An Absorbance Peak Template for Clinical Assessment of Sound Conduction in Newborn Ears.

PURPOSE: Power absorbance measures recorded over a wide range of frequencies allow for clinical inferences about the outer/middle ears' acoustic mechanics. A frequency-dependent feature in the newborn wideband absorbance response, the prominent mid-frequency absorbance peak, has been linked to middle-ear resonance. However, current normative methods were not designed to assess subtle changes in such features. This work aims to develop and validate an absorbance peak template (APT) for assessment of absorbance peaks in newborns. Additional objectives are to compare test performance of absorbance peaks and APTs to existing normative methods, to demonstrate APT-based methods for categorization of abnormal absorbance peaks, and to describe absorbance peak test-retest variability. METHOD: Peak absorbance and peak frequency were analyzed in a training data set (490 measurements in 84 newborn ears who passed transient evoked otoacoustic emissions [TEOAEs] screenings), and an APT was developed by computing normal limits on these two absorbance peak variables. Split-set analysis evaluated the reproducibility of APT, and test-retest analysis was performed. Test performance analysis, conveyed by area under the receiver operating characteristic curve (AROC) and 95% confidence intervals (CIs), compared absorbance peak variables to absorbance area indices (AAIs) in a validation data set (359 ears that passed distortion-product OAE [DPOAE] screening and 64 ears that failed). APT-based assessment paradigms for normal and abnormal ears were compared to the common absorbance normative range paradigm. RESULTS: Split-set analysis demonstrated a good reproducibility of APT, and test-retest of absorbance peak variables showed that they were stable measures for clinical assessment. Test performance of peak absorbance (AROC = 0.83; 95% CI [0.77, 0.88]) was comparable to the top-performing AAI variables (AROC = 0.85; 95% CI [0.80, 0.90]). APT-based assessment categorized measurements based on their peak absorbance and peak frequency and enhanced the detection of subtle frequency changes that were missed by the normative range method. CONCLUSION: Analysis of absorbance peaks guided by APT has the potential to simplify and improve assessments of sound conduction pathways in newborn ears and can be used together with or in-place of current methods for analysis of wideband absorbance data.

Experiences of peer work in drug use service settings: A systematic review of qualitative evidence.

BACKGROUND: People with lived or living experiences of drug use and services have been increasingly incorporated into nonpeer-led mainstream organizational settings as a unique workforce. Despite the much discussed effectiveness of peer services in achieving measurable outcomes, limited attention has been given to the experiential aspects of peer work from the perspectives of peers, clients, or others involved. This systematic review synthesized qualitative evidence examining the experiences of peer work in nonpeer-led drug use service settings. It focused on the benefits of incorporating peers as a unique workforce, the challenges they face, and the organizational factors that influence their practices. METHODS: A search of 15 databases identified 3,940 unique citations, 33 of which met inclusion criteria. Thematic analysis was utilized to synthesize their findings. RESULTS: Foregrounding the uniqueness of peers' shared experience, studies have shown that incorporating peers into nonpeer-led settings can provide benefits at the client, organizational, and societal levels while promoting peers' personal and professional growth. The unique shared experience of peers can also present multidimensional challenges, such as triggering, boundary negotiation, and feelings of being trapped by their peer identity. To fully integrate peers into the system, organizations need to work with them to reconstruct organizational mission, culture, and structures in a way that recognizes and genuine commits to peers' unique values. CONCLUSION: This review highlights the significance of understanding peer uniqueness for organizations to create nourishing conditions for peer services and calls for future research exploring context- and setting-specific peer roles and organizational enablers and barriers.

Sex-specific and generational effects of alcohol and tobacco use on epigenetic age acceleration in the Michigan longitudinal study.

Background: Excessive alcohol and tobacco use are risk factors for poor health in both men and women, but use patterns and relationships with diseases and mortality differ between sexes. The impact of substance use on the epigenome, including DNA methylation profiles, may also differ by sex. It is also unknown whether parental substance use during childhood is associated with epigenetic changes that persist into adulthood. This study assessed the sex-specific effects of individuals' alcohol and tobacco use, as well as paternal alcohol and paternal/maternal tobacco use, on offspring's cellular aging as measured by epigenetic age acceleration. Methods: Four measures of epigenetic age acceleration (HorvathAA, HannumAA, PhenoAA, and GrimAA), the difference between chronological age and inferred age based on DNA methylation, were estimated from saliva samples. Linear mixed models tested associations between alcohol/tobacco use and epigenetic age acceleration in parents and offspring. Results: Current tobacco smoking was associated with a 4.61-year increase in GrimAA, and former tobacco smoking was associated with a 3.60-year increase in HannumAA after accounting for multiple testing (p < 0.0125). In males only, current tobacco smoking was nominally associated with a 2.19-year increase in HannumAA (p < 0.05), and this effect was significantly different than the female-specific effect (p < 0.0125). Paternal heavy alcohol use when the offspring was 12 or younger was associated with a 4.43-year increase in GrimAA among offspring (p < 0.0125). Conclusions: This study found evidence of sex-specific effects of alcohol and tobacco use, as well as paternal heavy alcohol use, on epigenetic age acceleration.

