Gene mutations as a non-invasive measure of adult cochlear implant performance: Variable outcomes in patients with select TMPRSS3 mutations.

BACKGROUND: The cochlear implant (CI) has proven to be a successful treatment for patients with severe-to-profound sensorineural hearing loss, however outcome variance exists. We sought to evaluate particular mutations discovered in previously established sensory and neural partition genes and compare post-operative CI outcomes. MATERIALS AND METHODS: Utilizing a prospective cohort study design, blood samples collected from adult patients with non-syndromic hearing loss undergoing CI were tested for 54 genes of interest with high-throughput sequencing. Patients were categorized as having a pathogenic variant in the sensory partition, pathogenic variant in the neural partition, pathogenic variant in both sensory and neural partition, or with no variant identified. Speech perception performance was assessed pre- and 12 months post-operatively. Performance measures were compared to genetic mutation and variant status utilizing a Wilcoxon rank sum test, with P<0.05 considered statistically significant. RESULTS: Thirty-six cochlear implant patients underwent genetic testing and speech understanding measurements. Of the 54 genes that were interrogated, three patients (8.3%) demonstrated a pathogenic mutation in the neural partition (within TMPRSS3 genes), one patient (2.8%) demonstrated a pathogenic mutation in the sensory partition (within the POU4F3 genes). In addition, 3 patients (8.3%) had an isolated neural partition variance of unknown significance (VUS), 5 patients (13.9%) had an isolated sensory partition VUS, 1 patient (2.8%) had a variant in both neural and sensory partition, and 23 patients (63.9%) had no mutation or variant identified. There was no statistically significant difference in speech perception scores between patients with sensory or neural partition pathogenic mutations or VUS. Variable performance was found within patients with TMPRSS3 gene mutations. CONCLUSION: The impact of genetic mutations on post-operative outcomes in CI patients was heterogenous. Future research and dissemination of mutations and subsequent CI performance is warranted to elucidate exact mutations within target genes providing the best non-invasive prognostic capability.

Socioeconomic Disparities in the Pursuit of Care at a High-Volume Institution for Surgical Resection of Vestibular Schwannomas.

OBJECTIVE: Increased institutional surgical resection case volume for vestibular schwannomas (VSs) has been associated with improved patient outcomes, including reduced risk of prolonged hospital stay and readmission. Socioeconomic disparities in the pursuit of care at these high-volume institutions remain unknown. STUDY DESIGN: Retrospective cohort epidemiological study. SETTING: National Cancer Database, a hospital-based registry of over 1,500 facilities in the United States. PATIENTS: Adult VS patients (age, >18 years) treated surgically. INTERVENTIONS: High- versus low-volume facilities, defined using a facility case volume threshold of 25 cases per year. A risk-adjusted restricted cubic spline model was previously used to identify this risk threshold beyond which the incremental benefit of increasing case volume began to plateau. MAIN OUTCOME MEASURES: Sociodemographic factors, including race, ethnicity, income, insurance status, and rurality. Multivariable analyses were adjusted for patient and tumor characteristics, including age, sex, Charlson-Deyo score, and tumor size. RESULTS: A totoal of 10,048 patients were identified (median [interquartile range] age = 51 [41-60] years, 54% female, 87% Caucasian). Patients with Spanish/Hispanic ethnicity (OR = 0.71, 95% confidence interval [CI] = 0.52-0.96), income below median (OR = 0.63, 95% CI = 0.55-0.73]), and Medicare, Medicaid, or other government insurance versus private insurance (OR = 0.63, 95% CI = 0.53-0.74) had reduced odds of treatment at a high-volume facility. Further sensitivity analyses in which facility volume was operationalized continuously reinforced direction and significance of these associations. CONCLUSIONS: Socioeconomic disparities exist in the propensity for VS patients to be treated at a high-volume facility. Further work is needed to understand the nature of these associations and whether interventions can be designed to mitigate them.

The Effect of Immediate Microsurgical Resection of Vestibular Schwannoma on Hearing Preservation.

