Chemical Senses

BackgroundThe construct of Hidden Hearing Loss (HHL) proposes a link between patient-reported hearing difficulties and underlying neural deficits not captured by the standard audiogram. However, the heterogeneity of this population challenges the utility of HHL as a unitary diagnosis. This study presents an exploratory analysis aimed at deconstructing the HHL symptom complex. MethodsIn 30 participants with a range of hearing abilities and complaints, we measured binaural unmasking using the Binaural Intelligibility Level Difference (BILD). We employed a two-stage analysis. First, a "lumping" analysis tested whether participants could be grouped into a unitary "HHL profile" that predicted a BILD deficit, using both theory-driven classification and data-driven clustering. Second, after this approach failed, a pre-planned exploratory "splitting" analysis used a Linear Mixed-Effects Model (LMM) to investigate whether individual clinical markers (tinnitus, self-reported speech difficulty) were independently associated with the BILD. ResultsThe "lumping" analyses failed to find a significant difference in the BILD between subgroups, questioning the utility of a unitary HHL profile. In contrast, the exploratory "splitting" analysis found a significant interaction between tinnitus and listening condition ({beta} = 1.57, p = 0.009), suggesting that participants with tinnitus exhibited a smaller BILD. The complaint of speech perception difficulty was not significantly associated with a BILD deficit (p = 0.086) but was associated with lower scores on a test of short-term memory (forward digit span, p = 0.046). ConclusionOur findings challenge the value of a unitary HHL profile for predicting this specific binaural deficit. Instead, our exploratory analysis generated a specific, testable hypothesis of a sensory-cognitive dissociation: in our sample, tinnitus was associated with a reduced capacity for binaural unmasking, while the complaint of speech difficulty was associated with poorer short-term memory. These preliminary findings, derived from post-hoc analysis of an underpowered study, require rigorous validation in larger, pre-registered studies.

ObjectiveThis binational cross-centre study analyses a consented audiological-vestibular test battery for characterising age-related hearing loss, enabling precise phenotyping of suprathreshold functional, physiological, and vestibular factors beyond audibility. DesignStatistical analysis of centre effects to assess comparability of the test battery measured at two centres (Germany and France); statistical analysis of age and pure-tone average (PTA) effects per test to identify potential covariates. Samplen = 55 (39 German and 16 French) participants with hearing thresholds better than the age-dependent median of the PTA, aged 40 years or older. ResultsAge- and PTA-dependent reference data were derived. Due to negligible centre effects, all data were pooled across centres. Age and PTA effects were identified for some tests, especially for audiological-functional tests. No age effects were found for vestibular tests. ConclusionsNormative values for a clinically feasible, multidimensional audiological-vestibular test battery were provided, including several measures whose age and PTA dependencies were previously unclear. Age and PTA should be considered as covariates for interpretation of these tests in future applications such as, e.g., phenotype-genotype relations in specified cohorts.

PurposeReal-world evidence (RWE) is of practical significance as it enables the evaluation of whether findings observed in rigorously controlled clinical trial settings are generalizable to routine clinical practice. While Lenire, a bimodal neuromodulation tinnitus treatment device, has demonstrated efficacy and safety within controlled trials, further RWE from clinics is needed to reinforce these results. This is the first real-world study to assess the therapeutic effects of Lenire on tinnitus using the Tinnitus Functional Index (TFI), a multidimensional instrument designed to capture tinnitus severity and treatment responsiveness. The study correlates findings with the Tinnitus Handicap Inventory (THI), a well-established tool that assesses the perceived functional, emotional, and catastrophic impact of tinnitus that was used in previous clinical trials and real-world studies. The use of an alternative validated outcome measure in a real-world study may add more feasible, relevant and patient-centered research findings to the body of evidence for Lenire, while maintaining scientific credibility. MethodsA single-site, single-arm retrospective study examining patients fitted with the Lenire device was conducted. Ninety-seven patients with moderate or greater tinnitus severity used the Lenire device for 12 weeks, for up to 60 minutes a day. The primary outcome was change in tinnitus severity, assessed using the TFI at 6-week (FU1) and 12-week (FU2) follow-ups. The THI was included as a secondary outcome measure. Responder rates and mean score changes between initial assessment and FU1 and FU2 were compared using Z-tests for proportions and t-tests, respectively. Pearsons correlations were used to examine the relationship between the TFI and THI change scores. ResultsAfter just 12 weeks of treatment, 73.4% [95% CI: 62.6%, 84.3%] of patients achieved a clinically significant improvement, defined as a reduction of at least 13 points on the TFI. This improvement was strongly supported by results from the THI, where 84.1% [95% CI: 75.1%, 93.2%] of patients met the minimum clinically important difference of 7 points. Mean score reductions were-25.9 (2.4, SEM) for the TFI and - 28.0 (2.4, SEM) for the THI. Change scores from initial assessment to FU2 on the TFI and THI were highly correlated (r = 0.74, p < 0.001), indicating strong agreement between the two measures in capturing treatment related improvements. All eight TFI subdomains showed reductions ranging from 18.5 to 31.4 points at FU2. ConclusionsThis retrospective study demonstrates that 12 weeks of treatment with the Lenire device resulted in clinically meaningful improvements in tinnitus severity on the TFI which was strongly supported by the THI. The high correlation between TFI and THI change scores indicates strong correlation between the two questionnaires in capturing treatment effects. Furthermore, all eight TFI subdomains showed notable reductions, underscoring the multidimensional impact of the treatment. These findings support the clinical utility of both the TFI and THI as complementary tools for evaluating treatment outcomes and guiding tinnitus management in routine practice.