A novel sulfur mustard (HD) vapor inhalation exposure model of pulmonary toxicity for the efficacy evaluation of candidate medical countermeasures.

OBJECTIVE: To develop a novel inhalation exposure system capable of delivering a controlled inhaled HD dose through an endotracheal tube to anesthetized rats to investigate the lung pathophysiology and evaluate potential medical countermeasures. MATERIALS AND METHODS: Target HD vapor exposures were generated by a temperature-controlled vapor generator, while concentration was monitored near real-time by gas chromatography. Animal breathing parameters were monitored real-time by in-line EMKA/SciReq pulmonary analysis system. Individual exposures were halted when the target inhaled doses were achieved. Animals were observed daily for clinical observations and lethality with scheduled termination at 28 days post-exposure. Upon scheduled or unscheduled death, animals underwent a gross necropsy and lung and trachea were collected for histopathology. RESULTS: Controlled HD concentrations ranged from 60 to 320 mg/m3. Delivered inhaled doses range from 0.3 to 3.20 mg/kg with administered doses within 3% of the target. The 28-day inhaled LD50 is 0.80 mg/kg (95% CI = 0.42-1.18 mg/kg). Post exposure respiratory abnormalities were observed across all dose levels though the higher dose levels had earlier onset and higher frequency of occurrence. Histopathologic alterations were not qualitatively altered in accordance with dose but instead showed a relationship to an animals' time of death, with early deaths demonstrating acute damage and later deaths displaying signs of repair. DISCUSSION/CONCLUSION: This novel exposure system administers targeted HD inhaled doses to generate a small animal model that can be used to evaluate physiological toxicities of inhaled HD on the lungs and for evaluation of potential medical countermeasure treatments.

Open-source 128-channel bioamplifier module for ambulatory monitoring of gastrointestinal electrical activity.

We present an open-source, low-cost, portable, 128-channel bioamplifier module designed specifically for ambulatory, long-term (≥24 hr) monitoring of gastrointestinal (GI) electrical activity. The electronics hardware integrates stateof-the-art, commercial-off-the-shelf components on a custom PCB. Features include on-board data logging, wireless data streaming, subject motion monitoring, and stable operation up to the maximum 2 kHz/channel sampling rate tested. The new device operates for ≈ 30 hr continuously powered by a single 3.7 V, 2500 mAh LiPo battery. The 3D-printed ABS mechanical enclosure is robust and small (13.1 × 8.8 × 2.5 cm), so that the device can be carried in a standard Holter monitor pouch. Results from initial 128-channel, high spatial resolution body surface colon mapping experiments demonstrate the utility of this new device for GI applications. The new bioamplifier module could also be used for multichannel recording experiments in a variety of biomedical domains to study electrical activity patterns of the neuromuscular system (EMG), uterus (EHG), heart (ECG), and brain (EEG).

Discovery of Isoxazole Amides as Potent and Selective SMYD3 Inhibitors.

We report herein the discovery of isoxazole amides as potent and selective SET and MYND Domain-Containing Protein 3 (SMYD3) inhibitors. Elucidation of the structure-activity relationship of the high-throughput screening (HTS) lead compound 1 provided potent and selective SMYD3 inhibitors. The SAR optimization, cocrystal structures of small molecules with SMYD3, and mode of inhibition (MOI) characterization of compounds are described. The synthesis and biological and pharmacokinetic profiles of compounds are also presented.

Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors.

Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders.

How and How Much: Combined Services for Domestic Violence and Substance Abuse.

This study generates practice-based evidence about organizational strategies for addressing co-occurring domestic violence (DV) and substance abuse (SA) using a survey of organizations working on both issues (N = 204). How (the strategies) and how much (the extensiveness) organizations attend to both issues vary by organizational type (DV, SA, or multiservice) and populations served. While most SA and multiservice organizations address DV internally, most DV organizations use external collaborations; all offer services to DV perpetrators at similar rates. Findings underscore the importance of including multiple, nuanced measures of organizational activities related to co-occurring DV and SA in future research.

