Refractive results with SMILE using lower energy settings in the United States.

PURPOSE: To report the visual and refractive results of small incision lenticule extraction (SMILE) with low energy settings in the United States (US) and to evaluate outcomes for low astigmatism treatment. SETTING: Private clinical practice. DESIGN: Retrospective cohort study. METHODS: This study retrospectively reviewed 462 consecutive eyes that underwent SMILE with lower energy settings. Inclusion criteria included all patients between the ages of 19-39 with myopic astigmatism up to -11.25 diopters (D) spherical equivalent (sphere up to -10.00 D, astigmatism up to -3.00 D), and corrected distance visual acuity of at least 20/25. Eyes with low astigmatism (0.25 D-0.50 D) were also included. Outcome analysis was performed according to the Standard Graphs for Reporting Refractive Surgery at postoperative month (POM) 1, and POM 3-6 when data were available. RESULTS: The mean preoperative spherical equivalent treated was -4.96 ± 2.07; at POM 1, 92% of eyes achieved uncorrected visual acuity (UCVA) of 20/20 or better and maintained visual stability throughout the remainder of the study. At last visit, 431 eyes (93%) achieved UCVA of 20/20 or better, and 461 eyes (99.8%) were 20/25 or better. Ninety-seven (21%) eyes gained at least 1 Snellen line of corrected distance visual acuity and no eyes lost 2 or more lines. Almost all eyes (n = 453, 98%) were within 0.5D of target; 85% of eyes with low astigmatism had ≤0.25 D at last visit compared to 80% of eyes with moderate astigmatism. CONCLUSIONS: SMILE with U.S.-approved low energy settings is safe, predictable, and efficacious and provides patients with a fast visual recovery.

Development and validation of a 4-color multiplexing spinal muscular atrophy (SMA) genotyping assay on a novel integrated digital PCR instrument.

Digital PCR (dPCR) technology has been proven to be highly sensitive and accurate in detecting copy number variations (CNV). However, a higher-order multiplexing dPCR assay for measuring SMN1 and SMN2 copy numbers in spinal muscular atrophy (SMA) samples has not been reported. Described here is a rapid multiplex SMA dPCR genotyping assay run on a fully integrated dPCR instrument with five optical channels. The hydrolysis probe-based multiplex dPCR assay quantifies SMN1, SMN2, and the total SMN (SMN1 + SMN2) while using RPPH1 gene as an internal reference control. The quadruplex assay was evaluated with characterized control DNA samples and validated with 15 blinded clinical samples from a previously published study. SMN1 and SMN2 copy numbers were completely concordant with previous results for both the control and blinded samples. The dPCR-based SMA copy number determination was accomplished in 90 min with a walk-away workflow identical to real-time quantitative PCR (qPCR). In summary, presented here is a simple higher-order multiplexing solution on a novel digital PCR platform to meet the growing demand for SMA genotyping and prognostics.

Safety of bloodless autologous stem cell transplantation in Jehovah's Witness patients.

Due to the curative potential and improvement in progression-free survival (PFS), high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is considered the standard of care for several hematologic malignancies, such as multiple myeloma, and lymphomas. ASCT typically involves support with blood product transfusion. Thus, difficulties arise when Jehovah's Witness patients refuse blood transfusions. In order to demonstrate the safety of performing "bloodless" ASCT (BL-ASCT), we performed a retrospective analysis of 66 Jehovah's Witnesses patients who underwent BL-ASCT and 1114 non-Jehovah's Witness patients who underwent transfusion-supported ASCT (TF-ASCT) at Cedars-Sinai Medical Center between January 2000 and September 2018. Survival was compared between the two groups. Transplant-related complications, mortality, engraftment time, length of hospital stay, and number of ICU transfers were characterized for the BL-ASCT group. One year survival was found to be 87.9% for both groups (P = 0.92). In the BL-ASCT group, there was one death prior to the 30 days post transplant due to CNS hemorrhage, and one death prior to 100 days due to sepsis. Based on our data, BL-ASCT can be safely performed with appropriate supportive measures, and we encourage community oncologists to promptly refer JW patients for transplant evaluation when ASCT is indicated.

