Costs of Severe to Profound Hearing Loss & Cost Savings of Cochlear Implants.

OBJECTIVE: To estimate costs of severe to profound hearing loss, including costs and cost-savings associated with cochlear implantation. METHODS: Data was obtained from the National Health Interview Survey, the National Health and Nutrition Examination Survey and national Medicare rates. We used continuous time state transition models with individual patient simulations to estimate the costs of severe to profound hearing loss (SPHL) across the lifespan. The model included four states, normal hearing, severe to profound hearing loss, cochlear implantation, and death. RESULTS: The estimated lifetime cost of an individual born with SPHL is $489,274 [377,518; 616,519]. Costs are lower for those who received a cochlear implant before 18 months of age $390,931 [311,976; 471,475], compared to those who are not implanted $608,167 [442,544; 791,719]. For individuals with a later onset of hearing loss (60 years old) lifetime costs were $154,536 [7,093; 302,936]. The annual societal costs for the US population were estimated to be $37 [8; 187] billion. CONCLUSIONS: SPHL is a costly condition, with the primary driver being lost productivity. Medical costs were higher for cochlear implantation, however, the higher income earnings offset the higher medical costs. Overall, early implantation substantially reduced lifetime costs. Access to hearing health care and technology is critical given the documented benefits for language, education, and quality of life. Government and insurance policies should be modified to allow for equal access and coverage for hearing technology, which will ultimately reduce lifetime and societal costs. LEVELS OF EVIDENCE: N/A The current study used existing nationally representative datasets. Thus, these levels of evidence do not apply. Laryngoscope, 2024.

Cognitive representations of intracranial self-stimulation of midbrain dopamine neurons depend on stimulation frequency.

Dopamine neurons in the ventral tegmental area support intracranial self-stimulation (ICSS), yet the cognitive representations underlying this phenomenon remain unclear. Here, 20-Hz stimulation of dopamine neurons, which approximates a physiologically relevant prediction error, was not sufficient to support ICSS beyond a continuously reinforced schedule and did not endow cues with a general or specific value. However, 50-Hz stimulation of dopamine neurons was sufficient to drive robust ICSS and was represented as a specific reward to motivate behavior. The frequency dependence of this effect is due to the rate (not the number) of action potentials produced by dopamine neurons, which differently modulates dopamine release downstream.

Copolymers of Gelatin-graft-poly(3-hexylthiophene) for Transient Electronics.

As transient electronics continue to advance, the demand for new materials has given rise to the exploration of conducting polymer (CP)-based electronic materials. The big challenge lies in balancing conductivity while introducing controlled degradable properties into CP-based transient materials. In response to this, we present in this work a concept of using conducting polymers attached to an enzymatically biodegradable biopolymer to create transient polymer electronics materials. Specifically, poly(3-hexyl thiophene) (P3HT) is covalently grafted onto biopolymer gelatin, affording graft copolymer gelatin-graft-poly(3-hexyl thiophene) (termed Gel-g-P3HT). The thin films of Gel-g-P3HT that were produced by optimized processing solvent (THF/H2O cosolvent) showed enhanced π-π stacking domains of P3HT, resulting in semiconducting thin films with good electroactivity. Due to the presence of amide bonds in the gelatin backbone, Gel-g-P3HT underwent degradation over a period of 5 days, resulting in the formation of amphiphilic micellar nanoparticles that are biocompatible and nontoxic. The potential of these conductive and degradable graft copolymers was demonstrated in a pressure sensor. This research paves the way for developing biocompatible and enzymatically degradable polymer materials based on P3HT, enabling the next generation of transient polymer electronics for diverse applications, such as skin, implantable, and environmental electronics.

Intermedianin, a new furofuran lignan from the leaves of Knema intermedia Warb.