OBJECTIVE: Evaluate for differences in postoperative hearing in patients who undergo immediate versus delayed hearing preservation microsurgical resection of vestibular schwannomas (VS). STUDY DESIGN: Retrospective single-institution cohort study spanning November 2017 to November 2021. SETTING: Single-institution tertiary care hospital. PATIENTS: Sporadic VS in patients with American Academy of Otolaryngology-Head and Neck Surgery hearing classification A or B, with tumor size less than or equal to 2 cm and undergoing hearing preservation microsurgical resection. INTERVENTIONS: Delayed surgical intervention defined by time from first diagnostic MRI to date of surgery being greater than 3 months. MAIN OUTCOME MEASURES: Preoperative and postoperative audiometric performance. RESULTS: In total, 193 patients met inclusion criteria. Within the cohort, 70 (36%) proceeded with surgery within 3 months of diagnostic MRI with a mean observation time of 62 days, whereas 123 (63%) underwent surgery after 3 months with a mean observation time of 301 days. There was no difference in preoperative hearing between the two groups with word recognition score 99% in early intervention group and 100% in delayed intervention group ( p = 0.6). However, 64% of those who proceeded with immediate surgery had successful hearing preservation, compared to a 42% of those who had delayed intervention ( p < 0.01). In a multivariable logistic regression accounting for preoperative word recognition score, tumor size, and age at diagnosis, the odds of hearing preservation were lower in those who delayed surgery compared to immediate surgery (odds ratio, 0.31; 95% confidence interval, 0.15-0.61). CONCLUSIONS: Patients who underwent microsurgical resection within 3 months of diagnosis demonstrated a hearing preservation advantage compared to those who did not. Findings of this study highlight the counseling challenges associated with the timing of surgical treatment of VS in patients presenting with good preoperative hearing and small tumors.

Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom.

This study assessed the contribution of five genes previously known to be involved in cholestatic liver disease in British Bangladeshi and Pakistani people. Five genes (ABCB4, ABCB11, ATP8B1, NR1H4, TJP2) were interrogated by exome sequencing data of 5236 volunteers. Included were non-synonymous or loss of function (LoF) variants with a minor allele frequency < 5%. Variants were filtered, and annotated to perform rare variant burden analysis, protein structure, and modelling analysis in-silico. Out of 314 non-synonymous variants, 180 fulfilled the inclusion criteria and were mostly heterozygous unless specified. 90 were novel and of those variants, 22 were considered likely pathogenic and 9 pathogenic. We identified variants in volunteers with gallstone disease (n = 31), intrahepatic cholestasis of pregnancy (ICP, n = 16), cholangiocarcinoma and cirrhosis (n = 2). Fourteen novel LoF variants were identified: 7 frameshift, 5 introduction of premature stop codon and 2 splice acceptor variants. The rare variant burden was significantly increased in ABCB11. Protein modelling demonstrated variants that appeared to likely cause significant structural alterations. This study highlights the significant genetic burden contributing to cholestatic liver disease. Novel likely pathogenic and pathogenic variants were identified addressing the underrepresentation of diverse ancestry groups in genomic research.

Association Between Facility Surgical Volume and Excess Time in the Hospital After Surgical Resection of Vestibular Schwannomas.

