Institutional Usage of Ferric Pyrophosphate Citrate (FPC) Delivered Via Dialysate in Reducing Erythropoiesis Stimulating Agents (ESAs) and IV Iron Cost.

Dialysis patients are often iron deficient due to a multiple factors. Ferric pyrophosphate citrate is a complex iron salt that can be given via dialysate allowing maintenance of hemoglobin (Hgb) concentration and iron balance while reducing the need for IV iron. The purpose of this study is to perform a cost evaluation of FPC and the effect it has on lowering the dose/use of ESAs and IV iron therapy. This study reviewed the same 100 hemodialysis patient's charts before and after the use of FPC. The data points that were collected and analyzed are as follows: hemoglobin, ferritin levels, average weekly ESA dosing, and IV iron replacement therapy dose. Out of 100 patients, there was no statistical difference in the average hemoglobin, ferritin, and iron saturation levels observed in the patients before and after FPC use. The average weekly dose of darbepoetin alfa per patient was 52.74 µg before the FPC group compared to 39.27 µg in the post FPC group (P < .0001). The total dose of ferric gluconate per patient was 3290.01 mg in the before FPC group and 585.60 mg in the post FPC group (P < .0001). The average total iron sucrose dose per patient in the before FPC group was 3097.92 mg versus 1216.67 mg in the post FPC group (P < .1563). When comparing FPC's cost and implementation into both of our outpatient dialysis centers, this yielded a net savings of $296 751.49.

Assessment of Safety of Remdesivir in Covid - 19 Patients with Estimated Glomerular Filtration Rate (eGFR) < 30 ml/min per 1.73†m2.

PURPOSE: Safety of remdesivir in patients with renal impairment is unknown. Incidence of liver injury secondary to remdesivir is also unknown. The objective of this study is to assess the incidence of acute kidney injury (AKI) and to trend the liver enzymes during remdesivir treatment and change in eGFR from baseline to end of treatment as well as 48 h post completion of remdesivir therapy. METHODS: This is a retrospective chart review study including adult patients admitted with COVID-19 receiving remdesivir with a baseline eGFR < 30 ml/min per 1.73 m^2 from December 2020 to May 2021. The primary outcome was to assess the incidence of AKI and hepatic injury. The secondary outcome was to assess the efficacy of remdesivir defined by change in oxygen requirement. RESULTS: Seventy-one patients were included in the study. Patients experienced an improvement in eGFR from baseline (T0) to end of remdesivir treatment (T1), as well as 48 h after the end of the treatment (T2) ( + 30.3% and + 30.6% respectively, P < .0001). Creatinine reduced from baseline (T0) to T1 and T2 (-20.9% and -20.5% respectively, P < .0001). Creatinine clearance improved from baseline to T1 and T2 ( + 26.6% and + 26.2% respectively, p < .0001). Elevation of aminotransferase (AST) was observed at T1 ( + 2.5%, P = .727), however, AST reduction was seen at T2 (-15.8%, P = .021). Elevation in alanine transaminase (ALT) was observed at T1 and T2 ( + 25% and + 12%, P = .004 and P = .137 respectively). Both direct and total bilirubin remained stable and were not significantly changed from baseline. CONCLUSION: Our study showed that remdesivir use in renally-impaired patients with eGFR < 30 ml/min is safe. Remdesivir may be considered as a therapeutic option in this population with COVID-19 infection.

Temporally precise population coding of dynamic sounds by auditory cortex.

