Individual differences in the perception of phonetic category structure predict speech-in-noise performance.

Speech sounds exist in a complex acoustic-phonetic space, and listeners vary in the extent to which they are sensitive to variability within the speech sound category ("gradience") and the degree to which they show stable, consistent responses to phonetic stimuli. Here, we investigate the hypothesis that individual differences in the perception of the sound categories of one's language may aid speech-in-noise performance across the adult lifespan. Declines in speech-in-noise performance are well documented in healthy aging, and are, unsurprisingly, associated with differences in hearing ability. Nonetheless, hearing status and age are incomplete predictors of speech-in-noise performance, and long-standing research suggests that this ability draws on more complex cognitive and perceptual factors. In this study, a group of adults ranging in age from 18 to 67 years performed online assessments designed to measure phonetic category sensitivity, questionnaires querying recent noise exposure history and demographic factors, and crucially, a test of speech-in-noise perception. Results show that individual differences in the perception of two consonant contrasts significantly predict speech-in-noise performance, even after accounting for age and recent noise exposure history. This finding supports the hypothesis that individual differences in sensitivity to phonetic categories mediates speech perception in challenging listening situations.

Neurodegenerative disorders, metabolic icebergs, and mitohormesis.

Neurodegenerative disorders are typically "split" based on their hallmark clinical, anatomical, and pathological features, but they can also be "lumped" by a shared feature of impaired mitochondrial biology. This leads us to present a scientific framework that conceptualizes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) as "metabolic icebergs" comprised of a tip, a bulk, and a base. The visible tip conveys the hallmark neurological symptoms, neurodegenerative regions, and neuronal protein aggregates for each disorder. The hidden bulk depicts impaired mitochondrial biology throughout the body, which is multifaceted and may be subdivided into impaired cellular metabolism, cell-specific mitotypes, and mitochondrial behaviours, functions, activities, and features. The underlying base encompasses environmental factors, especially modern industrial toxins, dietary lifestyles, and cognitive, physical, and psychosocial behaviours, but also accommodates genetic factors specific to familial forms of AD, PD, and ALS, as well as HD. Over years or decades, chronic exposure to a particular suite of environmental and genetic factors at the base elicits a trajectory of impaired mitochondrial biology that maximally impacts particular subsets of mitotypes in the bulk, which eventually surfaces as the hallmark features of a particular neurodegenerative disorder at the tip. We propose that impaired mitochondrial biology can be repaired and recalibrated by activating "mitohormesis", which is optimally achieved using strategies that facilitate a balanced oscillation between mitochondrial stressor and recovery phases. Sustainably harnessing mitohormesis may constitute a potent preventative and therapeutic measure for people at risk of, or suffering with, neurodegenerative disorders.

Internalizing and somatic symptoms influence the discrepancy between subjective and objective cognitive difficulties in adults with ADHD who have valid and invalid test scores.

OBJECTIVES: This study investigated the relationship between various intrapersonal factors and the discrepancy between subjective and objective cognitive difficulties in adults with attention-deficit hyperactivity disorder (ADHD). The first aim was to examine these associations in patients with valid cognitive symptom reporting. The next aim was to investigate the same associations in patients with invalid scores on tests of cognitive symptom overreporting. METHOD: The sample comprised 154 adults who underwent a neuropsychological evaluation for ADHD. Patients were divided into groups based on whether they had valid cognitive symptom reporting and valid test performance (n = 117) or invalid cognitive symptom overreporting but valid test performance (n = 37). Scores from multiple symptom and performance validity tests were used to group patients. Using patients' scores from a cognitive concerns self-report measure and composite index of objective performance tests, we created a subjective-objective discrepancy index to quantify the extent of cognitive concerns that exceeded difficulties on objective testing. Various measures were used to assess intrapersonal factors thought to influence the subjective-objective cognitive discrepancy, including demographics, estimated premorbid intellectual ability, internalizing symptoms, somatic symptoms, and perceived social support. RESULTS: Patients reported greater cognitive difficulties on subjective measures than observed on objective testing. The discrepancy between subjective and objective scores was most strongly associated with internalizing and somatic symptoms. These associations were observed in both validity groups. CONCLUSIONS: Subjective cognitive concerns may be more indicative of the extent of internalizing and somatic symptoms than actual cognitive impairment in adults with ADHD, regardless if they have valid scores on cognitive symptom overreporting tests.

Multiparametric Cranberry (Vaccinium macrocarpon Ait.) Fruit Textural Trait Development for Harvest and Postharvest Evaluation in Representative Cultivars.