Importance: High surgical vestibular schwannoma case volume in a medical institution may decrease the risk of adverse outcomes among patients undergoing vestibular schwannoma surgery. Objective: To study the association between surgical vestibular schwannoma case volume and excess time in the hospital after vestibular schwannoma surgery. Design, Setting, and Participants: This cohort study evaluated data from the National Cancer Database from January 1, 2004, through December 31, 2019, on Commission on Cancer-accredited facilities in the US. The hospital-based sample comprised adult patients aged 18 years or older with a vestibular schwannoma treated with surgery. Exposures: Facility case volume, defined as the mean number of surgical vestibular schwannoma cases per year in the 2 years preceding the index case. Main Outcomes and Measures: The primary outcome was a composite of prolonged hospital stay (>90th percentile) or 30-day readmission. Risk-adjusted restricted cubic splines were used to model the probability of the outcome according to facility volume. The inflection point (in cases per year) when the declining risk of excess time in the hospital began to plateau was selected as the threshold to define high- and low-volume facilities. Outcomes were compared among patients treated at high- and low-volume facilities, with mixed-effects logistic regression models adjusting for patient sociodemographic characteristics, comorbidities, tumor size, and clustering within facilities. Collected data were analyzed between June 24 and August 31, 2022. Results: Among 11 524 eligible patients (mean [SD] age, 50.2 [12.8] years; 53.5% female; 46.5% male) who underwent surgical resection of vestibular schwannoma at 66 reporting facilities, the median length of stay was 4 (IQR, 3-5) days, and 655 patients (5.7%) were readmitted within 30 days. The median case volume was 16 (IQR, 9-26) cases per year. An adjusted restricted cubic spline model identified a downtrending probability of excess time in the hospital with increasing volume. The declining risk of excess time in the hospital began to plateau at a facility volume of 25 cases per year. Surgery at a facility with an annual case volume at or above this threshold was independently associated with a 42% reduction in the odds of excess time in the hospital compared with surgery at a low-volume center (odds ratio, 0.58; 95% CI, 0.44-0.77). Conclusions and Relevance: This cohort study found that among adults undergoing vestibular schwannoma surgery, a higher facility case volume was associated with a reduced risk of prolonged hospital stay or 30-day readmission. A facility case volume of 25 cases per year may represent a risk-defining threshold.

Health State Utility Values Associated with Cochlear Implants in Adults: A Systematic Review and Network Meta-Analysis.

OBJECTIVES: The cost-effectiveness of bilateral cochlear implants in adults remains uncertain despite established clinical benefits. In cost-effectiveness studies, benefit is often measured by change in health state utility value (HSUV), a single number summary of health-related quality of life anchored at 0 (state of being dead) and 1 (perfect health). Small differences in bilateral cochlear implant HSUV change conclusions of published models, and invalid estimates can therefore mislead policy and funding decisions. As such, we aimed to review and synthesize published HSUV estimates associated with cochlear implants. DESIGN: We included observational or experimental studies reporting HSUV for adult patients (age ≥18 years) with at least moderate-profound sensorineural hearing loss in both ears who received unilateral or bilateral cochlear implants. We searched MEDLINE, EMBASE, PsycINFO, and Cochrane Library databases up to May 1, 2021. Study and participant characteristics and HSUV outcomes were extracted. Narrative synthesis is reported for all studies. A Bayesian network meta-analysis was conducted to generate pooled estimates for the mean difference in HSUV for three comparisons: (1) unilateral cochlear implant versus preimplant, (2) bilateral cochlear implants versus preimplant, (3) bilateral versus unilateral cochlear implants. Our principal measure was pooled mean difference in HSUV. RESULTS: Thirty-six studies reporting unique patient cohorts were identified. Health Utilities Index, 3 (HUI-3) was the most common HSUV elicitation method. HSUV from 19 preimplant mean estimates (1402 patients), 19 unilateral cochlear implant mean estimates (1701 patients), and 5 bilateral cochlear implants mean estimates (83 patients) were pooled to estimate mean differences in HUI-3 HSUV by network meta-analysis. Compared with preimplant, a unilateral cochlear implant was associated with a mean change in HSUV of +0.17 (95% credible interval [CrI] +0.12 to +0.23) and bilateral cochlear implants were associated with a mean change of +0.25 (95% CrI +0.12 to +0.37). No significant difference in HSUV was detected for bilateral compared with unilateral cochlear implants (+0.08 [95% CrI -0.06 to +0.21]). Overall study quality was moderate. CONCLUSIONS: The findings of this review and network meta-analysis comprise the best-available resource for parameterization of cost-utility models of cochlear implantation in adults and highlight the need to critically evaluate the validity of available HSUV instruments for bilateral cochlear implant populations.Protocol registration: PROSPERO (CRD42018091838).