Fluctuations in the amplitude envelope of complex sounds provide critical cues for hearing, particularly for speech and animal vocalizations. Responses to amplitude modulation (AM) in the ascending auditory pathway have chiefly been described for single neurons. How neural populations might collectively encode and represent information about AM remains poorly characterized, even in primary auditory cortex (A1). We modeled population responses to AM based on data recorded from A1 neurons in awake squirrel monkeys and evaluated how accurately single trial responses to modulation frequencies from 4 to 512 Hz could be decoded as functions of population size, composition, and correlation structure. We found that a population-based decoding model that simulated convergent, equally weighted inputs was highly accurate and remarkably robust to the inclusion of neurons that were individually poor decoders. By contrast, average rate codes based on convergence performed poorly; effective decoding using average rates was only possible when the responses of individual neurons were segregated, as in classical population decoding models using labeled lines. The relative effectiveness of dynamic rate coding in auditory cortex was explained by shared modulation phase preferences among cortical neurons, despite heterogeneity in rate-based modulation frequency tuning. Our results indicate significant population-based synchrony in primary auditory cortex and suggest that robust population coding of the sound envelope information present in animal vocalizations and speech can be reliably achieved even with indiscriminate pooling of cortical responses. These findings highlight the importance of firing rate dynamics in population-based sensory coding.NEW & NOTEWORTHY Fundamental questions remain about population coding in primary auditory cortex (A1). In particular, issues of spike timing in models of neural populations have been largely ignored. We find that spike-timing in response to sound envelope fluctuations is highly similar across neuron populations in A1. This property of shared envelope phase preference allows for a simple population model involving unweighted convergence of neuronal responses to classify amplitude modulation frequencies with high accuracy.

Extracellular voltage thresholds for maximizing information extraction in primate auditory cortex: implications for a brain computer interface.

Objective. Research by Oby (2016J. Neural. Eng.13036009) demonstrated that the optimal threshold for extracting information from visual and motor cortices may differ from the optimal threshold for identifying single neurons via spike sorting methods. The optimal threshold for extracting information from auditory cortex has yet to be identified, nor has the optimal temporal scale for representing auditory cortical activity. Here, we describe a procedure to jointly optimize the extracellular threshold and bin size with respect to the decoding accuracy achieved by a linear classifier for a diverse set of auditory stimuli.Approach. We used linear multichannel arrays to record extracellular neural activity from the auditory cortex of awake squirrel monkeys passively listening to both simple and complex sounds. We executed a grid search of the coordinate space defined by the voltage threshold (in units of standard deviation) and the bin size (in units of milliseconds), and computed decoding accuracy at each point.Main results. The optimal threshold for information extraction was consistently near two standard deviations below the voltage trace mean, which falls significantly below the range of three to five standard deviations typically used as inputs to spike sorting algorithms in basic research and in brain-computer interface (BCI) applications. The optimal binwidth was minimized at the optimal voltage threshold, particularly for acoustic stimuli dominated by temporally dynamic features, indicating that permissive thresholding permits readout of cortical responses with temporal precision on the order of a few milliseconds.Significance. The improvements in decoding accuracy we observed for optimal readout parameters suggest that standard thresholding methods substantially underestimate the information present in auditory cortical spiking patterns. The fact that optimal thresholds were relatively low indicates that local populations of cortical neurons exhibit high temporal coherence that could be leveraged in service of future auditory BCI applications.

Amplitude modulation coding in awake mice and squirrel monkeys.

Both mice and primates are used to model the human auditory system. The primate order possesses unique cortical specializations that govern auditory processing. Given the power of molecular and genetic tools available in the mouse model, it is essential to understand the similarities and differences in auditory cortical processing between mice and primates. To address this issue, we directly compared temporal encoding properties of neurons in the auditory cortex of awake mice and awake squirrel monkeys (SQMs). Stimuli were drawn from a sinusoidal amplitude modulation (SAM) paradigm, which has been used previously both to characterize temporal precision and to model the envelopes of natural sounds. Neural responses were analyzed with linear template-based decoders. In both species, spike timing information supported better modulation frequency discrimination than rate information, and multiunit responses generally supported more accurate discrimination than single-unit responses from the same site. However, cortical responses in SQMs supported better discrimination overall, reflecting superior temporal precision and greater rate modulation relative to the spontaneous baseline and suggesting that spiking activity in mouse cortex was less strictly regimented by incoming acoustic information. The quantitative differences we observed between SQM and mouse cortex support the idea that SQMs offer advantages for modeling precise responses to fast envelope dynamics relevant to human auditory processing. Nevertheless, our results indicate that cortical temporal processing is qualitatively similar in mice and SQMs and thus recommend the mouse model for mechanistic questions, such as development and circuit function, where its substantial methodological advantages can be exploited. NEW & NOTEWORTHY To understand the advantages of different model organisms, it is necessary to directly compare sensory responses across species. Contrasting temporal processing in auditory cortex of awake squirrel monkeys and mice, with parametrically matched amplitude-modulated tone stimuli, reveals a similar role of timing information in stimulus encoding. However, disparities in response precision and strength suggest that anatomical and biophysical differences between squirrel monkeys and mice produce quantitative but not qualitative differences in processing strategy.