Precision cancer monitoring using a novel, fully integrated, microfluidic array partitioning digital PCR platform.

A novel digital PCR (dPCR) platform combining off-the-shelf reagents, a micro-molded plastic microfluidic consumable with a fully integrated single dPCR instrument was developed to address the needs for routine clinical diagnostics. This new platform offers a simplified workflow that enables: rapid time-to-answer; low potential for cross contamination; minimal sample waste; all within a single integrated instrument. Here we showcase the capability of this fully integrated platform to detect and quantify non-small cell lung carcinoma (NSCLC) rare genetic mutants (EGFR T790M) with precision cell-free DNA (cfDNA) standards. Next, we validated the platform with an established chronic myeloid leukemia (CML) fusion gene (BCR-ABL1) assay down to 0.01% mutant allele frequency to highlight the platform's utility for precision cancer monitoring. Thirdly, using a juvenile myelomonocytic leukemia (JMML) patient-specific assay we demonstrate the ability to precisely track an individual cancer patient's response to therapy and show the patient's achievement of complete molecular remission. These three applications highlight the flexibility and utility of this novel fully integrated dPCR platform that has the potential to transform personalized medicine for cancer recurrence monitoring.

Artificial neural networks-based classification of emotions using wristband heart rate monitor data.

Heart rate variability (HRV) is an objective measure of emotional regulation. This study aimed to estimate the accuracy with which an artificial neural network (ANN) algorithm could classify emotions using HRV data that were obtained using wristband heart rate monitors.Four emotions were evoked during gameplay: pleasure, happiness, fear, and anger. Seven normalized HRV features (i.e., 3 time-domain features, 3 frequency-domain features, and heart rate), which yielded 29,727 segments during gameplay, were collected and analyzed first by statistics and then classified by the trained ANN model.General linear model adjusted for individual differences in HRV showed that all HRV features significantly differed across emotions, despite disparities in their magnitudes and associations. When compared to neutral status (i.e., no emotion evoked), the mean of R-R interval was significantly higher for pleasure and fear but lower for happiness and anger. In addition, pleasure evidenced the HRV features that suggested a superior parasympathetic to sympathetic activation. Happiness was associated with a prominent sympathetic activation. These statistical findings suggest that HRV features significantly differ across emotions evoked by gameplay. When further utilizing ANN-based emotion classification, the accuracy rates for prediction were above 75.0% across the 4 emotions with accuracy rates for classification of paired emotions ranging from 82.0% to 93.4%.For classifying emotion in an individual person, the trained ANN model utilizing HRV features yielded a high accuracy rate in our study. ANN is a time-efficient and accurate means to classify emotions using HRV data obtained from wristband heart rate monitors. Thus, this integrated platform can help monitor and quantify human emotions and physiological biometrics.

Favorable response to asthma-dosed subcutaneous mepolizumab in eosinophilic pneumonia.

Introduction: Mepolizumab targets eosinophils in the treatment of asthma. The dose used for asthma is considerably lower than that used for treating eosinophilic granulomatosis with polyangiitis, a recently approved indication. While intravenous mepolizumab use has reported utility in non-asthma eosinophilic disorders, the efficacy of the subcutaneous asthma dosing of the drug for eosinophilic pneumonia is not known. Case study: A middle-aged female was diagnosed with eosinophilic pneumonia. The patient's clinical/radiologic/laboratory findings, response to treatment, and respiratory function studies are described. Results: A woman, born in 1962, had repeated pneumonia hospitalizations from 2007 through 2010. In October 2010, a lung biopsy showed findings consistent with chronic eosinophilic pneumonia and chronic asthma. The patient also had chronic sinusitis. Long term systemic corticosteroids were prescribed but the patient became oxygen dependent by 2014. Omalizumab was administered for 1 year starting in 2015 without improvement in symptoms. In 2016, mepolizumab 100 mg subcutaneously every 4 weeks was initiated. Symptomatic improvement with decreased oxygen and systemic corticosteroid requirements were noted. A chest CT performed in February 2018 showed marked improvement compared to a study in 2016. Interval spirometric improvements were noted. Peripheral blood eosinophils/mm3 prior to mepolizumab were 237, and while on mepolizumab were 10. Conclusion: Parenchymal eosinophilic lung disease may respond to asthma-dosed mepolizumab. Mepolizumab treatment in asthma where concomitant interstitial disease is suspected, may offer an advantage over omalizumab in the ability to reduce eosinophils not only in airways, but also in lung parenchyma.

