be acceptable. CONCLUSIONS: As yoga research grows, there is a need to understand and promote acceptability for typically under-represented populations. This study attempts to inform the expansion of multicultural research designed to recruit and retain those from diverse backgrounds.

Effect of Garlic, Gingko, and St. John's Wort Extracts on the Pharmacokinetics of Fexofenadine: A Mechanistic Study.

The aim of this study was to determine the effects of garlic and ginkgo herbal extracts on the pharmacokinetics of the P-glycoprotein (P-gp)/organic anion-transporting polypeptides (Oatps) substrate fexofenadine. Male rats were dosed orally with garlic (120 mg/kg), ginkgo (17 mg/kg), St. John's wort (SJW; 1000 mg/kg; positive control), or Milli-Q water for 14 days. On day 15, rats either were administered fexofenadine (orally or i.v.), had their livers isolated and perfused with fexofenadine, or had their small intestines divided into four segments (SI-SIV) and analyzed for P-gp and Oatp1a5. In vivo, SJW increased the clearance of i.v. administered fexofenadine by 28%. Garlic increased the area under the curve0-∞ and maximum plasma concentration of orally administered fexofenadine by 47% and 85%, respectively. Ginkgo and SJW had no effect on the oral absorption of fexofenadine. In the perfused liver, garlic, ginkgo, and SJW increased the biliary clearance of fexofenadine with respect to perfusate by 71%, 121%, and 234%, respectively. SJW increased the biliary clearance relative to the liver concentration by 64%. The ratio of liver to perfusate concentrations significantly increased in all treated groups. The expression of Oatp1a5 in SI was increased by garlic (88%) and SJW (63%). There were no significant changes in the expression of P-gp. Induction of intestinal Oatp1a5 by garlic may explain the increased absorption of orally administered fexofenadine. Ginkgo had no effect on the expression of intestinal P-gp or Oatp1a5. A dual inductive effect by SJW on opposing intestinal epithelial transport by Oatp1a5 and P-gp remains a possibility.

Recent clinical trials in lupus nephritis.

Recent clinical trials have provided evidence for the efficacy of low-dose intravenous cyclophosphamide and mycophenolate mofetil as induction treatment for patients with proliferative lupus nephritis in comparative trials with standard-dose intravenous cyclophosphamide. Trials of maintenance treatments have had more variable results, but suggest that the efficacy of mycophenolate mofetil may be similar to that of quarterly standard-dose intravenous cyclophosphamide and somewhat more efficacious than azathioprine. Differential responses to mycophenolate mofetil based on ethnicity suggest that it may be more effective in black and Hispanic patients. Rituximab was not efficacious as an adjunct to induction treatment with mycophenolate mofetil.

Use of secondary stroke prevention medicines in Australia: national trends, 2003-2009.

OBJECTIVE: To examine recent trends in the use of secondary stroke prevention medicines by transient ischaemic attack (TIA) and ischaemic stroke survivors. DESIGN, SETTING AND PARTICIPANTS: Retrospective observational study of patients aged ≥ 65 years who were hospitalised with a TIA or ischaemic stroke between January 2000 and December 2009. Use of antihypertensive, antithrombotic and lipid-lowering medicines by patients was determined monthly, using claims data from the Australian Government Department of Veterans' Affairs, commencing in January 2003. MAIN OUTCOME MEASURE: Monthly prevalence of use of secondary stroke prevention medicines. RESULTS: Between 2003 and 2009, small increases in use (less than 2% relative increase annually) were observed for antihypertensive and antithrombotic medicines among 19 019 patients. There was a 9% relative increase in use of lipid-lowering therapy each year. The proportion of patients dispensed all three recommended medicine classes nearly doubled over the 7-year period. By December 2009, about 80% of patients were dispensed an antihypertensive, 75% received an antithrombotic and 60% were dispensed lipid-lowering therapy. Almost half of the population were dispensed all three recommended classes by the end of the study period. CONCLUSIONS: Increased use of secondary stroke prevention medicines was shown in this study, in accordance with national stroke guideline recommendations and initiatives supporting quality use of medicines in Australia. There may be opportunity to further increase use of these medicines among older Australians who have had a TIA or ischaemic stroke.

Identification of doctors at risk of recurrent complaints: a national study of healthcare complaints in Australia.