Phytochemical investigation of the leaves of Knema intermedia has led to the isolation of a new furofuran lignan, intermedianin 1 together with five known lignans, α-cubebin 2, ß-cubebin 3, bicubebin A 4, bicubebin B 5, and bicubebin C 6. The characterisation and structural elucidation of the isolated compounds were established by extensive spectroscopic data analysis and comparison with literature data. The antifungal activity was tested using the broth microdilution assay, whereas the microbial biofilms were determined using a semi-quantitative static biofilm. Compound 1 exhibited activity against C. albicans, C. lusitanae, and C. auris, (each with MIC/MFC value 250 µg/mL) and increased the biofilm of C. auris (64.07 ± 3.83%) and Candida lusitanae (62.90 ± 3.41%) when treated with 500 µg/mL.

Investigation Into Novel Mukanadin B, Mukanadin D and Mukanadin F Derivatives as Antagonists of 5-HT1A Signalling.

Marine bromopyrrole alkaloids are a diverse family of natural products with a large array of biological applications. The mukanadin family is a group of molecules consisting of seven members (mukanadin A-G) that possess a range of biological activities. Inhibition of serotonergic signaling has been demonstrated by mukanadin B derivatives, presenting this chemical scaffold as a candidate for further SAR exploration. A library of thirteen novel mukanadin B and D derivatives with structural variation targeted at the pyrrole ring, central linker and hydantoin ring, were synthesized. These analogues were subsequently assessed for serotonergic antagonism, in addition to natural products, mukanadin B, D, F and 9-hydroxy mukanadin B. A collection of compounds exhibited significant 5-HT1A signaling, including five of the novel derivatives and two of the naturally occurring bromopyrroles, mukanadin B and F. Particular SAR information could be determined from these results, such as modification of the pyrrole ring being a well-tolerated strategy for improving serotonergic inhibition. Other changes to the pharmacophore led to significant reduction in activity such as saturation of the linker region, or no conclusive improvement in inhibitory activity such as a 9-OH group or replacement of the hydantoin ring with a triazole moiety.

Antimicrobial fibres derived from aryl-diazonium conjugation of chitosan with Harakeke (Phormium tenax) and Hemp (Cannabis sativa) Hurd.

Surface functionalisation of natural materials to develop sustainable and environmentally friendly antimicrobial fibres has received great research interest in recent years. Herein, chitosan covalent conjugation via aryl-diazonium based chemistry onto Phormium tenax fibres (PTF) and hemp hurds (HH) was investigated. PTF are fibres derived from Harakeke/New Zealand flax, an indigenous and abundant plant source of leaf fibres, which served as an important 19th century export commodity of New Zealand. HH are obtained as a by-product from the hemp (Cannabis sativa) industry and find applications as traditional construction material, animal bedding, chemical absorbent, insulation, fireboard etc. This study reports aryl-diazonium covalent attachment of chitosan and PD13 (6-O-(3-(2-(N,N-dimethylamino)ethylamino)-2-hydroxypropyl)chitosan), a chitosan derivative with improved antibacterial activity, on to PTF and HH. The modification was confirmed using FTIR, XPS, SEM and water contact angle studies. Comparison of aryl-diazonium versus the use of succinic anhydride bridging for chitosan attachment was also investigated, with the diazonium method giving improved results. The treated PTF and HH fibres had good antibacterial activity against Staphylococcus aureus and this study contributes to the development of sustainable antibacterial fibres using bio-based materials.

Encapsulation of the growth factor neurotrophin-3 in heparinised poloxamer hydrogel stabilises bioactivity and provides sustained release.