Age-related hearing loss is the leading sensory deficit in older adults, yet audiometric thresholds at conventional frequencies often poorly predict speech understanding. Two competing hypotheses have emerged: extended high-frequency (eHF) hearing loss beyond 8 kHz may unmask variance in speech performance, while hidden hearing loss from cochlear synaptopathy---detectable via auditory brainstem response (ABR) wave I amplitude reduction---may degrade temporal coding independent of audiometry. Here, in 526 ears from 263 tinnitus-free adults in the Swedish Tinnitus Outreach Project (STOP) cohort, we show that eHF pure-tone average (10-16 kHz) is the single most age-sensitive auditory measure, explaining 64% of age-related variance (R{superscript 2} = 0.64) compared to only 16% for conventional audiometry (R{superscript 2} = 0.16). Moreover, eHF thresholds robustly predict both word and phoneme recognition in speech-weighted noise (+4 dB SNR), explaining 34-36% of speech variance (R{superscript 2} = 0.34-0.36)--substantially exceeding conventional pure-tone average (22-25%) and all ABR features (5-13%). In contrast, ABR Wave I amplitude--the putative marker of cochlear synaptopathy--contributes no additional explanatory power even in high-reliability recordings (ICC = 0.96). These findings challenge the translational relevance of cochlear synaptopathy to age-related speech deficits and suggest conduction delays, not synaptic loss, as the peripheral neural mechanism underlying speech comprehension decline in aging.

IntroductionVestibular schwannoma (VS) is a benign tumor of the vestibulocochlear nerve, often causing hearing loss, balance disturbances, and psychosocial challenges. While surgical resection is standard, the long-term biopsychosocial impact of surgery is poorly understood. Research questionWhat are the physical, psychological, and social challenges experienced by patients up to five years after VS surgery? Material and MethodsA qualitative study was conducted using semi-structured video call interviews with 12 patients recruited via a patient advocacy group. Interviews explored postoperative experiences across physical, psychological, and social domains. Transcripts were analyzed using thematic content analysis with a coding system developed deductively and refined inductively. Data saturation was reached after 12 interviews. ResultsParticipants reported diverse physical symptoms, including hearing loss, tinnitus, dizziness, pain, fatigue, and facial nerve palsy. Psychological challenges included anxiety, depression, cognitive difficulties, and reduced stress tolerance. Social changes encompassed strained relationships, withdrawal from work and leisure activities, and limited social participation. Physical, psychological, and social challenges interacted dynamically, with emotional distress amplifying social isolation and healthcare provider support influencing coping and adaptation. Discussion and ConclusionVS surgery has a multifaceted, long-term impact on patients lives. The interplay of physical, psycho-logical, and social challenges underscores the need for holistic, multidisciplinary care, early patient education, and integration of supportive interventions. Engagement from healthcare providers plays a key role in mitigating distress and facilitating adaptation. These findings highlight the importance of addressing biopsychosocial aspects to improve long-term recovery and health-related quality of life in VS patients.