OBJECTIVES: (1) To determine the distribution of formal patient complaints across Australia's medical workforce and (2) to identify characteristics of doctors at high risk of incurring recurrent complaints. METHODS: We assembled a national sample of all 18 907 formal patient complaints filed against doctors with health service ombudsmen ('Commissions') in Australia over an 11-year period. We analysed the distribution of complaints among practicing doctors. We then used recurrent-event survival analysis to identify characteristics of doctors at high risk of recurrent complaints, and to estimate each individual doctor's risk of incurring future complaints. RESULTS: The distribution of complaints among doctors was highly skewed: 3% of Australia's medical workforce accounted for 49% of complaints and 1% accounted for a quarter of complaints. Short-term risks of recurrence varied significantly among doctors: there was a strong dose-response relationship with number of previous complaints and significant differences by doctor specialty and sex. At the practitioner level, risks varied widely, from doctors with <10% risk of further complaints within 2 years to doctors with >80% risk. CONCLUSIONS: A small group of doctors accounts for half of all patient complaints lodged with Australian Commissions. It is feasible to predict which doctors are at high risk of incurring more complaints in the near future. Widespread use of this approach to identify high-risk doctors and target quality improvement efforts coupled with effective interventions, could help reduce adverse events and patient dissatisfaction in health systems.

A pilot study of yoga as self-care for arthritis in minority communities.

BACKGROUND: While arthritis is the most common cause of disability, non-Hispanic blacks and Hispanics experience worse arthritis impact despite having the same or lower prevalence of arthritis compared to non-Hispanic whites. People with arthritis who exercise regularly have less pain, more energy, and improved sleep, yet arthritis is one of the most common reasons for limiting physical activity. Mind-body interventions, such as yoga, that teach stress management along with physical activity may be well suited for investigation in both osteoarthritis and rheumatoid arthritis. Yoga users are predominantly white, female, and college educated. There are few studies that examine yoga in minority populations; none address arthritis. This paper presents a study protocol examining the feasibility and acceptability of providing yoga to an urban, minority population with arthritis. METHODS/DESIGN: In this ongoing pilot study, a convenience sample of 20 minority adults diagnosed with either osteoarthritis or rheumatoid arthritis undergo an 8-week program of yoga classes. It is believed that by attending yoga classes designed for patients with arthritis, with racially concordant instructors; acceptability of yoga as an adjunct to standard arthritis treatment and self-care will be enhanced. Self-care is defined as adopting behaviors that improve physical and mental well-being. This concept is quantified through collecting patient-reported outcome measures related to spiritual growth, health responsibility, interpersonal relations, and stress management. Additional measures collected during this study include: physical function, anxiety/depression, fatigue, sleep disturbance, social roles, and pain; as well as baseline demographic and clinical data. Field notes, quantitative and qualitative data regarding feasibility and acceptability are also collected. Acceptability is determined by response/retention rates, positive qualitative data, and continuing yoga practice after three months. DISCUSSION: There are a number of challenges in recruiting and retaining participants from a community clinic serving minority populations. Adopting behaviors that improve well-being and quality of life include those that integrate mental health (mind) and physical health (body). Few studies have examined offering integrative modalities to this population. This pilot was undertaken to quantify measures of feasibility and acceptability that will be useful when evaluating future plans for expanding the study of yoga in urban, minority populations with arthritis. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01617421.

Stereochemical control of polymorph transitions in nanoscale reactors.

Crystallization of glycine in the cylindrical nanopores of anodic aluminum oxide (AAO) revealed the formation of metastable ß-glycine in pores having diameters less than 200 nm. Two-dimensional X-ray microdiffraction indicated that the [010] axis of the embedded ß-glycine nanocrystals coincided with the pore direction, identical to behavior observed previously in the cylindrical nanopores of polymer monoliths. Whereas the ß-glycine nanocrystals were stable indefinitely in ambient air and persisted upon heating, they transformed to the α polymorph upon standing at room temperature and 90% relative humidity (RH). The α-glycine nanocrystals were oriented with the [010] axis nearly perpendicular to the pore direction, reflecting a nearly 90° rotation of the glycine molecules during the transition. When the ß-glycine nanocrystals were formed in the AAO cylinders in the presence of small amounts of racemic hydrophobic amino acid auxiliaries, which are known to bind selectively to the (010) and (010) faces on the fast-growing end of ß-glycine enantiomorphs, the ß â†’ α phase transition at 90% RH was suppressed. In contrast, ß-glycine nanocrystals grown in the presence of an enantiopure amino acid auxiliary, which binds to the fast-growing end of only one of the enantiomorphs, thus suppressing its formation and leaving the other enantiomorph unperturbed, transformed into the α polymorph under the same conditions. This observation confirms that binding of an amino acid to the {010} faces is stereoselective and that access of water to these faces is essential for the transition to the α polymorph.