Fruit texture is a priority trait that guarantees the long-term economic sustainability of the cranberry industry through value-added products such as sweetened dried cranberries (SDCs). To develop a standard methodology to measure texture, we conducted a comparative analysis of 22 textural traits using five different methods under both harvest and postharvest conditions in 10 representative cranberry cultivars. A set of textural traits from the 10%-strain compression and puncture methods were identified that differentiate between cultivars primarily based on hardness/stiffness and elasticity properties. The complementary use of both methodologies allowed for a detailed evaluation by capturing the effect of key texture-determining factors such as structure, flesh, and skin. Furthermore, the high effectiveness of this approach in different conditions and its ability to capture high phenotypic variation in cultivars highlights its great potential for applicability in various areas of the value chain and research. Therefore, this study provides an informed reference for unifying future efforts to enhance cranberry fruit texture and quality.

Metabolic immaturity and breastmilk bile acid metabolites are central determinants of heightened newborn vulnerability to norovirus diarrhea.

The pathogenic outcome of enteric virus infections is governed by a complex interplay between the virus, intestinal microbiota, and host immune factors, with metabolites serving as a key mediator. Noroviruses bind bile acid metabolites, which are produced by the host and then modified by commensal bacteria. Paradoxically, bile acids can have both proviral and antiviral roles during norovirus infections. Working in an infant mouse model of norovirus infection, we demonstrate that microbiota and their bile acid metabolites protect from norovirus diarrhea, whereas host bile acids promote disease. We also find that maternal bile acid metabolism determines the susceptibility of newborn mice to norovirus diarrhea during breastfeeding. Finally, targeting maternal and neonatal bile acid metabolism can protect newborn mice from norovirus disease. In summary, neonatal metabolic immaturity and breastmilk bile acids are central determinants of heightened newborn vulnerability to norovirus disease.

Beyond CREA: Evolutionary patterns of non-allometric shape variation and divergence in a highly allometric clade of murine rodents.

The shared functions of the skull are thought to result in common evolutionary patterns in mammalian cranial shape. Craniofacial evolutionary allometry (CREA) is a particularly prominent pattern where larger species display proportionally elongate facial skeletons and smaller braincases. It was recently proposed that CREA arises from biomechanical effects of cranial scaling when diets are similar. Thus, deviations from CREA should occur with changes in cranial biomechanics, for example due to dietary change. Here, we test this using 3D geometric morphometric analysis in a dataset of Australian murine crania, which are highly allometric. We contrast allometric and non-allometric variation in the cranium by comparing evolutionary mode, allometry, ordinations, as well as allometry, integration, and modularity in functional modules. We found evidence of stabilising selection in allometry-containing and size-free shape, and substantial non-allometric variation aligned with dietary specialisation in parallel with CREA. Integration among cranial modules was higher, and modularity lower, with size included, but integration between rostrum and cranial vault, which are involved in the CREA pattern, dropped dramatically after size removal. Our results thus support the hypothesis that CREA is a composite arising from selection on cranial function, with substantial non-allometric shape variation occurring alongside CREA where dietary specialisation impacts selection on gnawing function. This emphasises the need to research mammalian cranial evolution in the context of allometric and non-allometric selection on biomechanical function.

The differential burden of 3 health care-associated infections on hospital costs and lengths of stay: A quasi-experimental case-control observation.

In patients with a health care-associated infection (HAI), lengths of stay and costs increased >150% from 2019 to 2023, and were 2 to 6 times greater compared to concurrent non-HAI patients with the same diagnoses. Unlike surgical HAI, no device-associated HAI occurred before hospital day 12. These findings highlight the possibly under-recognized influence of delayed discharges on device-associated HAIs.

Auditory Processing of Speech and Nonspeech in People Who Stutter.

PURPOSE: We investigated speech and nonspeech auditory processing of temporal and spectral cues in people who do and do not stutter. We also asked whether self-reported stuttering severity was predicted by performance on the auditory processing measures. METHOD: People who stutter (n = 23) and people who do not stutter (n = 28) completed a series of four auditory processing tasks online. These tasks consisted of speech and nonspeech stimuli differing in spectral or temporal cues. We then used independent-samples t-tests to assess differences in phonetic categorization slopes between groups and linear mixed-effects models to test differences in nonspeech auditory processing between stuttering and nonstuttering groups, and stuttering severity as a function of performance on all auditory processing tasks. RESULTS: We found statistically significant differences between people who do and do not stutter in phonetic categorization of a continuum differing in a temporal cue and in discrimination of nonspeech stimuli differing in a spectral cue. A significant proportion of variance in self-reported stuttering severity was predicted by performance on the auditory processing measures. CONCLUSIONS: Taken together, these results suggest that people who stutter process both speech and nonspeech auditory information differently than people who do not stutter and may point to subtle differences in auditory processing that could contribute to stuttering. We also note that these patterns could be the consequence of listening to one's own speech, rather than the cause of production differences.