Cluster-based analysis improves predictive validity of spike-triggered receptive field estimates.

Spectrotemporal receptive field (STRF) characterization is a central goal of auditory physiology. STRFs are often approximated by the spike-triggered average (STA), which reflects the average stimulus preceding a spike. In many cases, the raw STA is subjected to a threshold defined by gain values expected by chance. However, such correction methods have not been universally adopted, and the consequences of specific gain-thresholding approaches have not been investigated systematically. Here, we evaluate two classes of statistical correction techniques, using the resulting STRF estimates to predict responses to a novel validation stimulus. The first, more traditional technique eliminated STRF pixels (time-frequency bins) with gain values expected by chance. This correction method yielded significant increases in prediction accuracy, including when the threshold setting was optimized for each unit. The second technique was a two-step thresholding procedure wherein clusters of contiguous pixels surviving an initial gain threshold were then subjected to a cluster mass threshold based on summed pixel values. This approach significantly improved upon even the best gain-thresholding techniques. Additional analyses suggested that allowing threshold settings to vary independently for excitatory and inhibitory subfields of the STRF resulted in only marginal additional gains, at best. In summary, augmenting reverse correlation techniques with principled statistical correction choices increased prediction accuracy by over 80% for multi-unit STRFs and by over 40% for single-unit STRFs, furthering the interpretational relevance of the recovered spectrotemporal filters for auditory systems analysis.

Effects of Signal-to-Noise Ratio on Auditory Cortical Frequency Processing.

The neural mechanisms that support the robust processing of acoustic signals in the presence of background noise in the auditory system remain largely unresolved. Psychophysical experiments have shown that signal detection is influenced by the signal-to-noise ratio (SNR) and the overall stimulus level, but this relationship has not been fully characterized. We evaluated the neural representation of frequency in rat primary auditory cortex by constructing tonal frequency response areas (FRAs) in primary auditory cortex for different SNRs, tone levels, and noise levels. We show that response strength and selectivity for frequency and sound level depend on interactions between SNRs and tone levels. At low SNRs, jointly increasing the tone and noise levels reduced firing rates and narrowed FRA bandwidths; at higher SNRs, however, increasing the tone and noise levels increased firing rates and expanded bandwidths, as is usually seen for FRAs obtained without background noise. These changes in frequency and intensity tuning decreased tone level and tone frequency discriminability at low SNRs. By contrast, neither response onset latencies nor noise-driven steady-state firing rates meaningfully interacted with SNRs or overall sound levels. Speech detection performance in humans was also shown to depend on the interaction between overall sound level and SNR. Together, these results indicate that signal processing difficulties imposed by high noise levels are quite general and suggest that the neurophysiological changes we see for simple sounds generalize to more complex stimuli. SIGNIFICANCE STATEMENT: Effective processing of sounds in background noise is an important feature of the mammalian auditory system and a necessary feature for successful hearing in many listening conditions. Even mild hearing loss strongly affects this ability in humans, seriously degrading the ability to communicate. The mechanisms involved in achieving high performance in background noise are not well understood. We investigated the effects of SNR and overall stimulus level on the frequency tuning of neurons in rat primary auditory cortex. We found that the effects of noise on frequency selectivity are not determined solely by the SNR but depend also on the levels of the foreground tones and background noise. These observations can lead to improvement in therapeutic approaches for hearing-impaired patients.

Modulation-frequency-specific adaptation in awake auditory cortex.