Use of a Novel Clinical Decision-Making Tool in Vestibular Schwannoma Treatment.

OBJECTIVE: To determine the usefulness of a personalized tool and its effect on the decision-making process for those with vestibular schwannoma (VS). STUDY DESIGN: Prospective study. SETTING: Single institution, academic tertiary care lateral skull base surgery program. PATIENTS: Patients diagnosed with VS. INTERVENTIONS: A comprehensive clinical decision support (CDS) tool was constructed from a previously published retrospective patient-reported data obtained from members of the Acoustic Neuroma Association from January to March 2017. Demographic, tumor, and treatment modality data, including associated side effects, were collected for 775 patients and integrated in an interactive and personalized web-based tool. MAIN OUTCOME MEASURES: Pre- and posttool questionnaires assessing the process of deciding treatment for VS using a decisional conflict scale (DCS) and satisfaction with decision (SWD) scale were compared. RESULTS: A pilot study of 33 patients evaluated at a single institution tertiary care center with mean ± SD age of 63.9 ± 13.5 years and with average tumor size of 7.11 ± 4.75 mm were surveyed. CDS implementation resulted in a mean ± SD total DCS score decrease from 43.6 ± 15.5 to 37.6 ± 16.4 ( p < 0.01) and total SWD score increase from 82.8 ± 16.1 to 86.2 ± 14.4 ( p = 0.04), indicating a significant decrease in decisional conflict and increase in satisfaction. CONCLUSIONS: Implementing a decision-making tool after diagnosis of VS reduced decisional conflict and improved satisfaction with decision. Patients considered the tool to be an aid to their medical knowledge, further improving their comfort and understanding of their treatment options. These findings provide a basis for developing predictive tools that will assist patients in making informed medical decisions in the future.

Improving the Hearing Status Discrimination of the Health Utilities Index, Mark 3: Design of the Hearing Status Classification System.

OBJECTIVE: Redesign the health status classification system of the Health Utilities Index, Mark 3 (HUI-3) "hearing" attribute to improve its discrimination of hearing-impaired health states. STUDY DESIGN: Domain and item selection from a previously generated item set guided by a domain and item importance survey, structural independence, and cognitive interviews with patients. SETTING: Tertiary referral center. PARTICIPANTS: Patients with a range of hearing loss severities, etiologies, and treatment experiences participated in the domain and item importance survey (n = 108) and hour-long cognitive interviews (n = 10). MAIN OUTCOME AND MEASURES: Subattributes and levels for the novel Hearing attribute. Domain and item importance was scored on a seven-point Likert scale (1, not at all important; 7, extremely important). RESULTS: Mean domain importance was highest for "speech in noise" (6.21; 95% confidence interval, 5.98-6.43) and lowest for "benefits of hearing loss" (3.46; 95% confidence interval, 3.03-3.89). Domains with moderate or greater ( r ≥ 0.5) domain importance Pearson correlation or construct overlap that interfered with structural independence were combined into single subattributes. Iterative adjustments to instructions, items, and phrasing were guided by cognitive interviews to derive the final instrument with seven subattributes: speech, environmental sounds, localization, listening effort, tinnitus, music, and assistive devices. The novel hearing attribute defines 25,920 unique hearing states. CONCLUSION: The novel HUI-hearing is part of a comprehensive health utility instrument designed for individuals with hearing loss. Pending derivation of a hearing single attribute utility function and evaluation of measurement properties, our innovative approach could be used to improve health utility measurement for impairments described by any of the other HUI-3 attributes.

Large-scale phenotyping and characterization of age-related hearing loss in outbred CFW mice.