Defect-Free, Few-Atomic-Layer Thin ZnO Nanosheets with Superior Excitonic Properties for Optoelectronic Devices.

Two-dimensional (2D) wide bandgap materials are gaining significant interest for next-generation optoelectronic devices. However, fabricating electronic-grade 2D nanosheets from non-van der Waals (n-vdW) oxide semiconductors poses a great challenge due to their stronger interlayer coupling compared with vdW crystals. This strong coupling typically introduces defects during exfoliation, impairing the optoelectronic properties. Herein, we report the liquid-phase exfoliation of few-atomic-layer thin, defect-free, free-standing ZnO nanosheets. These micron-sized, ultrathin ZnO structures exhibit three different orientations aligned along both the polar c-plane as well as the nonpolar a- and m-planes. The superior crystalline quality of the ZnO nanosheets is validated through comprehensive characterization techniques. This result is supported by density functional theory (DFT) calculations, which reveals that the formation of oxygen vacancies is energetically less favorable in 2D ZnO and that the c-plane loses its polarity upon exfoliation. Unlike bulk ZnO, which is typically dominated by defect-induced emission, the exfoliated nanosheets exhibit a strong, ambient-stable excitonic UV emission. We further demonstrate the utility of solution processing of ZnO nanosheets by their hybrid integration with organic components to produce stable light emitting diodes (LEDs) for display applications.

Effect of processing speed and memory performance on classification accuracy of the dot counting test in a mixed neuropsychiatric sample.

OBJECTIVE: This study examined the impact of impairment in two specific cognitive abilities, processing speed and memory, on Dot Counting Test (DCT) classification accuracy by evaluating performance validity classification accuracy across cognitively unimpaired, single-domain impairment, and multidomain impairment subgroups within a mixed clinical sample. METHOD: Cross-sectional data were analyzed from 348 adult outpatients classified as valid (n = 284) or invalid (n = 64) based on four independent criterion performance validity tests (PVTs). Unimpaired (n = 164), single-domain processing speed impairment (n = 24), single-domain memory impairment (n = 53), and multidomain processing speed and memory impairment (n = 43) clinical subgroups were established among the valid group. Both the traditional DCT E-score and unrounded E-score were examined. RESULTS: Overall, the DCT demonstrated acceptable to excellent classification accuracy across the unimpaired (area under the curve [AUC] traditional E-score=.855; unrounded E-score=.855) and single-domain impairment groups (traditional E-score AUCs = .690-.754; unrounded E-score AUCs = .692-747). However, it did not reliably discriminate the multidomain processing speed and memory impairment group from the invalid performers (traditional and unrounded E-scores AUC = .557). CONCLUSIONS: Findings support the DCT as a non-memory-based freestanding PVT for use with single-domain cognitive impairment, with traditional E-score ≥17 (unrounded E-score ≥16.95) recommended for those with memory impairment and traditional E-score ≥19 (unrounded ≥18.08) with processing speed impairment. Moreover, results replicated previously established optimal cutoffs for unimpaired groups using both the traditional (≥14) and unrounded (≥13.84) E-scores. However, the DCT did not reliably discriminate between invalid performance and multidomain cognitive impairment, indicating caution is warranted when using the DCT with patients suspected of greater cognitive impairment.

Characterising illness stages and recovery trajectories of eating disorders in young people via remote measurement technology (STORY): a multi-centre prospective cohort study protocol.

