Melatonin in Newborn Infants Undergoing Surgery: A Pilot Study on Its Effects on Postoperative Oxidative Stress.

Surgery is frequently associated with excessive oxidative stress. Melatonin acts as an antioxidant and transient melatonin deficiency has been described in neonatal surgical patients. This randomized, blinded, prospective pilot study tested the hypothesis that oral melatonin supplementation in newborn infants undergoing surgery is effective in reducing perioperative oxidative stress. A total of twenty-three newborn infants requiring surgery were enrolled: 10 received a single dose of oral melatonin 0.5 mg/kg in the morning, before surgery (MEL group), and 13 newborns served as the control group (untreated group). Plasma concentrations of melatonin, Non-Protein-Bound Iron (NPBI), Advanced Oxidation Protein Products (AOPP), and F2-Isoprostanes (F2-IsoPs) were measured. Both in the pre- and postoperative period, melatonin concentrations were significantly higher in the MEL group than in the untreated group (preoperative: 1265.50 ± 717.03 vs. 23.23 ± 17.71 pg/mL, p < 0.0001; postoperative: 1465.20 ± 538.38 vs. 56.47 ± 37.18 pg/mL, p < 0.0001). Melatonin significantly increased from the pre- to postoperative period in the untreated group (23.23 ± 17.71 vs. 56.47 ± 37.18 pg/mL; pg/mL p = 0.006). In the MEL group, the mean blood concentrations of NPBI, F2-IsoPs, and AOPP significantly decreased from the pre- to the postoperative period (4.69 ± 3.85 vs. 1.65 ± 1.18 micromol/dL, p = 0.049; 128.40 ± 92.30 vs. 50.25 ± 47.47 pg/mL, p = 0.037 and 65.18 ± 15.50 vs. 43.98 ± 17.92 micromol/dL, p = 0.022, respectively). Melatonin concentration increases physiologically from the pre- to the postoperative period, suggesting a defensive physiologic response to counteract oxidative stress. The administration of exogenous melatonin in newborn infants undergoing surgery reduces lipid and protein peroxidation in the postoperative period, showing a potential role in protecting babies from the deleterious consequences of oxidative stress.

Improvisation is a novel tool to study musicality.

Humans spontaneously invent songs from an early age. Here, we exploit this natural inclination to probe implicit musical knowledge in 33 untrained and poor singers (amusia). Each sang 28 long improvisations as a response to a verbal prompt or a continuation of a melodic stem. To assess the extent to which each improvisation reflects tonality, which has been proposed to be a core organizational principle of musicality and which is present within most music traditions, we developed a new algorithm that compares a sung excerpt to a probability density function representing the tonal hierarchy of Western music. The results show signatures of tonality in both nonmusicians and individuals with congenital amusia, who have notorious difficulty performing musical tasks that require explicit responses and memory. The findings are a proof of concept that improvisation can serve as a novel, even enjoyable method for systematically measuring hidden aspects of musicality across the spectrum of musical ability.

Invasive Treatments for Low Back Disorders.

OBJECTIVE: This abbreviated version of the American College of Occupational and Environmental Medicine's Low Back Disorders guideline reviews the evidence and recommendations developed for invasive treatments used to manage low back disorders. METHODS: Comprehensive systematic literature reviews were accomplished with article abstraction, critiquing, grading, evidence table compilation, and guideline finalization by a multidisciplinary expert panel and extensive peer-review to develop evidence-based guidance. Consensus recommendations were formulated when evidence was lacking and often relied on analogy to other disorders for which evidence exists. A total of 47 high-quality and 321 moderate-quality trials were identified for invasive management of low back disorders. RESULTS: Guidance has been developed for the invasive management of acute, subacute, and chronic low back disorders and rehabilitation. This includes 49 specific recommendations. CONCLUSION: Quality evidence should guide invasive treatment for all phases of managing low back disorders.

Enhanced Memory for Vocal Melodies in Autism Spectrum Disorder and Williams Syndrome.