Gender differences in the transmission of risk for antisocial behavior problems across generations.

Previous studies have shown that children of alcohol use disorder (AUD) parents are more likely to develop alcohol problems as well as antisocial and other behavior problems. The purpose of this study was to examine gender discordance in the effect of early maternal and paternal influences on antisocial behaviors of boys and girls, as well as the environmental factors that moderate the parental effects. Specifically, we examined the effects of childhood and adulthood antisocial behavior of the parents on offspring antisocial behavior as young adults. We also examined whether mothers' and fathers' drinking problems when offspring were young children (6-8 years) affected offspring antisocial behavior as young adults (18-21 years). We evaluated 655 children from 339 families in the Michigan Longitudinal Study (MLS), a prospective study of AUD and non-AUD families. Path models were constructed in order to test for the parental contributions to offspring outcomes. We found that both mothers' and fathers' antisocial behavior contributed to the children's young adult antisocial behavior. Only mothers' drinking problems while their children were little had a significant effect on their sons' later drinking, but not on their daughters'. These different parental effects suggest that maternal and paternal influences may be mediated by different mechanisms.

Human butyrylcholinesterase efficacy against nerve agent exposure.

Acetylcholinesterase is vital for normal operation of many processes in the body. Following exposure to organophosphorus (OP) nerve agents, death can ensue without immediate medical intervention. Current therapies mitigate the cholinergic crisis caused by nerve agents but do not fully prevent long-term health concerns, for example, brain damage following seizures. Human butyrylcholinesterase (HuBChE) is a stoichiometric bioscavenger being investigated as an antidote for OP nerve agent poisoning. HuBChE sequesters OP nerve agent in the bloodstream preventing the nerve agent from reaching critical target organ systems. HuBChE was effective when used as both a pre-treatment and as a post-exposure therapy. HuBChE has potential for use in both military settings and to protect civilian first responders in situations where nerve agent usage is suspected. We reviewed various animal models studies evaluating the efficacy of HuBChE against nerve agent exposure, pursuant to its submission for approval under the FDA Animal Rule.

Sex differences, gender and addiction.

This review discusses alcohol and other forms of drug addiction as both a sociocultural and biological phenomenon. Sex differences and gender are not solely determined by biology, nor are they entirely sociocultural. The interactions among biological, environmental, sociocultural, and developmental influences result in phenotypes that may be more masculine or more feminine. These gender-related sex differences in the brain can influence the responses to drugs of abuse, progressive changes in the brain after exposure to drugs of abuse and whether addiction results from drug-taking experiences. In addition, the basic laboratory evidence for sex differences is discussed within the context of four types of sex/gender differences. © 2016 Wiley Periodicals, Inc.

Sociocultural context for sex differences in addiction.

In this review, we discuss the importance of investigating both sex and gender differences in addiction and relapse in studies of humans and in animal models. Addiction is both a cultural and biological phenomenon. Sex and gender differences are not solely determined by our biology, nor are they entirely cultural; they are interactions between biology and the environment that are continuously played out throughout development. Lessons from the historical record illustrate how context and attitudes affect the way that substance use in men and women is regarded. Finally, cultural and environmental influences may differentially affect men and women, and affect how they respond to drugs of abuse and to treatment protocols. We recommend that both animal models and clinical research need to be developed to consider how contextual and social factors may influence the biological processes of addiction and relapse differentially in men and women.

Thermal decomposition of CH3CHO studied by matrix infrared spectroscopy and photoionization mass spectroscopy.

