Procedural volume and survival after lung transplantation in the United States: the need to look beyond volume in the establishment of quality metrics.

BACKGROUND: We sought to evaluate the effect of center volume on patient survival. METHODS: We performed a retrospective analysis on nationwide data from the Scientific Registry of Transplant Recipients provided by United Network for Organ Sharing pertaining to lung transplantation (LT) recipients transplanted between 2005 and 2013. Centers were categorized into 4 groups based on their annual volume as follows: less than 20, 20 to 29, 30 to 39, and greater than or equal to 40 LTs. Baseline characteristics were compared and Kaplan-Meier analysis was used to estimate survival. RESULTS: A total of 13,506 adult recipients underwent LT during the study period. Of these, 2,491 (18.4%) patients were transplanted in centers with volume less than 20, 2,562 (19.0%) in centers with volume 20 to 29, 2,998 (22.2%) in centers with volume 30 to 39, and 5,455(40.4%) in centers with volume greater than or equal to 40. Survival was poorest in the lowest volume centers (1-year 81.4% vs 85.5% and 5-year 49.7% vs 56.5%, respectively). CONCLUSIONS: Post-LT survival in low volume centers is significantly lower than in high volume centers but the explanatory power of volume as a predictor of survival is low.

Extracorporeal membrane oxygenation as a bridge to lung transplantation: what lessons might we learn from volume and expertise?

OBJECTIVES: We sought to evaluate the effect of centre volume on survival when extracorporeal membrane oxygenation (ECMO) is used as a bridge to lung transplantation (LTx). METHODS: We performed a retrospective analysis of the United Network for Organ Sharing data on adult lung transplantations performed between 2000 and 2014. Centres were categorized based on volume of transplants into low-, medium- and high-volume centres (1-5, 6-15 and >15, respectively). Baseline characteristics were assessed and a Kaplan-Meier analysis was used to estimate survival with log-rank test. We used multivariate Cox regression analysis to estimate the risk of post-transplant 1-year mortality between centres. RESULTS: A total of 342 adult recipients were bridged on ECMO. Of these recipients, 88 (25.7%) were bridged in low, 89 (26%) in medium and 165 (48.2%) in high-volume centres. Patients in medium-volume centres were more likely to be older compared with those in low-volume and high-volume centres with a median age of 56, 46 and 49 years, respectively. High-volume centres reported the highest proportion (94.6%) of bilateral lung recipients, followed by low-volume (86.4%) and medium-volume centres (77.5%). The 30-day survival for the three groups was similar but 1-year survival was higher in high-volume centres (80.8) compared with medium-volume centres (70.0%) and low-volume centres (61.9%). The risk of 1-year mortality in low-volume centres was higher compared with high-volume centres in adjusted analysis (hazard ratio 2.74, 95% confidence interval 1.61-4.68, P = 0.01). CONCLUSIONS: Lowest volume centres have lowest survival and there exists a volume threshold at which better outcomes are achieved.

Lung Transplantation in Patients with High Lung Allocation Scores in the US: Evidence for the Need to Evaluate Score Specific Outcomes.

Objective. The lung allocation score (LAS) resulted in a lung transplantation (LT) selection process guided by clinical acuity. We sought to evaluate the relationship between LAS and outcomes. Methods. We analyzed Scientific Registry of Transplant Recipient (SRTR) data pertaining to recipients between 2005 and 2012. We stratified them into quartiles based on LAS and compared survival and predictors of mortality. Results. We identified 10,304 consecutive patients, comprising 2,576 in each LAS quartile (quartile 1 (26.3-35.5), quartile 2 (35.6-39.3), quartile 3 (39.4-48.6), and quartile 4 (48.7-95.7)). Survival after 30 days (96.9% versus 96.8% versus 96.0% versus 94.8%), 90 days (94.6% versus 93.7% versus 93.3% versus 90.9%), 1 year (87.2% versus 85.0% versus 84.8% versus 80.9%), and 5 years (55.4% versus 54.5% versus 52.5% versus 48.8%) was higher in the lower groups. There was a significantly higher 5-year mortality in the highest LAS group (HR 1.13, p = 0.030, HR 1.17, p = 0.01, and HR 1.17, p = 0.02) comparing quartiles 2, 3, and 4, respectively, to quartile 1. Conclusion. Overall, outcomes in recipients with higher LAS are worse than those in patients with lower LAS. These data should inform more individualized evidence-based discussion during pretransplant counseling.