Age-related hearing loss (ARHL), or presbycusis, is one of the most prevalent conditions affecting the global population. A substantial fraction of patients with ARHL have no identifiable mutation despite over a hundred having been discovered, suggesting unidentified monogenic or polygenic causes. In this study, we investigated the hearing function of the aging outbred CFW mice through auditory brainstem response (ABR) thresholds. Through the characterization of 1,132 ABRs, we observed significant variation in both absolute thresholds and the effect of aging. We identify eight distinct patterns of hearing loss and were able to categorize nearly all data within these eight categories. Proportions within each category varied immensely between aging timepoints. We observe a small but consistent hearing deficit in female CFW mice. The resulting phenotypic data are a necessity for ARHL association mapping at a higher resolution than has previously been achieved and provides a new resource for studying ARHL.

Machine Learning to Predict Hearing Preservation After Middle Cranial Fossa Approach for Sporadic Vestibular Schwannomas.

OBJECTIVE: Predict hearing preservation after middle cranial fossa approach for vestibular schwannomas. STUDY DESIGN: Application of machine learning algorithms, including classification and regression trees and random forest models to observational data. SETTING: Single-tertiary referral center. PARTICIPANTS: Patients (n = 144) with a previously untreated sporadic vestibular schwannoma who underwent microsurgical resection by middle cranial fossa approach between November 2017 and November 2021. INTERVENTIONS: Middle cranial fossa approach. MAIN OUTCOME AND MEASURES: Hearing preservation, defined by postoperative word recognition score of 50% or greater and pure tone average below 50 dB HL or less than 10% reduction in word recognition score. Model performance was evaluated with classification accuracy in an independent validation sample. Variable importance for the random forest model is reported according to entropy, a measure of mean decrease in model accuracy incurred by excluding each variable from the model. RESULTS: Hearing preservation was achieved in 60% of patients (86 of 144) overall. The classification and regression tree model identified preoperative pure tone average with a cut point of 30 dB HL, and more posterior tumor position to be the most important prognostic features for hearing preservation. Model accuracy was 0.68. The random forest model demonstrated perfect accuracy (1). Baseline pure tone average, word recognition score, and anteroposterior tumor position were among the most influential features for hearing preservation prediction. CONCLUSION: Machine learning algorithms have the potential for accurate prediction of hearing preservation rates after middle fossa approach for vestibular schwannomas at a single institution. These models have the capacity for continued refinement with ongoing addition of data.

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5-2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility.

Ethical and economic implications of the adoption of novel plant-based beef substitutes in the USA: a general equilibrium modelling study.

BACKGROUND: Slowing climate change is crucial to the future wellbeing of human societies and the greater environment. Current beef production systems in the USA are a major source of negative environmental impacts and raise various animal welfare concerns. Nevertheless, beef production provides a food source high in protein and many nutrients as well as providing employment and income to millions of people. Cattle farming also contributes to individual and community identities and regional food cultures. Novel plant-based meat alternatives have been promoted as technologies that could transform the food system by reducing negative environmental, animal welfare, and health effects of meat production and consumption. Recent studies have conducted static analyses of shifts in diets globally and in the USA, but have not considered how the whole food system would respond to these changes, nor the ethical implications of these responses. We aimed to better explore these dynamics within the US food system and contribute a multiple perspective ethical assessment of plant-based alternatives to beef. METHODS: In this national modelling analysis, we explored multiple ethical perspectives and the implications of the adoption of plant-based alternatives to beef in the USA. We developed USAGE-Food, a modified version of USAGE (a detailed computable general equilibrium model of the US economy), by improving the representation of sector interactions and dependencies, and consumer behaviour to better reflect resource use across the food system and the substitutability of foods within households. We further extended USAGE, by linking estimates of the environmental footprint of US agriculture, to estimate how changes across the agriculture sector could alter the environmental impact of primary food production across the whole sector, not only the beef sector. Using USAGE-Food, we simulated four beef replacement scenarios against a baseline of current beef demand in the USA: BEEF10, in which beef expenditure is replaced by other foods and three scenarios wherein 10%, 30%, or 60% of beef expenditure is replaced by plant-based alternatives. FINDINGS: The adoption of plant-based beef alternatives is likely to reduce the carbon footprint of US food production by 2·5-13·5%, by reducing the number of animals needed for beef production by 2-12 million. Impacts on other dimensions are more ambiguous, as the agricultural workforce and natural resources, such as water and cropland, are reallocated across the food system. The shifting allocation of resources should lead to a more efficient food system, but could facilitate the expansion of other animal value chains (eg, pork and poultry) and increased exports of agricultural products. In aggregate, these changes across the food system would have a small, potentially positive, impact on national gross domestic product. However, they would lead to substantial disruptions within the agricultural economy, with the cattle and beef processing sectors decreasing by 7-45%, challenging the livelihoods of the more than 1·5 million people currently employed in beef value chains (primary production and animal processing) in the USA. INTERPRETATION: Economic modelling suggests that the adoption of plant-based beef alternatives can contribute to reducing greenhouse gas emissions from the food system. Relocation of resources across the food system, simulated by our dynamic modelling approach, might mitigate gains across other environmental dimensions (ie, water or chemical use) and might facilitate the growth of other animal value chains. Although economic consequences at the country level are small, there would be concentrated losses within the beef value chain. Reduced carbon footprint and increased resource use efficiency of the food system are reasons for policy makers to encourage the continued development of these technologies. Despite this positive outcome, policy makers should recognise the ethical assessment of these transitions will be complex, and should remain vigilant to negative outcomes and be prepared to target policies to minimise the worst effects. FUNDING: The Stavros Niarchos Foundation, the Bill & Melinda Gates Foundation, Johns Hopkins University, the Commonwealth Scientific and Industrial Research Organisation, Cornell University, and Victoria University.

