Reconsidering Donor Race in Predicting Allograft and Patient Survival Among Kidney Transplant Recipients.

Donor race should not be used in models to predict allograft and patient survival.Removing donor race from the Kidney Donor Risk Index may reduce kidney discard by reclassifying approximately 50% of high kidney donor profile index kidneys.Future prediction models should focus on using relevant biologic factors rather than social constructs when trying to predict outcomes.

Becoming a better parent: Mice learn sounds that improve a stereotyped maternal behavior.

While mothering is often instinctive and stereotyped in species-specific ways, evolution can favor genetically "open" behavior programs that allow experience to shape infant care. Among experience-dependent maternal behavioral mechanisms, sensory learning about infants has been hard to separate from motivational changes arising from sensitization with infants. We developed a paradigm in which sensory learning of an infant-associated cue improves a stereotypical maternal behavior in female mice. Mice instinctively employed a spatial memory-based strategy when engaged repetitively in a pup search and retrieval task. However, by playing a sound from a T-maze arm to signal where a pup will be delivered for retrieval, mice learned within 7 days and retained for at least 2 weeks the ability to use this specific cue to guide a more efficient search strategy. The motivation to retrieve pups also increased with learning on average, but their correlation did not explain performance at the trial level. Bilaterally silencing auditory cortical activity significantly impaired the utilization of new strategy without changing the motivation to retrieve pups. Finally, motherhood as compared to infant-care experience alone accelerated how quickly the new sensory-based strategy was acquired, suggesting a role for the maternal hormonal state. By rigorously establishing that newly formed sensory associations can improve the performance of a natural maternal behavior, this work facilitates future studies into the neurochemical and circuit mechanisms that mediate novel sensory learning in the maternal context, as well as more learning-based mechanisms of parental behavior in rodents.

Experience-Dependent Coding of Time-Dependent Frequency Trajectories by Off Responses in Secondary Auditory Cortex.

Time-dependent frequency trajectories are an inherent feature of many behaviorally relevant sounds, such as species-specific vocalizations. Dynamic frequency trajectories, even in short sounds, often convey meaningful information, which may be used to differentiate sound categories. However, it is not clear what and where neural responses in the auditory cortical pathway are critical for conveying information about behaviorally relevant frequency trajectories, and how these responses change with experience. Here, we uncover tuning to subtle variations in frequency trajectories in auditory cortex of female mice. We found that auditory cortical responses could be modulated by variations in a pure tone trajectory as small as 1/24th of an octave, comparable to what has been reported in primates. In particular, late spiking after the end of a sound stimulus was more often sensitive to the sound's subtle frequency variation compared with spiking during the sound. Such "Off" responses in the adult A2, but not those in core auditory cortex, were plastic in a way that may enhance the representation of a newly acquired, behaviorally relevant sound category. We illustrate this with the maternal mouse paradigm for natural vocalization learning. By using an ethologically inspired paradigm to drive auditory responses in higher-order neurons, our results demonstrate that mouse auditory cortex can track fine frequency changes, which allows A2 Off responses in particular to better respond to pitch trajectories that distinguish behaviorally relevant, natural sound categories.SIGNIFICANCE STATEMENT A whistle's pitch conveys meaning to its listener, as when dogs learn that distinct pitch trajectories whistled by their owner differentiate specific commands. Many species use pitch trajectories in their own vocalizations to distinguish sound categories, such as in human languages, such as Mandarin. How and where auditory neural activity encodes these pitch trajectories as their meaning is learned but not well understood, especially for short-duration sounds. We studied this in mice, where infants use ultrasonic whistles to communicate to adults. We found that late neural firing after a sound ends can be tuned to how the pitch changes in time, and that this response in a secondary auditory cortical field changes with experience to acquire a pitch change's meaning.

Familiarity with social sounds alters c-Fos expression in auditory cortex and interacts with estradiol in locus coeruleus.