A heated SiC microtubular reactor has been used to decompose acetaldehyde and its isotopomers (CH(3)CDO, CD(3)CHO, and CD(3)CDO). The pyrolysis experiments are carried out by passing a dilute mixture of acetaldehyde (roughly 0.1%-1%) entrained in a stream of a buffer gas (either He or Ar) through a heated SiC reactor that is 2-3 cm long and 1 mm in diameter. Typical pressures in the reactor are 50-200 Torr with the SiC tube wall temperature in the range 1200-1900 K. Characteristic residence times in the reactor are 50-200 µs after which the gas mixture emerges as a skimmed molecular beam at a pressure of approximately 10 µTorr. The reactor has been modified so that both pulsed and continuous modes can be studied, and results from both flow regimes are presented. Using various detection methods (Fourier transform infrared spectroscopy and both fixed wavelength and tunable synchrotron radiation photoionization mass spectrometry), a number of products formed at early pyrolysis times (roughly 100-200 µs) are identified: H, H(2), CH(3), CO, CH(2)=CHOH, HC≡CH, H(2)O, and CH(2)=C=O; trace quantities of other species are also observed in some of the experiments. Pyrolysis of rare isotopomers of acetaldehyde produces characteristic isotopic signatures in the reaction products, which offers insight into reaction mechanisms that occur in the reactor. In particular, while the principal unimolecular processes appear to be radical decomposition CH(3)CHO (+M) → CH(3) + H + CO and isomerization of acetaldehyde to vinyl alcohol, it appears that the CH(2)CO and HCCH are formed (perhaps exclusively) by bimolecular reactions, especially those involving hydrogen atom attacks.

Alcohol-impaired driving: average quantity consumed and frequency of drinking do matter.

OBJECTIVE: The objective of this article is to estimate and validate a logistic model of alcohol-impaired driving using previously ignored alcohol consumption behaviors, other risky behaviors, and demographic characteristics as independent variables. METHODS: The determinants of impaired driving are estimated using the US Centers for Disease Control and Prevention's (CDC) Behavioral Risk Factor Surveillance System (BRFSS) surveys. Variables used in a logistic model to explain alcohol-impaired driving are not only standard sociodemographic variables and bingeing but also frequency of drinking and average quantity consumed, as well as other risky behaviors. We use interactions to understand how being female and being young affect impaired driving. Having estimated our model using the 1997 survey, we validated our model using the BRFSS data for 1999. RESULTS: Drinking 9 or more times in the past month doubled the odds of impaired driving. The greater average consumption of alcohol per session, the greater the odds of driving impaired, especially for persons in the highest quartile of alcohol consumed. Bingeing has the greatest effect on impaired driving. Seat belt use is the one risky behavior found to be related to such driving. Sociodemographic effects are consistent with earlier research. Being young (18-30) interacts with two of the alcohol consumption variables and being a woman interacts with always wearing a seat belt. Our model was robust in the validation analysis. CONCLUSIONS: All 3 dimensions of drinking behavior are important determinants of alcohol-impaired driving, including frequency and average quantity consumed. Including these factors in regressions improves the estimates of the effects of all variables.

OxyContin misuse on a reservation: qualitative reports by American Indians in talking circles.

Few studies have addressed OxyContin use among American Indians (AIs) on reservations. Eight focus groups were conducted as "talking circles" (2006 and 2007 ) with 49 AI adults and youth. An emergent design was utilized in which the initial two circles were planned, but the subsequent six circles evolved from tribal members' input. Participants reported an increase in OxyContin use; negative effects on individuals, families, and the tribe; a lack of treatment options; and a growing problem on other reservations. Results indicate the need to further research prevalence and patterns of use to design interventions to curtail OxyContin abuse on reservations.

Tetrahydro-4-quinolinamines identified as novel P2Y(1) receptor antagonists.

High-throughput screening of the GSK compound collection against the P2Y(1) receptor identified a novel series of tetrahydro-4-quinolinamine antagonists. Optimal substitution around the piperidine group was pivotal for ensuring activity. An exemplar analog from this series was shown to inhibit platelet aggregation.

Infrared-vacuum ultraviolet-pulsed field ionization-photoelectron study of CH(3)I(+) using a high-resolution infrared laser.

By using a high-resolution single mode infrared-optical parametric oscillator laser to prepare CH(3)I in single (J,K) rotational levels of the nu(1) (symmetric C-H stretching) =1 vibrational state, we have obtained rovibrationally resolved infrared-vacuum ultraviolet-pulsed field ionization-photoelectron (IR-VUV-PFI-PE) spectra of the CH(3)I(+)(X(2)E(32);nu(1)(+)=1;J(+),P(+)) band, where (J,K) and (J(+),P(+)) represent the respective rotational quantum numbers of CH(3)I and CH(3)I(+). The IR-VUV-PFI-PE spectra observed for K=0 and 1 are found to have nearly identical structures. The IR-VUV-PFI-PE spectra for (J,K)=(5,0) and (7, 0) are also consistent with the previous J-selected IR-VUV-PFI-PE measurements. The analysis of these spectra indicates that the photoionization cross section of CH(3)I depends strongly on DeltaJ(+)=J(+)-J: but not on J and K. This observation lends strong support for the major assumption adopted for the semiempirical simulation scheme, which has been used for the simulation of the origin bands observed in VUV-PFI-PE study of polyatomic molecules. Using the state-to-state photoionization cross sections determined in this IR-VUV study, we have obtained excellent simulation of the VUV-PFI-PE origin band of CH(3)I(+)(X (2)E(32)), yielding more precise IE(CH(3)I)=76 930.7+/-0.5 cm(-1) and nu(1) (+)=2937.8+/-0.2 cm(-1).