Amplitude modulations are fundamental features of natural signals, including human speech and nonhuman primate vocalizations. Because natural signals frequently occur in the context of other competing signals, we used a forward-masking paradigm to investigate how the modulation context of a prior signal affects cortical responses to subsequent modulated sounds. Psychophysical "modulation masking," in which the presentation of a modulated "masker" signal elevates the threshold for detecting the modulation of a subsequent stimulus, has been interpreted as evidence of a central modulation filterbank and modeled accordingly. Whether cortical modulation tuning is compatible with such models remains unknown. By recording responses to pairs of sinusoidally amplitude modulated (SAM) tones in the auditory cortex of awake squirrel monkeys, we show that the prior presentation of the SAM masker elicited persistent and tuned suppression of the firing rate to subsequent SAM signals. Population averages of these effects are compatible with adaptation in broadly tuned modulation channels. In contrast, modulation context had little effect on the synchrony of the cortical representation of the second SAM stimuli and the tuning of such effects did not match that observed for firing rate. Our results suggest that, although the temporal representation of modulated signals is more robust to changes in stimulus context than representations based on average firing rate, this representation is not fully exploited and psychophysical modulation masking more closely mirrors physiological rate suppression and that rate tuning for a given stimulus feature in a given neuron's signal pathway appears sufficient to engender context-sensitive cortical adaptation.

Representation of loudness in the auditory cortex.

Changes in stimulus intensity are reflected in changes in the fundamental perceptual attribute of loudness. Stimulus intensity changes also profoundly impact the evoked neural responses throughout the auditory system. A fundamental question is how measurements of neural activity, from the single-neuron level to mass-activity metrics such as functional magnetic resonance imaging or magnetoencephalography, reflect the physical properties of stimulus intensity as opposed to perceived loudness. In this chapter we discuss findings from psychophysics and animal neurophysiology as well as human brain activity measurements to clarify our current understanding of the neural mechanisms that contribute to the perceptual correlate of stimulus intensity.

Possible hepatotoxicity associated with intravenous acetaminophen in a 36-year-old female patient.

We present a case of a 36-year-old female who came into the emergency department with right-side abdominal pain. She went to the operating room for a diagnostic laparoscopy and appendectomy. She received intravenous (IV) acetaminophen every six hours both preoperatively and postoperatively for pain control. The patient's aspartate aminotransferase and alanine aminotransferase levels were elevated and peaked at 4,833 and 6,600 IU/L, respectively, from baselines of 14 and 15, respectively, while she was receiving 16 doses of IV acetaminophen. The patient was transferred to a regional liver transplant center for evaluation for a transplant. She was treated with IV N-acetylcysteine and discharged with a normal liver-function test without a transplant. This case report supports the possibility of hepatotoxicity associated with IV acetaminophen.

Diverse cortical codes for scene segmentation in primate auditory cortex.

The temporal coherence of amplitude fluctuations is a critical cue for segmentation of complex auditory scenes. The auditory system must accurately demarcate the onsets and offsets of acoustic signals. We explored how and how well the timing of onsets and offsets of gated tones are encoded by auditory cortical neurons in awake rhesus macaques. Temporal features of this representation were isolated by presenting otherwise identical pure tones of differing durations. Cortical response patterns were diverse, including selective encoding of onset and offset transients, tonic firing, and sustained suppression. Spike train classification methods revealed that many neurons robustly encoded tone duration despite substantial diversity in the encoding process. Excellent discrimination performance was achieved by neurons whose responses were primarily phasic at tone offset and by those that responded robustly while the tone persisted. Although diverse cortical response patterns converged on effective duration discrimination, this diversity significantly constrained the utility of decoding models referenced to a spiking pattern averaged across all responses or averaged within the same response category. Using maximum likelihood-based decoding models, we demonstrated that the spike train recorded in a single trial could support direct estimation of stimulus onset and offset. Comparisons between different decoding models established the substantial contribution of bursts of activity at sound onset and offset to demarcating the temporal boundaries of gated tones. Our results indicate that relatively few neurons suffice to provide temporally precise estimates of such auditory "edges," particularly for models that assume and exploit the heterogeneity of neural responses in awake cortex.