Adults and children with typical development (TD) remember vocal melodies (without lyrics) better than instrumental melodies, which is attributed to the biological and social significance of human vocalizations. Here we asked whether children with autism spectrum disorder (ASD), who have persistent difficulties with communication and social interaction, and adolescents and adults with Williams syndrome (WS), who are highly sociable, even indiscriminately friendly, exhibit a memory advantage for vocal melodies like that observed in individuals with TD. We tested 26 children with ASD, 26 adolescents and adults with WS of similar mental age, and 26 children with TD on their memory for vocal and instrumental (piano, marimba) melodies. After exposing them to 12 unfamiliar folk melodies with different timbres, we required them to indicate whether each of 24 melodies (half heard previously) was old (heard before) or new (not heard before) during an unexpected recognition test. Although the groups successfully distinguished the old from the new melodies, they differed in overall memory. Nevertheless, they exhibited a comparable advantage for vocal melodies. In short, individuals with ASD and WS show enhanced processing of socially significant auditory signals in the context of music. LAY SUMMARY: Typically developing children and adults remember vocal melodies better than instrumental melodies. In this study, we found that children with Autistic Spectrum Disorder, who have severe social processing deficits, and children and adults with Williams syndrome, who are highly sociable, exhibit comparable memory advantages for vocal melodies. The results have implications for musical interventions with these populations.

The singing voice is special: Persistence of superior memory for vocal melodies despite vocal-motor distractions.

Vocal melodies sung without lyrics (la la) are remembered better than instrumental melodies. What causes the advantage? One possibility is that vocal music elicits subvocal imitation, which could promote enhanced motor representations of a melody. If this motor interpretation is correct, distracting the motor system during encoding should reduce the memory advantage for vocal over piano melodies. In Experiment 1, participants carried out movements of the mouth (i.e., chew gum) or hand (i.e., squeeze a beanbag) while listening to 24 unfamiliar folk melodies (half vocal, half piano). In a subsequent memory test, they rated the same melodies and 24 timbre-matched foils from '1-Definitely New' to '7-Definitely Old'. There was a memory advantage for vocal over piano melodies with no effect of group and no interaction. In Experiment 2, participants carried out motor activities during encoding more closely related to singing, either silently articulating (la la) or vocalizing without articulating (humming continuously). Once again, there was a significant advantage for vocal melodies with no effect or interaction of group. In Experiment 3, participants audibly whispered (la la) repeatedly during encoding. Again, the voice advantage was present and did not differ appreciably from prior research with no motor task during encoding. However, we observed that the spontaneous phase-locking of whisper rate and musical beat tended to predict enhanced memory for vocal melodies. Altogether the results challenge the notion that subvocal rehearsal of the melody drives enhanced memory for vocal melodies. Instead, the voice may enhance engagement.

Non-Invasive and Minimally Invasive Management of Low Back Disorders.

OBJECTIVE: This abbreviated version of the American College of Occupational and Environmental Medicine's (ACOEM) Low Back Disorders Guideline reviews the evidence and recommendations developed for non-invasive and minimally invasive management of low back disorders. METHODS: Systematic literature reviews were accomplished with article abstraction, critiquing, grading, evidence table compilation, and guideline finalization by a multidisciplinary expert panel and extensive peer-review to develop evidence-based guidance. Consensus recommendations were formulated when evidence was lacking. A total of 70 high-quality and 564 moderate-quality trials were identified for non-invasive low back disorders. Detailed algorithms were developed. RESULTS: Guidance has been developed for the management of acute, subacute, and chronic low back disorders and rehabilitation. This includes 121 specific recommendations. CONCLUSION: Quality evidence should guide treatment for all phases of managing low back disorders.

Substitution of an Internal Disulfide Bridge with a Diselenide Enhances both Foldability and Stability of Human Insulin.