The Epidemiology of Anaphylaxis.

Anaphylaxis is a dramatic expression of systemic allergy. The lifetime prevalence of anaphylaxis is currently estimated at 0.05-2 % in the USA and ~3 % in Europe. Several population-specific studies have noted a rise in the incidence, particularly in the hospitalizations and ER visits due to anaphylaxis. The variable signs and symptoms that constitute the diagnostic criteria for anaphylaxis, the differences in diagnostic algorithms, and the limitations in the current coding systems have made summarizing epidemiologic data and comparing study results challenging. Nevertheless, across all studies, the most common triggers continue to be medications, food, and venom. Various risk factors for more severe reactions generally include older age, history of asthma, and having more comorbid diseases. Interesting seasonal, geographic, and latitude differences have been observed in anaphylaxis prevalence and incidence rates, suggesting a possible role of vitamin D and sun exposure in modifying anaphylaxis risk. While the incidence and prevalence of anaphylaxis appear to be increasing in certain populations, the overall fatality rate remains relatively low.

Fatal Anaphylaxis: Mortality Rate and Risk Factors.

Up to 5% of the US population has suffered anaphylaxis. Fatal outcome is rare, such that even for people with known venom or food allergy, fatal anaphylaxis constitutes less than 1% of total mortality risk. The incidence of fatal anaphylaxis has not increased in line with hospital admissions for anaphylaxis. Fatal drug anaphylaxis may be increasing, but rates of fatal anaphylaxis to venom and food are stable. Risk factors for fatal anaphylaxis vary according to cause. For fatal drug anaphylaxis, previous cardiovascular morbidity and older age are risk factors, with beta-lactam antibiotics, general anesthetic agents, and radiocontrast injections the commonest triggers. Fatal food anaphylaxis most commonly occurs during the second and third decades. Delayed epinephrine administration is a risk factor; common triggers are nuts, seafood, and in children, milk. For fatal venom anaphylaxis, risk factors include middle age, male sex, white race, cardiovascular disease, and possibly mastocytosis; insect triggers vary by region. Upright posture is a feature of fatal anaphylaxis to both food and venom. The rarity of fatal anaphylaxis and the significant quality of life impact of allergic conditions suggest that quality of life impairment should be a key consideration when making treatment decisions in patients at risk for anaphylaxis.

Amygdala activity associated with social choice in mice.

Studies suggest that the amygdala is a key region for regulation of anxiety, fear and social function. Therefore, dysfunction of the amygdala has been proposed as a potential mechanism for negative symptoms in schizophrenia. This may be due to NMDA receptor-mediated hypofunction, which is thought to be related to the pathogenesis of schizophrenia. In this study, electroencephalographic amygdala activity was assessed in mice during the three-chamber social test. This activity was also evaluated following exposure to the NMDA receptor antagonist ketamine. Vehicle-treated mice spent significantly more time in the social than the non-social chamber. This social preference was eliminated by ketamine. However, ketamine-treated mice spent significantly less time in the social chamber and significantly more time in the nonsocial chamber than vehicle-treated mice. There were no significant differences in induced powers between social and non-social chamber entries in vehicle-treated mice, except for theta frequencies, which featured greater induced theta power during non-social chamber entry. Ketamine eliminated differences in induced theta power between social and non-social chamber entries. Moreover, ketamine increased the induced gamma power during social chamber entry compared to that of vehicle-treated mice. All other frequency ranges were not significantly influenced by zone or drug condition. All significant findings were upon entry to chambers not during interaction. Results suggest that impaired function of NMDA receptor-mediated glutamate transmission can induce social impairments and amygdala dysfunction, similar to the pattern in schizophrenia. Future studies will utilize this method to evaluate mechanisms of social dysfunction and development of treatments of social impairments in schizophrenia.