When a social sound category initially gains behavioral significance to an animal, plasticity events presumably enhance the ability to recognize that sound category in the future. In the context of learning natural social stimuli, neuromodulators such as norepinephrine and estrogen have been associated with experience-dependent plasticity and processing of newly salient social cues, yet continued plasticity once stimuli are familiar could disrupt the stability of sensorineural representations. Here we employed a maternal mouse model of natural sensory cortical plasticity for infant vocalizations to ask whether the engagement of the noradrenergic locus coeruleus (LC) by the playback of pup-calls is affected by either prior experience with the sounds or estrogen availability, using a well-studied cellular activity and plasticity marker, the immediate early gene c-Fos. We counted call-induced c-Fos immunoreactive (c-Fos-IR) cells in both LC and physiologically validated fields within the auditory cortex (AC) of estradiol or blank-implanted virgin female mice with either 0 or 5-days prior experience caring for vocalizing pups. Estradiol and pup experience interacted both in the induction of c-Fos-IR in the LC, as well as in behavioral measures of locomotion during playback, consistent with the neuromodulatory center's activity being an online reflection of both hormonal and experience-dependent influences on arousal. Throughout core AC, as well as in a high frequency sub-region of AC and in secondary AC, a main effect of pup experience was to reduce call-induced c-Fos-IR, irrespective of estradiol availability. This is consistent with the hypothesis that sound familiarity leads to less c-Fos-mediated plasticity, and less disrupted sensory representations of a meaningful call category. Taken together, our data support the view that any coupling between these sensory and neuromodulatory areas is situationally dependent, and their engagement depends differentially on both internal state factors like hormones and external state factors like prior experience.

Low serum sodium levels at hospital admission: Outcomes among 2.3 million hospitalized patients.

BACKGROUND: Hyponatremia is the most common electrolyte disorder among hospitalized patients. Controversies still exist over the relationship between hyponatremia and outcomes of hospitalized patients. METHODS: To analyze the association of low serum sodium levels at hospital admission with in-hospital mortality and patient disposition and to compare the distribution of the risk of death associated with hyponatremia across the lifespan of hospitalized patients, we conducted an observational study of 2.3 million patients using data extracted from the Cerner Health Facts database between 2000 and 2014. Logistic regression models were used in the analyses. RESULTS: At hospital admission 14.4% of hospitalized patients had serum sodium levels [Na] <135 mEq/L. In adjusted multinomial logistic regression analysis, we found that the risk of in-hospital mortality significantly increases for [Na] levels < 135 or ≥143 to ≤145 mEq/L compared to the reference interval of 140 to <143 mEq/L (p<0.001). We observed similar trends for the relationship between [Na] levels and discharge to hospice or to a nursing facility. We demonstrated that younger age groups (18 to <45, 45 to <65) had a higher risk of in-hospital mortality compared to older age groups (65 to <75, ≥75) for [Na] levels <130 mEq/L or 143 to ≤145 mEq/L (p<0.001). CONCLUSIONS: Hyponatremia is common among hospitalized patients and is significantly associated with in-hospital mortality, discharge to hospice or to a nursing facility. The risk of death and other outcomes was more evident for [Na] <135 mEq/L. The mortality associated with low [Na] was significantly higher in younger versus older patients.

Infrequent Provision of Palliative Care to Patients with Dialysis-Requiring AKI.

BACKGROUND AND OBJECTIVES: The use of palliative care in AKI is not well described. We sought to better understand palliative care practice patterns for hospitalized patients with AKI requiring dialysis in the United States. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using the 2012 National Inpatient Sample, we identified patients with AKI and palliative care encounters using validated International Classification of Diseases, Ninth Revision, Clinical Modification codes. We compared palliative care encounters in patients with AKI requiring dialysis, patients with AKI not requiring dialysis, and patients without AKI. We described the provision of palliative care in patients with AKI requiring dialysis and compared the frequency of palliative care encounters for patients with AKI requiring dialysis with that for patients with other illnesses with similarly poor prognoses. We used logistic regression to determine factors associated with the provision of palliative care, adjusting for demographics, hospital-level variables, and patient comorbidities. RESULTS: We identified 3,031,036 patients with AKI, of whom 91,850 (3%) received dialysis. We observed significant patient- and hospital-level differences in the provision of palliative care for patients with AKI requiring dialysis; adjusted odds were 26% (95% confidence interval, 12% to 38%) lower in blacks and 23% (95% confidence interval, 3% to 39%) lower in Hispanics relative to whites. Lower provision of palliative care was observed for rural and urban nonteaching hospitals relative to urban teaching hospitals, small and medium hospitals relative to large hospitals, and hospitals in the Northeast compared with the South. After adjusting for age and sex, there was low utilization of palliative care services for patients with AKI requiring dialysis (8%)-comparable with rates of utilization by patients with other illnesses with poor prognosis, including cardiogenic shock (9%), intracranial hemorrhage (10%), and acute respiratory distress syndrome (10%). CONCLUSIONS: The provision of palliative care varied widely by patient and facility characteristics. Palliative care was infrequently used in hospitalized patients with AKI requiring dialysis, despite its poor prognosis and the regular application of life-sustaining therapy.