Poloxamer-based hydrogels show promise to stabilise and sustain the delivery of growth factors in tissue engineering applications, such as following spinal cord injury. Typically, growth factors such as neurotrophin-3 (NT-3) degrade rapidly in solution. Similarly, poloxamer hydrogels also degrade readily and are, therefore, only capable of sustaining the release of a payload over a small number of days. In this study, we focused on optimising a hydrogel formulation, incorporating both poloxamer 188 and 407, for the sustained delivery of bioactive NT-3. Hyaluronic acid blended into the hydrogels significantly reduced the degradation of the gel. We identified an optimal hydrogel composition consisting of 20 % w/w poloxamer 407, 5 % w/w poloxamer 188, 0.6 % w/w NaCl, and 1.5 % w/w hyaluronic acid. Heparin was chemically bound to the poloxamer chains to enhance interactions between the hydrogel and the growth factor. The unmodified and heparin-modified hydrogels exhibited sustained release of NT-3 for 28 days while preserving the bioactivity of NT-3. Moreover, these hydrogels demonstrated excellent cytocompatibility and had properties suitable for injection into the intrathecal space, underscoring their suitability as a growth factor delivery system. The findings presented here contribute valuable insights to the development of effective delivery strategies for therapeutic growth factors for tissue engineering approaches, including the treatment of spinal cord injury.

Total Syntheses and Absolute Stereochemical Correction of Negundin B, Vitexin 1, and Vitexin 6.

A highly adaptable asymmetric synthetic route toward dihydronaphthalene lignans was developed, with its application to the syntheses of negundin B and vitexin 1/6 described herein. This developed pathway proceeded through an enantioselective aldol reaction to establish the contiguous stereocenters present in the final structures with subsequent functional group transformations yielding (-)-negundin B and (-)-vitexin 1/6. The enantioselective synthesis of vitexin 1/6 allowed the correction of absolute configuration, which has been widely incorrectly reported.

Total Synthesis of (-)-Amovillosumin A and Structure Correction of (-)-Amovillosumin C Using Chemical Synthesis.

Norlignans are a rare class of natural products isolated from a diverse range of plant species, many of which have interesting biological activities including antibacterial, antioxidant, phytotoxic, platelet aggregation inhibitory effects, and more. Isolated from Amomum villosum (Amomi Fructus), amovillosumins A (1) and C (3) are norlignans which were of interest to synthesize, due to their interesting bioactivities, specifically their ability to increase stimulation of glucagon-like peptide-1 (GLP-1) secretion. In this research, key intermediate 15 was used to stereoselectively synthesize (7R,8R)-amovillosumins A (1) and C (3). The developed method includes a Mitsunobu coupling, a modified rhodium-catalyzed Miyaura arylation, and an acid-catalyzed cyclization in key bond-forming steps. After synthesis, the structure of 1 was confirmed, but it was revealed that the benzodioxane-containing structure of amovillosumin C (3) that had been proposed in the literature was incorrect. Thus, with further investigation a structure correction of 3 was achieved by synthesis, the correct structure being 8-O-4'-oxynorlignan.

Altered sleep architecture following consecutive nights of presleep alcohol.

STUDY OBJECTIVES: Alcohol consumption before sleep decreases sleep latency, explaining the common use of alcohol as a sleep aid. The full impact of alcohol on sleep architecture is not well understood, particularly the potential cumulative effects of presleep alcohol consumption across consecutive nights. Here, we describe the effects of presleep alcohol on sleep architecture across three consecutive nights. METHODS: Thirty adult participants took part in a crossover, within-participants study consisting of two sets of three consecutive nights of in-lab polysomnography. For each series of nights, participants drank one of the two beverages: a mixer only or a mixer plus alcohol (targeting a BrAC of 0.08 mg/L), ending 1 hour before lights out. Polysomnography (PSG) was used to stage sleep, and standard sleep variables were extracted. Linear mixed-effect analysis and generalized additive modeling were used to examine the effect of alcohol on sleep architecture. RESULTS: Alcohol before sleep increased the rate of slow wave sleep (SWS) accumulation across all three nights and decreased the rate of rapid eye movement (REM) sleep accumulation at the start of each night. Alcohol also decreased the total amount of REM sleep but did not affect the total amount of SWS each night. CONCLUSIONS: These data indicate that drinking alcohol before sleep substantially affects sleep architecture, including changes to the rate of accumulation of SWS and REM sleep. We show that alcohol disrupts normal sleep architecture, leading to a significant decrease in REM sleep; thus, the use of alcohol as a sleep aid remains a public health concern.