BACKGROUND: Eating disorders (EDs) are serious, often chronic, conditions associated with pronounced morbidity, mortality, and dysfunction increasingly affecting young people worldwide. Illness progression, stages and recovery trajectories of EDs are still poorly characterised. The STORY study dynamically and longitudinally assesses young people with different EDs (restricting; bingeing/bulimic presentations) and illness durations (earlier; later stages) compared to healthy controls. Remote measurement technology (RMT) with active and passive sensing is used to advance understanding of the heterogeneity of earlier and more progressed clinical presentations and predictors of recovery or relapse. METHODS: STORY follows 720 young people aged 16-25 with EDs and 120 healthy controls for 12 months. Online self-report questionnaires regularly assess ED symptoms, psychiatric comorbidities, quality of life, and socioeconomic environment. Additional ongoing monitoring using multi-parametric RMT via smartphones and wearable smart rings ('Oura ring') unobtrusively measures individuals' daily behaviour and physiology (e.g., Bluetooth connections, sleep, autonomic arousal). A subgroup of participants completes additional in-person cognitive and neuroimaging assessments at study-baseline and after 12 months. DISCUSSION: By leveraging these large-scale longitudinal data from participants across ED diagnoses and illness durations, the STORY study seeks to elucidate potential biopsychosocial predictors of outcome, their interplay with developmental and socioemotional changes, and barriers and facilitators of recovery. STORY holds the promise of providing actionable findings that can be translated into clinical practice by informing the development of both early intervention and personalised treatment that is tailored to illness stage and individual circumstances, ultimately disrupting the long-term burden of EDs on individuals and their families.

Metabolic immaturity of newborns and breast milk bile acid metabolites are the central determinants of heightened neonatal vulnerability to norovirus diarrhea.

Noroviruses are the leading global cause of acute gastroenteritis, responsible for 685 million annual cases. While all age groups are susceptible to noroviruses, children are vulnerable to more severe infections than adults, underscored by 200 million pediatric cases and up to 200,000 deaths in children annually. Understanding the basis for the increased vulnerability of young hosts is critical to developing effective treatments. The pathogenic outcome of any enteric virus infection is governed by a complex interplay between the virus, intestinal microbiota, and host immune factors. A central mediator in these complex relationships are host- and microbiota-derived metabolites. Noroviruses bind a specific class of metabolites, bile acids, which are produced by the host and then modified by commensal bacterial enzymes. Paradoxically, bile acids can have both proviral and antiviral roles during norovirus infections. Considering these opposing effects, the microbiota-regulated balance of the bile acid pool may be a key determinant of the pathogenic outcome of a norovirus infection. The bile acid pool in newborns is unique due to immaturity of host metabolic pathways and developing gut microbiota, which could underlie the vulnerability of these hosts to severe norovirus infections. Supporting this concept, we demonstrate herein that microbiota and their bile acid metabolites protect from severe norovirus diarrhea whereas host-derived bile acids promote disease. Remarkably, we also report that maternal bile acid metabolism determines neonatal susceptibility to norovirus diarrhea during breastfeeding by delivering proviral bile acids to the newborn. Finally, directed targeting of maternal and neonatal bile acid metabolism can protect the neonatal host from norovirus disease. Altogether, these data support the conclusion that metabolic immaturity in newborns and ingestion of proviral maternal metabolites in breast milk are the central determinants of heightened neonatal vulnerability to norovirus disease.

Clinician perspectives of the implementation of an early intervention service for eating disorders in England: a mixed method study.

BACKGROUND: The First Episode Rapid Early Intervention for Eating Disorders (FREED) service has been shown to reduce the wait for care and improve clinical outcomes in initial evaluations. These findings led to the national scaling of FREED in England. To support this scaling, we conducted a mixed method evaluation of the perceptions and experiences of clinicians in the early phases of scaling. The Normalisation Process Theory (NPT) was used as a conceptual lens to understand if and how FREED becomes embedded in routine practice. METHODS: The convergent mixed method evaluation included 21 semi-structured interviews with clinicians from early adopter sites and 211 surveys administered to clinicians before, immediately after and 3 months after the FREED training. The interview guide and survey included questions evaluating attitudes towards early intervention for eating disorders (EDs) and NPT mechanisms. Interview data were analysed using an inductive thematic analysis. The NPT was applied to the inductively derived themes to evaluate if and how NPT domains impacted the implementation. Survey data were analysed using multilevel growth models. RESULTS: Six themes and 15 subthemes captured barriers and facilitators to implementation at the patient, clinician, service, intervention, implementation and wider system levels. These interacted with the NPT mechanisms to facilitate or hinder the embedding of FREED. Overall, clinicians were enthusiastic and positive towards early intervention for EDs and FREED, largely because of the expectation of improved patient outcomes. This was a considerable driver in the uptake and implementation of FREED. Clinicians also had reservations about capacity and the potential impact on other patients, which, at times, was a barrier for its use. The FREED training led to significant improvements in positive attitudes and NPT mechanisms that were largely maintained at the 3-month follow-up. However, negative attitudes did not significantly improve following training. CONCLUSIONS: Positive attitudes towards early intervention for EDs increased enthusiasm and engagement with the model. Features of the model and its implementation were effective at developing adopter commitment and capabilities. However, there were aspects of the model and its implementation which require attention in the future (e.g., capacity and the potential impact on the wider service).