BackgroundAuditory steady-state responses (ASSRs) provide an objective method for estimating hearing thresholds in individuals unable to provide behavioural responses. Bone conduction (BC) testing is required to differentiate conductive from sensorineural hearing loss. Accurate BC ASSR threshold estimation relies on "correction" factors, which are not yet well established. This meta-analysis evaluated the reliability of BC ASSR thresholds to estimate hearing thresholds at 500, 1000, 2000 and 4000 Hz. MethodsA systematic search of PubMed, the Cochrane Library, and Embase was conducted to identify studies involving normal-hearing (NH) and hearing-impaired (HI) participants of all ages. Outcomes were (1) the difference between ASSR behavioural and ASSR thresholds, and (2) ASSR thresholds. The risk of bias was evaluated using the Newcastle-Ottawa Scale. The mean and 95% confidence intervals (CI) were calculated for the thresholds at the four frequencies. The certainty of the evidence was assessed using GRADE approach. ResultsOf records identified, 11 records met the inclusion criteria, yielding a total of 27 studies. Sample sizes ranged from 60 to 249 participants across frequencies and age groups. The quality of records ranged from low to high. Data were synthesised using random-effects models due to heterogeneity. In NH adults, the mean differences ({+/-}95% CI) between BC ASSR thresholds and behavioural thresholds were 17.0 ({+/-}4.8), 15.5 ({+/-}6.0), 13.4 ({+/-}3.3), and 12.1 ({+/-}4.1) dB at 500, 1000, 2000, and 4000 Hz, respectively. In NH infants, mean ({+/-}95% CI) BC ASSR thresholds were 17.2 ({+/-}2.2), 10.5 ({+/-}3.6), 26.4 ({+/-}2.7), and 19.9 ({+/-}4.0) dB HL at the same frequencies. The certainty of the evidence was very low. ConclusionsBC ASSR can be a reliable method for estimating BC thresholds. However, age and frequency significantly impact BC ASSR thresholds, highlighting the need to develop of "correction" factors to accurately predict BC behavioural thresholds. RegistrationPROSPERO CRD42023422150.

IntroductionBecause hearing difficulties contribute significantly to years lived with disability and global economic burdens, finding ways to support hearing health is crucial. Despite decades of research investigating hearing loss and why some listeners struggle while listening to speech in noise more than others, answers remain elusive. Investigating modifiable lifestyle factors such as moderate-to-vigorous physical activity (MVPA) that have been shown to support brain and cognitive function may help answer these questions about hearing health. MethodsWe examined the association between time spent in MVPA and self-reported hearing problems in the UK Biobank, a comprehensive population dataset. A subset of 79,286 participants aged 39-70 years who had complete accelerometer, hearing, demographic, and medical data were used. In our sample, 54.57% were female. The duration of MVPA and proportion of participants meeting physical activity guidelines (>150 minutes of moderate-to-vigorous physical activity per week) were measured using wrist-worn accelerometry. Self-reported problems with hearing or understanding speech in noise were the primary outcomes. Logistic regressions were used to assess the relationship between MVPA and hearing problems while controlling for health and demographic factors. ResultsSpending more time in MVPA was associated with lower odds of reporting a hearing problem (OR=0.990, 95% CI [0.983, 0.997], p=0.005) and lower odds of reporting a speech-in-noise problem (OR= 0.991, 95% CI [0.985, 0.998], p= 0.007). Additionally, meeting physical activity guidelines was associated with lower odds of reporting problems with hearing (OR= 0.958, 95% CI [0.923, 0.995], p= 0.025) and speech in noise (OR= 0.953, 95% CI [0.922, 0.986], p= 0.005). ConclusionsThese findings suggest that spending more time in moderate-to-vigorous physical activity benefits hearing health as it is associated with lower odds of reporting hearing or speech-in-noise problems. Targeting physical activity as a non-invasive and low-cost intervention may make the common issue of hearing loss more manageable. Key MessagesWhat we already know: O_LIDecades of research has shown that moderate-to-vigorous physical activity benefits cognitive and brain health. Similarly, prior work has shown that speech in noise understanding relies on executive functions and hearing sensitivity relates to physical activity levels. While the link between these concepts loosely exists, insufficient work has looked at how MVPA affects overall hearing health. C_LI What this study adds: O_LIIn this prospective cohort study of 79,286 participants from the UK Biobank, we used logistic regressions to see whether spending more time in moderate-to-vigorous physical activity was associated with lower odds of reporting problems with hearing or understanding speech in noise. C_LI How this study might affect research, practice, or policy O_LIEstablishing the relationship between moderate-to-vigorous physical activity and overall hearing health can inform future interventions that aim to combat the decline in hearing that comes with age. C_LI