Incidental Parathyroidectomy Among Pediatric Patients Undergoing Thyroid Surgery.

OBJECTIVE: To evaluate rates of incidental parathyroidectomy(IP) and to determine risk factors among children undergoing thyroid surgery. STUDY DESIGN: Retrospective case-control study. METHODS: Pediatric patients undergoing thyroidectomy with or without neck dissection were included in this retrospective cohort study over a 20 year period. Demographics, clinical features, and surgical outcomes were evaluated. The primary outcome was the presence of parathyroid tissue in the surgical specimen. RESULTS: Two hundred and eighty-six patients were included (100 cases with ≥1 parathyroid gland found in the pathology specimen and 186 controls). The most common surgical indication was cancer (49%), followed by benign nodule (25%). Hemithyroidectomy was performed in 119 (42%) patients, total thyroidectomy in 138 (48%), and completion in 29 (10%). Central neck dissection (CND) and lateral neck dissection were performed in 41% and 13%, respectively. 27 (9%) patients had parathyroid reimplantation. On univariable analysis, diagnosis, adenopathy on preoperative ultrasound, extent of thyroidectomy, neck dissection, and parathyroid reimplantation were significant predictors of IP. On multivariate analysis, CND > 5 nodes were the sole predictor of IP. Patients with IP were more likely to require postoperative calcium/vitamin D supplementation compared to those without (44% vs. 16%; P < .001). CONCLUSIONS: Incidental parathyroidectomy during pediatric thyroidectomy is relatively common. CND was independently predictive of IP. There were increased rates of postoperative hypocalcemia when 1 or more parathyroid gland was identified in the specimen. Reimplantation of 1 parathyroid gland was predictive of another gland in the specimen. Anticipating outcomes may help optimize patient care by allowing for early supplementation, frequent monitoring, and consideration of ancillary monitoring modalities in high-risk procedures. LEVEL OF EVIDENCE: Level 4 Laryngoscope, 132:2262-2269, 2022.

Association of Plate Contouring With Hardware Complications Following Mandibular Reconstruction.