The associations between instructional approach, sleep characteristics and adolescent mental health: Lessons from the COVID-19 pandemic.

OBJECTIVES: To test whether adolescents' mental health during the COVID-19 pandemic is associated with the combination of their instructional approach(es) and their sleep patterns. DESIGN: Cross-sectional. SETTING: Adolescents were recruited through social media outlets in October and November 2020 to complete an online survey. PARTICIPANTS: Participants were 4442 geographically and racially diverse, community-dwelling students (grades 6-12, 51% female, 36% non-White, 87% high schoolers). MEASUREMENTS: Participants completed items from the PROMIS Pediatric Depressive Symptoms and Anxiety scales. Participants reported their instructional approach(es), bedtimes, and wake times for each day in the past week. Participants were categorized into five combined instructional approach groups. Average sleep opportunity was calculated as the average time between bedtime and waketime. Social jetlag was calculated as the difference between the average sleep midpoint preceding non-scheduled and scheduled days. RESULTS: Emotional distress was elevated in this sample, with a large proportion of adolescents reporting moderate-severe (T-score ≥ 65) levels of depressive symptoms (49%) and anxiety (28%). There were significant differences between instructional approach groups, such that adolescents attending all schooldays in-person reported the lowest depressive symptom and anxiety T-scores (P < .001, ηp2 = .012), but also the shortest sleep opportunity (P < .001, ηp2 = .077) and greatest social jetlag (P < .001, ηp2 = .037) of all groups. Adolescents attending school in person, with sufficient sleep opportunity (≥8-9 hours/night) and limited social jetlag (<2 hours) had significantly lower depressive (ηp2 = .014) and anxiety (ηp2 = .008) T-scores than other adolescents. CONCLUSIONS: Prioritizing in-person education and promoting healthy sleep patterns (more sleep opportunity, more consistent sleep schedules) may help bolster adolescent mental health.

Systematically missing data in causally interpretable meta-analysis.

Causally interpretable meta-analysis combines information from a collection of randomized controlled trials to estimate treatment effects in a target population in which experimentation may not be possible but from which covariate information can be obtained. In such analyses, a key practical challenge is the presence of systematically missing data when some trials have collected data on one or more baseline covariates, but other trials have not, such that the covariate information is missing for all participants in the latter. In this article, we provide identification results for potential (counterfactual) outcome means and average treatment effects in the target population when covariate data are systematically missing from some of the trials in the meta-analysis. We propose three estimators for the average treatment effect in the target population, examine their asymptotic properties, and show that they have good finite-sample performance in simulation studies. We use the estimators to analyze data from two large lung cancer screening trials and target population data from the National Health and Nutrition Examination Survey (NHANES). To accommodate the complex survey design of the NHANES, we modify the methods to incorporate survey sampling weights and allow for clustering.

Development of truncated Battacin antimicrobials featuring novel N-terminal fatty acids with an excellent safety profile.

Octapeptin B5 peptides containing a novel fatty acids have been found to have enhanced antibacterial activity against Staphylococcus aureus and also have an excellent safety profile. Cyclic lipopeptides such as the polymyxins and battacin are potent antibacterial agents. It has been shown that truncated, non-linear, versions of these agents (e.g. octapeptin B5) can retain the activity of the more complex cyclic compounds. In this work the synthesis of Octapeptin B5 peptides containing a range of novel fatty acids is reported. Many of these lipopeptides have been found to have enhanced antibacterial activity against Staphylococcus aureus compared to Octapeptin B5 whilst also having an excellent safety profile in haemolytic and cytotoxicity assays.

Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants: Follow-Up of the OPTIMIST-A Randomized Clinical Trial.

Importance: The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified. Objective: To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years' corrected age. Design, Setting, and Participants: Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years' corrected age was completed on December 9, 2022. Interventions: Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment. Main Outcomes and Measures: The key secondary outcome of death or moderate to severe NDD was assessed at 2 years' corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years. Results: Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, -7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90]). Conclusions and Relevance: In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Addressing Systematic Missing Data in the Context of Causally Interpretable Meta-analysis.