BackgroundAtopic diseases are estimated to affect 30-40% of the global population. However, the potential protective effect of hypoallergenic infant formula against conditions such as atopic dermatitis (AD), cows milk protein allergy (CMPA), and asthma remains uncertain. ObjectiveTo conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating hypoallergenic formula for atopic disease prevention in high-risk infants. The primary outcome was AD and secondary outcomes were CMPA and asthma. MethodsA systematic review and meta-analysis was conducted according to PRISMA 2020. RCTs involving high-risk infants were identified through PubMed, Cochrane Library, and Web of Science. Exclusion criteria included interventions not initiated at birth, enrolment of sick infants, and non-RCTs. Pooled Relative Risks (RR) with 95% confidence intervals (CI) were calculated using a random-effects model. ResultsWe included 9 RCTs that enrolled high-risk infants. The meta-analysis found a borderline significant protective effects of AD (RR=0.78 [0.59-1.03], p=0.059; I2=46.5%), a significant protective effect of hypoallergenic formula in prevention of CMPA (RR=0.51 [0.27-0.97], p=0.0228; I2=37.3%), and no significant risk reduction for asthma (RR=0.78 [0.51-1.20], p=0.059; I2=37.5%). ConclusionThis systematic review and meta-analysis found no statistically significant protective effect of hypoallergenic formula for AD or asthma, though a non-significant trend toward risk reduction was observed. A significant risk reduction was seen for CMPA (RR{approx}0.5), although not all diagnoses were confirmed by oral food challenge. These findings suggest potential patient-specific benefits, but larger, well-designed RCTs are needed to confirm them.

ObjectiveThis study aimed to evaluate the efficacy, safety, and optimal strains of probiotics for pediatric allergic rhinitis (AR) using meta-analysis and network meta-analysis. MethodsA systematic search was conducted in databases including PubMed, Web of Science, Cochrane Library, and China National Knowledge Infrastructure up to July 31, 2025, to identify randomized controlled trials (RCTs). Inclusion criteria were pediatric patients with AR, probiotic interventions, control groups receiving placebo or standard treatment, and reported outcomes such as Total Nasal Symptom Score (TNSS), Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ), serum IgE levels, clinical efficacy, or adverse events. Study quality was assessed using the JADAD scale, with meta-analysis and network meta-analysis (NMA) performed via RevMan and R software, calculating standardized mean differences (SMD), relative risks (RR), and surface under the cumulative ranking curve (SUCRA) values. ResultsTwenty-six RCTs were included, involving 3,014 patients (1,565 in the probiotic group and 1,404 in the control group). Meta-analysis showed that probiotics significantly reduced TNSS (SMD = -0.85, 95% CI [-1.25, -0.44], P < 0.05), improved PRQLQ scores (SMD = -3.94, 95% CI [-4.55, -3.33], P < 0.05), enhanced clinical efficacy (RR = 1.16, 95% CI [1.07, 1.25], P < 0.05), and decreased adverse events (RR = 0.22, 95% CI [0.06, 0.82], P < 0.05), but exerted no overall effect on serum IgE (SMD = -0.39, 95% CI [-0.99, 0.09], P = 0.11). Subgroup and NMA analyses indicated that mixed strains performed superiorly across multiple outcomes. ConclusionsProbiotics, particularly mixed strains, are a safe and effective adjunctive therapy for pediatric AR, improving symptoms and quality of life. Large-scale RCTs are required to validate optimal regimens.