Vision Recovery and Connectivity by Fetal Retinal Sheet Transplantation in an Immunodeficient Retinal Degenerate Rat Model.

Purpose: To characterize a recently developed model, the retinal degenerate immunodeficient S334ter line-3 rat (SD-Foxn1 Tg(S334ter)3Lav) (RD nude rat), and to test whether transplanted rat fetal retinal sheets can elicit lost responses to light. Methods: National Institutes of Health nude rats (SD-Foxn1 Tg) with normal retina were compared to RD nude rats with and without transplant for morphology and visual function. Retinal sheets from transgenic rats expressing human placental alkaline phosphatase (hPAP) were transplanted into the subretinal space of RD nude rats between postnatal day (P) 26 and P38. Transplant morphology was examined in vivo using optical coherence tomography (OCT). Visual function was assessed by optokinetic (OKN) testing, electroretinogram (ERG), and superior colliculus (SC) electrophysiology. Cryostat sections were analyzed for various retinal/synaptic markers and for the expression of donor hPAP. Results: Optical coherence tomography scans showed the placement and laminar development of retinal sheet transplants in the subretinal space. Optokinetic testing demonstrated a deficit in visual acuity in RD nude rats that was improved after retinal sheet transplantation. No ERG responses were detected in the RD nude rats with or without transplantation. Superior colliculus responses were absent in age-matched control and sham surgery RD nude rats; however, robust light-evoked responses were observed in a specific location in the SC of transplanted RD nude rats. Responsive regions corresponded to the area of transplant placement in the eye. The quality of visual responses correlated with transplant organization and placement. Conclusions: The data suggest that retinal sheet transplants integrate into the host retina of RD nude rats and recover significant visual function.

Suggested Guidelines for the Prescription of Orthotic Services, Device Delivery, Education, and Follow-up Care: A Multidisciplinary White Paper.

OBJECTIVES: This article establishes needed guidelines for determining orthotic prescriber authority, documenting medical necessity, and ensuring continuity of care for patients needing orthoses. It also identifies "off-the-shelf" (OTS) devices that can safely and appropriately be delivered to patients without professional adjustment as well as those that cannot. METHODS: A multidisciplinary task force made up of experts in orthopedics and physical medicine physicians, along with therapists and certified orthotists, applied a consensus approach to answer key questions: (i) When can a device be safely, effectively delivered to the patient OTS without professional guidance or education, and which caregivers have a role in that decision? (ii) What documentation is appropriate for physicians and other caregivers to determine medical necessity? (iii) What documentation/communication ensures continuity of care among physicians, therapists, and orthotists? RESULTS: Guidelines developed for consideration of OTS orthoses include accepting documentation from collaborating caregivers, including therapists and orthotists; keeping that documentation as part of the patient's total medical record for clinical, medical necessity determinations and reimbursement purposes; and using the physician's prescription for the device as the key determinant of whether a device is delivered OTS or as a custom-fitted device. CONCLUSION: This review provides expert guidance for patient safety, minimizing wasted expenditures, maximizing clinical outcomes, and providing efficient delivery of care for Medicare and other patients. Centers for Medicare and Medicaid Services guidelines should be directed toward recognizing the level of expertise of the orthotist, the value of their patient encounters, and their role in facilitating the timely, safe, and effective use of orthotic devices.

Orthotic Management of Deformational Plagiocephaly: Consensus Clinical Standards of Care.

OBJECTIVE: To establish consensus on definitive, actionable standards for the management of deformational plagiocephaly. DESIGN: Three-stage Delphi Survey process based on best practice statements obtained through literature review. SETTING: Electronic survey delivery. PARTICIPANTS: Review panel of 10 multidisciplinary subject matter experts (SMEs); survey panel of 30 cranial orthotists. RESULTS: Fifty-four best practice statements were accepted in four categories: diagnosis, presentation and severity, initiating treatment, and management principles. CONCLUSIONS: Clinical practice can be guided en route to robust evidence as to the efficacy of various plagiocephaly management strategies, in pursuit of definitive standards.