P-REX1 amplification promotes progression of cutaneous melanoma via the PAK1/P38/MMP-2 pathway.

P-REX1 (PIP3-dependent Rac exchange factor-1) is a guanine nucleotide exchange factor that activates Rac by catalyzing exchange of GDP for GTP bound to Rac. Aberrant up-regulation of P-REX1 expression has a role in metastasis however, copy number (CN) and function of P-REX1 in cutaneous melanoma are unclear. To explore the role of P-REX1 in melanoma, SNP 6.0 and Exon 1.0 ST microarrays were assessed. There was a higher CN (2.82-fold change) of P-REX1 in melanoma cells than in melanocytes, and P-REX1 expression was significantly correlated with P-REX1 CN. When P-REX1 was knocked down in cells by P-REX1 shRNA, proliferation, colony formation, 3D matrigel growth, and migration/invasiveness were inhibited. Loss of P-REX1 inhibited cell proliferation by inhibiting cyclin D1, blocking cell cycle, and increased cell apoptosis by reducing expression of the protein survivin. Knockdown of P-REX1 expression inhibited cell migration/invasiveness by disrupting P-REX1/RAC1/PAK1/p38/MMP-2 pathway. Assessment of patient tumors and disease outcome demonstrated lower distant metastasis-free survival among AJCC stage I/II/III patients with high P-REX1 expression compared to patients with low P-REX1 expression. These results suggest P-REX1 plays an important role in tumor progression and a potential theranostic target.

Risk for Overall Infection with Anti-TNF and Anti-integrin Agents Used in IBD: A Systematic Review and Meta-analysis.

BACKGROUND: The overall risk for infection with contemporary biological agents in treating Crohn's disease (CD) and ulcerative colitis (UC) has not been systematically assessed. METHODS: We performed a PubMed and Cochrane database literature search to evaluate randomized, placebo-controlled trials of biologics in treating UC and CD. Meta-analysis was performed using a DerSimonian and Laird random effects model. We determined relative risk (RR) of harm against placebo; number needed to harm (NNH) was reported when appropriate. Heterogeneity and publication bias were assessed. RESULTS: Fourteen trials (6 UC and 8 CD) evaluating 5107 patients were included. For anti-tumor necrosis factor agents used in the treatment of UC, golimumab {NNH of 9.3, RR = 1.4 (95% confidence interval [CI], 1.04-1.8)} and pooled studies of infliximab and adalimumab (NNH = 17.2, RR = 1.2 [95% CI, 1.0-1.3]) had a statistically significant higher risk for any infection versus placebo. Risk was not significantly increased in anti-tumor necrosis factor trials in CD (RR = 1.1 [95% CI, 0.8-1.5]). By contrast, anti-integrin agents in UC (RR = 1.0 [95% CI, 0.9-1.2]) or CD (RR = 1.1 [95% CI, 0.97-1.3]) did not confer a statistically significant excess risk of infection versus placebo. CONCLUSIONS: Anti-tumor necrosis factor therapy but not anti-integrin therapy is associated with a greater infection risk than placebo in treating UC. Neither class of therapy is associated with increased infection risk over placebo in treating CD. Our findings can help guide patient-centered discussions regarding the risk for infection with biological agents.

Why does quality of life remain an under-investigated issue in chronic kidney disease and why is it rarely set as an outcome measure in trials in this population?