Choices in fluid type and volume during resuscitation: impact on patient outcomes.

We summarize the emerging new literature regarding the pathophysiological principles underlying the beneficial and deleterious effects of fluid administration during resuscitation, as well as current recommendations and recent clinical evidence regarding specific colloids and crystalloids. This systematic review allows us to conclude that there is no clear benefit associated with the use of colloids compared to crystalloids and no evidence to support the unique benefit of albumin as a resuscitation fluid. Hydroxyethyl starch use has been associated with increased acute kidney injury (AKI) and use of renal replacement therapy. Other synthetic colloids (dextran and gelatins) though not well studied do not appear superior to crystalloids. Normal saline (NS) use is associated with hyperchloremic metabolic acidosis and increased risk of AKI. This risk is decreased when balanced salt solutions are used. Balanced crystalloid solutions have shown no harmful effects, and there is evidence for benefit over NS. Finally, fluid resuscitation should be applied in a goal-directed manner and targeted to physiologic needs of individual patients. The evidence supports use of fluids in volume-responsive patients whose end-organ perfusion parameters have not been met.

Diagnostic accuracy of history, physical examination, and bedside ultrasound for diagnosis of extremity fractures in the emergency department: a systematic review.

OBJECTIVES: Understanding history, physical examination, and ultrasonography (US) to diagnose extremity fractures compared with radiography has potential benefits of decreasing radiation exposure, costs, and pain and improving emergency department (ED) resource management and triage time. METHODS: The authors performed two electronic searches using PubMed and EMBASE databases for studies published between 1965 to 2012 using a strategy based on the inclusion of any patient presenting with extremity injuries suspicious for fracture who had history and physical examination and a separate search for US performed by an emergency physician (EP) with subsequent radiography. The primary outcome was operating characteristics of ED history, physical examination, and US in diagnosing radiologically proven extremity fractures. The methodologic quality of the studies was assessed using the quality assessment of studies of diagnostic accuracy tool (QUADAS-2). RESULTS: Nine studies met the inclusion criteria for history and physical examination, while eight studies met the inclusion criteria for US. There was significant heterogeneity in the studies that prevented data pooling. Data were organized into subgroups based on anatomic fracture locations, but heterogeneity within the subgroups also prevented data pooling. The prevalence of fracture varied among the studies from 22% to 70%. Upper extremity physical examination tests have positive likelihood ratios (LRs) ranging from 1.2 to infinity and negative LRs ranging from 0 to 0.8. US sensitivities varied between 85% and 100%, specificities varied between 73% and 100%, positive LRs varied between 3.2 and 56.1, and negative LRs varied between 0 and 0.2. CONCLUSIONS: Compared with radiography, EP US is an accurate diagnostic test to rule in or rule out extremity fractures. The diagnostic accuracy for history and physical examination are inconclusive. Future research is needed to understand the accuracy of ED US when combined with history and physical examination for upper and lower extremity fractures.

Clozapine-induced locomotor suppression is mediated by 5-HT2A receptors in the forebrain.