BackgroundImpulse oscillometry is a noninvasive pulmonary function test performed during quiet breathing and requires minimal patient cooperation. It is useful for detecting small airway disease and provides increased sensitivity for diagnosing asthma in younger children who may have difficulty completing standard spirometry. Bronchodilator testing, a standard assessment of airflow obstruction reversibility, is recommended in patients with suspected asthma who present obstructive airflow patterns. ObjectiveTo evaluate impulse oscillometry parameters before and after bronchodilator administration across different age groups and to examine the relationship between age and airway resistance in patients with clinician-diagnosed asthma. MethodsThis retrospective study included patients with clinician-diagnosed asthma who demonstrated obstructive airflow patterns and a positive bronchodilator response. Participants were grouped by age: younger than 6 years, 6 to 20 years, and older than 20 years. Key impulse oscillometry parameters--airway resistance at 5 Hz, airway resistance at 20 Hz, the difference between these values, and resonance frequency--were collected and compared across groups. A positive bronchodilator response was defined as a reduction in airway resistance of more than 30% in individuals younger than 18 years and more than 40% in adults. ResultsA total of 225 patients (123 males and 102 females) were included, with a median age of 6 years. At baseline, the median airway resistance at 5 Hz was 175.34% of the reference value (95% CI, 171.66-178.62), and airway resistance at 20 Hz was 121.68% (95% CI, 118.73-127.12). The median difference between these values was 52.32% (95% CI, 49.89-57.14), and the median resonance frequency was 5.11 Hz (95% CI, 4.62-5.35). After bronchodilator administration, airway resistance at 5 Hz decreased to 123.56% (95% CI, 119.07-126.77), corresponding to a median reduction of 52.8% (95% CI, 49.48-56.08; P < 0.0001). Age demonstrated a moderate positive correlation with airway resistance at 20 Hz (r = 0.51, P < 0.001). ConclusionsProximal airway resistance increases with age among patients with asthma, suggesting age-related differences in airway inflammation. Impulse oscillometry combined with bronchodilator assessment provides a practical approach for evaluating airflow reversibility and enhances diagnostic accuracy in suspected asthma.

BackgroundAtopic dermatitis (AD) is a chronic skin disease that typically occurs in early childhood. In this cross-sectional case-control study, our objective was to employ machine learning approaches to identify novel clusters of protective or susceptibility features associated with AD. Methods and FindingsWe utilised an integrated dataset comprising previously established environmental, cytokine, antibody, and gene expression data from AmaXhosa children, both healthy and with AD, living in either rural or urban settings of South Africa, aged 12-36 months. The applied machine learning methods included the GeneSelectR workflow to identify a subset of relevant genes, the calculation of SHAP values to explain the machine learning output, and the use of DIABLO to integrate the datasets for a comprehensive analysis. Key findings included the identification of a protective cluster of environmental features primarily found in the rural setting, which were correlated with plasma cytokine levels and with expression of autophagy-related genes. Additionally, we identified AD susceptibility clusters where levels of allergen-specific and total IgE antibodies correlated with the cytokines MCP-4 and TARC. Lastly, we identified an RNA-Seq feature signature specific to the disease endotype. ConclusionsThe application of various machine learning methods enabled the identification of significant factors associated with AD in a complex, multi-modular dataset, making the output explainable and potentially informing targeted interventions and improved diagnostic criteria.

BackgroundPeanut allergies continuously present urging public health challenges. Oral immunotherapy (OIT) is an important treatment option for peanut allergies, but its effectiveness varies, in terms of inducing desensitization (DS) or achieving long-term sustained unresponsiveness (SU). Identifying biomarkers to predict OIT outcomes is thus of great translational interests. MethodsWe thoroughly analyzed data from the POISED trial and our in-house OPIA trial, with a particular focus on the peanut-reactive T cells, in an attempt to identify potential biomarkers at baseline before OIT to distinguish DS and SU outcomes. ResultsIn both the POISED trial and OPIA trial, we found that functional profiles of peanut-reactive T cells at baseline before OIT, such as their type II T helper (Th2) cell cytokine productions, including IL-4, were associated with the DS versus SU outcomes after OIT cessation. ConclusionsBaseline peanut-reactive T cell functional profiles might provide new possibilities for biomarker discovery to predict peanut allergy OIT outcomes.

Identification of early interventions to reduce/eliminate asthma - the most common chronic disease among children - could significantly reduce burden on the healthcare system. Large-scale asthma Exposome-Wide Association Studies (ExWAS) could identify potential interventions, however integration of diverse data is required to address association confounders. The CHILD Cohort Study has followed 3,454 healthy Canadian children and their families from early pregnancy, collecting exceptionally diverse data including 24,852 variables from participant questionnaires, clinical data, household and neighbourhood-level exposures, and sample-derived chemical analytic/omic datasets. Here, we report integration of these datasets into the CHILDdb database platform, and use these data to perform ExWAS and machine learning analyses, identifying and further characterizing associations between childhood asthma and 2,954 diverse early exposures (pregnancy to age 5). Significant asthma associations include antibiotic use, human milk components, DEHP phthalate, and mothers prenatal cleaning product/disinfectant exposure. Subsequent analysis revealed epigenetic changes in the cord blood at birth, after prenatal cleaner exposure, and different microbiome and/or inflammatory cytokine changes associated with different asthma-associated exposures in the child. Collective results support asthma as a heterogeneous condition involving multiple etiologies, with associated endotypes, including prenatal exposures with potential transgenerational effects, and suggest targets for early interventions.