The growing importance of quality of life (QoL) measures in health care is reflected by the increased volume and rigor of published research on this topic. The ability to measure and assess patients' experience of symptoms and functions has transformed the development of disease treatments and interventions. However, QoL remains an under-investigated issue in chronic kidney disease (CKD) and is seldom set as an outcome measure in trials in this population. In this article, we present various challenges in using patient-reported outcome (PRO) end points in CKD trials. We outline the need for additional research to examine more closely patient experiences with specific kidney disease symptoms and conditions, as well as caregiver perspectives of patients' symptom burden and end-of-life experiences. These efforts will better guide the development or enhancement of PRO instruments that can be used in clinical trials to more effectively assess treatment benefit, and improve therapy and care. Better understanding of health-related QoL issues would enable providers to deliver more patient-centered care and improve the overall well-being of patients. Even small improvements in QoL could have a large impact on the population's overall health and disease burden.

Contrast Enhancement without Transient Map Expansion for Species-Specific Vocalizations in Core Auditory Cortex during Learning.

Tonotopic map plasticity in the adult auditory cortex (AC) is a well established and oft-cited measure of auditory associative learning in classical conditioning paradigms. However, its necessity as an enduring memory trace has been debated, especially given a recent finding that the areal expansion of core AC tuned to a newly relevant frequency range may arise only transiently to support auditory learning. This has been reinforced by an ethological paradigm showing that map expansion is not observed for ultrasonic vocalizations (USVs) or for ultrasound frequencies in postweaning dams for whom USVs emitted by pups acquire behavioral relevance. However, whether transient expansion occurs during maternal experience is not known, and could help to reveal the generality of cortical map expansion as a correlate for auditory learning. We thus mapped the auditory cortices of maternal mice at postnatal time points surrounding the peak in pup USV emission, but found no evidence of frequency map expansion for the behaviorally relevant high ultrasound range in AC. Instead, regions tuned to low frequencies outside of the ultrasound range show progressively greater suppression of activity in response to the playback of ultrasounds or pup USVs for maternally experienced animals assessed at their pups' postnatal day 9 (P9) to P10, or postweaning. This provides new evidence for a lateral-band suppression mechanism elicited by behaviorally meaningful USVs, likely enhancing their population-level signal-to-noise ratio. These results demonstrate that tonotopic map enlargement has limits as a construct for conceptualizing how experience leaves neural memory traces within sensory cortex in the context of ethological auditory learning.

The lack of documentation of preferences in a cohort of adults who died after ischemic stroke.

OBJECTIVE: To measure the extent and timing of physicians' documentation of communication with patients and families regarding limitations on life-sustaining interventions, in a population cohort of adults who died within 30 days after hospitalization for ischemic stroke. METHODS: We used the California Office of Statewide Health Planning and Development Patient Discharge Database to identify a retrospective cohort of adults with ischemic strokes at all California acute care hospitals from December 2006 to November 2007. Of 326 eligible hospitals, a representative sample of 39 was selected, stratified by stroke volume and mortality. Medical records of 981 admissions were abstracted, oversampled on mortality and tissue plasminogen activator receipt. Among 198 patients who died by 30 days postadmission, overall proportions and timing of documented preferences were calculated; factors associated with documentation were explored. RESULTS: Of the 198 decedents, mean age was 80 years, 78% were admitted from home, 19% had mild strokes, 11% received tissue plasminogen activator, and 42% died during the index hospitalization. Preferences about at least one life-sustaining intervention were recorded on 39% of patients: cardiopulmonary resuscitation 34%, mechanical ventilation 23%, nasogastric tube feeding 10%, and percutaneous enteral feeding 6%. Most discussions occurred within 5 days of death. Greater stroke severity was associated with increased in-hospital documentation of preferences (p < 0.05). CONCLUSIONS: Documented discussions about limitations on life-sustaining interventions during hospitalization were low, even though this cohort died within 30 days poststroke. Improving the documentation of preferences may be difficult given the 2015 Centers for Medicare and Medicaid 30-day stroke mortality hospital performance measure that is unadjusted for patient preferences regarding life-sustaining interventions.

Evaluating Study Withdrawal Among Biologics and Immunomodulators in Treating Ulcerative Colitis: A Meta-analysis of Controlled Clinical Trials.