The need for safer, more effective therapeutics for the treatment of schizophrenia is widely acknowledged. To optimally target novel pharmacotherapies, in addition to establishing the mechanisms responsible for the beneficial effects of antipsychotics, the pathways underlying the most severe side effects must also be elucidated. Here we investigate the role of serotonin 2A (5-HT(2A)), serotonin 2C (5-HT(2C)), and dopamine 2 receptors (D2) in mediating adverse effects associated with canonical first- and second-generation antipsychotic drugs in mice. Wild-type (WT) and 5-HT(2A) knockout (KO) mice treated with haloperidol, clozapine, and risperidone were assessed for locomotor activity and catalepsy. WT mice showed a marked reduction in locomotor activity following acute administration of haloperidol and high-dose risperidone, which was most likely secondary to the severe catalepsy caused by these compounds. Clozapine also dramatically reduced locomotor activity, but in the absence of catalepsy. Interestingly, 5-HT(2A) KO mice were cataleptic following haloperidol and risperidone, but did not respond to clozapine's locomotor-suppressing effects. Restoration of 5-HT(2A) expression to cortical glutamatergic neurons re-instated the locomotor-suppressing effects of clozapine in the open field. In sum, we confirm that haloperidol and risperidone caused catalepsy in rodents, driven by strong antagonism of D2. We also demonstrate that clozapine decreases locomotor activity in a 5-HT(2A)-dependent manner, in the absence of catalepsy. Moreover, we show that it is the cortical population of 5-HT(2A) that mediate the locomotor-suppressing effects of clozapine.

Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior.

Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect perception, cognition, and mood. All known drugs of this class are 5-HT(2A) receptor (2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactive properties. Why only certain 2AR agonists are hallucinogens and which neural circuits mediate their effects are poorly understood. By genetically expressing 2AR only in cortex, we show that 2AR-regulated pathways on cortical neurons are sufficient to mediate the signaling pattern and behavioral response to hallucinogens. Hallucinogenic and nonhallucinogenic 2AR agonists both regulate signaling in the same 2AR-expressing cortical neurons. However, the signaling and behavioral responses to the hallucinogens are distinct. While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric G(i/o) proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.

Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice.

Serotonin [5-hydroxytryptamine (5-HT)] neurotransmission in the central nervous system modulates depression and anxiety-related behaviors in humans and rodents, but the responsible downstream receptors remain poorly understood. We demonstrate that global disruption of 5-HT2A receptor (5HT2AR) signaling in mice reduces inhibition in conflict anxiety paradigms without affecting fear-conditioned and depression-related behaviors. Selective restoration of 5HT2AR signaling to the cortex normalized conflict anxiety behaviors. These findings indicate a specific role for cortical 5HT2AR function in the modulation of conflict anxiety, consistent with models of cortical, "top-down" influences on risk assessment.

Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice.

Reduced serotonin transporter (5-HTT) expression is associated with abnormal affective and anxiety-like symptoms in humans and rodents, but the mechanism of this effect is unknown. Transient inhibition of 5-HTT during early development with fluoxetine, a commonly used serotonin selective reuptake inhibitor, produced abnormal emotional behaviors in adult mice. This effect mimicked the behavioral phenotype of mice genetically deficient in 5-HTT expression. These findings indicate a critical role of serotonin in the maturation of brain systems that modulate emotional function in the adult and suggest a developmental mechanism to explain how low-expressing 5-HTT promoter alleles increase vulnerability to psychiatric disorders.

Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice.

BACKGROUND: As a key regulator of serotonergic activity and target of many antidepressant treatments, the serotonin transporter (SERT) represents a potential mediator of anxiety- and depression-related behaviors. Using mice lacking the SERT (SERT KO), we examined the role of SERT function in anxiety- and depression-related behaviors and serotonergic neuron function. METHODS: Serotonin transporter knockout mice were evaluated in paradigms designed to assess anxiety-, depression-, and stress-related behaviors. Dorsal raphe nucleus (DRN) function was assessed by quantitative serotonergic cell counting and extracellular electrical recording of neuronal firing properties. RESULTS: Serotonin transporter knockout mice showed an increase in latency to feed in a novel situation, more immobility in a forced swim, increased escape latency in a shock escape paradigm, and decreased immobility in tail suspension. No differences in anxiety-related behaviors were seen in the open field and the elevated plus maze. Serotonin transporter knockout mice exhibit a 50% reduction in serotonergic cell number and a fourfold decrease in firing rate in the DRN. CONCLUSIONS: Developmental loss of SERT produces altered behaviors in models of depression that are generally opposite to those produced by antidepressant treatment. The reduced serotonergic cell number and firing rate in the DRN of adult SERT KO mice suggest a mechanism for these altered behaviors.

Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex.

Most neuropharmacological agents and many drugs of abuse modulate the activity of heptahelical G-protein-coupled receptors. Although the effects of these ligands result from changes in cellular signaling, their neurobehavioral activity may not correlate with results of in vitro signal transduction assays. 5-Hydroxytryptamine 2A receptor (5-HT2AR) partial agonists that have similar pharmacological profiles differ in the behavioral responses they elicit. In vitro studies suggest that different agonists acting at the same receptor may establish distinct patterns of signal transduction. Testing this hypothesis in the brain requires a global signal transduction assay that is applicable in vivo. To distinguish the cellular effects of the different 5-HT2AR agonists, we developed an assay for global signal transduction on the basis of high throughput quantification of rapidly modulated transcripts. Study of the responses to agonists in human embryonic kidney 293 cells stably expressing 5-HT2ARs demonstrated that each agonist elicits a distinct transcriptome fingerprint. We therefore studied behavioral and cortical signal transduction responses in wild-type and 5-HT2AR null-mutant mice. The hallucinogenic chemicals (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and lysergic acid diethylamide (LSD) stimulated a head-twitch behavioral response that was not observed with the nonhallucinogenic lisuride hydrogen maleate (LHM) and was absent in receptor null-mutant mice. We also found that DOI, LSD, and LHM each induced distinct transcriptome fingerprints in somatosensory cortex that were absent in 5-HT2AR null-mutants. Moreover, DOI and LSD showed similarities in the transcriptome fingerprints obtained that were not observed with the behaviorally inactive drug LHM. Our results demonstrate that chemicals acting at the 5-HT2AR induce specific cellular response patterns in vivo that are reflected in unique changes in the somatosensory cortex transcriptome.

Hypothalamic paraventricular 5-hydroxytryptamine: receptor-specific inhibition of NPY-stimulated eating and energy metabolism.

The feeding effects of 5-hydroxytryptamine (5-HT)(1) and 5-HT(2) receptor agonists injected into the hypothalamic paraventricular nucleus (PVN) immediately prior to PVN administration of neuropeptide Y (NPY) were examined. The impact of these same compounds on NPY-induced alterations in energy metabolism was also assessed in an attempt to characterize further the potential interactive relationship of PVN NPY and 5-HT on feeding and whole body calorimetry. Specifically, several experiments examined the effect of various 5-HT receptor agonists on NPY-stimulated eating and alterations in energy substrate utilization [respiratory quotient (RQ)]. This included the 5-HT(1A) receptor agonist 8-OH-DPAT, the 5-HT(1B/1A) agonist RU 24969, the 5-HT(1D) agonist L-694,247, the 5-HT(2A/2C) agonist DOI, the 5-HT(2B) agonist BW 723C86 and the 5-HT(2C) agonist mCPP. In feeding tests conducted at the onset of the dark cycle, drugs were administered 5 min prior to PVN injection of NPY and food intake was measured 2 h postinjection. The metabolic effects of NPY following a similar pretreatment were monitored using an open-circuit calorimeter measuring the volume of oxygen consumed (VO(2)), carbon dioxide produced (VCO(2)) and RQ (VCO(2)/VO(2)). PVN injection of NPY (100 pmol) potentiated feeding and evoked reliable increases in RQ. Only DOI (2.5--5 nmol) pretreatment antagonized NPY-induced eating and blocked the peptide's effect on energy substrate utilization. Direct PVN pretreatment with spiperone (SPRN), a 5-HT(2A) receptor antagonist, and ketanserin (KTSN), a 5-HT(2A/2C) antagonist, but not SDZ SER 082, a 5-HT(2B/2C) antagonist, or the 5-HT(2C) antagonist RS 102221, blocked the effect of DOI in both feeding and metabolic tests providing additional evidence that activation of PVN 5-HT(2A) receptors inhibits NPY's action on feeding and substrate utilization.