Insulin analogues, mainstays in the modern treatment of diabetes mellitus, exemplify the utility of protein engineering in molecular pharmacology. Whereas chemical syntheses of the individual A and B chains were accomplished in the early 1960s, their combination to form native insulin remains inefficient because of competing disulfide pairing and aggregation. To overcome these limitations, we envisioned an alternative approach: pairwise substitution of cysteine residues with selenocysteine (Sec, U). To this end, CysA6 and CysA11 (which form the internal intrachain A6-A11 disulfide bridge) were each replaced with Sec. The A chain[C6U, C11U] variant was prepared by solid-phase peptide synthesis; while sulfitolysis of biosynthetic human insulin provided wild-type B chain-di-S-sulfonate. The presence of selenium atoms at these sites markedly enhanced the rate and fidelity of chain combination, thus solving a long-standing challenge in chemical insulin synthesis. The affinity of the Se-insulin analogue for the lectin-purified insulin receptor was indistinguishable from that of WT-insulin. Remarkably, the thermodynamic stability of the analogue at 25 °C, as inferred from guanidine denaturation studies, was augmented (ΔΔGu ≈0.8 kcal mol-1 ). In accordance with such enhanced stability, reductive unfolding of the Se-insulin analogue and resistance to enzymatic cleavage by Glu-C protease occurred four times more slowly than that of WT-insulin. 2D-NMR and X-ray crystallographic studies demonstrated a native-like three-dimensional structure in which the diselenide bridge was accommodated in the hydrophobic core without steric clash.

An ultra-stable single-chain insulin analog resists thermal inactivation and exhibits biological signaling duration equivalent to the native protein.

Thermal degradation of insulin complicates its delivery and use. Previous efforts to engineer ultra-stable analogs were confounded by prolonged cellular signaling in vivo, of unclear safety and complicating mealtime therapy. We therefore sought an ultra-stable analog whose potency and duration of action on intravenous bolus injection in diabetic rats are indistinguishable from wild-type (WT) insulin. Here, we describe the structure, function, and stability of such an analog, a 57-residue single-chain insulin (SCI) with multiple acidic substitutions. Cell-based studies revealed native-like signaling properties with negligible mitogenic activity. Its crystal structure, determined as a novel zinc-free hexamer at 2.8 Å, revealed a native insulin fold with incomplete or absent electron density in the C domain; complementary NMR studies are described in the accompanying article. The stability of the analog (ΔGU 5.0(±0.1) kcal/mol at 25 °C) was greater than that of WT insulin (3.3(±0.1) kcal/mol). On gentle agitation, the SCI retained full activity for >140 days at 45 °C and >48 h at 75 °C. These findings indicate that marked resistance to thermal inactivation in vitro is compatible with native duration of activity in vivo Further, whereas WT insulin forms large and heterogeneous aggregates above the standard 0.6 mm pharmaceutical strength, perturbing the pharmacokinetic properties of concentrated formulations, dynamic light scattering, and size-exclusion chromatography revealed only limited SCI self-assembly and aggregation in the concentration range 1-7 mm Such a combination of favorable biophysical and biological properties suggests that SCIs could provide a global therapeutic platform without a cold chain.

Pupils dilate for vocal or familiar music.

Previous research reveals that vocal melodies are remembered better than instrumental renditions. Here we explored the possibility that the voice, as a highly salient stimulus, elicits greater arousal than nonvocal stimuli, resulting in greater pupil dilation for vocal than for instrumental melodies. We also explored the possibility that pupil dilation indexes memory for melodies. We tracked pupil dilation during a single exposure to 24 unfamiliar folk melodies (half sung to la la, half piano) and during a subsequent recognition test in which the previously heard melodies were intermixed with 24 novel melodies (half sung, half piano) from the same corpus. Pupil dilation was greater for vocal melodies than for piano melodies in the exposure phase and in the test phase. It was also greater for previously heard melodies than for novel melodies. Our findings provide the first evidence that pupillometry can be used to measure recognition of stimuli that unfold over several seconds. They also provide the first evidence of enhanced arousal to vocal melodies during encoding and retrieval, thereby supporting the more general notion of the voice as a privileged signal. (PsycINFO Database Record

Pianists exhibit enhanced memory for vocal melodies but not piano melodies.

Nonmusicians remember vocal melodies (i.e., sung to la la) better than instrumental melodies. If greater exposure to the voice contributes to those effects, then long-term experience with instrumental timbres should elicit instrument-specific advantages. Here we evaluate this hypothesis by comparing pianists with other musicians and nonmusicians. We also evaluate the possibility that absolute pitch (AP), which involves exceptional memory for isolated pitches, influences melodic memory. Participants heard 24 melodies played in four timbres (voice, piano, banjo, marimba) and were subsequently required to distinguish the melodies heard previously from 24 novel melodies presented in the same timbres. Musicians performed better than nonmusicians, but both groups showed a comparable memory advantage for vocal melodies. Moreover, pianists performed no better on melodies played on piano than on other instruments, and AP musicians performed no differently than non-AP musicians. The findings confirm the robust nature of the voice advantage and rule out explanations based on familiarity, practice, and motor representations.