4-Chloroisocoumarins as Chlamydial Protease Inhibitors and Anti-Chlamydial Agents.

4-Chloroisocoumarin compounds have broad inhibitory properties against serine proteases. Here, we show that selected 3-alkoxy-4-chloroisocoumarins preferentially inhibit the activity of the conserved serine protease High-temperature requirement A of Chlamydia trachomatis. The synthesis of a new series of isocoumarin-based scaffolds has been developed, and their anti-chlamydial properties were investigated. The structure of the alkoxy substituent was found to influence the potency of the compounds against High-temperature requirement A, and modifications to the C-7 position of the 3-alkoxy-4-chloroisocoumarin structure attenuate anti-chlamydial properties.

Ketogenic metabolic therapy in conjunction with standard treatment for glioblastoma: A case report.

Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. The standard of care consists of surgical resection and concurrent chemoradiation, followed by adjuvant temozolomide chemotherapy. This protocol is associated with a median survival of 12-15 months, and <5% of patients survive >3 years. Ketogenic metabolic therapy (KMT) targets cancer cell metabolism by restricting glucose availability and evoking differential stress resistance and sensitization, which may augment the standard treatments and lead to therapeutic benefit. The present study reports the case of a 64-year-old woman with isocitrate dehydrogenase (IDH)-wildtype GBM who pursued the standard treatment protocol in conjunction with an intensive, multimodal KMT program for 3 years. The KMT program consisted of a series of prolonged (7-day, fluid-only) fasts, which were specifically timed to maximize the tolerability and efficacy of the standard treatments, combined with a time-restricted ketogenic diet on all other days. During the first and second treatment years the patient sustained a glucose ketone index (GKI) of 1.65 and 2.02, respectively, which coincided with complete clinical improvement, a healthy body-mass index and a high quality of life, with no visible progressive tumour detected on imaging at the end of the second year. In the setting of the death of an immediate family member leading to increased life stress, slightly relaxed KMT adherence, and a higher GKI of 3.20, slow cancer progression occurred during the third year. The adverse effects attributed to KMT were mild. Despite the limitations of this case report, it highlights the feasibility of implementing the standard treatment protocol for GBM in conjunction with an intensive, long-term, multimodal and specifically timed KMT program, the potential therapeutic efficacy of which may depend upon achieving as low a GKI as possible.

Infectious Diseases in a Changing Climate.

This JAMA Insights in the Climate Change and Health series discusses the importance of clinicians having awareness of changes in the geographic range, seasonality, and intensity of transmission of infectious diseases to help them diagnose, treat, and prevent these diseases.

HtrA, fatty acids, and membrane protein interplay in Chlamydia trachomatis to impact stress response and trigger early cellular exit.

Chlamydia trachomatis is an intracellular bacterial pathogen that undergoes a biphasic developmental cycle, consisting of intracellular reticulate bodies and extracellular infectious elementary bodies. A conserved bacterial protease, HtrA, was shown previously to be essential for Chlamydia during the reticulate body phase, using a novel inhibitor (JO146). In this study, isolates selected for the survival of JO146 treatment were found to have polymorphisms in the acyl-acyl carrier protein synthetase gene (aasC). AasC encodes the enzyme responsible for activating fatty acids from the host cell or synthesis to be incorporated into lipid bilayers. The isolates had distinct lipidomes with varied fatty acid compositions. A reduction in the lipid compositions that HtrA prefers to bind to was detected, yet HtrA and MOMP (a key outer membrane protein) were present at higher levels in the variants. Reduced progeny production and an earlier cellular exit were observed. Transcriptome analysis identified that multiple genes were downregulated in the variants especially stress and DNA processing factors. Here, we have shown that the fatty acid composition of chlamydial lipids, HtrA, and membrane proteins interplay and, when disrupted, impact chlamydial stress response that could trigger early cellular exit. IMPORTANCE: Chlamydia trachomatis is an important obligate intracellular pathogen that has a unique biphasic developmental cycle. HtrA is an essential stress or virulence protease in many bacteria, with many different functions. Previously, we demonstrated that HtrA is critical for Chlamydia using a novel inhibitor. In the present study, we characterized genetic variants of Chlamydia trachomatis with reduced susceptibility to the HtrA inhibitor. The variants were changed in membrane fatty acid composition, outer membrane proteins, and transcription of stress genes. Earlier and more synchronous cellular exit was observed. Combined, this links stress response to fatty acids, membrane proteins, and HtrA interplay with the outcome of disrupted timing of chlamydial cellular exit.