ObjectivesCochlear implants are an effective intervention for people with severe to profound hearing loss. However, only a small percentage of those who could benefit from cochlear implants have one. We aimed to understand the barriers to access and receipt of cochlear implants in the UK. DesignMixed-methods study. SettingThe University of Southampton Auditory Implant Service. ParticipantsData on referral route and personal characteristics of 456 patients over the age of 60 at the time of cochlear implantation, who received a cochlear implant before 2020 were included. Semi-structured interviews were held with six people who hear with an implant. Primary Outcome MeasuresDemographic factors and routes of referral for cochlear implantation for older adults who went on to receive an implant. Semi-structured interviews were designed to identify key motivators and barriers to receiving a cochlear implant. ResultsSex and ethnicity did not affect cochlear implant uptake, whereas socioeconomic status and differences in referral pathways were associated with differences in uptake. People from lower socioeconomic groups were underrepresented in the implanted population at USAIS. Certain health providers across the cohort catchment area were more likely to refer patients than others which in turn affected cochlear implant uptake. Barriers to uptake were poor knowledge about implants by patients and clinicians, and fear of surgery. A willingness by patients to explore a way to reduce the daily challenges associated with hearing loss and the support and encouragement of clinicians, family and friends and other people with implants were motivators to implant uptake. ConclusionThese findings will inform future research to address the key factors preventing eligible individuals from receiving cochlear implants. This will support the development of strategies to improve access to, and uptake of, cochlear implants for older adults. ARTICLE SUMMARYO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIStrength: Mixed-methods approach was used: O_LIA service evaluation where we analysed retrospective data from 456 patients from a UK cochlear implant centre. C_LIO_LISemi-structured interviews were used to gather rich qualitative data for a deeper insight into the barriers and motivators of cochlear implant uptake. C_LI C_LIO_LILimitation: Data from patients that were referred to USAIS but did not receive cochlear implants was not included. C_LIO_LILimitation: Sample size for interviews was small (six participants) due to time constrains of the (student) project. C_LI

BackgroundSinonasal malignancies frequently present with symptoms overlapping chronic inflammatory conditions such as chronic rhinosinusitis (CRS), complicating early detection and delaying treatment. A fast, scalable, non-invasive approach capable of resolving immune and epithelial cell states across inflammatory and malignant disease from routine nasal swabs could substantially improve clinical screening, leading to the initiation of appropriate treatment. MethodsWe developed a deep learning-enabled single-cell morpholomic framework using the REM-I platform to generate a reference atlas of >641K cell brightfield images from purified immune cell populations. This reference atlas was applied to >2.5 million images obtained from nasal swabs spanning a clinical spectrum of health, CRS, and sinonasal carcinoma. Embeddings were integrated using dimensionality reduction for differential feature testing and comparative feature enrichment across disease states. FindingsAcross the disease continuum, sinonasal carcinoma samples exhibited distinct immune remodeling, including increased myeloid-like cell abundance and elevated small dark pixel intensity consistent with enhanced granulocyte activity. Basophil/NK-enriched clusters contained tumor-associated cells with deep learning-derived morphologic signatures not observed in CRS or healthy samples. Tumor-associated epithelial cells were significantly smaller and displayed disease-specific morpholomic patterns distinct from chronic inflammation. ConclusionsThis study establishes a deep learning-enabled single-cell morpholomic atlas of nasal swabs spanning healthy epithelium, chronic inflammation and sinonasal malignancies. Morpholomic cytology reveals reproducible immune and epithelial states associated with inflammatory and malignant disease and provides a scalable, non-invasive framework for cellular stratification in sinonasal pathology, supporting future applications in early point-of-care diagnostics.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but commonly cause immune-related adverse events (irAEs), whether administered as monotherapy or in combination with other oncological agents. We present the first reported case of ICI-induced granulomatous sialadenitis in a male patient in his mid-fifties with BRAF-V600E-mutated papillary thyroid carcinoma who received sequential treatment with BRAF/MEK inhibitors followed by pembrolizumab. The patient experienced acute-onset severe xerostomia and salivary hypofunction, prompting ICI cessation and salivary gland biopsy. Integrative analysis using histology, single-cell RNA sequencing, and spatial transcriptomics revealed macrophage- and T-cell-mediated epithelial damage driven by epithelial senescence and Th1-polarized inflammation. Corticosteroid therapy reduced granuloma burden and improved salivary flow rates and tissue architecture; however, extensive fibrosis persisted despite treatment. These findings underscore the critical importance of early irAE recognition and intervention to preserve glandular function and enable continuation of cancer therapy.