Hypoxic-ischemic encephalopathy: a review for the clinician.

IMPORTANCE: Hypoxic-ischemic encephalopathy (HIE) occurs in 1 to 8 per 1000 live births in developed countries. Historically, the clinician has had little to offer neonates with HIE other than systemic supportive care. Recently, the neuroprotective therapy of hypothermia has emerged as the standard of care, and other complementary therapies are rapidly transitioning from the basic science to clinical care. OBJECTIVE: To examine the pathophysiology of HIE and the state of the art for the clinical care of neonates with HIE. EVIDENCE REVIEW: We performed a literature review using the PubMed database. Results focused on reviews and articles published from January 1, 2004, through December 31, 2014. Articles published earlier than 2004 were included when appropriate for historical perspective. Our review emphasized evidence-based management practices for the clinician. FINDINGS: A total of 102 articles for critical review were selected based on their relevance to the incidence of HIE, pathophysiology, neuroimaging, placental pathology, biomarkers, current systemic supportive care, hypothermia, and emerging therapies for HIE and were reviewed by both of us. Seventy-five publications were selected for inclusion in this article based on their relevance to these topics. The publications highlight the emergence of serum-based biomarkers, placental pathology, and magnetic resonance imaging as useful tools to predict long-term outcomes. Hypothermia and systemic supportive care form the cornerstone of therapy for HIE. CONCLUSIONS AND RELEVANCE: The pathophysiology of HIE is now better understood, and treatment with hypothermia has become the foundation of therapy. Several neuroprotective agents offer promise when combined with hypothermia and are entering clinical trials.

Enhanced processing of vocal melodies in childhood.

Music cognition is typically studied with instrumental stimuli. Adults remember melodies better, however, when they are presented in a biologically significant timbre (i.e., the human voice) than in various instrumental timbres (Weiss, Trehub, & Schellenberg, 2012). We examined the impact of vocal timbre on children's processing of melodies. In Study 1, 9- to 11-year-olds listened to 16 unfamiliar folk melodies (4 each of voice, piano, banjo, or marimba). They subsequently listened to the same melodies and 16 timbre-matched foils, and judged whether each melody was old or new. Vocal melodies were recognized better than instrumental melodies, which did not differ from one another, and the vocal advantage was consistent across age. In Study 2, 5- to 6-year-olds and 7- to 8-year-olds were tested with a simplified design that included only vocal and piano melodies. Both age groups successfully differentiated old from new melodies, but memory was more accurate for the older group. The older children recognized vocal melodies better than piano melodies, whereas the younger children tended to label vocal melodies as old whether they were old or new. The results provide the first evidence of differential processing of vocal and instrumental melodies in childhood.

Listening to the brainstem: musicianship enhances intelligibility of subcortical representations for speech.

Auditory experiences including musicianship and bilingualism have been shown to enhance subcortical speech encoding operating below conscious awareness. Yet, the behavioral consequence of such enhanced subcortical auditory processing remains undetermined. Exploiting their remarkable fidelity, we examined the intelligibility of auditory playbacks (i.e., "sonifications") of brainstem potentials recorded in human listeners. We found naive listeners' behavioral classification of sonifications was faster and more categorical when evaluating brain responses recorded in individuals with extensive musical training versus those recorded in nonmusicians. These results reveal stronger behaviorally relevant speech cues in musicians' neural representations and demonstrate causal evidence that superior subcortical processing creates a more comprehensible speech signal (i.e., to naive listeners). We infer that neural sonifications of speech-evoked brainstem responses could be used in the early detection of speech-language impairments due to neurodegenerative disorders, or in objectively measuring individual differences in speech reception solely by listening to individuals' brain activity.

ACOEM practice guidelines: opioids for treatment of acute, subacute, chronic, and postoperative pain.