OBJECTIVES/HYPOTHESIS: Despite considerable effort being dedicated to contouring reconstruction plates, there remains limited evidence demonstrating an association between contour and reconstructive outcomes. We sought to evaluate whether optimizing mandibular reconstruction plate contouring is associated with reduced postoperative hardware complications. STUDY DESIGN: Retrospective cohort study. METHODS: A cohort study was performed with adult patients (age ≥18 years) who underwent mandibulectomy and osseous free flap reconstruction following oncologic ablation at the University Health Network in Toronto, Canada, between January 1, 2003 and December 31, 2014. Patients with computed tomography scans performed within 1 year of reconstruction were included. Computer-based three-dimensional models were generated and used to calculate the mean plate-to-bone gap (mm). The primary outcome was plate exposure. Secondary outcome included a composite of plate exposure or intraoral dehiscence. Logistic regression models were fitted for each outcome accounting for other patient and surgical characteristics associated with the primary outcome. RESULTS: Ninety-four patients met inclusion criteria, with a mean age of 60.4 (standard deviation [SD] 14.9). The mean follow-up time was 31.4 months (range 3-94). Reconstruction was performed with fibular (57%) and scapular free flaps (43%). In the multivariable model, small mean plate-to-bone gap (<1 mm) was independently associated with 86% reduced odds of plate exposure (odds ratio [OR] 0.12; 95% confidence interval [CI] 0.02-0.55). Mean plate-to-bone gap less than 1 mm was also independently associated with reduced odds of developing a composite of plate exposure or intraoral dehiscence (OR, 0.29; 95%CI, 0.11-0.75). CONCLUSION: Optimizing plate contouring during mandibular reconstruction may decrease the development of postoperative hardware complications. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:61-66, 2022.

Coping with seasonality in a quarterly CGE model: COVID-19 and U.S. agriculture.

Most dynamic CGE models work with periods of 1 year. This limits their applicability for analysing the effects of shocks that operate over a short period or with different intensities through a year. It is relatively easy to convert an annual CGE model to shorter periodicity, for example a quarter, if we ignore seasonal differences in the pattern of economic activity, but this is not acceptable for agriculture. This paper introduces seasonal factors to the agricultural specification in a detailed quarterly CGE model of the United States. The model is then applied to analyse the effects of the COVID pandemic on U.S. farm industries. Taking account of the general features of the pandemic such as the reduction in household spending, we find that these effects are mild relative to the effects on most other industries. However, agriculture is subject to potential supply-chain disruptions. We apply our quarterly model to analyse two such possibilities: loss of labour at harvest time in Fruit & nut farms, and temporary closure of meat-processing plants. We find that these disruptions are unlikely to cause noticeable reductions in the supply of food products to U.S. households.

Glasgow Benefit Inventory in Cochlear Implantation: A Reliable Though Ancillary Quality of Life Metric.

OBJECTIVE: The Glasgow Benefit Inventory (GBI) is a health-related quality of life instrument used to detect changes in health status following otolaryngologic interventions. Despite its use in cochlear implant literature, assessment of utility, reliability, and validity of GBI in an adult cochlear implants (CI) patient population has yet to be performed. STUDY DESIGN: Retrospective case series. SETTING: Academic, tertiary referral center. PATIENTS: Postlingually deafened, adult CI patients with at least 1 year of device use. INTERVENTIONS: Five hundred fifty-two patients were administered GBI questionnaires at least 1 year following CI activation during follow-up visits. MAIN OUTCOME MEASURES: GBI total and subscale scoring were compared to either the Hearing Handicap Inventory for Adults or Hearing Handicap Inventory for the Elderly. Moreover, a factor analysis and Cronbach's alpha were performed to determine GBI validity and internal reliability, respectively. RESULTS: The average overall GBI score was 38.6 ±â€Š21.7. This was weakly correlated to the reduction in Hearing Handicap Inventory for Adults/Hearing Handicap Inventory for the Elderly (τb = 0.282, p < 0.05). High factor loading with minimal cross-loading was noted on a three-factor solution, which emulated the original GBI development. Internal reliability was acceptable for the general benefit (α = 0.913) and social support subclasses (α = 0.706), whereas physical health's was low (α = 0.643). CONCLUSIONS: Although GBI possesses adequate convergent and discriminant validity with acceptable reliability, its routine use to capture CI-specific health-related changes should not supersede validated CI-specific QoL instruments.