BACKGROUND: We conducted a systematic review and meta-analysis to evaluate the efficacy and adverse event (AE)-associated tolerability of treatment with immunomodulators and biologics in ulcerative colitis clinical trials. METHODS: We performed a literature search of PubMed and the Cochrane databases to identify randomized placebo-controlled trials of immunomodulators and biologics. Tolerability was defined through study withdrawal due to AEs and efficacy through clinical response in induction trials and clinical remission in maintenance trials. We performed meta-analyses using a random-effects model to determine relative risks (RRs) of efficacy and study withdrawal. Number needed to treat (NNT) and number needed to stop (NNS) were determined. The ratio of NNS/NNT was calculated, with a higher ratio indicating a greater number of patients in remission for every AE study discontinuation. RESULTS: We examined 13 single-agent trials representing biologics (infliximab, adalimumab, golimumab, and vedolizumab) and immunomodulators (tacrolimus and azathioprine). Induction therapy did not result in excess study withdrawal with immunomodulators (RR = 0.9, 95% CI 0.1-12.0) or biologics (RR = 0.7, 95% CI 0.3-1.8), therefore the NNS/NNT ratio could not be assessed because of high tolerability. Maintenance immunomodulator therapy resulted in a NNS of 14 (RR = 2.8, 95% CI 0.7-10.5) and NNS/NNT ratio of 2.4 in 2 trials. Biologics did not result in excess study withdrawal in maintenance (RR = 0.7, 95% CI 0.3-1.7) or combined induction-and-maintenance (RR = 0.6, 95% CI 0.4-1.0) trials. CONCLUSIONS: Biologics were not associated with a higher RR of study withdrawal due to AE than placebo. There were insufficient data to compare these results with immunomodulators.

A Systematic Review of Family Meeting Tools in Palliative and Intensive Care Settings.

PURPOSE: Family meetings can be challenging, requiring a range of skills and participation. We sought to identify tools available to aid the conduct of family meetings in palliative, hospice, and intensive care unit settings. METHODS: We systematically reviewed PubMed for articles describing family meeting tools and abstracted information on tool type, usage, and content. RESULTS: We identified 16 articles containing 23 tools in 7 categories: meeting guide (n = 8), meeting planner (n = 5), documentation template (n = 4), meeting strategies (n = 2), decision aid/screener (n = 2), family checklist (n = 1), and training module (n = 1). We found considerable variation across tools in usage and content and a lack of tools supporting family engagement. CONCLUSION: There is need to standardize family meeting tools and develop tools to help family members effectively engage in the process.

The CASC15 Long Intergenic Noncoding RNA Locus Is Involved in Melanoma Progression and Phenotype Switching.

In recent years, considerable advances have been made in the characterization of protein-coding alterations involved in the pathogenesis of melanoma. However, despite their growing implication in cancer, little is known about the role of long noncoding RNAs in melanoma progression. We hypothesized that copy number alterations (CNAs) of intergenic nonprotein-coding domains could help identify long intergenic noncoding RNAs (lincRNAs) associated with metastatic cutaneous melanoma. Among several candidates, our approach uncovered the chromosome 6p22.3 CASC15 (cancer susceptibility candidate 15) lincRNA locus as a frequently gained genomic segment in metastatic melanoma tumors and cell lines. The locus was actively transcribed in metastatic melanoma cells, and upregulation of CASC15 expression was associated with metastatic progression to brain metastasis in a mouse xenograft model. In clinical specimens, CASC15 levels increased during melanoma progression and were independent predictors of disease recurrence in a cohort of 141 patients with AJCC (American Joint Committee on Cancer) stage III lymph node metastasis. Moreover, small interfering RNA (siRNA) knockdown experiments revealed that CASC15 regulates melanoma cell phenotype switching between proliferative and invasive states. Accordingly, CASC15 levels correlated with known gene signatures corresponding to melanoma proliferative and invasive phenotypes. These findings support a key role for CASC15 in metastatic melanoma.

Patients with Crohn's Disease Are More Likely to Remain on Biologics than Immunomodulators: A Meta-Analysis of Treatment Durability.