DESCRIPTION: The American College of Occupational and Environmental Medicine's guidelines have been updated to develop more detailed guidance for treatment of acute, subacute, chronic, and postoperative pain with opioids. METHODS: Literature searches were performed using PubMed, EBSCO, Cochrane Review, and Google Scholar without publication date limits. Of 264,617 articles' titles screened and abstracts reviewed, 263 articles met inclusion criteria. Of these, a total of 157 were of high and moderate quality addressing pain treatment. Comprehensive literature reviews were accomplished with article abstraction, critiquing, grading, evidence table compilation, and guideline finalization by a multidisciplinary expert panel to develop evidence-based guidance. RECOMMENDATIONS: No quality evidence directly supports histories, physical examinations, and opioid treatment agreements, although they are thought to be important. No quality trials were identified showing superiority of opioids, compared with nonsteroidal anti-inflammatory and other medications for treatment of chronic, noncancer pain. The use of opioid-sparing treatments associated with lower doses of postoperative opioids is also associated with better long-term functional outcomes. Selective use of opioids is recommended for patients with acute and postoperative pain. Consensus recommendations also include consideration of carefully conducted trials of chronic opioid treatment for highly select patients with subacute and chronic pain and to maintenance opioid prescriptions only if documented objective functional gain(s) results. A strong and reproducible dose-response relationship identifies a recommended morphine equivalent dose limit of no more than 50 mg/day. Higher doses should be prescribed only with documented commensurately greater functional benefit(s), comprehensive monitoring for adverse effects, informed consent, and careful consideration of risk versus benefit of such treatment. Chronic opioid use should be accompanied by informed consent, a treatment agreement, tracking of functional benefits, drug screening, and attempts at tapering.

ACOEM practice guidelines: opioids and safety-sensitive work.

OBJECTIVE: ACOEM has updated the treatment guidelines concerning opioids. This report highlights the safety-sensitive work recommendation that has been developed. METHODS: Comprehensive literature reviews were accomplished with article abstraction, critiquing, grading, evidence table compilation, and guideline finalization by a multidisciplinary expert panel to develop evidence-based guidance. A total of 12 moderate-quality studies were identified to address motor vehicle crash risk, and none regarding other work among opioid-using patients. RESULTS: Acute or chronic opioid use is not recommended for patients who perform safety-sensitive jobs. These jobs include operating motor vehicles, other modes of transportation, forklift driving, overhead crane operation, heavy equipment operation and tasks involving high levels of cognitive function and judgment. CONCLUSION: Quality evidence consistently demonstrates increased risk of vehicle crashes and is recommended as the surrogate for other safety-sensitive work tasks.

Prioritizing partners across the continuum.

With the advent of accountable care organizations, bundled payments, value-based purchasing, and penalties for preventable hospital readmission, tight connections and collaboration across the care continuum will become critical to achieve successful patient outcomes and to reduce the cost of care delivery. Lehigh Valley Health Network (LVHN), the largest provider of health services in eastern Pennsylvania, set out on a journey to build collaborative relationships with skilled nursing facilities (SNFs) in their eastern Pennsylvania community. LVHN desired SNF partners with mutual interests in improving quality of care and lowering costs of delivery where possible. Recognizing that not all SNFs are alike, LVHN developed a Collaborative Partner Prioritization Tool to assess and prioritize skilled nursing facilities in an effort to determine those that would make the best collaborators. SNFs were reviewed based on their volume of mutual patients, quality of care delivery, and their perceived willingness to align with LVHN. Six variables were used to assess these facilities, including (1) patient discharge destination volume by SNF; (2) 30-day all-cause readmission rate to an LVHN hospital; (3) Medicare's Nursing Home Compare 5-Star Overall Rating; (4) the health network affiliation of the SNF's medical director; (5) the level of LVHN-employed or -affiliated physician presence at the SNF; and (6) the SNF's current participation in LVHN-sponsored programs and meetings. Through use of the Collaborative Partner Prioritization Tool, it was discovered that roughly 70% of LVHN patients who required skilled nursing care following their inpatient stay received care at 1 of 20 SNFs. Of these, 5 facilities performed well on the 6-variable assessment, deeming them the "Tier 1 Facilities" to initially focus collaborative efforts. LVHN has strategically deployed physician resources and has increased physician presence at these "Tier 1 SNFs." These facilities have also gained remote read-only access to LVHN's inpatient electronic medical record and have had opportunity to participate in LVHN-sponsored programs. Special projects have been co-developed with several SNFs, including a telemedicine-based Parkinson's disease program to increase patient access to a neurologist specially trained in movement disorders. The Collaborative Partner Prioritization Tool has become a powerful tool when used for prioritization of relationships and allocation of LVHN physicians and resources. Collaboration with strong SNF partners has offered a shared opportunity to improve quality of care, reduce costs, and prepare for the many policies affecting the health care industry. Future outcomes of this work will include quality metrics, such as readmissions, patient satisfaction with care, time for decision to admit, and overall costs of care. The data and metrics used to define the prioritization tool will continue to be adapted as the post-acute market and hospital-SNF relationships continue to evolve.