Evidence synthesis involves drawing conclusions from trial samples that may differ from the target population of interest, and there is often heterogeneity among trials in sample characteristics, treatment implementation, study design, and assessment of covariates. Stitching together this patchwork of evidence requires subject-matter knowledge, a clearly defined target population, and guidance on how to weigh evidence from different trials. Transportability analysis has provided formal identifiability conditions required to make unbiased causal inference in the target population. In this manuscript, we review these conditions along with an additional assumption required to address systematic missing data. The identifiability conditions highlight the importance of accounting for differences in treatment effect modifiers between the populations underlying the trials and the target population. We perform simulations to evaluate the bias of conventional random effect models and multiply imputed estimates using the pooled trials sample and describe causal estimators that explicitly address trial-to-target differences in key covariates in the context of systematic missing data. Results indicate that the causal transportability estimators are unbiased when treatment effect modifiers are accounted for in the analyses. Results also highlight the importance of carefully evaluating identifiability conditions for each trial to reduce bias due to differences in participant characteristics between trials and the target population. Bias can be limited by adjusting for covariates that are strongly correlated with missing treatment effect modifiers, including data from trials that do not differ from the target on treatment modifiers, and removing trials that do differ from the target and did not assess a modifier.

Nucleus accumbens shell neurons' early sensitivity to cocaine is associated with future increases in drug intake.

The striatum, both dorsal and ventral, is strongly implicated in substance use disorder. Chronic consumption of abused substances, such as cocaine, can cause an oversaturation of mesostriatal dopamine, which results in alterations in the firing of striatal neurons. While most preclinical studies of drug self-administration (S-A) are focused on these alterations, individual differences in a subject's early responses to drugs can also account for substantial differences in addiction susceptibility. In this study, we modeled longitudinal pharmacokinetics using data from a previous longitudinal study (Coffey et al., 2015) and aimed to determine if firing in specific dorsal and ventral striatal subregions was subject to changes across chronic cocaine S-A, and if individual animal differences in striatal firing in response to early drug exposure correlated with increases in drug intake. We observed that the firing patterns of nucleus accumbens (NAc) core and shell neurons exhibited increasing sensitivity to cocaine over the first 6 S-A sessions and maintained a strong negative correlation between drug intake and neuronal firing rates across chronic S-A. Moreover, we observed that the early sensitivity of NAc shell neurons to cocaine correlated with future increases in drug intake. Specifically, rats whose NAc shell neurons were most inhibited by increasing levels of cocaine upon first exposure exhibited the strongest increases in cocaine intake over time. If this difference can be linked to a genetic difference, or druggable targets, it may be possible to screen for similar addiction susceptibility in humans or develop novel preemptive pharmacotherapies.

Lateral preoptic area glutamate neurons relay nociceptive information to the ventral tegmental area.

The ventral tegmental area (VTA) has been proposed to play a role in pain, but the brain structures modulating VTA activity in response to nociceptive stimuli remain unclear. Here, we demonstrate that the lateral preoptic area (LPO) glutamate neurons relay nociceptive information to the VTA. These LPO glutamatergic neurons synapsing on VTA neurons respond to nociceptive stimulation and conditioned stimuli predicting nociceptive stimulation and also mediate aversion. In contrast, LPO GABA neurons synapsing in the VTA mediate reward. By ultrastructural quantitative synaptic analysis, ex vivo electrophysiology, and functional neuroanatomy we identify a complex circuitry between LPO glutamatergic and GABAergic neurons and VTA dopaminergic, GABAergic, and glutamatergic neurons. We conclude that LPO glutamatergic neurons play a causal role in the processing of nociceptive stimuli and in relaying information about nociceptive stimuli. The pathway from LPO glutamatergic neurons to the VTA represents an unpredicted interface between peripheral nociceptive information and the limbic system.