Dose planning objectives in anal canal cancer IMRT: the TROG ANROTAT experience.

INTRODUCTION: Intensity modulated radiotherapy (IMRT) is ideal for anal canal cancer (ACC), delivering high doses to irregular tumour volumes whilst minimising dose to surrounding normal tissues. Establishing achievable dose objectives is a challenge. The purpose of this paper was to utilise data collected in the Assessment of New Radiation Oncology Treatments and Technologies (ANROTAT) project to evaluate the feasibility of ACC IMRT dose planning objectives employed in the Australian situation. METHODS: Ten Australian centres were randomly allocated three data sets from 15 non-identifiable computed tomography data sets representing a range of disease stages and gender. Each data set was planned by two different centres, producing 30 plans. All tumour and organ at risk (OAR) contours, prescription and dose constraint details were provided. Dose-volume histograms (DVHs) for each plan were analysed to evaluate the feasibility of dose planning objectives provided. RESULTS: All dose planning objectives for the bone marrow (BM) and femoral heads were achieved. Median planned doses exceeded one or more objectives for bowel, external genitalia and bladder. This reached statistical significance for bowel V30 (P = 0.04), V45 (P < 0.001), V50 (P < 0.001), external genitalia V20 (P < 0.001) and bladder V35 (P < 0.001), V40 (P = 0.01). Gender was found to be the only significant factor in the likelihood of achieving the bowel V50 (P = 0.03) and BM V30 constraints (P = 0.04). CONCLUSION: The dose planning objectives used in the ANROTAT project provide a good starting point for ACC IMRT planning. To facilitate clinical implementation, it is important to prioritise OAR objectives and recognise factors that affect the achievability of these objectives.

Disproportionate effects of dementia on hospital discharge disposition in common hospitalization categories.

BACKGROUND: The impact of dementia on hospitalization discharge dispositions (HDDs) in the United States has not been quantified, and dementia prevalence in various hospitalization categories has not been detailed in recent years. OBJECTIVE: To characterize hospitalizations prevalent with dementia, and to examine the relationship between dementia and HDDs. DESIGN: A retrospective cross-sectional study. SETTING: 2000 to 2012 National Inpatient Sample databases. PATIENTS: Hospitalizations in persons ≥65 years old assigned to 1 of 12 Diagnosis Related Groups (DRGs) with a high number of dementia patients. INTERVENTION: None. MEASUREMENTS: The databases were queried for 12 DRGs (versions 18/24). Predictor effects for dementia on HDD categories were modeled adjusting for other defined comorbidities/covariates using logistic regression. Adjusted predictor effects of dementia on HDD in the DRG groupings were determined. Dementia prevalence and trends were assessed. RESULTS: Increasing proportions of dementia were noted in 4 DRGs studied. Dementia was strongly associated with being discharged to a nonhome setting. The most marked dementia effects were noted in DRGs 174 (gastrointestinal hemorrhage), 88 (chronic obstructive pulmonary disease), 182 (esophagitis/gastroenteritis), 138 (cardiac arrhythmias), 127 (congestive heart failure), and 89 (simple pneumonia and pleurisy), where there was at least a 76% reduction in the adjusted odds ratio (0.18-0.24) for home discharge. In contrast, DRGs 14 (stroke), 79 (respiratory infections/ inflammations), and 320 (kidney/urinary infections) had a smaller reduction in dementia-associated adjusted odds ratio (0.41-0.46) for home discharge. DRGs 79 and 320 had the highest proportions of dementia (>10%). CONCLUSIONS: Dementia proportions in many hospitalization categories have increased. The variable effect of dementia on home discharge suggests that dementia has a differential influence on hospital discharge disposition depending on the DRG. These findings have implications for healthcare allocation and long-term care planning.