Rovibrationally selected and resolved pulsed field ionization-photoelectron study of propyne: ionization energy and spin-orbit interaction in propyne cation.

By using a high-resolution infrared (IR) laser to prepare propyne (C(3)H(4)) in selected rotational levels of the excited nu(1) (acetylenic C-H stretching) vibration mode prior to vacuum ultraviolet (VUV) laser pulsed field ionization-photoelectron (PFI-PE) measurements, we have obtained rotationally resolved VUV-PFI-PE spectra for the C(3)H(4) (+)(X (2)E(32,12),nu(1) (+)=1) band. The analysis of these PFI-PE spectra leads to the determination of the spin-orbit constant of A=-13.0+/-0.2 cm(-1) for the C(3)H(4) (+)(X (2)E(32,12),nu(1) (+)=1) state. Using this A constant and the relative rotationally selected and resolved state-to-state photoionization cross sections thus measured, we have obtained an excellent simulation for the VUV-PFI-PE origin band of C(3)H(4) (+)(X (2)E(32,12)), yielding a value of 83 619.0+/-1.0 cm(-1) (10.367 44+/-0.000 12 eV) for the adiabatic ionization energy of C(3)H(4) [IE(C(3)H(4))]. The present two-color IR-VUV-PFI-PE study has also made possible the determination of the C-H stretching frequencies nu(1) (+)=3217.1+/-0.2 cm(-1) for C(3)H(4) (+)(X (2)E(32,12)). The spectral assignment and simulation were guided by high-level ab initio calculations on the IE(C(3)H(4)), Franck-Condon factors for photoionization transitions, and rotational constants and vibrational frequencies for C(3)H(4) (+).

Total synthesis of aigialomycin D: surprising chemoselectivity dependence on alkyne structure in nickel-catalyzed cyclizations.

The total synthesis of aigialomycin D was carried out using a nickel-catalyzed ynal macrocyclization as a key step. This key step allowed macrocycle assembly and formation of a disubstituted alkene and a secondary hydroxyl stereocenter in a single step, although the stereocenter was formed unselectively. An interesting side reaction involving five-membered-ring synthesis by an aldehyde/styrene cyclization was observed when macrocyclization of an alkynyl silane was attempted. A mechanistic basis for this surprising process is provided.

3s Rydberg and cationic States of pyrazine studied by photoelectron spectroscopy.

We have studied 3s(n-1 and pi-1) Rydberg states and D0(n-1) and D1(pi-1) cationic states of pyrazine [1,4-diazabenzene] by picosecond (2 + 1) resonance-enhanced multiphoton ionization (REMPI), (2 + 1) REMPI photoelectron imaging, He(I) ultraviolet photoelectron spectroscopy (UPS), and vacuum ultraviolet pulsed field ionization photoelectron spectroscopy (VUV-PFI-PE). The new He(I) photoelectron spectrum of pyrazine in a supersonic jet revealed a considerably finer vibrational structure than a previous photoelectron spectrum of pyrazine vapor. We performed Franck-Condon analysis on the observed photoelectron and REMPI spectra in combination with ab initio density functional theory and molecular orbital calculations to determine the equilibrium geometries in the D0 and 3s(n-1) states. The equilibrium geometries were found to differ slightly between the D0 and 3s states, indicating the influence of a Rydberg electron on the molecular structure. The locations of the D1-D0 and 3s(pi-1)-3s(n-1) conical intersections were estimated. From the line width in the D1 <-- S0 spectrum, we estimated the lifetime of D1 to be 12 fs for pyrazine and 15 fs for fully deuterated pyrazine. A similar lifetime was estimated for the 3s(pi-1) state of pyrazine by REMPI spectroscopy. The vibrational feature of D1 observed in the VUV-PFI-PE measurement differed dramatically from that in the UPS spectrum, which suggests that the high-n Rydberg (ZEKE) states converging to the D1 vibronic state are short-lived due to electronic autoionization to the D0 continuum.