Synthesis and Anti-Proliferative Activity of 5-Benzoyl and 5-Benzylhydroxy Derivatives of 3-Amino-2-Arylcarboxamido-Thieno[2-3-b]Pyridines.

3-Amino-2-arylcarboxamido-thieno[2-3-b]pyridines have been previously described as having potent anti-proliferative activity against MDA-MB-231 and HCT116 cancer cell lines. The mechanism by which these molecules prevent cancer cell growth is proposed to be through interfering with phospholipid metabolism via inhibition of PI-PLC, along with other cellular processes. Previously, 5-cinnamyl derivatives of these thieno[2-3-b]pyridines have been shown to have enhanced anti-proliferative activity compared to compounds lacking this moiety, indicating a tethered aromatic ring is important for this western region of the pharmacophore. Herein, we report the synthesis and biological evaluation of a library of 40 novel thieno[2-3-b]pyridine analogues containing shorter benzoyl or secondary benzyl alcohol tethers at the 5-position, in addition to various substituents on the two phenyl rings present on the molecule. Compounds bearing alcohol functionality had improved efficacy compared to their benzoyl counterparts, in addition to a 2-methyl-3-halogen substitution on the 2-arylcarboxamide ring being important for maximising anti-proliferative activity. The most potent molecules 7h and 7i demonstrated IC50 concentrations of 25-50 nM against HCT116 and MDA-MB-231 cells, a similar level of activity as previous thienopyridine compounds bearing cinnamyl moieties, suggesting that these novel derivatives with shorter tethers were able to maintain potent anti-proliferative activity, while allowing for a more concise synthesis.

Cochlear Implantation and Educational and Quality-of-Life Outcomes in Adolescence.

Importance: Cochlear implants (CIs) have been shown to be effective in improving auditory skills and speech and language development. However, less is known about the long-term outcomes of CIs on educational functioning or quality of life. Objective: To evaluate long-term educational outcomes and quality of life in adolescents over 13 years postimplantation. Design, Setting, and Participants: This longitudinal cohort study included 188 children with bilateral severe to profound hearing loss with CIs from the Childhood Development After Cochlear Implantation (CDaCI) study from hospital-based CI programs; a cohort of 340 children with severe to profound hearing loss without CIs from a nationally representative survey (National Longitudinal Transition Study-2; NLTS-2), and results from the literature of comparable children without CIs. Exposure(s): Cochlear implantation (early and late). Main Outcomes and Measures: Adolescent performance on measures of academic achievement (Woodcock Johnson), language (Comprehensive Assessment of Spoken Language), and quality of life (Pediatric Quality of Life Inventory, Youth Quality of Life Instrument-Deaf and Hard of Hearing). Results: The CDaCI cohort included 188 children, 136 of whom completed the wave 3 postimplantation follow-up visits (77 [55%] female) with CIs; mean [SD] age was 11.47 [1.27] years. The NLTS-2 cohort included 340 children (50% female) with severe to profound hearing loss without CIs. Children with CIs had better academic performance compared with children without CIs with similar levels of hearing loss. The largest benefits were seen for children who received implants early (prior to age 18 months), who performed at or above age and gender norms for language and academic achievement. Similarly, adolescents with CIs reported better quality of life on the Pediatric Quality of Life Inventory compared with children without CIs. On a condition-specific measure (Youth Quality of Life Instrument-Deaf and Hard of Hearing), children who received implants early scored higher across all 3 domains than comparisons without CIs. Conclusions and Relevance: To our knowledge, this is the first study to evaluate long-term educational outcomes and quality of life in adolescents using CIs. This longitudinal cohort study showed better outcomes of CIs in terms of language, academic performance, and quality of life. While the greatest benefits were observed for children who received implants before age 18 months, benefits were also noted for children who received implants later, providing evidence that children with severe to profound hearing loss with CIs can achieve at or above expected levels compared with hearing peers.