Sinonasal squamous cell carcinoma (SNSCC) is an aggressive head and neck cancer of the sinonasal cavity which has not benefitted from therapeutic advances over decades1. Though historically attributed to inhaled carcinogens such as hardwood dust and tobacco smoking2, SNSCC is incidentally associated with human papillomavirus (HPV)3,4. Importantly, HPV is the primary oncogenic driver of >80% of anatomically adjacent oropharyngeal cancers5. While viral status drives clinical staging and treatment guidelines in these malignancies6,7, the potentially oncogenic consequences and prognostic value of host-virus interactions in SNSCC remain incompletely defined. Here, through paired host and viral whole-genome sequencing (WGS), we map the genomic footprint of HPV in SNSCC. Strikingly, lesser studied strains such as HPV45, 51, and 39 constitute driver infections in this rare but clinically credentialed cancer, where extrachromosomal DNA (ecDNA)-associated viral integration and APOBEC mutagenesis are shown to underpin somatic tumor evolution. Statement of SignificancePaired host viral and whole-genome sequencing of SNSCC nominates HPV as a primary oncogenic driver of SNSCC. HPV-human ecDNA amplicons harboring noncanonical strains such as HPV45, 51 mediate viral carcinogenesis. Routine clinical diagnostic HPV panels should be expanded to capture the activity of lesser studied strains.

BackgroundFatal insulin intoxication remains difficult to diagnose because insulin undergoes rapid degradation after death, limiting the reliability of direct biochemical measurements. This creates diagnostic uncertainty when objective molecular confirmation of insulin excess are required. We hypothesised that insulin excess induces systemic metabolic alterations that persist beyond insulin degradation and can be captured using postmortem metabolomics in a forensic setting. MethodsHigh-resolution mass spectrometry (HRMS)-based metabolomics was applied to a national cohort comprising 51 fatal insulin intoxications. Orthogonal partial least squares-discriminant analysis (OPLS-DA) models were trained on cases collected between 2017-2022 to identify insulin-associated metabolite features using a shared-and-unique-structures approach. Performance was evaluated using two temporally distinct test sets (2023-2024): a matched validation cohort and a heterogeneous forensic cohort reflecting biological variability. ResultsHere we show that an insulin-associated metabolomic fingerprint comprising 91 features demonstrated reproducible discrimination across independent cohorts. In the matched cohort (n=59, including 14 insulin cases), insulin intoxication classification achieved 100% sensitivity and 73% specificity within the applicability domain. In the heterogeneous cohort (n=154, including 14 insulin cases), 100% sensitivity was maintained with a 72% specificity despite increased biological variability. Univariate analyses demonstrated significant alterations across multiple metabolite classes, including acylcarnitines, fatty acids/lipids, and purine/nucleoside metabolites, with moderate effect sizes, consistent with systemic effects of insulin-induced hypoglycaemia. ConclusionsFatal insulin intoxication is associated with a reproducible metabolomic fingerprint detectable after death. These findings demonstrate that postmortem metabolomics may serve as a complementary decision-support tool when conventional biomarkers are unreliable.