Hemithoracic radiation therapy after extrapleural pneumonectomy for malignant pleural mesothelioma: Toxicity and outcomes at an Australian institution.

INTRODUCTION: We aim to report the outcome of patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy (EPP) and adjuvant hemithoracic radiotherapy with or without chemotherapy at a single Australian institution. METHOD: Between July 2004 and March 2013, 53 patients were referred for radiation treatment following EPP, of whom 49 were suitable for adjuvant treatment. Radiation treatment initially involved a 3D conformal, mixed electron/photon technique, delivering 45-50.4 Gy in 25-28 fractions (31 patients) and subsequently a nine-field intensity-modulated radiotherapy technique, delivering 50.4-54 Gy in 28-30 fractions (18 patients). Fifty-five per cent of patients also received pre-operative chemotherapy. We assessed toxicity, disease-specific and overall survival in patients who commenced radiation treatment. RESULTS: Forty-one patients (84%) completed treatment as prescribed. Six patients stopped prematurely due to toxicity, and two with disease progression. Most patients discontinuing due to toxicity received over 90% of the prescribed dose. Common acute toxicities included nausea, fatigue, anorexia and dermatitis. Severe early toxicities were rare. Late toxicities were uncommon, with the exception of a persistent elevation in liver enzymes in those with right-sided disease. Neither clinical hepatitis nor radiation pneumonitis was documented. With a median follow up of 18.7 months, median disease-free and overall survival were 21.6 and 30.5 months, respectively, and 2-year overall survival was 57.3%. CONCLUSION: Hemithoracic radiotherapy following EPP, although associated with significant early toxicity, is well tolerated. Most patients complete the prescribed treatment, and clinically significant late toxicities are rare.

A lateral electrophoretic flow diagnostic assay.

Immunochromatographic assays are a cornerstone tool in disease screening. To complement existing lateral flow assays (based on wicking flow) we introduce a lateral flow format that employs directed electrophoretic transport. The format is termed a "lateral e-flow assay" and is designed to support multiplexed detection using immobilized reaction volumes of capture antigen. To fabricate the lateral e-flow device, we employ mask-based UV photopatterning to selectively immobilize unmodified capture antigen along the microchannel in a barcode-like pattern. The channel-filling polyacrylamide hydrogel incorporates a photoactive moiety (benzophenone) to immobilize capture antigen to the hydrogel without a priori antigen modification. We report a heterogeneous sandwich assay using low-power electrophoresis to drive biospecimen through the capture antigen barcode. Fluorescence barcode readout is collected via a low-resource appropriate imaging system (CellScope). We characterize lateral e-flow assay performance and demonstrate a serum assay for antibodies to the hepatitis C virus (HCV). In a pilot study, the lateral e-flow assay positively identifies HCV+ human sera in 60 min. The lateral e-flow assay provides a flexible format for conducting multiplexed immunoassays relevant to confirmatory diagnosis in near-patient settings.

Pyramidal cell selective ablation of N-methyl-D-aspartate receptor 1 causes increase in cellular and network excitability.

BACKGROUND: Neuronal activity at gamma frequency is impaired in schizophrenia (SZ) and is considered critical for cognitive performance. Such impairments are thought to be due to reduced N-methyl-D-aspartate receptor (NMDAR)-mediated inhibition from parvalbumin interneurons, rather than a direct role of impaired NMDAR signaling on pyramidal neurons. However, recent studies suggest a direct role of pyramidal neurons in regulating gamma oscillations. In particular, a computational model has been proposed in which phasic currents from pyramidal cells could drive synchronized feedback inhibition from interneurons. As such, impairments in pyramidal neuron activity could lead to abnormal gamma oscillations. However, this computational model has not been tested experimentally and the molecular mechanisms underlying pyramidal neuron dysfunction in SZ remain unclear. METHODS: In the present study, we tested the hypothesis that SZ-related phenotypes could arise from reduced NMDAR signaling in pyramidal neurons using forebrain pyramidal neuron specific NMDA receptor 1 knockout mice. RESULTS: The mice displayed increased baseline gamma power, as well as sociocognitive impairments. These phenotypes were associated with increased pyramidal cell excitability due to changes in inherent membrane properties. Interestingly, mutant mice showed decreased expression of GIRK2 channels, which has been linked to increased neuronal excitability. CONCLUSIONS: Our data demonstrate for the first time that NMDAR hypofunction in pyramidal cells is sufficient to cause electrophysiological, molecular, neuropathological, and behavioral changes related to SZ.