Something in the way she sings: enhanced memory for vocal melodies.

Across species, there is considerable evidence of preferential processing for biologically significant signals such as conspecific vocalizations and the calls of individual conspecifics. Surprisingly, music cognition in human listeners is typically studied with stimuli that are relatively low in biological significance, such as instrumental sounds. The present study explored the possibility that melodies might be remembered better when presented vocally rather than instrumentally. Adults listened to unfamiliar folk melodies, with some presented in familiar timbres (voice and piano) and others in less familiar timbres (banjo and marimba). They were subsequently tested on recognition of previously heard melodies intermixed with novel melodies. Melodies presented vocally were remembered better than those presented instrumentally even though they were liked less. Factors underlying the advantage for vocal melodies remain to be determined. In line with its biological significance, vocal music may evoke increased vigilance or arousal, which in turn may result in greater depth of processing and enhanced memory for musical details.

Hepatic interaction between quinidine and digoxin: role of inhibition of sinusoidal Na⁺/K⁺ ATPase digoxin binding.

The mechanism by which quinidine affects hepatic digoxin pharmacokinetics remains controversial. Here, we study the role of displacement of digoxin from hepatic sinusoidal binding sites by quinidine. We used the impulse-response technique in the single-pass perfused rat liver to describe the digoxin hepatic disposition by a physiologically-based pharmacokinetic liver model. The impulse-response study involved analysis of outflow curves following two consecutive doses of digoxin (42 and 125 µg) without and with quinidine (10 µM) in perfusate. In addition, the effect of quinidine on digoxin binding in liver subcellular fractions was quantified. Quinidine increased the peak outflow concentration for digoxin at the low digoxin dose but not at the high dose. This increase could be adequately described when digoxin displacement from sinusoidal and intrahepatic binding sites was included in the model. Inhibition of digoxin binding by quinidine was also observed in vitro. The decrease of biliary excretion of digoxin by quinidine was accompanied by a linear increase in sinusoidal efflux of digoxin's primary metabolite, digoxigenin bisdigitoxoside (Dg2). In contrast to biliary excretion, inhibition of sinusoidal uptake may become dominant only for high concentrations of quinidine.

An improved nonlinear model describing the hepatic pharmacokinetics of digoxin: evidence for two functionally different uptake systems and saturable binding.

PURPOSE: To develop a semi-distributed liver model for the evaluation of saturable sinusoidal uptake and binding kinetics of the Oatp1a4 substrate digoxin. METHODS: In the perfused rat liver, two successive digoxin doses of 42 and 125 microg were administered, and the outflow concentration was determined by LC/MS/MS. [14C]-sucrose was used as vascular reference. The data were analyzed simultaneously by a population approach using sucrose to determine the sinusoidal mixing of digoxin. RESULTS: The results suggest the existence of a high-affinity, low-capacity system, and a low-affinity, high-capacity system for sinusoidal uptake with apparent Michaelis constants (K(M)) of 0.24 and 332 microg/ml, respectively. Incorporation of saturable sinusoidal binding of digoxin considerably improved the fit, and the parameter estimates were consistent with those of binding to hepatic Na,K-ATPase. Simpler models that neglect the concentration gradient in flow direction failed to describe the outflow data in the high dose range. CONCLUSION: The semi-distributed liver model with saturable uptake should be useful for a functional characterization of transporters in the in situ rat liver.