BACKGROUND AND AIM: The comparative effectiveness of treatments for moderate-to-severe Crohn's disease can be influenced by the likelihood of remaining on medication. We aimed to clarify this treatment durability by assessing subject discontinuations from clinical trials in the context of treatment efficacy. METHODS: We conducted a literature search for double-blind RCT of Crohn's disease therapies recommended in international guidelines or with recent positive phase III trial results. Durability was defined through study discontinuation due to adverse events or disease exacerbation represented by number needed to discontinue (NND). Efficacy was defined as clinical remission represented by number needed to treat (NNT). The primary endpoint was NND/NNT, with a higher value representing more durable and effective treatment. RESULTS: Treatment with azathioprine/6-mercaptopurine (AZA/6MP) was associated with more discontinuations than with clinical remission (NND/NNT = 0.92) in maintenance trials. For induction, methotrexate was associated with similar rates of discontinuations and remission (NND/NNT = 1.4). In one maintenance trial, the remission rate for methotrexate was greater than the study discontinuation rate (NND/NNT = 23.3). In contrast, anti-TNF trials revealed greater durability among induction (no excess discontinuation) and maintenance (NND/NNT = 37.9) trials. Trials of anti-trafficking agents had fewer discontinuations in the drug treatment arms than placebo resulting in most favorable NND/NNT ratios. CONCLUSIONS: For patients with Crohn's disease, biologic therapies had higher durability than immunomodulators for induction and maintenance therapy. We also report the results of a novel NND/NNT ratio that should be validated in a prospective head-to-head placebo-controlled trial.

A direct plasma assay of circulating microRNA-210 of hypoxia can identify early systemic metastasis recurrence in melanoma patients.

Circulating cell-free(cf) microRNAs (miRNAs) have been reported to exist in plasma. MicroRNA-210(miR-210) is known to play important roles in the tumor hypoxic state. We hypothesized that the expression levels of cf-miR-210 in plasma would predict early clinical recurrence in melanoma patients. A direct miRNA assay on plasma (RT-qPCR-DP) was developed to improve cf-miRNA assay logistics, eliminate RNA extraction, and reduce specimen amount required. RNA was extracted from formalin-fixed paraffin-embedded (FFPE) melanoma tissues (n = 108) and assessed by RT-qPCR. Plasma (10 µl; n = 264) was procured from AJCC Stage III/IV patients in phase III clinical trials. A RT-qPCR-DP was performed to detect cf-miR-210. MiR-210 was significantly higher in metastatic tumors compared to primary tumors. Cf-miR-210 was significantly higher in melanoma patients versus healthy donor controls. In serial bloods within individual patients, cf-miR-210 < 3 months prior to disease recurrence significantly increased compared to baseline levels (p = 0.012). ROC curve analysis demonstrated that patients with elevated cf-miR-210 were more likely to have disease recurrence. Moreover, cf-miR-210 increase significantly correlated with poorer prognosis (p < 0.001). Lactate dehydrogenase (LDH) level was also assessed within patients, and the AIC values for proportional hazards regression models of cf-miR-210(120.01) and LDH (122.91) demonstrated that cf-miR-210 is a better recurrence indicator. We concluded enhanced cf-miR-210 provides identification of early systemic melanoma recurrence.

Behavioral relevance helps untangle natural vocal categories in a specific subset of core auditory cortical pyramidal neurons.

Sound categorization is essential for auditory behaviors like acoustic communication, but its genesis within the auditory pathway is not well understood-especially for learned natural categories like vocalizations, which often share overlapping acoustic features that must be distinguished (e.g., speech). We use electrophysiological mapping and single-unit recordings in mice to investigate how representations of natural vocal categories within core auditory cortex are modulated when one category acquires enhanced behavioral relevance. Taking advantage of a maternal mouse model of acoustic communication, we found no long-term auditory cortical map expansion to represent a behaviorally relevant pup vocalization category-contrary to expectations from the cortical plasticity literature on conditioning with pure tones. Instead, we observed plasticity that improved the separation between acoustically similar pup and adult vocalization categories among a physiologically defined subset of late-onset, putative pyramidal neurons, but not among putative interneurons. Additionally, a larger proportion of these putative pyramidal neurons in maternal animals compared with nonmaternal animals responded to the individual pup call exemplars having combinations of acoustic features most typical of that category. Together, these data suggest that higher-order representations of acoustic categories arise from a subset of core auditory cortical pyramidal neurons that become biased toward the combination of acoustic features statistically predictive of membership to a behaviorally relevant sound category.