Fatal anaphylaxis in the United States, 1999-2010: temporal patterns and demographic associations.

BACKGROUND: Anaphylaxis-related deaths in the United States have not been well characterized in recent years. OBJECTIVES: We sought to define epidemiologic features and time trends of fatal anaphylaxis in the United States from 1999 to 2010. METHODS: Anaphylaxis-related deaths were identified by using the 10th clinical modification of the International Classification of Diseases system diagnostic codes on death certificates from the US National Mortality Database. Rates were calculated by using census population estimates. RESULTS: There were a total of 2458 anaphylaxis-related deaths in the United States from 1999 to 2010. Medications were the most common cause (58.8%), followed by "unspecified" (19.3%), venom (15.2%), and food (6.7%). There was a significant increase in fatal drug-induced anaphylaxis over 12 years: from 0.27 (95% CI, 0.23-0.30) per million in 1999 to 2001 to 0.51 (95% CI, 0.47-0.56) per million in 2008 to 2010 (P < .001). Fatal anaphylaxis caused by medications, food, and unspecified allergens was significantly associated with African American race and older age (P < .001). Fatal anaphylaxis to venom was significantly associated with white race, older age, and male sex (P < .001). The rates of fatal anaphylaxis to foods in male African American subjects increased from 0.06 (95% CI, 0.01-0.17) per million in 1999 to 2001 to 0.21 (95% CI, 0.11-0.37) per million in 2008 to 2010 (P < .001). The rates of unspecified fatal anaphylaxis decreased over time from 0.30 (95% CI, 0.26-0.34) per million in 1999 to 2001 to 0.09 (95% CI, 0.07-0.11) per million in 2008 to 2010 (P < .001). CONCLUSION: There are strong and disparate associations between race and specific classes of anaphylaxis-related mortality in the United States. The increase in medication-related deaths caused by anaphylaxis likely relates to increased medication and radiocontrast use, enhanced diagnosis, and coding changes.

Parvalbumin cell ablation of NMDA-R1 causes increased resting network excitability with associated social and self-care deficits.

NMDA-receptor (NMDAR) hypofunction is strongly implicated in the pathophysiology of schizophrenia. Several convergent lines of evidence suggest that net excitation propagated by impaired NMDAR signaling on GABAergic interneurons may be of particular interest in mediating several aspects of schizophrenia. However, it is unclear which behavioral domains are governed by a net increase of excitation and whether modulating downstream GABAergic signaling can reverse neural and thus behavioral deficits. The current study determines the selective contributions of NMDAR dysfunction on PV-containing interneurons to electrophysiological, cognitive, and negative-symptom-related behavioral phenotypes of schizophrenia using mice with a PVcre-NR1flox-driven ablation of NR1 on PV-containing interneurons. In addition, we assessed the efficacy of one agent that directly modulates GABAergic signaling (baclofen) and one agent that indirectly modifies NMDAR-mediated signaling through antagonism of mGluR5 receptors (2-methyl-6-(phenylethynyl) pyridine (MPEP)). The data indicate that loss of NMDAR function on PV interneurons impairs self-care and sociability while increasing N1 latency and baseline gamma power, and reducing induction and maintenance of long-term potentiation. Baclofen normalized baseline gamma power without corresponding effects on behavior. MPEP further increased N1 latency and reduced social behavior in PVcre/NR1+/+ mice. These two indices were negatively correlated before and following MPEP such that as N1 latency increases, sociability decreases. This finding suggests a predictive role for N1 latency with respect to social function. Although previous data suggest that MPEP may be beneficial for core features of autism spectrum disorders, current data suggest that such effects require intact function of NMDAR on PV interneurons.