Encoding frequency contrast in primate auditory cortex.

Changes in amplitude and frequency jointly determine much of the communicative significance of complex acoustic signals, including human speech. We have previously described responses of neurons in the core auditory cortex of awake rhesus macaques to sinusoidal amplitude modulation (SAM) signals. Here we report a complementary study of sinusoidal frequency modulation (SFM) in the same neurons. Responses to SFM were analogous to SAM responses in that changes in multiple parameters defining SFM stimuli (e.g., modulation frequency, modulation depth, carrier frequency) were robustly encoded in the temporal dynamics of the spike trains. For example, changes in the carrier frequency produced highly reproducible changes in shapes of the modulation period histogram, consistent with the notion that the instantaneous probability of discharge mirrors the moment-by-moment spectrum at low modulation rates. The upper limit for phase locking was similar across SAM and SFM within neurons, suggesting shared biophysical constraints on temporal processing. Using spike train classification methods, we found that neural thresholds for modulation depth discrimination are typically far lower than would be predicted from frequency tuning to static tones. This "dynamic hyperacuity" suggests a substantial central enhancement of the neural representation of frequency changes relative to the auditory periphery. Spike timing information was superior to average rate information when discriminating among SFM signals, and even when discriminating among static tones varying in frequency. This finding held even when differences in total spike count across stimuli were normalized, indicating both the primacy and generality of temporal response dynamics in cortical auditory processing.

Spectral context affects temporal processing in awake auditory cortex.

Amplitude modulation encoding is critical for human speech perception and complex sound processing in general. The modulation transfer function (MTF) is a staple of auditory psychophysics, and has been shown to predict speech intelligibility performance in a range of adverse listening conditions and hearing impairments, including cochlear implant-supported hearing. Although both tonal and broadband carriers have been used in psychophysical studies of modulation detection and discrimination, relatively little is known about differences in the cortical representation of such signals. We obtained MTFs in response to sinusoidal amplitude modulation (SAM) for both narrowband tonal carriers and two-octave bandwidth noise carriers in the auditory core of awake squirrel monkeys. MTFs spanning modulation frequencies from 4 to 512 Hz were obtained using 16 channel linear recording arrays sampling across all cortical laminae. Carrier frequency for tonal SAM and center frequency for noise SAM was set at the estimated BF for each penetration. Changes in carrier type affected both rate and temporal MTFs in many neurons. Using spike discrimination techniques, we found that discrimination of modulation frequency was significantly better for tonal SAM than for noise SAM, though the differences were modest at the population level. Moreover, spike trains elicited by tonal and noise SAM could be readily discriminated in most cases. Collectively, our results reveal remarkable sensitivity to the spectral content of modulated signals, and indicate substantial interdependence between temporal and spectral processing in neurons of the core auditory cortex.

Transient receptor potential ankyrin 1 mediates chronic pancreatitis pain in mice.

Chronic pancreatitis (CP) is a devastating disease characterized by persistent and uncontrolled abdominal pain. Our lack of understanding is partially due to the lack of experimental models that mimic the human disease and also to the lack of validated behavioral measures of visceral pain. The ligand-gated cation channel transient receptor potential ankyrin 1 (TRPA1) mediates inflammation and pain in early experimental pancreatitis. It is unknown if TRPA1 causes fibrosis and sustained pancreatic pain. We induced CP by injecting the chemical agent trinitrobenzene sulfonic acid (TNBS), which causes severe acute pancreatitis, into the pancreatic duct of C57BL/6 trpa1(+/+) and trpa1(-/-) mice. Chronic inflammatory changes and pain behaviors were assessed after 2-3 wk. TNBS injection caused marked pancreatic fibrosis with increased collagen-staining intensity, atrophy, fatty replacement, monocyte infiltration, and pancreatic stellate cell activation, and these changes were reflected by increased histological damage scores. TNBS-injected animals showed mechanical hypersensitivity during von Frey filament probing of the abdomen, decreased daily voluntary wheel-running activity, and increased immobility scores during open-field testing. Pancreatic TNBS also reduced the threshold to hindpaw withdrawal to von Frey filament probing, suggesting central sensitization. Inflammatory changes and pain indexes were significantly reduced in trpa1(-/-) mice. In conclusion, we have characterized in mice a model of CP that resembles the human condition, with marked histological changes and behavioral measures of pain. We have demonstrated, using novel and objective pain measurements, that TRPA1 mediates inflammation and visceral hypersensitivity in CP and could be a therapeutic target for the treatment of sustained inflammatory abdominal pain.