Effects of dehydroepiandrosterone supplementation during stressful military training: a randomized, controlled, double-blind field study.

Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are anabolic prehormones involved in the synthesis of testosterone. Both have been shown to exert neuroprotective effects during stress. In this randomized, controlled, double-blind field study, we examined the effects of a 12-day DHEA regimen on stress indices in military men undergoing survival training. Forty-eight men were randomized to either a DHEA treatment group or placebo control group. The treatment group received 50 mg of oral DHEA supplementation daily for 5 days during classroom training followed by 7 days of 75 mg during stressful field operations. Control subjects received identical placebo pills. Salivary assays (DHEA[S], testosterone, and cortisol) were conducted at four time points: distal pre-stress (T1), proximal pre-stress (T2), mock-captivity stress (T3), and 24 h recovery (T4). Subjective distress was also assessed at T1, T3, and T4. As expected, DHEA treatment resulted in higher salivary concentrations of DHEA and DHEAS during daily living, mock-captivity stress, and recovery. Similar patterns were observed for salivary markers of anabolic balance: DHEA/cortisol, DHEAS/cortisol, and testosterone/cortisol concentration ratios. Despite notable time effects, no group differences emerged for subjective distress. A brief, low dose DHEA regimen yielded large increases in salivary DHEA(S) concentrations and enhanced anabolic balance throughout sustained military stress. These physiological changes did not extrapolate to subjective distress.

Effect of psychological skills training during military survival school: a randomized, controlled field study.

In this randomized, controlled field study, we examined the effects of a brief psychological skills training (PST) intervention on stress responses during military survival school. A second purpose was to build upon prior research in this unique environment by extending the follow-up window to 3 months. Baseline subjective distress (dissociative) symptoms were measured in 65 male military subjects, who were then randomized either to PST or a control group that received no training beyond the normal survival school curriculum. PST received training in arousal control, mental imagery, goal setting, and positive self-talk in two separate 40-minute sessions before stressful field exercises. Stress symptoms were then assessed during a mock-captivity phase of training, as well as 24 hours, 1 month, and 3 months after completion of training. Repeated-measures analyses of variance with follow-up paired t tests examined differences between groups and across time. Survival training precipitated remarkable increases in subjective distress, but few substantive group differences emerged. This study extends prior work quantifying the human stress response to intense military training.

Emergency department throughput, crowding, and financial outcomes for hospitals.

Emergency department (ED) crowding has been identified as a major public health problem in the United States by the Institute of Medicine. ED crowding not only is associated with poorer patient outcomes, but it also contributes to lost demand for ED services when patients leave without being seen and hospitals must go on ambulance diversion. However, somewhat paradoxically, ED crowding may financially benefit hospitals. This is because ED crowding allows hospitals to maximize occupancy with well-insured, elective patients while patients wait in the ED. In this article, the authors propose a more holistic model of hospital flow and revenue that contradicts this notion and offer suggestions for improvements in ED and hospital management that may not only reduce crowding and improve quality, but also increase hospital revenues. Also proposed is that increased efficiency and quality in U.S. hospitals will require changes in systematic microeconomic and macroeconomic incentives that drive the delivery of health services in the United States. Finally, the authors address several questions to propose mutually beneficial solutions to ED crowding that include the realignment of hospital incentives, changing culture to promote flow, and several ED-based strategies to improve ED efficiency.

Auditory verbal working memory load and thalamic activation in nonpsychotic relatives of persons with schizophrenia: an fMRI replication.

First-degree relatives of persons with schizophrenia are at genetic risk for the illness and show deficits on high-load information-processing tasks. In a prior study of auditory working memory (WM) using functional MRI (fMRI), the authors demonstrated that adult relatives had significantly increased activation in the dorsomedial (DM) thalamus, anterior cingulate, and prefrontal cortex (H. W. Thermenos et al., 2004). In this study, the authors extended this work using a parametric WM task designed for fMRI in an independent, unmedicated sample. Twelve nonpsychotic relatives of persons with schizophrenia and 13 healthy controls were administered multiple versions of an auditory continuous performance test during fMRI. Data were analyzed using Statistical Parametric Mapping software. Compared with controls, relatives showed significantly greater task-elicited activation in the DM thalamus. When fMRI signal change was modeled as a function of increasing WM load, there was a significant Group x Load interaction, with relatives showing significantly greater task-elicited activation in the right DM thalamus compared with controls. Greater DM thalamic activation in the relatives remained significant when WM performance, vocabulary score, and education were controlled. This replication suggests that altered thalamic activation is a feature of neurobiological risk for schizophrenia.