The BACH project protocol: an international multicentre total Bile Acid Comparison and Harmonisation project and sub-study of the TURRIFIC randomised trial.

OBJECTIVES: Multicentre international trials relying on diagnoses derived from biochemical results may overlook the importance of assay standardisation from the participating laboratories. Here we describe a study protocol aimed at harmonising results from total bile acid determinations within the context of an international randomised controlled Trial of two treatments, URsodeoxycholic acid and RIFampicin, for women with severe early onset Intrahepatic Cholestasis of pregnancy (TURRIFIC), referred to as the Bile Acid Comparison and Harmonisation (BACH) study, with the aims of reducing inter-laboratory heterogeneity in total bile acid assays. METHODS: We have simulated laboratory data to determine the feasibility of total bile acid recalibration using a reference set of patient samples with a consensus value approach and subsequently used regression-based techniques to transform the data. RESULTS: From these simulations, we have demonstrated that mathematical recalibration of total bile acid results is plausible, with a high probability of successfully harmonising results across participating laboratories. CONCLUSIONS: Standardisation of bile acid results facilitates the commutability of laboratory results and collation for statistical analysis. It may provide the momentum for broader application of the described techniques in the setting of large-scale multinational clinical trials dependent on results from non-standardised assays.

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis.

BACKGROUND: Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes. METHODS: In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 µmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495. FINDINGS: The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35-3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04-2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86-1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39-0·91; p=0·016). INTERPRETATION: Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment. FUNDING: Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research.

A multi-centre, open label, randomised, parallel-group, superiority Trial to compare the efficacy of URsodeoxycholic acid with RIFampicin in the management of women with severe early onset Intrahepatic Cholestasis of pregnancy: the TURRIFIC randomised trial.

BACKGROUND: Severe early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders. Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach. METHODS: We have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool. DISCUSSION: Our study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing "standard" UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP. It will also allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial. TRIAL IDENTIFIERS: Australian New Zealand Clinical Trials Registration Number (ANZCTR): 12618000332224p (29/08/2018). HREC No: HREC/18/WCHN/36. EudraCT number: 2018-004011-44. IRAS: 272398. NHMRC registration: APP1152418 and APP117853.

Survival of viral haemorrhagic septicaemia virus and infectious haematopoietic necrosis virus in the environment and dried on stainless steel.

Viral haemorrhagic septicaemia virus (VHSV) and infectious haematopoietic necrosis virus (IHNV) are important viral pathogens posing a serious threat to salmonid fish. Survival of two isolates of IHNV and one of VHSV was assessed at temperatures ranging from 4 to 25°C: (a) after drying on stainless steel, (b) in cell culture medium, (c) in filtered river water, (d) in unfiltered river water, and (e) survival, adsorption and desorption in river sediment and five typical soil types. The viruses survived 1 hr to > 84 days depending on the conditions. Survival was inversely related to temperature and organic and inorganic content. Both viruses remained infectious after being dried on stainless steel for several weeks highlighting the risk of mechanical transmission and persistence in a dry environment. Both adsorbed to the soils from the river water inoculum, with titres between 5.56x104 and 2.58x108 TCID50 /ml after 1 hr. Clay soils adsorbed the least virus but had the greatest decrease in the river water inoculum (undetectable in ≤ 1 hr), and there was no desorption. Virus desorbed from the other soils into the surrounding water at different rates dependant on soil type (longest desorption was from chalk loam and sandy soil-detected at 28 days). When desorption was no longer detectable, virus persisted, adsorbed to the soil and remained infectious (the longest adsorption was detected in clay loam for ≥ 49 days, but all the viruses adsorbed to soils were likely to have survived longer than that detected, based on their rate of decay). The long survival of the viruses, particularly at cooler temperatures, highlights the risk of survival in the environment and waterborne spread. The data presented here are highly relevant for assessing risk of pathogen introduction via fomites (stainless steel) and for deciding on best control measures in the context of disease outbreaks.