Role of alvimopan (entereg) in gastrointestinal recovery and hospital length of stay after bowel resection.

PURPOSE: Postoperative ileus (POI) can delay gastrointestinal (GI) recovery after bowel resection. Alvimopan (Entereg), a peripherally acting mu-opioid receptor antagonist, is thought to favorably reduce various outcome measures such as the length of stay (LOS) and time from surgery to hospital discharge following partial-bowel, large-bowel, or small-bowel resection surgery with primary anastomosis. We undertook a study to compare these outcome measures in alvimopan-treated patients undergoing laparoscopic or open-bowel resection against a control group. We also sought to determine whether any other factors-Diagnosis-Related Group (DRG) status, complications, inflammatory bowel disease, type of surgery, age, sex, intestinal cancer, diverticular disease, number of chronic conditions, and operative time-were predictive of a more favorable (shorter) time to GI recovery. METHODS: Patients' charts were retrospectively reviewed at a large 591-bed teaching hospital in suburban New York City between June and August 2010. We applied descriptive statistics for five outcome variables to compare alvimopan-treated patients with non-users. The main outcome variable was the time from surgery to hospital discharge. Secondary outcome variables were the time to pass gas, time to a liquid diet, time to a solid diet, and total LOS. We compared the outcome variables for three groups of DRG codes (329, the most complicated cases; 330, intermediate; and 331, least complicated) to determine which variables influenced these outcome measures. Multivariate analysis with stepwise multiple linear regression analysis was performed to determine independent predictors of shorter times of outcome variables. RESULTS: Of 80 patients, 43 received alvimopan (53.75%), and 37 (46.25%) did not. The female-to-male ratio was about 50:50 (56.25% vs. 43.75%). The mean age (standard deviation) was 66.0 (14.9) years (range, 30-92 years). In the multivariate analysis (adjusted for demographics, DRG status, type of surgery, complications, comorbidities, and operative time), for all of our outcome variables (except for time to a liquid diet), patients receiving alvimopan had shorter times to GI recovery (about 25% less) than controls did (p < 0.05). DRG status, complications, inflammatory bowel disease, type of surgery, and age were also significantly predictive of one or more outcome variables, whereas sex, intestinal cancer, diverticular disease, the number of chronic conditions, and operative time were not predictive of any outcomes. CONCLUSION: GI recovery times were generally shorter for alvimopan-treated patients than for those who did not receive the study drug (P < 0.05). Alvimopan improved quality of life and reduced the cost of surgical care. This medication was considered to be a good choice for the perioperative management of patients requiring segmental bowel resection with primary anastomosis.

Transformation of temporal processing across auditory cortex of awake macaques.

The anatomy and connectivity of the primate auditory cortex has been modeled as a core region receiving direct thalamic input surrounded by a belt of secondary fields. The core contains multiple tonotopic fields (including the primary auditory cortex, AI, and the rostral field, R), but available data only partially address the degree to which those fields are functionally distinct. This report, based on single-unit recordings across four hemispheres in awake macaques, argues that the functional organization of auditory cortex is best understood in terms of temporal processing. Frequency tuning, response threshold, and strength of activation are similar between AI and R, validating their inclusion as a unified core, but the temporal properties of the fields clearly differ. Onset latencies to pure tones are longer in R (median, 33 ms) than in AI (20 ms); moreover, synchronization of spike discharges to dynamic modulations of stimulus amplitude and frequency, similar to those present in macaque and human vocalizations, suggest distinctly different windows of temporal integration in AI (20-30 ms) and R (100 ms). Incorporating data from the adjacent auditory belt reveals that the divergence of temporal properties within the core is in some cases greater than the temporal differences between core and belt.