ObjectiveThis study aimed to characterize the activation of lower urinary tract (LUT) targets in response to pudendal nerve stimulation (PNS) in awake human participants. Materials and MethodsIn this single center study, recruited participants had an implanted pudendal neurostimulator for treatment of their symptoms including overactive bladder, incontinence, urinary retention, and/or pelvic pain. Participants came in for a modified urodynamic study where a multichannel manometry catheter was placed in the lower urinary tract alongside a dual sensor urodynamics catheter. The bladder was filled and after each participant expressed a strong desire to void, PNS was applied and LUT pressures were measured. Participants attempted voids with the catheters in place to characterize LUT behavior and voiding efficiency with and without stimulation. ResultsThe study consisted of 15 participants including 13 women. Across 133 total trials contractions were observed at the distal urethra 52 times (39%) and at the proximal urethra 46 times (35%). The maximum observed pressure change occurred significantly more often at the proximal urethra than the distal urethra (p = 0.007). There was a significantly higher maximum tolerable stimulation amplitude for low frequency stimulation (2-3.1 Hz) when compared to high frequency stimulation (30-33 Hz) (p = 0.041). In one participant there were four instances of stimulation driven bladder contractions with an average pressure change of 24.3 cmH2O (standard deviation = 10.5). There was not a significant difference in voiding efficiency or maximum flow rate with and without stimulation (p = 0.76 and p = 0.45, respectively). ConclusionsPNS can affect LUT pressures at tolerable stimulation amplitudes. The absence of an effect of PNS on voiding characteristics suggests a similar mechanism of action as sacral neuromodulation.

Infectious disease forecasts can inform public health decision-making. Wastewater monitoring is a relatively new epidemiological data source with multiple potential applications, including forecasting. Incorporating wastewater data into epidemiological forecasting models is challenging, and relatively few studies have assessed whether this improves forecast performance. We present and evaluate a semi-mechanistic wastewater-informed forecasting model. The model forecasts COVID-19 hospital admissions at the state and territorial levels in the United States, based on incident hospital admissions data and, optionally, SARS-CoV-2 wastewater concentration data from multiple wastewater sampling sites. From February through April 2024, we produced real-time wastewater-informed COVID-19 forecasts using development versions of the model and submitted them to the United States COVID-19 Forecast Hub ("the Hub"). We then published an open-source R package, wwinference, that implements the model with or without wastewater as an input. Using proper scoring rules and measures of model calibration, we assess both our real-time submissions to the Hub and retrospective hypothetical forecasts from wwinference made with and without wastewater data. While the models performed similarly with and without the wastewater signal included, there was substantial heterogeneity for individual locations and dates where wastewater data meaningfully improved or degraded the models forecast performance. Compared to other models submitted to the Hub during the period spanned by our submissions, the real-time wastewater-informed version of our model ranked fourth of 10 models, with the hospital admissions-only version of our model ranking second out of 10 models. Across the 2023-2024 winter epidemic wave, retrospective forecasts from wwinference would have performed similarly with and without the wastewater signal included: fifth and fourth out of 10 models, respectively. To better understand the drivers of differential forecast performance with and without wastewater, we performed an exploratory analysis investigating the relationship between characteristics of the input data and improved and reduced performance in our model. Based on that analysis, we identify and discuss key areas for further model development. To our knowledge, this is the first work that conducts an evaluation of real-time and retrospective infectious disease forecasts across the United States both with and without wastewater data and compared to other forecasting models. Author SummaryWastewater-based epidemiology, in combination with clinical surveillance, has the potential to improve situational awareness and inform outbreak responses. We developed a model that uses data on the pathogen concentration in wastewater from one or more wastewater treatment plants in combination with hospital admissions to produce short-term forecasts of hospital admissions. We produced and submitted forecasts of 28-day ahead COVID-19 hospital admissions from this model to the U.S. COVID-19 Forecast Hub during the spring of 2024 and found that it performed well in comparison to other models during that limited time period. To assess the added value of incorporating wastewater data into the model and to investigate how it would have performed had we submitted it during the entire 2023-2024 winter epidemic wave, we performed a retrospective analysis in which we produced forecasts from the model with and without including wastewater data, using data that would have been available in real-time as of each forecast date. Both versions of the model would have been median overall performers had they been submitted to the Hub throughout the season. When comparing the models performance with and without wastewater data included, we found that overall forecast performance was very similar, with wastewater data slightly reducing overall average forecast performance. Within this result, there was significant heterogeneity, with clear instances of wastewater data improving and detracting from forecast performance. We used trends in the observed data to generate hypotheses as to the drivers of improved and reduced relative forecast performance within our model. We conclude by suggesting future work to improve the model and more broadly the application of wastewater-based epidemiology to forecasting.