Temporal codes for amplitude contrast in auditory cortex.

The encoding of sound level is fundamental to auditory signal processing, and the temporal information present in amplitude modulation is crucial to the complex signals used for communication sounds, including human speech. The modulation transfer function, which measures the minimum detectable modulation depth across modulation frequency, has been shown to predict speech intelligibility performance in a range of adverse listening conditions and hearing impairments, and even for users of cochlear implants. We presented sinusoidal amplitude modulation (SAM) tones of varying modulation depths to awake macaque monkeys while measuring the responses of neurons in the auditory core. Using spike train classification methods, we found that thresholds for modulation depth detection and discrimination in the most sensitive units are comparable to psychophysical thresholds when precise temporal discharge patterns rather than average firing rates are considered. Moreover, spike timing information was also superior to average rate information when discriminating static pure tones varying in level but with similar envelopes. The limited utility of average firing rate information in many units also limited the utility of standard measures of sound level tuning, such as the rate level function (RLF), in predicting cortical responses to dynamic signals like SAM. Response modulation typically exceeded that predicted by the slope of the RLF by large factors. The decoupling of the cortical encoding of SAM and static tones indicates that enhancing the representation of acoustic contrast is a cardinal feature of the ascending auditory pathway.

Representation of dynamic interaural phase difference in auditory cortex of awake rhesus macaques.

Neurons in auditory cortex of awake primates are selective for the spatial location of a sound source, yet the neural representation of the binaural cues that underlie this tuning remains undefined. We examined this representation in 283 single neurons across the low-frequency auditory core in alert macaques, trained to discriminate binaural cues for sound azimuth. In response to binaural beat stimuli, which mimic acoustic motion by modulating the relative phase of a tone at the two ears, these neurons robustly modulate their discharge rate in response to this directional cue. In accordance with prior studies, the preferred interaural phase difference (IPD) of these neurons typically corresponds to azimuthal locations contralateral to the recorded hemisphere. Whereas binaural beats evoke only transient discharges in anesthetized cortex, neurons in awake cortex respond throughout the IPD cycle. In this regard, responses are consistent with observations at earlier stations of the auditory pathway. Discharge rate is a band-pass function of the frequency of IPD modulation in most neurons (73%), but both discharge rate and temporal synchrony are independent of the direction of phase modulation. When subjected to a receiver operator characteristic analysis, the responses of individual neurons are insufficient to account for the perceptual acuity of these macaques in an IPD discrimination task, suggesting the need for neural pooling at the cortical level.

Warfarin pharmacogenomics.

Warfarin, an anticoagulant, is used to prevent and treat thromboembolic disease. One of the drawbacks of this agent, also known as Coumadin (Bristol-Myers Squibb), is that it is difficult to administer at the correct dose as a result of its narrow therapeutic index, its tendency to cause bleeding, and the individual variability in patient response. Achieving safe and effective doses of warfarin therapy is both an urgent and important concern for many clinicians.Recent research has focused on single-nucleotide polymorphisms (SNPs) of genes that encode two proteins: the cytochrome P450 2C9 enzyme and VKORC1 (vitamin K epoxide reductase complex). Studies suggest that CYP 2C9 influences warfarin metabolism, whereas VKORC1 plays a role in the pharmacodynamic response in expression of the enzymatic target of warfarin. Patients who carry CYP 2C9*2 and CYP 2C9*3 alleles tend to require lower warfarin maintenance doses because of their slowed metabolism compared with patients who carry the "wild-type" allele. Patients who carry the VKORC1 A haplotype tend to require lower wafarin maintenance doses as a result of a decreased expression of messenger RNA (mRNA), which produces the proteins necessary for the formation of VKORC1.